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Kawachi H, Yamada T, Tamiya M, Negi Y, Kijima T, Goto Y, Nakao A, Shiotsu S, Tanimura K, Takeda T, Okada A, Harada T, Date K, Chihara Y, Hasegawa I, Tamiya N, Katayama Y, Nishioka N, Morimoto K, Iwasaku M, Tokuda S, Shimose T, Takayama K. Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy. Oncoimmunology 2025; 14:2442116. [PMID: 39681395 PMCID: PMC11651275 DOI: 10.1080/2162402x.2024.2442116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 12/18/2024] Open
Abstract
This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/complications
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Cachexia/etiology
- Male
- Female
- Lung Neoplasms/drug therapy
- Lung Neoplasms/complications
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Aged
- Middle Aged
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/administration & dosage
- Retrospective Studies
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/metabolism
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged, 80 and over
- Adult
- Prognosis
- Treatment Outcome
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Affiliation(s)
- Hayato Kawachi
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Yoshiki Negi
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Akira Nakao
- Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Fukuoka, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Kyoto, Japan
| | - Keiko Tanimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Asuka Okada
- Department of Respiratory Medicine, Saiseikai Suita Hospital, Suita, Osaka, Japan
| | - Taishi Harada
- Department of Medical Oncology, Fukuchiyama City Hospital, Fukuchiyama, Kyoto, Japan
| | - Koji Date
- Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Kyoto, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Isao Hasegawa
- Department of Respiratory Medicine, Saiseikai Shigaken Hospital, Shiga, Japan
| | - Nobuyo Tamiya
- Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto, Kyoto, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Naoya Nishioka
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Shinsaku Tokuda
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Takayuki Shimose
- Department of Statistics and Data Center, Clinical Research Support Center Kyushu, Fukuoka, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
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Corre R, Decroisette C, Auliac JB, Falchero L, Curcio H, Amrane K, Perol M, Hominal S, Vieillot S, Huchot E, Desage AL, Bernardi M, Veillon R, Doubre H, Bota S, Legarff G, Justeau G, Bylicki O, Roa M, Descourt R, Chouaïd C, Greillier L. First-Line Pembrolizumab Efficacy in Octogenarians With NSCLCs Expressing ≥ 50% PD-L1 (ESCKEYP GFPC 05-2018). Clin Lung Cancer 2025; 26:331-337. [PMID: 40122771 DOI: 10.1016/j.cllc.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/21/2025] [Accepted: 03/01/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Pembrolizumab alone is a first-line therapeutic option for patients with metastatic non-small cell lung cancer (NSCLC) with ≥ 50% PD-L1 expression, but few data are available for elderly patients, specifically octogenarians. METHODS This retrospective, multicenter study included all consecutive patients with metastatic NSCLC PD-L1 ≥ 50% treated with first-line pembrolizumab monotherapy between May 2017 and November 2019. Information was collected from medical files with local evaluation of therapeutic response and progression-free survival (PFS). RESULTS Among the 844 patients included, 73 (8.4%) were ≥ 80 (median: 82) years old, 74% men, 23.3% with ECOG-PS ≥ 2, 26% had ≥ 5% weight loss, PD-L1 50%-75%/≥ 75%: 45.2%/46.6%, respectively, with significantly more nonsmokers and (17.4% vs. 5.6%, P = .0002) and fewer adenocarcinomas (57.5% vs. 70.8%, P = .0217) than those < 80 years. After median follow-up of 45.7 (95% CI: 43.0-49.1) months, respective median overall survival (OS) for octogenarians versus younger patients lasted 12.0 (95% CI: 7.7-16.2) versus 23.9 (95% CI: 19.5-27.4) months (P = .0002), and median PFS for 5.0 (95% CI: 2.8-9.2) versus 8.3 (95% CI: 7.2-9.8) months (P = .039). Their respective objective response rates did not differ significantly: 42% (95% CI: 24-60) vs. 49% (95% CI: 43-54). CONCLUSIONS Based on the results of this large multicenter population, first-line pembrolizumab efficacy against NSCLCs expressing ≥ 50% PD-L1 in octogenarians seems inferior to that obtained in younger patients. The higher percentage of nonsmokers and fewer adenocarcinomas could partially explain that finding.
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Affiliation(s)
- Romain Corre
- Centre Hospitalier de Cornouaille, Quimper, France
| | | | | | | | | | - Karim Amrane
- Centre Hospitalier des Pays de Morlaix, Morlaix, France
| | | | | | | | | | | | - Marie Bernardi
- Centre Hospitalier du Pays d'Aix, Aix-en-Provence, France
| | | | | | | | | | | | - Oliver Bylicki
- Hôpital d'Instruction des Armées Sainte-Anne, Toulon, France
| | - Magali Roa
- CHI Fréjus-Saint-Raphaël, Fréjus, France
| | - Renaud Descourt
- CHRU Morvan Institut de Cancérologie et d'Hématologie Oncologie Thoracique, Brest, France
| | | | - Laurent Greillier
- Hopital Nord, APHM, Multidisciplinaire et Innovations Thérapeutiques, Marseille, France
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3
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Wu Y, Tao L, Liu C, Wang F, Sun S. Cost-effectiveness analysis of PD-L1 testing associated with pembrolizumab for first-line treatment of advanced non-small cell lung cancer in China. Int J Clin Pharm 2025; 47:737-746. [PMID: 39804416 DOI: 10.1007/s11096-025-01865-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/04/2025] [Indexed: 06/01/2025]
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related deaths in China, and pembrolizumab shows differential efficacy in advanced non-small cell lung cancer (NSCLC) with different PD-L1 expression levels. AIM To assess the cost-effectiveness of PD-L1 testing associated with pembrolizumab for first-line treatment of NSCLC from the perspective of Chinese healthcare system. METHOD Over a lifetime horizon, a three-state partitioned survival model was developed to assess the cost-effectiveness of PD-L1 testing and no PD-L1 testing. In the PD-L1 testing group, patients were stratified by PD-L1 tumor proportion score ≥ 50%, 1-49%, or < 1% and received pembrolizumab monotherapy, pembrolizumab plus chemotherapy, or chemotherapy alone, respectively. In the non-PD-L1 testing group, all patients received pembrolizumab plus chemotherapy. Model inputs were obtained from published literature and a healthcare price database, and clinical outcomes from two randomized clinical trials were used. The net monetary benefit (NMB) was estimated for the PD-L1 testing group versus the non-PD-L1 testing group. Deterministic and probabilistic sensitivity analyses, and scenario analyses were conducted to assess robustness of results. RESULTS Using PD-L1 testing to guide treatment led to cost savings of $49,392.7 and a reduction in quality-adjusted life years (QALYs) of 0.234, resulting in a positive NMB of $46,421.7 at a willingness-to-pay (WTP) threshold of $12,680.8/QALY (GDP per capita in China, 2023). Findings were robust across sensitivity and scenario analyses. CONCLUSION Using PD-L1 testing to guide first-line pembrolizumab treatment in patients with advanced NSCLC is a cost-effective strategy at a WTP threshold of $12,680.8/QALY for China.
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MESH Headings
- Humans
- Cost-Benefit Analysis/methods
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/economics
- Antibodies, Monoclonal, Humanized/economics
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Lung Neoplasms/drug therapy
- Lung Neoplasms/economics
- B7-H1 Antigen/analysis
- China/epidemiology
- Antineoplastic Agents, Immunological/economics
- Antineoplastic Agents, Immunological/therapeutic use
- Quality-Adjusted Life Years
- Male
- Female
- Middle Aged
- Cost-Effectiveness Analysis
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Affiliation(s)
- Yao Wu
- Center for Health Policy and Technology Evaluation, Peking University Health Science Center, Beijing, 100191, China
| | - Libo Tao
- Center for Health Policy and Technology Evaluation, Peking University Health Science Center, Beijing, 100191, China.
- Department of Health Policy and Management, School of Public Health, Peking University, Beijing, 100191, China.
| | - Chang Liu
- Center for Health Policy and Technology Evaluation, Peking University Health Science Center, Beijing, 100191, China
| | - Fangxu Wang
- Center for Health Policy and Technology Evaluation, Peking University Health Science Center, Beijing, 100191, China
| | - Shuang Sun
- Center for Health Policy and Technology Evaluation, Peking University Health Science Center, Beijing, 100191, China
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Raphael A, Kamm Feldman A, Lazarev I, Kian W, Peled N, Hod K, Shalata W, Dudnik E. Lung Immune Prognostic Index-Based Predictive Score in Advanced Non-Small Cell Lung Cancer with a Programmed Death Ligand-1 Tumor Proportion Score ≥ 50. J Clin Med 2025; 14:3543. [PMID: 40429538 DOI: 10.3390/jcm14103543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/12/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: The Lung Immune Prognostic Index (LIPI) has emerged as a promising biomarker for predicting outcomes in advanced non-small cell lung cancer (aNSCLC). We assessed whether LIPI, in combination with baseline clinical characteristics, can guide first-line treatment selection between pembrolizumab (P) and pembrolizumab plus platinum-based chemotherapy (PCT) in patients with PD-L1 tumor proportion score (TPS) ≥ 50% and EGFR/ALK/ROS1 wild-type. Methods: A predictive score was developed using baseline clinical variables, including age, sex, smoking status, and LIPI, in a proof-of-concept cohort (n = 241). This model was then validated in an independent cohort of 409 patients. OS was compared between patients treated with P versus PCT, stratified by predictive score. Results: In the proof-of-concept cohort, the median OS was 18.3 months for P and 26.6 months for PCT (p = 0.001). In the validation cohort, the median OS was 28.0 months for P and 22.2 months for PCT (p = 0.062). Stratification using the predictive score showed that patients with high scores (3-5) had improved OS with PCT compared to P (31.2 vs. 25.5 months, p = 0.001), while those with low scores (0-2) derived similar benefits from both treatments. Conclusions: This LIPI-based predictive score may assist in identifying aNSCLC patients who derive greater benefit from chemo-immunotherapy over immunotherapy. Its simplicity and clinical relevance support integration into treatment decision-making, pending prospective validation.
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Affiliation(s)
- Ari Raphael
- Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva 4941492, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ayelet Kamm Feldman
- Goldman School of Medicine, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Irina Lazarev
- Goldman School of Medicine, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Waleed Kian
- Department of Oncology, Assuta Ashdod Medical Center, Ashdod 7747629, Israel
| | - Nir Peled
- Department of Oncology, Shaare Zedek Medical Center, Jerusalem 9103102, Israel
| | - Keren Hod
- Department of Nutrition Sciences, School of Health Sciences, Ariel University, Ariel 4070000, Israel
| | - Walid Shalata
- Department of Oncology, Soroka Medical Center, Beer Sheva 8410501, Israel
| | - Elizabeth Dudnik
- Goldman School of Medicine, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel
- Thoracic Oncology Department, Assuta Medical Centers, Tel Aviv 6329302, Israel
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5
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Mountzios G. Immunotherapy With or Without Chemotherapy in Advanced NSCLC-A Delicate Balance of Harm and Benefit. JAMA Oncol 2025:2833554. [PMID: 40338569 DOI: 10.1001/jamaoncol.2025.0897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Affiliation(s)
- Giannis Mountzios
- Fourth Oncology Department and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece
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6
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Hektoen HH, Tsuruda KM, Brustugun OT, Neumann K, Andreassen BK. Real-world comparison of pembrolizumab alone and combined with chemotherapy in metastatic lung adenocarcinoma patients with PD-L1 expression ≥50. ESMO Open 2025; 10:105073. [PMID: 40305908 PMCID: PMC12088754 DOI: 10.1016/j.esmoop.2025.105073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 03/10/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
OBJECTIVES The frontline treatment of metastatic lung adenocarcinoma with high Programmed death-ligand 1 (PD-L1) expression (≥50%) includes immune checkpoint inhibitors (ICIs) either as monotherapy or combined with chemotherapy. The added benefit of chemotherapy in this context lacks direct comparison in head-to-head trials. We aimed to compare these two ICI treatment modalities both overall and within relevant patient subgroups in a real-world setting. MATERIALS AND METHODS This retrospective, nationwide study included 410 individuals diagnosed in Norway during 2017 to 2021 with stage IV non-small-cell lung adenocarcinoma, PD-L1 expression ≥50%, and treated first line with the ICI pembrolizumab, either as monotherapy (n = 317) or in combination with platinum-based chemotherapy (n = 93). We analyzed early (6-month) and overall (3-year) risk of death after treatment initiation using Cox regression, adjusted for and stratified by sex, age, stage, PD-L1 expression, performance status, and education. RESULTS Patients treated with combination therapy had a higher median overall survival compared with monotherapy (22.6 months versus 14.2 months), and reduced risk of overall death, although not statistically significant after adjustment [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.54-1.00]. However, the risk of early death was significantly lower in patients receiving combination therapy, even after adjustment (HR 0.41, 95% CI 0.23-0.76). Across most subgroups, patients receiving combination therapy had comparable or superior survival outcomes relative to those receiving monotherapy. Particularly noteworthy were the observed benefits from combination therapy over monotherapy among females, individuals with stage IVB disease, and those with PD-L1 expression exceeding 75%. CONCLUSION Our real-world study demonstrates that combination therapy with ICI and chemotherapy provides superior early survival benefits over monotherapy in PD-L1-high patients. Additionally, certain subgroups showed enhanced overall survival. These findings challenge current treatment practices and underscore the need for further validation to optimize patient selection for monotherapy versus combination therapy, in particular to reassess the role of PD-L1 in treatment decisions.
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Affiliation(s)
- H H Hektoen
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health Oslo, Norway; Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. https://twitter.com/HektoenHH
| | - K M Tsuruda
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health Oslo, Norway
| | - O T Brustugun
- Section of Oncology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - K Neumann
- Department of Pulmonology, Akershus University Hospital, Lørenskog, Norway
| | - B K Andreassen
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health Oslo, Norway.
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7
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Deng JY, Gao M, Fan X, Yan HH, Luo WC, Yang MY, Yang XR, Chen ZH, Xu CR, Zhou Q. Clinical and dynamic circulating cytokines profile features of long-term progression-free survival benefit to immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer Immunol Immunother 2025; 74:173. [PMID: 40244472 PMCID: PMC12006652 DOI: 10.1007/s00262-025-03984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/17/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) offer durable progression-free survival (PFS) benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, the predictors of long-term PFS (LTPFS) remain unclear. METHODS Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and August 2022 were identified. Predictive value of different characteristics was evaluated in LTPFS (PFS ≥ 24 months) compared with short-term PFS (STPFS, PFS ≤ 3 months). Circulating cytokine levels were evaluated in paired peripheral blood samples collected before and after ICIs treatment. RESULTS Among 202 patients identified and 171 included (median follow-up: 41.0 months), 44 (25.7%) experienced LTPFS, associated with a 5-year overall survival (OS) rate of 81.2%. Squamous NSCLC, intermediate or poor lung immune prognostic index (LIPI) score, and liver metastases, were negatively associated with LTPFS. High tumor mutational burden (TMB, ≥ 10 mutations/megabase) was enriched in LTPFS compared to STPFS (P = 0.002). Patients with both high TMB and PD-L1 demonstrated the greatest survival benefit from first-line ICIs monotherapy (median PFS: 24.5 months, median OS: 67.0 months). Thirty-eight peripheral blood samples were collected before and after ICIs treatment from 10 patients with LTPFS and 9 with STPFS, which revealed increased CCL11 (P = 0.013) and decreased IL1RA (P = 0.001) and IL17A (P = 0.003) levels in LTPFS after ICIs treatment. CONCLUSION Distinct clinical characteristics, including TMB, PD-L1, pathologic subtypes, LIPI score, number of organs involved, metastatic sites, and dynamic circulating cytokines profile features, can distinguish NSCLC patients achieving LTPFS from those with STPFS following first-line ICIs monotherapy.
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Affiliation(s)
- Jia-Yi Deng
- School of Medicine, South China University of Technology, Guangzhou, 510006, People's Republic of China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Ming Gao
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People's Republic of China
| | - Xue Fan
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Hong-Hong Yan
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Wei-Chi Luo
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Ming-Yi Yang
- School of Medicine, South China University of Technology, Guangzhou, 510006, People's Republic of China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Xiao-Rong Yang
- School of Medicine, South China University of Technology, Guangzhou, 510006, People's Republic of China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Chong-Rui Xu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Qing Zhou
- School of Medicine, South China University of Technology, Guangzhou, 510006, People's Republic of China.
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China.
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8
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Gille R, Pérol M. [First line treatment of non-oncogene-addicted metastatic non-small cell lung cancer]. Bull Cancer 2025; 112:3S64-3S74. [PMID: 40155079 DOI: 10.1016/s0007-4551(25)00159-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Since 2017, anti-PD-(L)1 immunotherapy has been the cornerstone of first-line treatment for stage IV non-oncogene-addicted non-small cell lung cancer. Its phase I development has established that the level of PD-L1 expression by tumor cells is predictive of response rate and progression-free survival. Above 50%, it makes chemotherapy not mandatory, with a median survival for pembrolizumab monotherapy of around 26 months and five-year survival of 32%. Large phase III studies have also validated the combination of anti-PD-(L)1 immunotherapy and platinum-based chemotherapy regardless of PD-L1 level of expression, increasing five-year survival from 10% to 18%. Dual immunotherapy combining anti-CTLA-4 and anti-PD-(L)1 might be interesting, especially in PD-L1 negative tumors, but is not available in France. Treatment personalization, particularly in the case of PD-L 1 expression >50%, should be based on response and non-response factors to immunotherapy, including patient-related factors such as performans status, age, smoking status, as well as tumor-related factors such as disease aggressiveness, tumor volume, mutational profile, along with concomitant medications. The optimal duration of immunotherapy is uncertain and arbitrarily set at two years. Many options are currently being explored to improve first-line treatment outcomes, as the majority of patients experience resistance to immunotherapy.
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Affiliation(s)
- Romane Gille
- Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, France.
| | - Maurice Pérol
- Centre Léon-Bérard, 28 rue Laennec, 69008 Lyon, France
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9
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Wang Y, Safi M, Hirsch FR, Lu S, Peters S, Govindan R, Rosell R, Park K, Zhang JJ. Immunotherapy for advanced-stage squamous cell lung cancer: the state of the art and outstanding questions. Nat Rev Clin Oncol 2025; 22:200-214. [PMID: 39762577 DOI: 10.1038/s41571-024-00979-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2024] [Indexed: 02/26/2025]
Abstract
Immune-checkpoint inhibitors (ICIs) have transformed the treatment paradigm for advanced-stage squamous non-small-cell lung cancer (LUSC), a histological subtype associated with inferior outcomes compared with lung adenocarcinoma. However, only a subset of patients derive durable clinical benefit. In the first-line setting, multiple ICI regimens are available, including anti-PD-(L)1 antibodies as monotherapy, in combination with chemotherapy, or with an anti-CTLA4 antibody with or without chemotherapy. Several important questions persist regarding the optimal regimen for individual patients, particularly how to identify patients who might benefit from adding chemotherapy and/or anti-CTLA4 antibodies to anti-PD-(L)1 antibodies. An urgent need exists for predictive biomarkers beyond PD-L1 to better guide precision oncology approaches. Deeper knowledge of the underlying molecular biology of LUSC and its implications for response to ICIs will be important in this regard. Integration of this knowledge into multi-omics methods coupled with artificial intelligence might enable the development of more robust biomarkers. Finally, several novel therapeutic strategies, including novel ICIs, bispecific antibodies and personalized cancer vaccines, are emerging. Addressing these unresolved questions through innovative clinical trials and translational research will be crucial to further improving the outcomes of patients with LUSC. In this Review, we provide a comprehensive overview of current immunotherapeutic approaches, unresolved challenges and emerging strategies for patients with LUSC.
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Affiliation(s)
- Yibei Wang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Mohammed Safi
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Fred R Hirsch
- Center for Thoracic Oncology, Tisch Cancer Institute and Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Shun Lu
- Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Solange Peters
- Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | | | - Rafael Rosell
- Dr. Rosell Oncology Institute, Dexeus University Hospital, Barcelona, Spain
| | - Keunchil Park
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
- Division of Hematology/Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Jianjun J Zhang
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genomic Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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10
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Abushanab AK, Mustafa MT, Mousa MT, Albanawi RF, Alkhalaileh RM, Alqudah GN, Abu Zaina RF, Abu Sitta ZA, Almasri IM, Abuquteish D. Immune checkpoint inhibitors plus taxane-based chemotherapy for patients with advanced/metastatic NSCLC: a systematic review and meta-analysis across different PD-L1 expression levels. Expert Rev Anticancer Ther 2025; 25:167-179. [PMID: 39874440 DOI: 10.1080/14737140.2025.2460537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are currently the primary approach for managing NSCLC. However, numerous combination therapies are currently under investigation. Our goal is to investigate the overall efficacy and safety of ICIs and taxane-based chemotherapy. METHODS We conducted a systematic review and meta-analysis, searching web databases for relevant literature. We limited our eligibility to phase II/III randomized clinical trials involving advanced/metastatic NSCLC patients. RESULTS We performed a meta-analysis encompassing nineteen studies derived from sixteen RCTs. For patients with sq-NSCLC PD-L1 ≥ 50%, using ICIs plus taxane significantly improve PFS and OS with HR of 0.58 (95% CI, 0.45-0.74, p < 0.0001) and 0.41 (95% CI, 0.33-0.50, p < 0.00001), respectively. For patients with non-sq NSCLC PD-L1 1-49%, the analysis revealed significant improvement of OS and PFS with HR of 0.64 (95% CI, 0.47-0.88, p = 0.005) and 0.62 (95% CI, 0.47-0.81, p = 0.0004), respectively. For TRAEs of all grades, ICIs plus taxane resulted with no significant difference compared to control group with risk ratio (RR) 1.00 (95% CI 0.99-1.02). CONCLUSION The analysis revealed significant improvement in efficacy of ICIs with taxane in advanced/metastatic NSCLC patients compared with ICI/taxane monotherapy.Registration: PROSPERO (CRD42023447532).
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Dua Abuquteish
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
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11
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Uhlenbruch M, Polke M, von Eiff D, Koryllos A, Krüger S. The Comorbidity of Lung Cancer and ILD: A Review. Pneumologie 2025. [PMID: 39842452 DOI: 10.1055/a-2512-8349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Patients with interstitial lung disease (ILD) and especially with idiopathic pulmonary fibrosis(IPF) suffer from reduced survival expectation and risk of exacerbations. Lung cancer is a relevant comorbidity in ILD patients and associated with impaired survival.The most frequent ILD among patients with NSCLC (Non-small cell lung cancer) is idiopathic pulmonary fibrosis (IPF), which is associated with an greater decline in lung function and a higher risk of death.The prevalence of lung cancer in patients with ILD is up to 10% and in autopsy studies a prevalence up to 48% has been found.There are no guidelines for patients with lung cancer and ILD. Moreover, no adequate evidence is available.Therefore, we reviewed currently available literature to present an overview of the state of the art.In this review we focus on staging and treatment of the comorbidity of lung cancer and ILD.
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Affiliation(s)
- Mark Uhlenbruch
- Klinik für Pneumologie, Kardiologie, internistische Intensivmedizin, Florence-Nightingale-Krankenhaus, Düsseldorf, Germany
| | - Markus Polke
- Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Damian von Eiff
- Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Aris Koryllos
- Klinik für Thoraxchirurgie, Florence-Nightingale-Krankenhaus, Düsseldorf, Germany
| | - Stefan Krüger
- Klinik für Pneumologie, Kardiologie, internistische Intensivmedizin, Florence-Nightingale-Krankenhaus, Düsseldorf, Germany
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12
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Schmitt AM, Larkin J, Patel SP. Dual Immune Checkpoint Inhibition in Melanoma and PD-L1 Expression: The Jury Is Still Out. J Clin Oncol 2025; 43:122-124. [PMID: 39374477 DOI: 10.1200/jco-24-01572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/28/2024] [Accepted: 09/09/2024] [Indexed: 10/09/2024] Open
Abstract
This comment discusses the use of PD-L1 as a biomarker to guide treatment decisions for metastatic melanoma.
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Affiliation(s)
| | - James Larkin
- Department of Medical Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
| | - Sapna P Patel
- Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO
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13
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Hu J, Zhang J, Wan S, Zhang P. Neoadjuvant immunotherapy for non-small cell lung cancer: Opportunities and challenges. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2024; 2:224-239. [PMID: 39834585 PMCID: PMC11742355 DOI: 10.1016/j.pccm.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Indexed: 01/22/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for resectable non-small cell lung cancer. Numerous trials have explored the use of ICIs, either as monotherapy or in combination with other therapies, in the neoadjuvant setting for stage I-III non-small cell lung cancer. Most trials have demonstrated neoadjuvant immunotherapy to be safe and to have remarkable efficacy, with a high pathological response rate and significantly improved event-free survival. This review summarizes the findings of Phase I-III clinical trials investigating various neoadjuvant regimens, including ICI monotherapy, ICI therapy combined with chemotherapy, ICI plus anti-angiogenic therapy, dual ICI therapy, and ICI therapy in combination with radiotherapy or chemoradiotherapy. We discuss the benefits and outcomes associated with each approach. Despite the results being promising, several unresolved issues remain, including identification of reliable biomarkers, the appropriate duration of therapy, the optimal treatment regimen for tumors with high programmed cell death ligand 1 (PD-L1) expression, the false-negative pathological complete response rate, and the role of digital pathology in assessing the response to treatment. Resistance to immunotherapy, in particular, remains a significant barrier to effective use of ICIs. Given the critical influence of the tumor microenvironment (TME) on the response to treatment, we examine the characteristics of the TME in both responsive and resistant tumors as well as the dynamic changes that occur in the TME in response to neoadjuvant immunotherapy. We also summarize the mechanisms underlying T cell responses following neoadjuvant immunotherapy and provide a perspective on strategies to enhance the understanding of tumor heterogeneity, therapy-driven TME remodeling, and overcoming resistance to therapy. Finally, we propose future directions for advancements in personalized neoadjuvant immunotherapy.
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Affiliation(s)
- Junjie Hu
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Shiyue Wan
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- The 1st School of Medicine, the 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Shihezi University Medical College, Shihezi, Xinjiang 832000, China
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Li H, Liu J, Zhang L, Xu Y, Wang X, Lan S, Cui P, Wang G, Cai S, Cheng Y. Mutation-guided chemotherapy-free strategy in first-line immunotherapy for low PD-L1-expressing non-squamous NSCLC. J Immunother Cancer 2024; 12:e009693. [PMID: 39615893 PMCID: PMC11624766 DOI: 10.1136/jitc-2024-009693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 11/05/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND The necessity of platinum-doublet chemotherapy in first-line immunotherapy for non-squamous non-small cell lung cancer (nsqNSCLC) with programmed death-ligand 1 (PD-L1) expression on less than 50% of tumor cells remains poorly investigated. Biomarkers predicting this necessity can guide chemotherapy-free treatment to minimize unnecessary toxicity. METHODS Treated with immune checkpoint inhibitor monotherapy (ICI-mono), chemotherapy, or combination (ICI-chemo), 790 low PD-L1-expressing nsqNSCLCs (in-house: n=83; public: n=707) were analyzed for development and validation of the interaction score for additional chemotherapy (ISAC). Transcriptomic (public, n=11) and multiplex immunofluorescence data (in-house, n=100) were analyzed to evaluate the immune microenvironment. RESULTS ICI-chemo, compared with ICI-mono, tended to prolong progression-free survival (PFS; HR=0.72, p=0.004) and overall survival (OS; HR=0.77, p=0.071) as first-line therapy in low PD-L1-expressing nsqNSCLCs. The added value of chemotherapy was observed in the ISAC-low subgroup (PFS: HR=0.48, p<0.001; OS: HR=0.53, p=0.001) rather than the ISAC-high subgroup (PFS: HR=1.08, p=0.65; OS: HR=1.14, p=0.56). This predictive utility was independent of tumor mutational burden and PD-L1 expression, indicated by subgroup and multivariable analyses. A high ISAC was associated with adaptive immune resistance reflected by more proinflammatory (eg, CD8+ T cells and M1 macrophages) rather than anti-inflammatory tumor-infiltrating immune cells (eg, M2 macrophages) and high expression of immune checkpoints except for PD-L1 (eg, programmed cell death protein-1). CONCLUSION A high ISAC was identified as a significant predictor for virtually no added value of platinum-doublet chemotherapy for first-line ICI treatment in low PD-L1-expressing nsqNSCLC. Our findings may help refine personalized therapeutic strategies for nsqNSCLC, thereby improving efficacy and reducing undue toxicity.
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Affiliation(s)
- Hui Li
- Translational Oncology Research Lab, Jilin Provincial Key Laboratory of Molecular Diagnostics for Lung Cancer, Jilin Cancer Hospital, Changchun, Jilin, China
| | - Jingjing Liu
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, Jilin, China
| | - Liang Zhang
- Oncology Department, Jilin Cancer Hospital, Changchun, Jilin, China
| | - Yu Xu
- Burning Rock Biotech, Guangzhou, Guangdong, China
| | - Xinyue Wang
- Postdoctoral Research Workstation, Jilin Cancer Hospital, Changchun, Jilin, China
| | - Shaowei Lan
- Translational Oncology Research Lab, Jilin Provincial Key Laboratory of Molecular Diagnostics for Lung Cancer, Jilin Cancer Hospital, Changchun, Jilin, China
| | - Peng Cui
- Burning Rock Biotech, Guangzhou, Guangdong, China
| | | | - Shangli Cai
- Burning Rock Biotech, Guangzhou, Guangdong, China
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, Jilin, China
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15
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Apter L, Sharman Moser S, Arunachalam A, Gazit S, Hoshen M, Chodick G, Siegelmann-Danieli N. Real-world treatment patterns, biomarker testing, and clinical outcomes of metastatic non-small cell lung cancer patients in the immunotherapy era. Front Oncol 2024; 14:1442909. [PMID: 39512773 PMCID: PMC11543355 DOI: 10.3389/fonc.2024.1442909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 10/01/2024] [Indexed: 11/15/2024] Open
Abstract
Background Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy. We describe treatment utilization and clinical outcomes in a real-world mNSCLC cohort in a 2.7-million-member state-mandated health provider. Methods Newly diagnosed mNSCLC patients initiating systemic anti-cancer treatment (January 2017-December 2020) were identified from the National Cancer Registry. Real-world time on treatment (rwToT) was defined as the length of time between the first and last administration date of treatment. Real-world overall survival (rwOS) was estimated using Kaplan-Meier analysis. Outcomes were assessed at a minimum of 6 months' follow-up (cutoff: 30 June 2021). Results Among 843 patients, 85% had adenocarcinoma (NSQ) and 15% had squamous cell carcinoma (SQ) histology: of these, 43% and 26% were women, median age was 67 and 69 years, and 55% and 48% had 0-1 ECOG performance status, respectively (missing: 27% and 30%, respectively). Median follow-up for the entire cohort was 27.1 months (95% CI: 24.7-29.6). NSQ patients with no known EGFR/ALK/ROS1 aberrations received PD-1 inhibitor monotherapy (PDM) (N = 147) or combination (PDC) (N = 194) or platinum-based chemotherapy (PBC, N = 133). Median rwToT was 4.5 (95% CI: 3.5-7.6), 5.2 (95% CI: 4.6-7.6), and 2.3 (95% CI: 2.1-3.0) months, respectively; for the subgroup of patients with ECOG PS 0-1, rwToT was 9.4 (95% CI: 5.0-20.8), 7.1 (95% CI: 5.0-10.1), and 2.9 (95% CI: 2.2-4.1) months, respectively. Median rwOS from 1L was 12.5 (95% CI: 9.9-17.9), 14.8 (95% CI: 10.5-19.4), and 9.1 (95% CI: 7.1-11.5) months; for the subgroup of patients with ECOG PS 0-1, median rwOS was 25.1 [95% CI: 14.9-not reached (NR)], 17.6 (95% CI: 14.3-NR), and 11.3 (95% CI: 9.2-21.3) months, respectively. For ECOG PS 0-1 and PD-L1 ≥50% patients, median rwOS was 25.1 months (95% CI: 13.9-NR) and NR for PDM and PDC, respectively. For ECOG PS 0-1 and PD-L1 <50% patients, median rwOS was 14.3 (95% CI: 10.1-NR) and 11.2 (95% CI: 9.1-21.3) months for PDC and PBC, respectively. Conclusion Our real-world data support the benefit of single-agent PD-1 inhibitor monotherapy for patients with PD-L1 high expression or PD-1 inhibitor combination for all patients diagnosed with mNSCLC with no known EGFR/ALK/ROS1 aberrations, initiating 1L treatment.
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Affiliation(s)
- Lior Apter
- Health Division, Maccabi Healthcare Services, Tel Aviv, Israel
- Department of Health Policy and Management, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er-Sheva, Israel
| | - Sarah Sharman Moser
- KSM Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
| | - Ashwini Arunachalam
- Outcomes Research, Value & Implementation, Merck & Co., Inc., Rahway, NJ, United States
| | - Sivan Gazit
- KSM Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
| | - Moshe Hoshen
- KSM Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
| | | | - Nava Siegelmann-Danieli
- Health Division, Maccabi Healthcare Services, Tel Aviv, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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16
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Tachibana Y, Morimoto K, Yamada T, Kawachi H, Tamiya M, Negi Y, Goto Y, Nakao A, Shiotsu S, Tanimura K, Takeda T, Okada A, Harada T, Date K, Chihara Y, Hasegawa I, Tamiya N, Katayama Y, Nishioka N, Iwasaku M, Tokuda S, Kijima T, Takayama K. Depth of response and treatment outcomes of immune checkpoint inhibitor-based therapy in patients with advanced non-small cell lung cancer and high PD-L1 expression: An exploratory analysis of retrospective multicenter cohort. Invest New Drugs 2024; 42:538-546. [PMID: 39168900 DOI: 10.1007/s10637-024-01467-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024]
Abstract
The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 = ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.
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Affiliation(s)
- Yusuke Tachibana
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan.
| | - Hayato Kawachi
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Yoshiki Negi
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Akira Nakao
- Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Fukuoka, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Kyoto, Japan
| | - Keiko Tanimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Asuka Okada
- Department of Respiratory Medicine, Saiseikai Suita Hospital, Suita, Osaka, Japan
| | - Taishi Harada
- Department of Medical Oncology, Fukuchiyama City Hospital, Fukuchiyama, Kyoto, Japan
| | - Koji Date
- Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Nantan, Kyoto, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Isao Hasegawa
- Department of Respiratory Medicine, Saiseikai Shigaken Hospital, Ritto, Shiga, Japan
| | - Nobuyo Tamiya
- Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto, Kyoto, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Naoya Nishioka
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Shinsaku Tokuda
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
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17
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Kang DH, Choi CM, Park CK, Oh IJ, Kim YC, Yoon SH, Kim Y, Lee JE. Immune Checkpoint Inhibitor Score Predicts Survival Benefit of Immunotherapy in Patients with Non-small Cell Lung Cancer. Tuberc Respir Dis (Seoul) 2024; 87:483-493. [PMID: 38749491 PMCID: PMC11468437 DOI: 10.4046/trd.2023.0190] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/15/2024] [Accepted: 05/12/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. METHODS This was a prospective multicenter study in patients with advanced nonsmall cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. RESULTS A total of 143 patients from four institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p=0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p<0.001). CONCLUSION Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.
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Affiliation(s)
- Da Hyun Kang
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Chang-Min Choi
- Department of Pulmonary and Critical Care Medicine/Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Cheol-Kyu Park
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - In-Jae Oh
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Young-Chul Kim
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Seong Hoon Yoon
- Department of Pulmonology and Allergy, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Yoonjoo Kim
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Jeong Eun Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
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18
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Nigen B, Bodergat T, Vaugier L, Pons-Tostivint E. [First-line immunotherapy in non-small cell lung cancer diagnosed with brain metastases]. Rev Mal Respir 2024; 41:571-582. [PMID: 38926022 DOI: 10.1016/j.rmr.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/14/2024] [Indexed: 06/28/2024]
Abstract
INTRODUCTION Up to 30% patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) present with brain metastases. In the absence of oncogenic addiction, first-line immunotherapy, alone or in combination with chemotherapy, is the current standard of care. This review aims to synthesize the available data regarding the efficacy of immunotherapy in these patients, and to discuss the possibility of its being coordinated with local treatments such as radiotherapy. STATE OF THE ART NSCLC patients with brain metastases appear to have survival benefits with immunotherapy similar to those of NSCLC patients without brain metastases. However, this finding is based on mainly prospective studies having included highly selected patients with pre-treated and stable brain metastases. Several retrospective studies and two prospective single-arm studies have confirmed the intracranial efficacy of immunotherapy, either alone or in combination with chemotherapy. PERSPECTIVES The indications and optimal timing for cerebral radiotherapy remain subjects of debate. To date, there exists no randomized study assessing the addition of brain radiotherapy to first-line immunotherapy. That said, a recent meta-analysis showed increased intracerebral response when radiotherapy complemented immunotherapy. CONCLUSIONS For NSCLC patients with brain metastases, the available data suggest a clear benefit of first-line immunotherapy, whether alone or combined with chemotherapy. However, most of these data are drawn from retrospective, non-randomized studies with small sample sizes.
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Affiliation(s)
- B Nigen
- Service de pneumologie, centre hospitalier Les Sables-d'Olonne, Les Sables-d'Olonne, France
| | - T Bodergat
- Oncologie médicale, centre hospitalier universitaire Nantes, Nantes université, Nantes, France
| | - L Vaugier
- Département de radiothérapie, institut de cancérologie de l'Ouest, Saint-Herblain, France
| | - E Pons-Tostivint
- Oncologie médicale, centre hospitalier universitaire Nantes, Nantes université, Nantes, France; Nantes université, Inserm UMR 1307, CNRS UMR 6075, université d'Angers, CRCI2NA, Nantes, France.
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19
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Deng JY, Yang MY, Yang XR, Chen ZH, Xu CR, Zhou Q. Patterns of failure and the subsequent treatment after progression on first-line immunotherapy monotherapy in advanced non-small cell lung cancer: a retrospective study. BMC Cancer 2024; 24:1190. [PMID: 39333978 PMCID: PMC11438227 DOI: 10.1186/s12885-024-12888-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have become the recommended first-line treatment for advanced non-small cell lung cancer (NSCLC) without driver gene mutations. However, data on the failure patterns of first-line ICIs monotherapy is limited, and the optimal strategy for subsequent treatment remains controversial. METHODS Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and October 2021 were identified. The progressive sites were recorded to analyze failure patterns. Post-progression survival (PPS) was compared between different treatment regimens. RESULTS A total of 121 patients receiving first-line ICIs monotherapy were identified, with a median progression-free survival of 8.6 months. Sixty-five patients had available imaging at diagnosis as well as progressive disease, with 56.9% showing oligoprogression. For those with progression in existing lesions, the most common sites were the liver (77.8%) and lung parenchyma (62.5%), while progression with new lesions frequently occurred in the liver (32.0%). Fifty patients with recorded subsequent treatment were included in the analysis of subsequent treatment patterns. Patients treated with anti-angiogenesis therapy could get better PPS (HR: 0.275, P = 0.013). Isolated oligoprogression occurred most often in the lung parenchyma and intracranial lesions. More than half of these patients continued immunotherapy after local treatment, with a 2.5-year PPS rate of 51.4%. CONCLUSION The liver was the most common site of progression on first-line ICIs monotherapy. Anti-angiogenesis-based therapy might be an optimal regimen at the time of progression. Patients with isolated oligoprogressive could still benefit from immunotherapy after local treatment.
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Affiliation(s)
- Jia-Yi Deng
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 511400, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510030, China
| | - Ming-Yi Yang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 511400, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510030, China
| | - Xiao-Rong Yang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 511400, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510030, China
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510030, China
| | - Chong-Rui Xu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510030, China
| | - Qing Zhou
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, 511400, China.
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510030, China.
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20
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Xu Z, Zhang H, Ma G, Meng W, Du J, Wu X, Yang B, Wang N, Ding Y, Zhang Q, Li N, Zhang X, Yu G, Liu S, Li Z. Real‑world evidence of advanced non‑small cell lung carcinoma treated with an immune checkpoint inhibitor plus chemotherapy. Oncol Lett 2024; 28:405. [PMID: 38983127 PMCID: PMC11228919 DOI: 10.3892/ol.2024.14538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 06/06/2024] [Indexed: 07/11/2024] Open
Abstract
Immunotherapy is an effective treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). Although clinical trials on immunotherapy have provided promising results, real-world research in clinical practice is needed to assess the effectiveness and safety of immunotherapy. The present study aimed to characterize real-world outcomes in patients with advanced NSCLC treated with immune checkpoint inhibitor (ICI)-based regimens. The medical records of patients with advanced NSCLC, who were treated with programmed cell death protein-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitors, were reviewed for data collection. The primary objectives were to evaluate progression-free survival (PFS) and overall survival (OS). Therefore, multiple Cox regression models were used to investigate the predictive factors for survival outcomes. Furthermore, survival curves for PFS and OS were created using Kaplan-Meier estimates and compared using the log-rank test. The present study included a total of 133 patients with advanced NSCLC who received therapy with ICIs between January 1, 2019 and December 31, 2022. The final follow-up date was August 24, 2023. The median PFS and OS times were 9.8 and 27.2 months, respectively. Univariate Cox regression analysis demonstrated that sex, clinical stage, PD-L1 status, previous systemic therapy, and brain and liver metastases were associated with PFS, while Eastern Cooperative Oncology Group (ECOG) status, clinical stage, PD-L1 status and brain metastasis were associated with OS. Furthermore, multivariate Cox regression analysis demonstrated that a PD-L1 tumor proportion score (TPS) of ≥50% was an indicator of favorable PFS and OS. An ECOG performance status score of ≥1 was also associated with poor OS but not with PFS. Furthermore, brain metastasis was an indicator for poor PFS and OS, while liver metastasis was only associated with a poor PFS. Finally, the results of the present study demonstrated that PD-L1 status was an independent predictor for PFS and OS in patients with advanced NSCLC, especially adenocarcinoma, who were treated with ICIs plus chemotherapy. The results also suggested that patients with a PD-L1 TPS of ≥50% could benefit when the aforementioned regimens were administrated as a first-line or later-line therapy.
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Affiliation(s)
- Zihan Xu
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
- Department of Pneumology, Sunshine Union Hospital, Weifang, Shandong 261000, P.R. China
| | - Huien Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Guikai Ma
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Wenjuan Meng
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Junliang Du
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Xin Wu
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Baohong Yang
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Ningning Wang
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Yanhong Ding
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Qingyun Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Na Li
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Xuede Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Guohua Yu
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Shuzhen Liu
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Zhenhua Li
- Department of Oncology, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
- Department of Pathology, Shanghai Clinical Research and Trial Center, Shanghai 201203, P.R. China
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21
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Gandara DR, Subramanian J, Santos ES, Brody Y, Sela I, Elon Y, Harel M, Reiner-Benaim A, Lahav C, McGregor K. Impact of PROphet Test in Changing Physicians' Therapeutic Decision-Making for Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer. Clin Lung Cancer 2024; 25:e252-e261.e4. [PMID: 39034168 DOI: 10.1016/j.cllc.2024.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/23/2024]
Abstract
PURPOSE Immune Checkpoint Inhibitor (ICI) regimens are approved for first-line treatment of metastatic nononcogene-driven NSCLC. Guidelines do not differentiate which patients with PD-L1 ≥ 50% should receive ICI monotherapy. The clinically validated PROphet NSCLC plasma proteomic-based test is designed to inform this therapeutic decision. METHODS One hundred oncologists were presented with 3 "virtual" metastatic NSCLC cases with PD-L1 scores and asked to recommend an approved first-line regimen. They then watched an online educational webinar on the PROphetNSCLC test. Postwebinar, the same cases were represented with the addition of a PROphet result, and oncologists again recommended a first-line regimen. Responses were compared to assess the impact on first-line treatment selection. RESULTS Treatment recommendation changed in 39.6% of PROphet-tested cases, with 93% of physicians changing at least 1 case. In the PD-L1 ≥ 50% group, 89% of physicians changed their recommendation, followed by 77%, in PD-L1 < 1%, and 36% in PD-L1 1% to 49%. In the PD-L1 ≥ 50%, PROphet POSITIVE group, the recommendation for ICI monotherapy increased from 60% to 89%. For the PD-L1 ≥ 50%, PROphet NEGATIVE group, the recommendation for monotherapy dropped from 60% to 9%. In the PD-L1 < 1%, PROphet NEGATIVE group, 35% of patients were spared toxicity from ICI compared to 11% in PROphet untested cases. CONCLUSION Adding PROphet to PD-L1 expression impacted therapeutic decision making in first-line NSCLC. PROphet identifies those predicted to have an overall survival benefit from ICI monotherapy versus combination versus chemotherapy, improving the probability of efficacy and reducing toxicity for some patients.
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Affiliation(s)
- David R Gandara
- Division of Hematology and Oncology, University of California, Davis Medical Center, Sacramento, CA.
| | | | | | - Yehuda Brody
- Research and Development, OncoHost, Binyamina, Israel
| | - Itamar Sela
- Research and Development, OncoHost, Binyamina, Israel
| | | | - Michal Harel
- Research and Development, OncoHost, Binyamina, Israel
| | - Anat Reiner-Benaim
- Department of Epidemiology, Biostatistics and Community Health Sciences, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Coren Lahav
- Research and Development, OncoHost, Binyamina, Israel
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22
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Li Y, Yang X, Ma L. Comparative analysis of adverse event risks in breast cancer patients receiving pembrolizumab combined with paclitaxel versus paclitaxel monotherapy: insights from the FAERS database. Front Pharmacol 2024; 15:1345671. [PMID: 39234109 PMCID: PMC11372242 DOI: 10.3389/fphar.2024.1345671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 08/07/2024] [Indexed: 09/06/2024] Open
Abstract
Objective This study aimed to evaluate the risk of adverse events (AEs) in breast cancer patients treated with pembrolizumab combined with paclitaxel versus those receiving pembrolizumab or paclitaxel monotherapy, using the FDA Adverse Event Reporting System (FAERS) database. Methods Data were extracted from the FAERS database for breast cancer patients treated with pembrolizumab combined with paclitaxel or with pembrolizumab or paclitaxel monotherapy from Q1 2016 to Q2 2023. Disproportionation analysis was performed by calculating the reporting odds ratio (ROR) with corresponding 95% confidence interval (95% CI), the information component (IC), and the lower bound of the information component 95% confidence interval (IC025) to identify potential safety signals. Results No significant difference in AEs was observed between the combined treatment group and the pembrolizumab monotherapy group. However, the combined treatment group exhibited a substantial increase in AE risk compared to the paclitaxel monotherapy group. The most significant increases in AE risk were adrenal insufficiency (ROR = 189.94, 95% CI 25.41-1419.7, IC = 3.37, IC025 = 1.59), hypophysitis (ROR = 99.46, 95% CI 12.72-777.4, IC = 3.31, IC025 = 1.44), and myocarditis (ROR = 69.5, 95% CI 8.55-565.23, IC = 3.25, IC025 = 1.33). The time-to-event for combined treatment was 35 (34-70) days, for pembrolizumab was 43 (35-90) days, and for paclitaxel was 42 (37-76) days. The combination therapy group demonstrated significantly shorter intervals to the onset of adrenal insufficiency (p = 0.008), myocarditis (p < 0.001), and immune-related enterocolitis (p = 0.009). Conclusion Analysis of the FAERS database indicates that combination therapy significantly elevates the risk of adrenal insufficiency, myocarditis, hypophysitis, and immune-related enterocolitis compared to paclitaxel monotherapy. These findings provide critical insights for clinicians in predicting and managing potential AEs associated with this treatment regimen.
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Affiliation(s)
- Yilun Li
- Department of Breast Disease Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Breast Cancer Molecular Medicine, Shijiazhuang, China
| | - Xiaolu Yang
- Department of Breast Disease Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Medical University, Shijiazhuang, China
| | - Li Ma
- Department of Breast Disease Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Breast Cancer Molecular Medicine, Shijiazhuang, China
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23
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Budczies J, Romanovsky E, Kirchner M, Neumann O, Blasi M, Schnorbach J, Shah R, Bozorgmehr F, Savai R, Stiewe T, Peters S, Schirmacher P, Thomas M, Kazdal D, Christopoulos P, Stenzinger A. KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma. Br J Cancer 2024; 131:524-533. [PMID: 38866964 PMCID: PMC11300455 DOI: 10.1038/s41416-024-02746-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. METHODS The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data. RESULTS An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours. CONCLUSIONS KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.
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Affiliation(s)
- Jan Budczies
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
- Center for Personalized Medicine (ZPM), Heidelberg, Germany.
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
| | - Eva Romanovsky
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Olaf Neumann
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Miriam Blasi
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Johannes Schnorbach
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Rajiv Shah
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Farastuk Bozorgmehr
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Rajkumar Savai
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), Philipps-University, Marburg, Germany
| | - Solange Peters
- Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, Lausanne, Switzerland
| | - Peter Schirmacher
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Center for Personalized Medicine (ZPM), Heidelberg, Germany
| | - Michael Thomas
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Daniel Kazdal
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Center for Personalized Medicine (ZPM), Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Petros Christopoulos
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Center for Personalized Medicine (ZPM), Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
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24
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Elkrief A, Méndez-Salazar EO, Maillou J, Vanderbilt CM, Gogia P, Desilets A, Messaoudene M, Kelly D, Ladanyi M, Hellmann MD, Zitvogel L, Rudin CM, Routy B, Derosa L, Schoenfeld AJ. Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy. NPJ Precis Oncol 2024; 8:143. [PMID: 39014160 PMCID: PMC11252311 DOI: 10.1038/s41698-024-00630-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 06/13/2024] [Indexed: 07/18/2024] Open
Abstract
Anti-PD(L)-1 inhibition combined with platinum doublet chemotherapy (Chemo-IO) has become the most frequently used standard of care regimen in patients with non-small cell lung cancer (NSCLC). The negative impact of antibiotics on clinical outcomes prior to anti-PD(L)-1 inhibition monotherapy (IO) has been demonstrated in multiple studies, but the impact of antibiotic exposure prior to initiation of Chemo-IO is controversial. We assessed antibiotic exposures at two time windows: within 60 days prior to therapy (-60 d window) and within 60 days prior to therapy and 42 days after therapy (-60 + 42d window) in 2028 patients with advanced NSCLC treated with Chemo-IO and IO monotherapy focusing on objective response rate (ORR: rate of partial response and complete response), progression-free survival (PFS), and overall survival (OS). We also assessed impact of antibiotic exposure in an independent cohort of 53 patients. Univariable and multivariable analyses were conducted along with a meta-analysis from similar studies. For the -60 d window, in the Chemo-IO group (N = 769), 183 (24%) patients received antibiotics. Antibiotic exposure was associated with worse ORR (27% vs 40%, p = 0.001), shorter PFS (3.9 months vs. 5.9 months, hazard ratio [HR] 1.35, 95%CI 1.1,1.6, p = 0.0012), as well as shorter OS (10 months vs. 15 months, HR 1.50, 95%CI 1.2,1.8, p = 0.00014). After adjusting for known prognostic factors in NSCLC, antibiotic exposure was independently associated with worse PFS (HR 1.39, 95%CI 1.35,1.7, p = 0.002) and OS (HR 1.61, 95%CI 1.28,2.03, p < 0.001). Similar results were obtained in the -60 + 42d window, and also in an independent cohort. In a meta-analysis of patients with NSCLC treated with Chemo-IO (N = 4) or IO monotherapy (N = 13 studies) antibiotic exposure before treatment was associated with worse OS among all patients (n = 11,351) (HR 1.93, 95% CI 1.52, 2.45) and Chemo-IO-treated patients (n = 1201) (HR 1.54, 95% CI 1.28, 1.84). Thus, antibiotics exposure prior to Chemo-IO is common and associated with worse outcomes, even after adjusting for other factors. These results highlight the need to implement antibiotic stewardship in routine oncology practice.
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Affiliation(s)
- Arielle Elkrief
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada.
- Department of Hematology-Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
| | | | - Jade Maillou
- University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada
| | - Chad M Vanderbilt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pooja Gogia
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Antoine Desilets
- Department of Hematology-Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada
| | | | - Daniel Kelly
- Informatics Systems, Memorial Sloan Kettering Cancer, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew D Hellmann
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Laurence Zitvogel
- INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
| | - Charles M Rudin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Bertrand Routy
- University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada
- Department of Hematology-Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada
| | - Lisa Derosa
- INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
| | - Adam J Schoenfeld
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
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25
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Li YN, Su JL, Tan SH, Chen XL, Cheng TL, Jiang Z, Luo YZ, Zhang LM. Machine learning based on metabolomics unveils neutrophil extracellular trap-related metabolic signatures in non-small cell lung cancer patients undergoing chemoimmunotherapy. World J Clin Cases 2024; 12:4091-4107. [PMID: 39015934 PMCID: PMC11235537 DOI: 10.12998/wjcc.v12.i20.4091] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/10/2024] [Accepted: 05/28/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the primary form of lung cancer, and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease. However, the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies. Consequently, it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments. AIM To identify the metabolic signatures associated with neutrophil extracellular traps (NETs) and chemoimmunotherapy efficacy in NSCLC patients. METHODS In total, 159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled. We first investigated the characteristics influencing clinical efficacy. Circulating levels of NETs and cytokines were measured by commercial kits. Liquid chromatography tandem mass spectrometry quantified plasma metabolites, and differential metabolites were identified. Least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and random forest algorithms were employed. By using plasma metabolic profiles and machine learning algorithms, predictive metabolic signatures were established. RESULTS First, the levels of circulating interleukin-8, neutrophil-to-lymphocyte ratio, and NETs were closely related to poor efficacy of first-line chemoimmunotherapy. Patients were classed into a low NET group or a high NET group. A total of 54 differential plasma metabolites were identified. These metabolites were primarily involved in arachidonic acid and purine metabolism. Three key metabolites were identified as crucial variables, including 8,9-epoxyeicosatrienoic acid, L-malate, and bis(monoacylglycerol)phosphate (18:1/16:0). Using metabolomic sequencing data and machine learning methods, key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy. CONCLUSION The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.
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Affiliation(s)
- Yu-Ning Li
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Jia-Lin Su
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Shu-Hua Tan
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
| | - Xing-Long Chen
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Tian-Li Cheng
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Zhou Jiang
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Yong-Zhong Luo
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Le-Meng Zhang
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
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Naratornsirakul D, Chewaskulyong B, Kongkarnka S, Oranratnachai S. Comparison of treatment outcome between first-line combination immunotherapy (anti-PD-L1 or anti-PD1) with or without chemotherapy and chemotherapy alone in advanced non-small cell lung cancer patients in tertiary care hospital. Cancer Med 2024; 13:e70007. [PMID: 39030820 PMCID: PMC11257996 DOI: 10.1002/cam4.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/26/2024] [Accepted: 06/30/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Despite promising outcomes of first-line immunotherapy with or without chemotherapy in advanced non-small cell lung cancer (NSCLC), limited accessibility due to reimbursement was remain the problem in low to middle income countries. This study aimed to evaluate real-world effectiveness of immunotherapy in patients with advanced NSCLC in Northern Thailand. METHOD A retrospective, single-centered cohort, was conducted. Patients with advanced NSCLC who underwent PD-L1 testing (excluding EGFR and ALK mutations) and were treated with immunotherapy or without chemotherapy or chemotherapy alone were included. The primary end point was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events. RESULTS A total of 123 patients, of which 21 patients received immunotherapy-based regimen and 102 patients received chemotherapy alone. The median PFS was 11.9 months in immunotherapy-based group compared to 5.93 months in the chemotherapy group, with a. hazard ratio (HR) of 0.4 (95% confidence interval [CI], 0.23 to 0.68; p = 0.001). Similarly, the median OS was 26.68 months in the immunotherapy-based group and 11.21 months in the chemotherapy group, with HR of 0.42 (95% CI 0.22-0.8; p = 0.009). ORRs were significantly higher in the immunotherapy-based group, with 65% of patients showing a response compared to 32% in the chemotherapy group (p = 0.006). CONCLUSION The result of this real-world study in patients with advanced stage NSCLC indicate that first-line immunotherapy-based regimen was associated with significantly greater PFS, OS, and ORR with a safety profile consistent with pivotal studies.
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Affiliation(s)
- Danainut Naratornsirakul
- Division of Medical Oncology, Department of Internal Medicine, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
| | - Busyamas Chewaskulyong
- Division of Medical Oncology, Department of Internal Medicine, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
| | - Sarawut Kongkarnka
- Department of Pathology, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
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Cuppens K, Du Pont B, Knegjens J, Maes B, Baas P. Immune checkpoint inhibition in early-stage non-small cell lung cancer. Lung Cancer 2024; 193:107855. [PMID: 38896941 DOI: 10.1016/j.lungcan.2024.107855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/06/2024] [Accepted: 06/09/2024] [Indexed: 06/21/2024]
Abstract
The introduction of immune checkpoint inhibitors significantly advanced outcomes in both metastatic and locally advanced non-small cell lung cancer. Despite these advancements, the 5-year survival rate remains suboptimal. Even in early-stage disease a significant portion of patients relapse and die from metastatic progression. The integration of immunotherapy in the management of early-stage NSCLC demonstrated promising results, supported by a plethora of positive clinical trials conducted in recent years. Nonetheless, numerous questions persist. In this manuscript we comprehensively review the currently available data on adjuvant, neoadjuvant, and perioperative treatment strategies. We also address the challenges inherent to these approaches from different stakeholders' perspective.
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Affiliation(s)
- Kristof Cuppens
- Department of Pulmonology and Thoracic Oncology and Jessa & Science, Jessa Hospital Hasselt, Belgium; Faculty of Medicine and Life Sciences, LCRC, UHasselt, Diepenbeek, Belgium; Department of Thoracic Oncology, The Netherlands Cancer Institute and Leiden University Medical Center, Amsterdam, the Netherlands.
| | - Bert Du Pont
- Department of Thoracic and Vascular Surgery, Jessa Hospital Hasselt, Belgium
| | - Joost Knegjens
- Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Brigitte Maes
- Faculty of Medicine and Life Sciences, LCRC, UHasselt, Diepenbeek, Belgium; Laboratory for Molecular Diagnostics, Department of Laboratory Medicine, Jessa Hospital Hasselt, Belgium
| | - Paul Baas
- Department of Thoracic Oncology, The Netherlands Cancer Institute and Leiden University Medical Center, Amsterdam, the Netherlands
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Zhang C, Shao J, Tang X, Wu J, Li P, Li W, Wang C. The real-world treatment characteristic and efficacy of immune checkpoint inhibitors in non-small cell lung cancer: Data from a retrospective cohort study. Int Immunopharmacol 2024; 134:112152. [PMID: 38761777 DOI: 10.1016/j.intimp.2024.112152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 04/21/2024] [Accepted: 04/22/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND The efficacy and prognosis of immune checkpoint inhibitors (ICIs) remain unresolved issues. Here, we assessed the treatment characteristics and efficacy of ICIs in non-small cell lung cancer (NSCLC) using real-world data and evaluated the predictive value of factors, including programmed death-ligand 1 (PD-L1) expression, for the clinical outcome of ICIs in NSCLC. METHODS Analyzed data was collected from hospitalized patients in the West China Hospital of Sichuan University between January 2017 and March 2023. The Kaplan-Meier method was utilized for analyzing real-world progression-free survival (rwPFS), while Cox regression models was employed to access the correlation between the efficacy of immunotherapy and sociodemographic characteristics, disease information, and characteristics of ICI treatment. RESULTS A total of 545 patients were included in the retrospective study and characteristics of immunotherapy varied significantly among PD-L1 expression groups. The median rwPFS for the entire population was 9.76 months. Subgroup analyses revealed that patients with high PD-L1 expression, early TNM stage, first-line immunotherapy, EGFR wild-type and those who have not received radiotherapy and targeted therapy previously were more likely to have better rwPFS. Furthermore, multivariate Cox regression analyses identified PD-L1 expression, EGFR mutation status and previous radiotherapy as the most influential predictors of the response to ICI treatment. CONCLUSIONS This study presents the real-world experience of Chinese NSCLC patients undergoing ICI treatment, offering guidance for clinical decision-making based on various patient conditions, preferences, and indications for ICIs, through the evaluation of immunotherapy efficacy and predictors in NSCLC patients.
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Affiliation(s)
- Chenyang Zhang
- Institute of Hospital Management, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Jun Shao
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Xiaolong Tang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiayang Wu
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Peiyi Li
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu, China.
| | - Weimin Li
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
| | - Chengdi Wang
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
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Brown LJ, Ahn J, Gao B, Gee H, Nagrial A, Hau E, da Silva IP. Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy. Cancers (Basel) 2024; 16:2136. [PMID: 38893255 PMCID: PMC11172392 DOI: 10.3390/cancers16112136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/26/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.
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Affiliation(s)
- Lauren Julia Brown
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia (A.N.); (I.P.d.S.)
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
- Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
| | - Julie Ahn
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
- Sydney West Radiation Oncology Network (SWRON), Sydney, NSW 2145, Australia
| | - Bo Gao
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia (A.N.); (I.P.d.S.)
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
| | - Harriet Gee
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
- Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Sydney West Radiation Oncology Network (SWRON), Sydney, NSW 2145, Australia
- Children’s Medical Research Institute, Westmead, NSW 2145, Australia
| | - Adnan Nagrial
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia (A.N.); (I.P.d.S.)
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
| | - Eric Hau
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
- Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Sydney West Radiation Oncology Network (SWRON), Sydney, NSW 2145, Australia
| | - Inês Pires da Silva
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia (A.N.); (I.P.d.S.)
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW 2148, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
- Melanoma Institute Australia, Wollstonecraft, NSW 2065, Australia
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Frost N, Reck M. Non-Small Cell Lung Cancer Metastatic Without Oncogenic Alterations. Am Soc Clin Oncol Educ Book 2024; 44:e432524. [PMID: 38669613 DOI: 10.1200/edbk_432524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
This overview provides a thorough review of current treatment approaches for first-line management of nononcogenic addicted non-small cell lung cancer. We also address pertinent clinical decision-making queries encountered in everyday practice, such as the optimal treatment strategy for PD-L1-high patients, predictive factors for response to immune checkpoint inhibitors (ICI) both in terms of patient and cancer characteristics, the potential benefits of dual checkpoint blockade, and the unresolved issue of safe discontinuation strategies for long-term responders. Around one in five patients falls into this latter category while the majority develop either primary or acquired resistance to ICI-based first-line therapy, necessitating effective subsequent lines of treatment. Docetaxel, with or without combination of antiangiogenic agents, serves as the backbone of treatment, although evidence in the post-ICI setting is limited. Given that an inflamed tumor microenvironment (TME) is crucial for ICI responses, targeting the TME in cases of acquired resistance alongside continued ICI administration appears rational, although clinical trials so far have failed to confirm this hypothesis. Antibody-drug conjugates have emerged as a promising treatment modality, offering the potential for reduced toxicity and improved efficacy by targeting specific cancer antigens. Moreover, several chemotherapy-free approaches are currently under investigation for treatment-naïve patients, including alternative ICI and drugs targeting epitopes on both cancer and immune cells.
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Affiliation(s)
- Nikolaj Frost
- Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin, Germany
| | - Martin Reck
- Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungenClinic, Grosshansdorf, Germany
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Tsiouda T, Domvri K, Boutsikou E, Bikos V, Kyrka K, Papadaki K, Pezirkianidou P, Porpodis K, Cheva A. Prognostic Value of KRAS Mutations in Relation to PDL1 Expression and Immunotherapy Treatment in Adenocarcinoma and Squamous Cell Carcinoma Patients: A Greek Cohort Study. J Pers Med 2024; 14:457. [PMID: 38793038 PMCID: PMC11121847 DOI: 10.3390/jpm14050457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 04/15/2024] [Accepted: 04/21/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. PATIENTS AND METHODS The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. RESULTS The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1 > 49% in combination with a negative KRAS result had a median overall survival of 40 months compared to patients with a positive KRAS result (9 months, p < 0.05). In addition, patients diagnosed with adenocarcinoma, PDL1 < 49% and negative KRAS result had a median overall survival of 39 months compared to patients with a positive result (28 months, p < 0.05). CONCLUSIONS Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.
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Affiliation(s)
- Theodora Tsiouda
- Pulmonary-Oncology Department, ‘Theageneio’ Cancer Hospital, 540 07 Thessaloniki, Greece; (T.T.); (E.B.); (V.B.); (K.K.); (K.P.); (P.P.)
| | - Kalliopi Domvri
- Laboratory of Histology-Embryology, Medical School, Aristotle University, 541 24 Thessaloniki, Greece
- Laboratory of Pathology, “G. Papanikolaou” General Hospital, Exohi, 570 10 Thessaloniki, Greece
| | - Efimia Boutsikou
- Pulmonary-Oncology Department, ‘Theageneio’ Cancer Hospital, 540 07 Thessaloniki, Greece; (T.T.); (E.B.); (V.B.); (K.K.); (K.P.); (P.P.)
| | - Vasileios Bikos
- Pulmonary-Oncology Department, ‘Theageneio’ Cancer Hospital, 540 07 Thessaloniki, Greece; (T.T.); (E.B.); (V.B.); (K.K.); (K.P.); (P.P.)
| | - Krystallia Kyrka
- Pulmonary-Oncology Department, ‘Theageneio’ Cancer Hospital, 540 07 Thessaloniki, Greece; (T.T.); (E.B.); (V.B.); (K.K.); (K.P.); (P.P.)
| | - Konstantina Papadaki
- Pulmonary-Oncology Department, ‘Theageneio’ Cancer Hospital, 540 07 Thessaloniki, Greece; (T.T.); (E.B.); (V.B.); (K.K.); (K.P.); (P.P.)
| | - Persefoni Pezirkianidou
- Pulmonary-Oncology Department, ‘Theageneio’ Cancer Hospital, 540 07 Thessaloniki, Greece; (T.T.); (E.B.); (V.B.); (K.K.); (K.P.); (P.P.)
| | - Konstantinos Porpodis
- Pulmonary Department, Medical School, Aristotle University of Thessaloniki, “G. Papanikolaou” General Hospital, Exohi, 570 10 Thessaloniki, Greece;
| | - Angeliki Cheva
- Department of Pathology, AHEPA University Hospital of Thessaloniki, Aristotle University, 541 24 Thessaloniki, Greece;
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Kagamu H. Immunotherapy for non-small cell lung cancer. Respir Investig 2024; 62:307-312. [PMID: 38310751 DOI: 10.1016/j.resinv.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 12/19/2023] [Accepted: 01/19/2024] [Indexed: 02/06/2024]
Abstract
Immune checkpoint inhibitors (ICI) bind to programmed cell death-1 (PD-1)/PD-1 ligand-1 (PD-L1) and Cytotoxic T-lymphocyte antigen-4 (CTLA-4), which suppress T-cell function and inhibit their inhibitory function, resulting in T-cell activation. ICI have been approved for a wide range of cancers, including malignant melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck cancer, Hodgkin's disease, small-cell lung cancer, malignant pleural mesothelioma, gastric cancer, esophageal cancer, breast cancer, uterine cancer, and hepatocellular carcinoma, and the number of indications continues to grow. In addition to the treatment of advanced disease, the anti-tumor effect has been demonstrated across disease stages, from locally advanced disease to early-stage operative disease. The treatment of lung cancer is at the forefront of this trend and long-term durable responses and survival benefits in lung cancer have been exhibited that were unimaginable when cytotoxic anticancer agents were the only treatment options. However, treatment efficacy varies greatly from case to case, and no biomarkers have been developed to accurately predict efficacy. In this article, we discuss the past and future of ICI therapy for lung cancer, based on clinical and basic evidence accumulated to-date.
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Affiliation(s)
- Hiroshi Kagamu
- Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
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Hazama D, Nakahama K, Kodama H, Miyazaki A, Azuma K, Kawashima Y, Sato Y, Ito K, Shiraishi Y, Miura K, Takahama T, Oizumi S, Namba Y, Ikeda S, Yoshioka H, Tsuya A, Yasuda Y, Negi Y, Hara A, Toda M, Tachihara M. Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma. JTO Clin Res Rep 2024; 5:100613. [PMID: 38229769 PMCID: PMC10788284 DOI: 10.1016/j.jtocrr.2023.100613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 01/18/2024] Open
Abstract
Introduction Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.
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Affiliation(s)
- Daisuke Hazama
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Kenji Nakahama
- Department of Respiratory Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Kodama
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Akito Miyazaki
- Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan
| | - Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Yosuke Kawashima
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan
| | - Yuki Sato
- Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Kentaro Ito
- Respiratory Center, Matsusaka Municipal Hospital, Mie, Japan
| | - Yoshimasa Shiraishi
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keita Miura
- Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takayuki Takahama
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Satoshi Oizumi
- Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan
| | - Yoshinobu Namba
- Department of Respiratory Medicine and Medical Oncology, Takarazuka City Hospital, Hyogo, Japan
| | - Satoshi Ikeda
- Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan
| | - Hiroshige Yoshioka
- Department of Thoracic Oncology, Kansai Medical University, Osaka, Japan
| | - Asuka Tsuya
- Department of Medical Oncology, Izumi City General Hospital, Osaka, Japan
| | - Yuichiro Yasuda
- Department of Thoracic Oncology, Hyogo Cancer Center, Hyogo, Japan
| | - Yoshiki Negi
- Department of Respiratory Medicine and Hematology, Hyogo Medical University, School of Medicine, Hyogo, Japan
| | - Ayako Hara
- Department of Respiratory Medicine, Itami City Hospital, Hyogo, Japan
| | - Michihito Toda
- Department of General Thoracic Surgery, Kansai Rosai Hospital, Hyogo, Japan
| | - Motoko Tachihara
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan
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Vokes NI, Galan Cobo A, Fernandez-Chas M, Molkentine D, Treviño S, Druker V, Qian Y, Patel S, Schmidt S, Hong L, Lewis J, Rinsurongkawong W, Rinsurongkawong V, Lee JJ, Negrao MV, Gibbons DL, Vaporciyan A, Le X, Wu J, Zhang J, Rigney U, Iyer S, Dean E, Heymach JV. ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC. Clin Cancer Res 2023; 29:4958-4972. [PMID: 37733794 PMCID: PMC10690143 DOI: 10.1158/1078-0432.ccr-23-1122] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/16/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023]
Abstract
PURPOSE Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated. EXPERIMENTAL DESIGN Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models. RESULTS Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q < 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy. CONCLUSIONS ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.
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Affiliation(s)
- Natalie I. Vokes
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ana Galan Cobo
- Department of Molecular Diagnostics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - David Molkentine
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Santiago Treviño
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vitaly Druker
- Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Yu Qian
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sonia Patel
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Stephanie Schmidt
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lingzhi Hong
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeff Lewis
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Waree Rinsurongkawong
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - J. Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Marcelo V. Negrao
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Don L. Gibbons
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ara Vaporciyan
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiuning Le
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jia Wu
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianjun Zhang
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Una Rigney
- Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Sonia Iyer
- Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Emma Dean
- Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - John V. Heymach
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Jackson A, Chang N, Akurang D, Wheatley-Price P, Moore S. Real-World Immunotherapy Use and Effectiveness in Advanced NSCLC With Programmed Death-Ligand 1 Greater Than or Equal to 50% and Greater Than or Equal to 90. JTO Clin Res Rep 2023; 4:100601. [PMID: 38162175 PMCID: PMC10755357 DOI: 10.1016/j.jtocrr.2023.100601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 01/03/2024] Open
Abstract
Background Immunotherapy has vastly changed the treatment landscape for patients with advanced NSCLC. With high programmed death-ligand 1 (PD-L1) expression (tumor proportion score ≥50%), options include programmed cell death protein 1 or PD-L1 inhibitor with or without chemotherapy. A cut-point of greater than or equal to 50% defines PD-L1-high, but a more precise PD-L1 tumor proportion score may be an important predictor of outcomes. Methods We reviewed all patients with PD-L1-high NSCLC who received pembrolizumab from June 2019 to June 2021. Demographic, diagnosis, treatment, and outcomes data were collected retrospectively. The primary end point was a descriptive analysis of pembrolizumab prescribing patterns. Secondary end points included overall survival (OS) by treatment choice and absolute PD-L1 expression. Results Overall, 132 patients received pembrolizumab; 124 (94%) as monotherapy, and 8 (6%) with chemotherapy. Baseline characteristics include the following: (1) median age 70 years (50-89); (2) 55% men; (3) 79% Eastern Cooperative Oncology Group performance status 0 to 1; and (4) 96% current or former smokers. There were 39% who have PD-L1 greater than or equal to 90% versus 61% with PD-L1 of 50% to 89%. The median OS in the overall population was 14.4 months. The median OS in the pembrolizumab monotherapy cohort and combination cohort were 13.6 months and 16.6 months, respectively (p = 0.67). Within the monotherapy cohort, the median OS was longer for PD-L1 greater than or equal to 90% (19.8 mo) versus PD-L1 50% to 89% (11.9 mo, p = 0.039). The 24-month OS was 27.8% among patients with PD-L1 50% to 89% and 47.4% among patients with PD-L1 greater than or equal to 90%. Conclusions Most patients with advanced PD-L1-high NSCLC received pembrolizumab monotherapy, among whom OS was strongly correlated with PD-L1 expression, with PD-L1 greater than or equal to 90% of patients experiencing substantially longer survival. PD-L1 expression level could be an important determinant in immunotherapy prescribing patterns and a predictor of success in advanced NSCLC.
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Affiliation(s)
- Ashley Jackson
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Nina Chang
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Deborah Akurang
- Ottawa Hospital Research Institute, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
| | - Paul Wheatley-Price
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
| | - Sara Moore
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
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Morimoto K, Yamada T, Kawachi H, Tamiya M, Negi Y, Goto Y, Nakao A, Shiotsu S, Tanimura K, Takeda T, Okada A, Harada T, Date K, Chihara Y, Hasegawa I, Tamiya N, Nishioka N, Katayama Y, Iwasaku M, Tokuda S, Kijima T, Takayama K. Chemoimmunotherapy Versus Pembrolizumab as a First-Line Treatment for Patients with Advanced Non-small Cell Lung Cancer and High PD-L1 Expression: Focus on the Role of Performance Status. Target Oncol 2023; 18:915-925. [PMID: 37902896 DOI: 10.1007/s11523-023-01012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defined. OBJECTIVE The aim of this study was to identify a treatment option that is better for these patients in a real-world setting. PATIENTS AND METHODS A total of 425 patients with NSCLC and high PD-L1 expression were included retrospectively. All patients received either pembrolizumab monotherapy or ICI plus chemotherapy as the first-line treatment. Patients were subdivided into good (PS score 0 or 1; n = 354) and poor PS groups (PS score 2 or 3; n = 71). Early progressive disease (PD) was defined as PD within 3 months of ICI-based therapy initiation. RESULTS The good PS group had significantly longer progression-free survival (PFS) and overall survival (OS) than the poor PS group upon ICI-based therapy administration. In the poor PS group, no significant difference was observed in PFS and OS between pembrolizumab monotherapy and ICI plus chemotherapy. In the good PS group, pembrolizumab monotherapy, PD-L1 50-89%, and liver metastasis were associated with early PD, as determined using multivariate logistic regression analyses. However, in the poor PS group, the multivariate logistic regression analyses did not show an association between pembrolizumab monotherapy and early PD. CONCLUSIONS In patients with NSCLC exhibiting poor PS and high PD-L1 expression, ICI plus chemotherapy did not confer PFS or OS benefit compared with pembrolizumab monotherapy.
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Affiliation(s)
- Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan.
| | - Hayato Kawachi
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Yoshiki Negi
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Akira Nakao
- Department of Respiratory Medicine, Fukuoka University Hospital, Hakata, Fukuoka, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Kyoto, Japan
| | - Keiko Tanimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Asuka Okada
- Department of Respiratory Medicine, Saiseikai Suita Hospital, Suita, Osaka, Japan
| | - Taishi Harada
- Department of Medical Oncology, Fukuchiyama City Hospital, Fukuchiyama, Kyoto, Japan
| | - Koji Date
- Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Nantan, Kyoto, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Isao Hasegawa
- Department of Respiratory Medicine, Saiseikai Shiga Hospital, Rittou, Shiga, Japan
| | - Nobuyo Tamiya
- Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto, Kyoto, Japan
| | - Naoya Nishioka
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
| | - Shinsaku Tokuda
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajiicho, Kawaramachidori-hiro, Kyoto, Kyoto, 602-0841, Japan
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Tanimura K, Takeda T, Kataoka N, Yoshimura A, Nakanishi K, Yamanaka Y, Yoshioka H, Honda R, Uryu K, Fukui M, Chihara Y, Takei S, Kawachi H, Yamada T, Tamiya N, Okura N, Yamada T, Murai J, Shiotsu S, Kurata T, Takayama K. First-Line Chemoimmunotherapy versus Sequential Platinum-Based Chemotherapy Followed by Immunotherapy in Patients with Non-Small Cell Lung Cancer with ≤49% Programmed Death-Ligand 1 Expression: A Real-World Multicenter Retrospective Study. Cancers (Basel) 2023; 15:4988. [PMID: 37894357 PMCID: PMC10605814 DOI: 10.3390/cancers15204988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. METHODS This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. RESULTS Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1-49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1-49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7-14.8) vs. SEQ:5.5 months (95% CI: 4.5-6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9-15.3) vs. 6.4 months (95% CI: 4.9-7.5); p = 0.024). CONCLUSIONS CIT is recommended for patients with NSCLC with 1-49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions.
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Affiliation(s)
- Keiko Tanimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan; (K.T.); (N.K.); (A.Y.)
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan; (K.T.); (N.K.); (A.Y.)
| | - Nobutaka Kataoka
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan; (K.T.); (N.K.); (A.Y.)
| | - Akihiro Yoshimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan; (K.T.); (N.K.); (A.Y.)
| | - Kentaro Nakanishi
- Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata 573-1191, Japan; (K.N.); (Y.Y.); (H.Y.); (T.K.)
| | - Yuta Yamanaka
- Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata 573-1191, Japan; (K.N.); (Y.Y.); (H.Y.); (T.K.)
| | - Hiroshige Yoshioka
- Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata 573-1191, Japan; (K.N.); (Y.Y.); (H.Y.); (T.K.)
| | - Ryoichi Honda
- Department of Respiratory Medicine, Asahi General Hospital, Asahi 289-2511, Japan;
| | - Kiyoaki Uryu
- Department of Respiratory Medicine, Yao Tokushukai General Hospital, Yao 581-0011, Japan;
| | - Mototaka Fukui
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji 611-0041, Japan; (M.F.); (Y.C.)
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji 611-0041, Japan; (M.F.); (Y.C.)
| | - Shota Takei
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (S.T.); (H.K.); (T.Y.); (K.T.)
| | - Hayato Kawachi
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (S.T.); (H.K.); (T.Y.); (K.T.)
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (S.T.); (H.K.); (T.Y.); (K.T.)
| | - Nobuyo Tamiya
- Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto 607-8062, Japan;
| | - Naoko Okura
- Department of Respiratory Medicine, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan; (N.O.); (T.Y.)
| | - Takahiro Yamada
- Department of Respiratory Medicine, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan; (N.O.); (T.Y.)
| | - Junji Murai
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 605-0981, Japan; (J.M.); (S.S.)
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 605-0981, Japan; (J.M.); (S.S.)
| | - Takayasu Kurata
- Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata 573-1191, Japan; (K.N.); (Y.Y.); (H.Y.); (T.K.)
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (S.T.); (H.K.); (T.Y.); (K.T.)
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Nigen B, Goronflot T, Herbreteau G, Mathiot L, Sagan C, Raimbourg J, Bennouna J, Thillays F, Pons-Tostivint E. Impact of first-line immunotherapy on survival and intracranial outcomes in a cohort of non-small cell lung cancer patients with brain metastases at diagnosis. Lung Cancer 2023; 184:107321. [PMID: 37586178 DOI: 10.1016/j.lungcan.2023.107321] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 08/03/2023] [Accepted: 08/05/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Although brain metastases (BM) at diagnosis are common in non-squamous NSCLC patients (ns-NSCLC), they have been mostly excluded from randomized trials. The aim of this retrospective study was to evaluate real-word outcomes of frontline immune checkpoint inhibitor (ICI) in these patients. METHODS Our study assess the intracranial and overall efficacy of first-line ICI-based therapy compared to chemotherapy (CT) in ns-NSCLC patients diagnosed with BM, showing no targetable alterations. Patients were divided according to systemic therapy: CT, ICI, or CT-ICI. Primary endpoint was overall survival (OS), compared using Kaplan-Meier and Cox methodology. Secondary endpoint was intracranial progression free survival (icPFS). RESULTS Between 01 and 2018 and 05-2021, 118 patients were included (52 CT, 38 ICI and 28 CT-ICI). Median follow-up was 30.0 months. Intracranial radiotherapy was delivered for 75.0%, 68.4% and 67.9% of patients for CT, ICI and CT-ICI groups (p = 0.805). After adjustment, ICI and CT-ICI were associated with a better OS compared to CT (HR = 0.46, 95 %CI: 0.23-0.89, and HR = 0.52, 95 %CI: 0.27-1.01, respectively). ICI and CT-ICI were associated with a significant reduction in the risk of intracranial progression by 54% (HR = 0.46, 95 %CI: 0.25-0.84) and 59% (HR = 0.41, 95 %CI: 0.23-0.77) compared to CT. Stereotactic radiosurgery was associated with an increased icPFS compared to systemic therapy alone (HR = 0.51, 95% CI: 0.29 - 0.92), whereas whole-brain was not. CONCLUSIONS Real-life ns-NSCLC patients with BM at diagnosis treated frontline with ICI presented OS and icPFS benefit compared to CT alone. A prospective assessment of the ideal type and sequence of systemic and local therapy should be conducted.
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Affiliation(s)
- Benoit Nigen
- Nantes University, Centre Hospitalier Universitaire Nantes, Pneumology, F-44000 Nantes, France
| | - Thomas Goronflot
- Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire, 11 : Santé Publique, Clinique des données, INSERM, CIC, 1413, F-44000 Nantes, France
| | - Guillaume Herbreteau
- Biochemistry Laboratory and Molecular Cancer Genetics Plateform, University Hospital, 44093 Nantes, France
| | - Laurent Mathiot
- Nantes University, Centre Hospitalier Universitaire Nantes, Medical Oncology, F-44000 Nantes, France
| | - Christine Sagan
- Departement of Pathological Anatomy and Cytology, Centre Hospitalier Universitaire Nantes, 44093 Nantes, France
| | - Judith Raimbourg
- Department of Medical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de l'Ouest, Saint-Herblain, France; Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Jaafar Bennouna
- Department of Medical Oncology, Hospital Foch, Suresnes, France
| | - François Thillays
- Department of radiotherapy, Comprehensive Cancer Center, Institut de Cancérologie de l'Ouest, Saint-Herblain, France
| | - Elvire Pons-Tostivint
- Nantes University, Centre Hospitalier Universitaire Nantes, Medical Oncology, F-44000 Nantes, France; Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France.
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Frost N, Bleckmann A, Griesinger F, Grohé C, Janning M, Kollmeier J, Reinmuth N, Sebastian M, Thomas M, Reck M. Rationale and Design of the Phase II ANTELOPE Study of Atezolizumab, Carboplatin and nab-Paclitaxel vs. Pembrolizumab, Platinum and Pemetrexed in TTF-1 Negative, Metastatic Lung Adenocarcinoma (AIO-TRK-0122). Clin Lung Cancer 2023; 24:568-572. [PMID: 37169628 DOI: 10.1016/j.cllc.2023.04.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/02/2023] [Accepted: 04/08/2023] [Indexed: 05/13/2023]
Abstract
INTRODUCTION Pemetrexed-based immunochemotherapy represents an established standard of care as first line treatment for non-oncogenic driven metastatic non-small cell lung adenocarcinoma (NSCLC/ADC). However, retrospective analyses revealed better outcomes for pemetrexed-free regimens compared to pemetrexed-containing regimens in patients with thyroid transcription factor 1 (TTF-1) negative NSCLC/ADC. The multicenter, phase II, randomized, open-label ANTELOPE trial evaluates whether atezolizumab, carboplatin and nab-paclitaxel is superior to pembrolizumab, cis-/carboplatin and pemetrexed in TTF-1 negative NSCLC/ADC. METHODS Eligible participants are ≥18 years of age, with histologically or cytologically confirmed, treatment-naïve stage IV TTF-1 negative NSCLC/ADC without actionable genomic alterations or PD-L1-overexpression (TPS ≥50%) and will be randomized in a 1:1 fashion to pemetrexed-free (group A) vs. pemetrexed-based (group B) immunochemotherapy. The primary endpoint of this trial is overall survival (OS). RESULTS Enrollment will start in Q2 2023 at 30 sites in Germany with a planned inclusion of 136 participants. CONCLUSION ANTELOPE will provide efficacy outcomes of the current standard-of-care for the specific subset of TTF-1 negative NSCLC/ADC in a head-to-head comparison of approved immunochemotherapy regimens.
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Affiliation(s)
- Nikolaj Frost
- Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin, Germany.
| | - Annalen Bleckmann
- West German Cancer Center, University Hospital Münster, Münster, Germany; Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
| | - Frank Griesinger
- Pius Hospital, Department Internal Medicine-Oncology, Oldenburg, Germany
| | - Christian Grohé
- Klinik für Pneumologie - Evangelische Lungenklinik Berlin Buch, Berlin, Germany
| | - Melanie Janning
- DKFZ-Hector Cancer Institute and Department of Personalized Oncology at the University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim; Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Jens Kollmeier
- Helios Klinikum Emil von Behring, Lungenklinik Heckeshorn, Berlin, and Berlin Lung Institute, Berlin, Germany
| | | | - Martin Sebastian
- Department of Internal Medicine II, University Clinic of Frankfurt, Frankfurt, Germany
| | - Michael Thomas
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany, and Translational Research Center Heidelberg, member of the German Center for Lung Research (DZL)
| | - Martin Reck
- Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungenClinic, Grosshansdorf, Germany
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Özgüroğlu M, Kilickap S, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, Nechaeva M, Schenker M, Cicin I, Ho GF, Kulyaba Y, Zyuhal K, Scheusan RI, Garassino MC, He X, Kaul M, Okoye E, Li Y, Li S, Pouliot JF, Seebach F, Lowy I, Gullo G, Rietschel P. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2023; 24:989-1001. [PMID: 37591293 DOI: 10.1016/s1470-2045(23)00329-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/28/2023] [Accepted: 06/30/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. METHODS EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540. FINDINGS Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. FUNDING Regeneron Pharmaceuticals and Sanofi.
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Affiliation(s)
- Mustafa Özgüroğlu
- Cerrahpaşa Faculty of Medicine, Division of Medical Oncology, Istanbul University Cerrahpaşa, Istanbul, Türkiye.
| | - Saadettin Kilickap
- Faculty of Medicine, Department of Internal Medicine and Medical Oncology, Istinye University Istanbul, Türkiye
| | - Ahmet Sezer
- Department of Medical Oncology, Başkent University, Adana, Türkiye
| | - Mahmut Gümüş
- Department of Medical Oncology, School of Medicine, Istanbul Medeniyet University, Istanbul, Türkiye
| | - Igor Bondarenko
- Department of Oncology and Medical Radiology, Dnipropetrovsk Medical Academy, Dnipro, Ukraine
| | | | - Marina Nechaeva
- Division Arkhangelsk Clinical Oncology Center, Arkhangelsk, Russia
| | | | - Irfan Cicin
- Department of Medical Oncology, Trakya University, Edirne, Türkiye
| | - Gwo Fuang Ho
- Clinical Oncology Unit, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | | | - Kasimova Zyuhal
- Multiprofile Hospital for Active Treatment, Dobrich, Bulgaria
| | | | - Marina Chiara Garassino
- Department of Medicine, Section of Hematology/Oncology, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Xuanyao He
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Manika Kaul
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | - Yuntong Li
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Siyu Li
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | | | - Israel Lowy
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
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Elkrief A, Alessi JMV, Ricciuti B, Brown S, Rizvi H, Preeshagul IR, Wang X, Pecci F, Di Federico A, Lamberti G, Egger JV, Chaft JE, Rudin CM, Riely GJ, Kris MG, Ladanyi M, Chen Y, Hellmann MD, Shen R, Awad MM, Schoenfeld AJ. Efficacy of PD-(L)1 blockade monotherapy compared with PD-(L)1 blockade plus chemotherapy in first-line PD-L1-positive advanced lung adenocarcinomas: a cohort study. J Immunother Cancer 2023; 11:e006994. [PMID: 37487667 PMCID: PMC10373730 DOI: 10.1136/jitc-2023-006994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathological, and genomic features were associated with differential response to Chemotherapy-IO versus IO. METHODS This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted Cox proportional hazards models using estimated propensity scores. RESULTS The cohort analyzed included 866 patients. Relative to IO, Chemotherapy-IO was associated with improved objective response rate (ORR) (44% vs 35%, p=0.007) and progression-free survival (PFS) in patients with tumor PD-L1≥1% (HR 0.84, 95% CI 0.72 to 0.97, p=0.021) or PD-L1≥50% (ORR 55% vs 38%, p<0.001; PFS HR 0.68, 95% CI 0.53 to 0.87, p=0.002). Using propensity-adjusted analyses, only never-smokers in the PD-L1≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.013). Among patients with very high tumor PD-L1 expression (≥90%), there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO versus IO. CONCLUSIONS While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification.
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Affiliation(s)
- Arielle Elkrief
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joao M Victor Alessi
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Biagio Ricciuti
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Samantha Brown
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Hira Rizvi
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Isabel R Preeshagul
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Xinan Wang
- Environmental Health, Harvard University, Boston, Massachusetts, USA
| | - Federica Pecci
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Alessandro Di Federico
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Giuseppe Lamberti
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Jacklynn V Egger
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jamie E Chaft
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, New York, USA
| | - Charles M Rudin
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, New York, USA
| | - Gregory J Riely
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, New York, USA
| | - Mark G Kris
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, New York, USA
| | - Marc Ladanyi
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yuan Chen
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Matthew D Hellmann
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, New York, USA
| | - Ronglai Shen
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Adam J Schoenfeld
- Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medical College, New York, New York, USA
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Pelicon V, Cufer T, Knez L. Real-world outcomes of immunotherapy with or without chemotherapy in first-line treatment of advanced non-small cell lung cancer. Front Oncol 2023; 13:1182748. [PMID: 37404771 PMCID: PMC10316645 DOI: 10.3389/fonc.2023.1182748] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/30/2023] [Indexed: 07/06/2023] Open
Abstract
Background Immunotherapy alone (mono-IT) or combined with chemotherapy (chemo-IT) has recently become the cornerstone of first-line treatment for advanced non-small cell lung cancer (NSCLC) patients. Here, real-world outcomes of first-line mono-IT and chemo-IT of advanced NSCLC treated within routine clinical practice at a single academic center in the Central Eastern European (CEE) region are presented. Materials and methods A total of 176 consecutive patients with advanced NSCLC treated with mono-IT (118 patients) or chemo-IT (58 patients) were included. At the participating institution, all medical data relevant for providing oncology care are collected prospectively and in a standardized manner using purposely created pro-forms. Adverse events (AEs) were recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE). The Kaplan-Meier method was used to estimate median overall survival (mOS) and median duration of treatment (mDOT). Results The 118 patients in the mono-IT cohort had a median age of 64 years, most were male (59%), 20% had ECOG PS ≥2, and 14% had controlled CNS metastases at baseline. With a median follow-up time (mFU) of 24.1 months, the mOS was 19.4 months (95% CI, 11.1-27.6), and the mDOT was 5.0 months (95% CI, 3.5-6.5). The 1-year OS was 62%. The 58 patients in the chemo-IT cohort had a median age of 64 years, most were male (64%), 9% had ECOG PS ≥2, and 7% had controlled CNS metastases at baseline. With a mFU of 15.5 months, the mOS was 21.3 months (95% CI, 15.9-26.7), and the mDOT was 12.0 months (95% CI, 8.3-15.6). The 1-year OS was 75%. Adverse events of severe grade were recorded in 18% and 26% of patients, and immunotherapy discontinuation due to AEs occurred in 19% and 9% in the mono-IT and chemo-IT groups, respectively. No treatment-related deaths were recorded. Conclusion The results from the present real-world observational study from a CEE country suggest similar effectiveness and safety of first-line mono-IT and chemo-IT in patients with advanced NSCLC to those observed in randomized clinical trials. However, continuous follow-up will offer better insight into the magnitude of long-term benefits in routine clinical practice.
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Affiliation(s)
- Veronika Pelicon
- Department of Pharmacy, University Clinic Golnik, Golnik, Slovenia
| | - Tanja Cufer
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Lea Knez
- Department of Pharmacy, University Clinic Golnik, Golnik, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
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Lai J, Lin X, Zheng H, Xie B, Fu D. Characterization of stemness features and construction of a stemness subtype classifier to predict survival and treatment responses in lung squamous cell carcinoma. BMC Cancer 2023; 23:525. [PMID: 37291533 DOI: 10.1186/s12885-023-10918-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/04/2023] [Indexed: 06/10/2023] Open
Abstract
BACKGROUND Cancer stemness has been proven to affect tumorigenesis, metastasis, and drug resistance in various cancers, including lung squamous cell carcinoma (LUSC). We intended to develop a clinically applicable stemness subtype classifier that could assist physicians in predicting patient prognosis and treatment response. METHODS This study collected RNA-seq data from TCGA and GEO databases to calculate transcriptional stemness indices (mRNAsi) using the one-class logistic regression machine learning algorithm. Unsupervised consensus clustering was conducted to identify a stemness-based classification. Immune infiltration analysis (ESTIMATE and ssGSEA algorithms) methods were used to investigate the immune infiltration status of different subtypes. Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenotype Score (IPS) were used to evaluate the immunotherapy response. The pRRophetic algorithm was used to estimate the efficiency of chemotherapeutic and targeted agents. Two machine learning algorithms (LASSO and RF) and multivariate logistic regression analysis were performed to construct a novel stemness-related classifier. RESULTS We observed that patients in the high-mRNAsi group had a better prognosis than those in the low-mRNAsi group. Next, we identified 190 stemness-related differentially expressed genes (DEGs) that could categorize LUSC patients into two stemness subtypes. Patients in the stemness subtype B group with higher mRNAsi scores exhibited better overall survival (OS) than those in the stemness subtype A group. Immunotherapy prediction demonstrated that stemness subtype A has a better response to immune checkpoint inhibitors (ICIs). Furthermore, the drug response prediction indicated that stemness subtype A had a better response to chemotherapy but was more resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Finally, we constructed a nine-gene-based classifier to predict patients' stemness subtype and validated it in independent GEO validation sets. The expression levels of these genes were also validated in clinical tumor specimens. CONCLUSION The stemness-related classifier could serve as a potential prognostic and treatment predictor and assist physicians in selecting effective treatment strategies for patients with LUSC in clinical practice.
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Affiliation(s)
- Jinzhi Lai
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China
| | - Xinyi Lin
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China
| | - Huangna Zheng
- Department of Hematology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China
| | - Bilan Xie
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China.
| | - Deqiang Fu
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China.
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Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, Peters S, Planchard D, Smit EF, Solomon BJ, Veronesi G, Reck M. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34:358-376. [PMID: 36669645 DOI: 10.1016/j.annonc.2022.12.013] [Citation(s) in RCA: 269] [Impact Index Per Article: 134.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 01/18/2023] Open
Affiliation(s)
- L E Hendriks
- Department of Pulmonology, GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - K M Kerr
- Aberdeen Royal Infirmary, Aberdeen University Medical School, Aberdeen, UK
| | - J Menis
- Medical Oncology Department, University and Hospital Trust of Verona, Verona, Italy
| | - T S Mok
- Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - U Nestle
- Department of Radiation Oncology, University Hospital Freiburg, Freiburg; Department of Radiation Oncology, Kliniken Maria Hilf, Moenchengladbach, Germany
| | - A Passaro
- Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - S Peters
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland
| | - D Planchard
- Department of Medical Oncology, Thoracic Group, Gustave-Roussy, Villejuif, France
| | - E F Smit
- Thoracic Oncology Service, Netherlands Cancer Institute, Amsterdam; Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - B J Solomon
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - G Veronesi
- Faculty of Medicine and Surgery-Vita-Salute San Raffaele University, Milan; Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - M Reck
- Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, Lung Clinic, Grosshansdorf, Germany
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Hong L, Aminu M, Li S, Lu X, Petranovic M, Saad MB, Chen P, Qin K, Varghese S, Rinsurongkawong W, Rinsurongkawong V, Spelman A, Elamin YY, Negrao MV, Skoulidis F, Gay CM, Cascone T, Gandhi SJ, Lin SH, Lee PP, Carter BW, Wu CC, Antonoff MB, Sepesi B, Lewis J, Gibbons DL, Vaporciyan AA, Le X, Jack Lee J, Roy-Chowdhuri S, Routbort MJ, Gainor JF, Heymach JV, Lou Y, Wu J, Zhang J, Vokes NI. Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer. Nat Commun 2023; 14:695. [PMID: 36755027 PMCID: PMC9908867 DOI: 10.1038/s41467-023-36328-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 01/24/2023] [Indexed: 02/10/2023] Open
Abstract
The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.
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Affiliation(s)
- Lingzhi Hong
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad Aminu
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shenduo Li
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Xuetao Lu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Milena Petranovic
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - Maliazurina B Saad
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pingjun Chen
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kang Qin
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Susan Varghese
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Waree Rinsurongkawong
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vadeerat Rinsurongkawong
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amy Spelman
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yasir Y Elamin
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marcelo V Negrao
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ferdinandos Skoulidis
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carl M Gay
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tina Cascone
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Saumil J Gandhi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Steven H Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Percy P Lee
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brett W Carter
- Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carol C Wu
- Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mara B Antonoff
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Boris Sepesi
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeff Lewis
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Don L Gibbons
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ara A Vaporciyan
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiuning Le
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sinchita Roy-Chowdhuri
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark J Routbort
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Justin F Gainor
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yanyan Lou
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Jia Wu
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianjun Zhang
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Natalie I Vokes
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Du X, Wen S, Shi R, Xia J, Wang R, Zhang Y, Pan B, Wu X, Zhu W, Feng J, Wang X, Shen B. Peripheral blood lymphocytes differentiation patterns in responses / outcomes to immune checkpoint blockade therapies in non-small cell lung cancer: a retrospective study. BMC Cancer 2023; 23:83. [PMID: 36698098 PMCID: PMC9875514 DOI: 10.1186/s12885-023-10502-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 01/02/2023] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVES Programmed Cell Death-1/ Programmed Death-ligand 1 (PD-1 / PD-L1) inhibitor therapies targeting immunocytes induce persistent tumor remission in various cancers. However, the appropriate biomarkers for the therapeutic efficacy of PD-L1 and PD-1 blockade remain elusive. MATERIALS AND METHODS For a comprehensive analysis of peri-treatment lymphocyte differentiation, in the current study, we enrolled 146 non-small cell lung cancer patients who received α-PD-1 therapies for exploring the peripheral blood lymphocyte differentiation pattern at baseline and post-treatment (dynamic changes) by flow cytometry. RESULTS At baseline, CD4+ / CD8+ T cell ratio predicts good responses and outcomes, but activated T cell and cytotoxic T cell counts predict poor responses and outcomes. And for dynamic changes, after 6 weeks of immune checkpoint blockade (ICB) treatment, compared with baseline level, the elevation of total T and B cell counts indicate poor responses, and total T and TH cell counts indicate poor prognosis while activated T cell predicts good prognosis. And after 12 weeks, elevated total lymphocyte, cytotoxic T cell counts, and decreased total T cell counts and CD4+ / CD8+ T cell ratio predict good responses / outcomes. Our clinical predicting model shows good performance in predicting ICB treatment responses / outcomes. CONCLUSION Patients with favorable clinical responses / outcomes have distinctive peripheral blood immunocyte differentiation characteristics, indicating the potential of utilizing the peripheral immunocyte differentiation patterns for predicting ICB responses / outcomes.
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Affiliation(s)
- Xiaoyue Du
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Shaodi Wen
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Run Shi
- grid.412676.00000 0004 1799 0784Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jingwei Xia
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Ruotong Wang
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yihan Zhang
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Banzhou Pan
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xiaoliu Wu
- grid.452509.f0000 0004 1764 4566Flow Cytometry Core Facility, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Wei Zhu
- grid.440785.a0000 0001 0743 511XSchool of Medicine, Jiangsu University, Zhenjiang, China
| | - Jifeng Feng
- grid.452509.f0000 0004 1764 4566Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xin Wang
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
| | - Bo Shen
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
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Pons-Tostivint E, Hulo P, Guardiolle V, Bodot L, Rabeau A, Porte M, Hiret S, Demontrond P, Curcio H, Boudoussier A, Veillon R, Mayenga M, Dumenil C, Chatellier T, Gourraud PA, Mazieres J, Bennouna J. Real-world multicentre cohort of first-line pembrolizumab alone or in combination with platinum-based chemotherapy in non-small cell lung cancer PD-L1 ≥ 50. Cancer Immunol Immunother 2023; 72:1881-1890. [PMID: 36690799 DOI: 10.1007/s00262-022-03359-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/23/2022] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Pembrolizumab alone (IO-mono) or in combination with platinum-based chemotherapy (CT-IO) is first-line standard of care for advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥ 50%. This retrospective multicentre study assessed real-world use and efficacy of both strategies. METHODS Patients with advanced NSCLC PD-L1 ≥ 50% from eight hospitals who had received at least one cycle of IO-mono or CT-IO were included. Overall survival (OS) and real-word progression-free-survival were estimated using Kaplan-Meier methodology. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs, and a Cox model with inverse propensity treatment weighting was carried out. RESULTS Among the 243 patients included, 141 (58%) received IO-mono and 102 (42%) CT-IO. Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. With a median follow-up of 11.5 months (95% CI 10.4-13.3), median OS was not reached, but no difference was observed between groups (p = 0.51). Early deaths at 12 weeks were 11% (95% CI 4.6-16.9) and 15.2% (95% CI 9.0-20.9) in CT-IO and IO groups (p = 0.32). After adjustment for age, gender, performance status, histology, brain metastases, liver metastases and tobacco status, no statistically significant difference was found for OS between groups, neither in the multivariate adjusted model [HR 1.07 (95% CI 0.61-1.86), p = 0.8] nor in propensity adjusted analysis [HR 0.99 (95% CI 0.60-1.65), p = 0.99]. Male gender (HR 2.01, p = 0.01) and PS ≥ 2 (HR 3.28, p < 0.001) were found to be negative independent predictive factors for OS. CONCLUSION Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. However, sparing the chemotherapy in first-line does not appear to impact survival outcomes, even regarding early deaths.
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Affiliation(s)
- E Pons-Tostivint
- Centre Hospitalier Universitaire Nantes, Medical Oncology, Nantes University, 44000, Nantes, France.
| | - P Hulo
- Medical Oncology Unit, Clinique Mutualiste de L'Estuaire, Saint-Nazaire, France
| | - V Guardiolle
- Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Santé Publique, Clinique Des Données, Inserm CIC 1413, Centre Hospitalier Universitaire de Nantes, Nantes University, 44000, Nantes, France
| | - L Bodot
- Thoracic Oncology Department, Hôpital Larrey, CHU Toulouse, 31000, Toulouse, France
| | - A Rabeau
- Thoracic Oncology Department, Hôpital Larrey, CHU Toulouse, 31000, Toulouse, France
| | - M Porte
- Department of Medical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de L'Ouest, Saint-Herblain, France
| | - S Hiret
- Department of Medical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de L'Ouest, Saint-Herblain, France
| | - P Demontrond
- Department of Pneumology, Centre François Baclesse, Caen, France
| | - H Curcio
- Department of Pneumology, Centre François Baclesse, Caen, France
| | - A Boudoussier
- Department of Pneumology, University Hospital of Bordeaux, Pessac, France
| | - R Veillon
- Department of Pneumology, University Hospital of Bordeaux, Pessac, France
| | - M Mayenga
- Department of Medical Oncology, Hospital Foch, Suresnes, France
| | - C Dumenil
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Pare, 92100, Boulogne-Billancourt, France
| | - T Chatellier
- Medical Oncology Unit, Clinique Mutualiste de L'Estuaire, Saint-Nazaire, France
| | - P A Gourraud
- Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Santé Publique, Clinique Des Données, Inserm CIC 1413, Centre Hospitalier Universitaire de Nantes, Nantes University, 44000, Nantes, France
| | - J Mazieres
- Thoracic Oncology Department, Hôpital Larrey, CHU Toulouse, 31000, Toulouse, France
| | - J Bennouna
- Department of Medical Oncology, Hospital Foch, Suresnes, France
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Peng L, Guo J, Kong L, Huang Y, Tang N, Zhang J, Wang M, He X, Li Z, Peng Y, Wang Z, Han X. Efficacy of immunotherapy in KRAS-mutant advanced NSCLC: A real-world study in a Chinese population. Front Oncol 2023; 12:1070761. [PMID: 36741723 PMCID: PMC9892536 DOI: 10.3389/fonc.2022.1070761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023] Open
Abstract
Background Immunotherapy has improved the clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC). However, in patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, the superior efficacy of immunotherapy has not been elucidated and especially in real-world practice. Our study aimed to use real-world data to assess the efficacy of immunotherapy in KRAS-mutant NSCLC in a Chinese cohort. Methods In this retrospective cohort study, we extracted the clinical, molecular, and pathologic data from the electronic health records of patients with advanced KRAS-mutant NSCLC at Shandong Cancer Hospital between January 2018 and May 2022. Furthermore, we evaluated the progression-free survival (PFS) and overall survival (OS) of the included patients. Results Between January 2018 and November 2020, 793 patients were identified with stage IIIB-IV NSCLC and a total of 122 patients with KRAS mutations were included in the analysis. The majority of patients were diagnosed with stage IV (82.0%) adenocarcinoma (93.4%), along with a history of smoking (57.4%). Of these, 42% of patients received anti-PD-(L)1 with or without chemotherapy (Immunotherapy-based regimens), while 58.2% of patients received chemotherapy (Chemotherapy-based regimens). The median overall survival (mOS) in this cohort was 22.9 months (95% CI: 14.1-31.7), while the median-progression-free survival (mPFS) was 9.4 months (95% CI: 6.6-12.1). Patients receiving immunotherapy-based regimens displayed better mOS than those receiving chemotherapy-based regimens (45.2 vs. 11.3 months; P=1.81E-05), with no statistical difference observed in the mPFS (10.5 vs. 8.2 months; P=0.706). Patients receiving immunotherapy-based regimens either in the first line (P=0.00038, P=0.010, respectively) or second-line setting (P=0.010, P=0.026, respectively) showed benefits in both PFS and OS. Subgroup analysis indicated that in patients having KRAS G12C or non-KRAS G12C mutant types, immunotherapy showed benefits of better OS (P=0.0037, P=0.020, respectively) than chemotherapy. Moreover, in advanced NSCLCs patients with or without KRAS/TP53 co-mutation the immunotherapy-based regimen achieved longer OS and PFS than chemotherapy-based regimens. Conclusions In the Chinese population of patients with KRAS-mutant advanced NSCLC, immunotherapy-based regimens achieved longer OS than chemotherapy-based regimens, which was independent of first or second-line setting, as well as KRAS mutational subtypes.
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Affiliation(s)
- Lixiu Peng
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jun Guo
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Li Kong
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yong Huang
- Department of Imageology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ning Tang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Juguang Zhang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Minglei Wang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaohan He
- Department of Medical Science, Berry Oncology Corporation, Beijing, China
| | - Zhenzhen Li
- Department of Bioinformatics, Berry Oncology Corporation, Beijing, China
| | - Yonggang Peng
- Department of Medical Science, Berry Oncology Corporation, Beijing, China
| | - Zhehai Wang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China,*Correspondence: Zhehai Wang, ; Xiao Han,
| | - Xiao Han
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China,*Correspondence: Zhehai Wang, ; Xiao Han,
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Liu S, He Y, Li S, Gao X, Yang F. Kinesin family member 3A induces related diseases via wingless-related integration site/β-catenin signaling pathway. Sci Prog 2023; 106:368504221148340. [PMID: 36594221 PMCID: PMC10358705 DOI: 10.1177/00368504221148340] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Kinesin family member 3A is an important motor protein that participates in various physiological and pathological processes, including normal tissue development, homeostasis maintenance, tumor infiltration, and migration. The wingless-related integration site/β-catenin signaling pathway is essential for critical molecular mechanisms such as embryonic development, organogenesis, tissue regeneration, and carcinogenesis. Recent studies have examined the molecular mechanisms of kinesin family member 3A, among which the wingless-related integration site/β-catenin signaling pathway has gained attention. The interaction between kinesin family member 3A and the wingless-related integration site/β-catenin signaling pathway is compact and complex but is fascinating and worthy of further study. The upregulation and downregulation of kinesin family member 3A influence many diseases and patient survival through the wingless-related integration site/β-catenin signaling pathway. Therefore, this review mainly focuses on describing the kinesin family member 3A and wingless-related integration site/β-catenin signaling pathways and their associated diseases.
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Affiliation(s)
- Shupeng Liu
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Yang He
- Clinical Medicine College, North China University of Science and Technology, Tangshan, Hebei province, China
| | - Shifeng Li
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Xuemin Gao
- NHC Key Laboratory of Pneumoconiosis, Taiyuan, Shanxi Province, China
| | - Fang Yang
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, China
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Emerging Biomarkers in Immune Oncology to Guide Lung Cancer Management. Target Oncol 2023; 18:25-49. [PMID: 36577876 DOI: 10.1007/s11523-022-00937-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2022] [Indexed: 12/29/2022]
Abstract
Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools; however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer.
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