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Lim JU, Ryu WK, Park N, Choi J, Lee E, Lee SY, Lim JH. Current and future perspectives in extensive-stage small-cell lung cancer. Ther Adv Med Oncol 2025; 17:17588359251326705. [PMID: 40093978 PMCID: PMC11909689 DOI: 10.1177/17588359251326705] [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: 11/19/2024] [Accepted: 02/24/2025] [Indexed: 03/19/2025] Open
Abstract
Small-cell lung cancer (SCLC) is a highly aggressive and rapidly proliferative malignancy that has historically had limited therapeutic advancements. Recent advancements in the understanding of SCLC have led to attempts at subtyping the disease based on transcription factor characteristics, offering new insights into its biology and potential therapeutic targets. In addition, significant progress has been made in developing treatment regimens, providing new hope for improved patient outcomes. The introduction of immune checkpoint inhibitors, such as atezolizumab and durvalumab, in combination with traditional chemotherapy, has marked a significant advancement, demonstrating improved overall survival and progression-free survival compared to chemotherapy alone. Despite these advancements, the prognosis for extensive-stage SCLC (ES-SCLC), the more advanced form of SCLC, remains poor, highlighting the critical need for ongoing research and the development of novel therapeutic strategies. New treatment modalities, such as lurbinectedin and anti-Delta-like Canonical Notch Ligand 3 antibodies, are now included in the treatment options for refractory SCLC, and many more treatment strategies involving combination therapies are being studied. Advances in molecular profiling and the identification of biomarkers are aiding in the development of personalized treatment approaches. This review focuses on these recent advancements and emerging strategies in the treatment of ES-SCLC.
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Affiliation(s)
- Jeong Uk Lim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Woo Kyung Ryu
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Nuri Park
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Juwhan Choi
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Eunyoung Lee
- Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang-Yun Lee
- Department of Biomedical Engineering, Gachon University, Seongnam, Republic of Korea
- Central R&D Center, Medical & Bio Decision Co., Ltd., Suwon, Republic of Korea
| | - Jun Hyeok Lim
- Center for Lung Cancer, Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, 27, Inhang‑Ro, Jung‑Gu, Incheon 22332, Republic of Korea
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Wang B, Zhang J, Shi Y, Wang Y. Clinical significance of the combined systemic immune-inflammatory index and prognostic nutritional index in predicting the prognosis of patients with extensive-stage small-cell lung cancer receiving immune-combination chemotherapy. BMC Cancer 2024; 24:1574. [PMID: 39719567 DOI: 10.1186/s12885-024-13343-x] [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: 07/09/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
BACKGROUND The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model's performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). RESULT Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p < 0.05). In the meantime, PNI was considerably lower in the PD group than in the PR group (both p < 0.01). Kaplan-Meier curves demonstrated that patients with a low SII-PNI had prolonged progression-free survival (PFS) and overall survival (OS) compared to those with a high SII-PNI (all p < 0.01). Multivariate Cox analysis showed that PS = 1, bone metastasis, brain metastasis, and SII-PNI = 1,2 after four treatment cycles were independent risk factors for shorter OS and were included in the nomogram model. The ROC curves, C-index, and DCA curves confirm that the SII-PNI scores-based nomograms have strong predictive accuracy for OS. CONCLUSION There was a significant correlation between pre- and post-treatment SII-PNI and treatment effect in ES-SCLC. The SII-PNI score after four treatment cycles is a useful prognostic indicator for ES-SCLC patients receiving chemotherapy combined with immune checkpoint inhibitors (ICIs).
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Affiliation(s)
- Bingbing Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150000, China
| | - Jingdan Zhang
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, 028000, China
| | - Yingnan Shi
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150000, China
| | - Yan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150000, China.
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Joerger M, Koster KL, Janik T, de Jong FA. Combination Therapy with Immune Checkpoint Inhibitors and Histone Deacetylase Inhibitors or Alkylating Agents. Cancer Manag Res 2024; 16:855-869. [PMID: 39072340 PMCID: PMC11278095 DOI: 10.2147/cmar.s464245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/04/2024] [Indexed: 07/30/2024] Open
Abstract
Purpose Immune checkpoint inhibitors (CPIs) have been widely adopted in a number of early and advanced malignancies. Histone deacetylase inhibitors (HDACis) and alkylating agents (AAs) have been suggested to potentiate the actions of CPIs on tumor cells. We conducted a comprehensive literature review to explore the potential synergistic activity between CPIs, AAs, and HDACis. Patients and Methods Clinical and non-clinical studies describing outcomes in patients with cancer receiving CPIs and either concomitant or sequential (pre- or post-CPI) AAs or HDACis were identified in PubMed using pre-defined search strings. Manual searches of key oncology congresses were similarly performed. All relevant articles and abstracts were manually screened for relevance, classified according to the specific anticancer agents used (CPIs, AAs, or HDACis), tumor entity, and whether treatment was concomitant or sequential. Results Overall, 227 unique clinical studies across a range of tumor types, both solid tumors and hematological malignancies, were identified. One hundred and fifty-nine publications on Phase I and II clinical studies together with 41 publications on Phase III studies were examined. The most commonly investigated tumor types were melanoma, triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. The randomized clinical studies identified, all of which reported on the combination of a CPI with an AA, demonstrated superior outcomes in the combination arm compared with CPI or AA monotherapy. Similarly, combination therapy with CPIs and HDACis demonstrated promising activity. Conclusion Sequential or concomitant administration of a CPI with an AA or an HDACi may improve outcomes for patients with a range of tumor types. There is a rationale to support further investigation into the potential for synergy between CPIs, alkylating agents and/or HDACis in both the non-clinical and clinical settings.
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Affiliation(s)
- Markus Joerger
- Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Kira-Lee Koster
- Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Tomas Janik
- Research & Development Department, Mundipharma Research Limited, Cambridge, UK
| | - Floris A de Jong
- Global Medical Affairs Department, Mundipharma Research Limited, Cambridge, UK
- Medical Affairs Department, Exact Sciences International GmbH, Baar, Switzerland
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Dang J, Xu G, Guo G, Zhang H, Shang L. Construction of a prognostic model for extensive-stage small cell lung cancer patients undergoing immune therapy in northernmost China and prediction of treatment efficacy based on response status at different time points. J Cancer Res Clin Oncol 2024; 150:255. [PMID: 38750370 PMCID: PMC11096247 DOI: 10.1007/s00432-024-05767-6] [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: 03/02/2024] [Accepted: 04/26/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND AND PURPOSE Recently, the emergence of immune checkpoint inhibitors has significantly improved the survival of patients with extensive-stage small cell lung cancer. However, not all patients can benefit from immunotherapy; therefore, there is an urgent need for precise predictive markers to screen the population for the benefit of immunotherapy. However, single markers have limited predictive accuracy, so a comprehensive predictive model is needed to better enable precision immunotherapy. The aim of this study was to establish a prognostic model for immunotherapy in ES-SCLC patients using basic clinical characteristics and peripheral hematological indices of the patients, which would provide a strategy for the clinical realization of precision immunotherapy and improve the prognosis of small cell lung cancer patients. METHODS This research retrospectively collected data from ES-SCLC patients treated with PD-1/PD-L1 inhibitors between March 1, 2019, and October 31, 2022, at Harbin Medical University Cancer Hospital. The study data was randomly split into training and validation sets in a 7:3 ratio. Variables associated with patients' overall survival were screened and modeled by univariate and multivariate Cox regression analyses. Models were presented visually via Nomogram plots. Model discrimination was evaluated by Harrell's C index, tROC, and tAUC. The calibration of the model was assessed by calibration curves. In addition, the clinical utility of the model was assessed using a DCA curve. After calculating the total risk score of patients in the training set, patients were stratified by risk using percentile partitioning. The Kaplan-Meier method was used to plot OS and PFS survival curves for different risk groups and response statuses at different milestone time points. Differences in survival time groups were compared using the chi-square test. Statistical analysis software included R 4.1.2 and SPSS 26. RESULTS This study included a total of 113 ES-SCLC patients who received immunotherapy, including 79 in the training set and 34 in the validation set. Six variables associated with poorer OS in patients were screened by Cox regression analysis: liver metastasis (P = 0.001), bone metastasis (P = 0.013), NLR < 2.14 (P = 0.005), LIPI assessed as poor (P < 0.001), PNI < 51.03 (P = 0.002), and LDH ≥ 146.5 (P = 0.037). A prognostic model for immunotherapy in ES-SCLC patients was constructed based on the above variables. The Harrell's C-index in the training and validation sets of the model was 0.85 (95% CI 0.76-0.93) and 0.88 (95% CI 0.76-0.99), respectively; the AUC values corresponding to 12, 18, and 24 months in the tROC curves of the training set were 0.745, 0.848, and 0.819 in the training set and 0.858, 0.904 and 0.828 in the validation set; the tAUC curves show that the overall tAUC is > 0.7 and does not fluctuate much over time in both the training and validation sets. The calibration plot demonstrated the good calibration of the model, and the DCA curve indicated that the model had practical clinical applications. Patients in the training set were categorized into low, intermediate, and high risk groups based on their predicted risk scores in the Nomogram graphs. In the training set, 52 patients (66%) died with a median OS of 15.0 months and a median PFS of 7.8 months. Compared with the high-risk group (median OS: 12.3 months), the median OS was significantly longer in the intermediate-risk group (median OS: 24.5 months, HR = 0.47, P = 0.038) and the low-risk group (median OS not reached, HR = 0.14, P = 0.007). And, the median PFS was also significantly prolonged in the intermediate-risk group (median PFS: 12.7 months, HR = 0.45, P = 0.026) and low-risk group (median PFS not reached, HR = 0.12, P = 0.004) compared with the high-risk group (median PFS: 6.2 months). Similar results were obtained in the validation set. In addition, we observed that in real-world ES-SCLC patients, at 6 weeks after immunotherapy, the median OS was significantly longer in responders than in non-responders (median OS: 19.5 months vs. 11.9 months, P = 0.033). Similar results were obtained at 12 weeks (median OS: 20.7 months vs 11.9 months, P = 0.044) and 20 weeks (median OS: 20.7 months vs 11.7 months, P = 0.015). Finally, we found that in the real world, ES-SCLC patients without liver metastasis (P = 0.002), bone metastasis (P = 0.001) and a total number of metastatic organs < 2 (P = 0.002) are more likely to become long-term survivors after receiving immunotherapy. CONCLUSION This study constructed a new prognostic model based on basic patient clinical characteristics and peripheral blood indices, which can be a good predictor of the prognosis of immunotherapy in ES-SCLC patients; in the real world, the response status at milestone time points (6, 12, and 20 weeks) can be a good indicator of long-term survival in ES-SCLC patients receiving immunotherapy.
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Affiliation(s)
- Junjie Dang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang, China
| | - Gang Xu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang, China
| | - Ge Guo
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang, China
| | - Huan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang, China
| | - Lihua Shang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang, China.
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Chen CQ, Huang MY, Pan M, Chen QQ, Wei FF, Huang H. Thymic carcinoid with multiple bone metastases: A case report. World J Clin Cases 2024; 12:2275-2280. [PMID: 38808334 PMCID: PMC11129134 DOI: 10.12998/wjcc.v12.i13.2275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 02/09/2024] [Accepted: 03/28/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Thymic carcinoid (TC) is a rare entity among anterior mediastinal malignancies. TCs are neuroendocrine carcinomas that constitute approximately 2%-5% of all thymic epithelial tumors. CASE SUMMARY The study reported a rare TC with multiple bone metastases. A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg. Magnetic resonance imaging scans revealed damage to the lumbar spine, sacrocaudal vertebrae and iliac crest, suggesting bone metastasis; computed tomography (CT) scan of the thorax showed a calcified anterior mediastinal mass; positron emission tomography-CT demonstrated multiple abnormal bone signals; and laboratory work-up showed no endocrine abnormalities. Fine-needle aspiration biopsy revealed predominantly single small, round to oval cells with scant cytoplasm and some loose clusters, suggesting endocrine manifestations. The pathological diagnosis was atypical carcinoid, which tend to originate from the thymus and was classified as intermediate-highly invasive. The patient underwent anlotinib-targeted therapy. Anlotinib (12 mg) was administered daily for 2 wk, after which the patient was allowed to rest for 21 d. Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29% after therapy. Treatment has a long stable disease benefit of more than 2.5 years. CONCLUSION These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.
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Affiliation(s)
- Chun-Qiao Chen
- Department of Oncology, People’s Hospital of Guilin, Guilin 541000, Guangxi Zhuang Autonomous Region, China
| | - Ming-Yue Huang
- Department of Oncology, People’s Hospital of Guilin, Guilin 541000, Guangxi Zhuang Autonomous Region, China
| | - Min Pan
- Department of Oncology, People’s Hospital of Guilin, Guilin 541000, Guangxi Zhuang Autonomous Region, China
| | - Qiu-Qiu Chen
- Department of Oncology, People’s Hospital of Guilin, Guilin 541000, Guangxi Zhuang Autonomous Region, China
| | - Fei-Fei Wei
- Department of Oncology, People’s Hospital of Guilin, Guilin 541000, Guangxi Zhuang Autonomous Region, China
| | - Hui Huang
- Department of Oncology, People’s Hospital of Guilin, Guilin 541000, Guangxi Zhuang Autonomous Region, China
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Grenda A, Krawczyk P, Obara A, Gajek Ł, Łomża-Łaba A, Milanowski J. Transitioning to a Personalized Approach in Molecularly Subtyped Small-Cell Lung Cancer (SCLC). Int J Mol Sci 2024; 25:4208. [PMID: 38673793 PMCID: PMC11050005 DOI: 10.3390/ijms25084208] [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: 02/29/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Lung cancer has become a major public health concern, standing as the leading cause of cancer-related deaths worldwide. Among its subtypes, small-cell lung cancer (SCLC) is characterized by aggressive and rapid growth, poor differentiation, and neuroendocrine features. Typically, SCLC is diagnosed at an advanced stage (extensive disease, ED-SCLC), with distant metastases, and is strongly associated with tobacco smoking and has a poor prognosis. Recent clinical trials, such as CASPIAN and IMpower133, have demonstrated promising outcomes with the incorporation of immune checkpoint inhibitors in first-line chemotherapy, leading to prolonged progression-free survival and overall survival in patients with ED-SCLC compared to standard chemotherapy. Other studies have emphasized the potential for future development of molecularly targeted therapies in SCLC patients, including inhibitors of IGF-1R, DLL3, BCL-2, MYC, or PARP. The molecular subdivision of SCLC based on transcriptomic and immunohistochemical analyses represents a significant advancement in both diagnostic and clinical approaches in SCLC patients. Specific molecular pathways are activated within distinct transcriptome subtypes of SCLC, offering the potential for personalized treatment strategies, such as targeted therapies and immunotherapies. Such tailored approaches hold promise for significantly improving outcomes in SCLC patients.
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Affiliation(s)
- Anna Grenda
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-950 Lublin, Poland; (P.K.); (A.Ł.-Ł.); (J.M.)
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-950 Lublin, Poland; (P.K.); (A.Ł.-Ł.); (J.M.)
| | - Adrian Obara
- Institute of Genetics and Immunology Genim LCC, Filaretów 27/2, 20-609 Lublin, Poland; (A.O.); (Ł.G.)
| | - Łukasz Gajek
- Institute of Genetics and Immunology Genim LCC, Filaretów 27/2, 20-609 Lublin, Poland; (A.O.); (Ł.G.)
| | - Aleksandra Łomża-Łaba
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-950 Lublin, Poland; (P.K.); (A.Ł.-Ł.); (J.M.)
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-950 Lublin, Poland; (P.K.); (A.Ł.-Ł.); (J.M.)
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Zhu L, Qin J. Predictive biomarkers for immunotherapy response in extensive-stage SCLC. J Cancer Res Clin Oncol 2024; 150:22. [PMID: 38245636 PMCID: PMC10799815 DOI: 10.1007/s00432-023-05544-x] [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: 10/09/2023] [Accepted: 12/13/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Small cell lung cancer (SCLC) accounts for about 13-15% of all lung cancers, and about 70% of SCLC patients have developed extensive-stage small cell lung cancer (ES-SCLC) at the time of diagnosis because of its highgrade malignancy, easy invasion, and metastasis. In recent years, immunotherapy combined with chemotherapy has become the standard first-line treatment for ES-SCLC. However, SCLC is a relatively immune-cold lung cancer subtype with a limited number of beneficiaries and a short benefit period. Therefore, the use of biomarkers to identify populations with significant benefits from immunotherapy will help improve the efficacy and survival benefits of immunotherapy. However, predictive biomarkers suitable for clinical practice have not been established in the field of SCLC. PURPOSE In order to find the predictive biomarkers of immunotherapy for ES-SCLC, we summarized the research progress of traditional biomarkers, such as programmed cell death ligand 1 (PD-L1) and tumor mutation burden (TMB), and summarizes the research of potential biomarkers associated with prognosis, such as molecular subtypes, special gene expression, expression of major histocompatibility complex (MHC) I and II classes, tumor immune microenvironment (TIME), and circulating tumor DNA (ctDNA) .We aim to provide new insights on biomarkers. CONCLUSION The exploration of biomarkers for immunotherapy of SCLC is still very difficult, and it is clear that conventional predictive biomarkers are not suitable for SCLC. At present, the molecular subtypes defined from transcription factors may have some guiding significance, which still needs to be confirmed by prospective clinical studies. In addition, the ctDNA positivity rate of SCLC is higher than that of other tumor types, which can also solve the dilemma of the difficulty of obtaining specimens of SCLC tissues. And the dynamic change of ctDNA also has great potential to predict the curative effect of SCLC, which is worth further clinical exploration.
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Affiliation(s)
- Lin Zhu
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Jing Qin
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, 310022, People's Republic of China.
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Desai A, Smith CJ, Ashara Y, Orme JJ, Zanwar S, Potter A, Hocum C, Moffett JN, Schwecke AJ, Manochakian R, Lou Y, Zhao Y, Ernani V, Savvides P, Molina J, Dimou A, Mansfield AS, Parikh K, Leventakos K. Real-World Outcomes With Lurbinectedin in Second-Line Setting and Beyond for Extensive Stage Small Cell Lung Cancer. Clin Lung Cancer 2023; 24:689-695.e1. [PMID: 37880074 DOI: 10.1016/j.cllc.2023.09.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND Lurbinectedin has emerged as a potential treatment option for relapsed small cell lung cancer (SCLC). While clinical trials have demonstrated its efficacy and safety, real-world data are limited. This study aimed to evaluate the safety and efficacy of lurbinectedin in a real-world setting, focusing on its use as a second-line agent and beyond in SCLC patients. METHODS A retrospective analysis was conducted on 90 patients who received lurbinectedin between June 2020 and June 2022 within the Mayo Clinic Health System. Of these, 50 patients received lurbinectedin as a second-line agent, and 14 patients received it as a third-line or later agent. The primary outcomes assessed were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. RESULTS Lurbinectedin was generally well tolerated in this real-world cohort, with a median OS of 5.1 months in the second-line cohort and 5.6 months in the third-line or later cohort. Median PFS was 2.1 months in the second-line cohort and 3.4 months in the third-line or later cohort. Adverse events were manageable, with the most common being neutropenia, anemia, fatigue, and febrile neutropenia. No treatment-related deaths or grade 5 toxicities were reported. CONCLUSION This real-world study provides valuable insights into the safety and efficacy of lurbinectedin in relapsed SCLC. Lurbinectedin demonstrated modest efficacy and a comparable safety profile to that observed in clinical trials. However, outcomes for relapsed SCLC remain suboptimal, particularly for patients with a shorter chemotherapy-free interval and central nervous system metastases.
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Affiliation(s)
- Aakash Desai
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Caleb J Smith
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Yash Ashara
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Jacob J Orme
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Saurabh Zanwar
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Ashley Potter
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | - Craig Hocum
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | | | | | - Yanyan Lou
- Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
| | - Yujie Zhao
- Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
| | | | - Panos Savvides
- Department of Medical Oncology, Mayo Clinic, Scottsdale, AZ
| | - Julian Molina
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
| | | | | | - Kaushal Parikh
- Division of Medical Oncology, Mayo Clinic, Rochester, MN
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Zhang S, Tian J, Wang X, Liu C. PPIs therapy has a negative impact on the clinical outcomes of advanced SCLC patients treated with PD-L1 inhibitors. BMC Pulm Med 2023; 23:438. [PMID: 37951887 PMCID: PMC10638834 DOI: 10.1186/s12890-023-02754-4] [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: 05/07/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Programmed death-ligand 1 (PD-L1) inhibitors has emerged as a first-line therapeutic strategy for advanced small cell lung cancer (SCLC), which can stimulate T-cell activation, thereby preventing tumor avoidance of immunologic surveillance, whereas, proton pump inhibitors (PPIs) can play an important role in regulating immune function. This study assessed whether the concomitantly use of PPIs affected outcomes of immunotherapy in advanced SCLC. METHODS Data from advanced SCLC patients who firstly treated with PD-L1 inhibitors between July 2018 and February 2021 was retrospectively analyzed. The impact of concomitant medications (especially PPIs) on objective response rate, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS Of 208 patients, 101 received immunotherapy concomitant PPIs. The median PFS of patients receiving PPIs (6.6 months) were significantly shorter than those without PPIs (10.6 months), and so was OS. There was associated with a 74.9% increased risk of progression and 58.3% increased risk of death. Both first-line and post-first-line immunotherapy, patients treated PPIs had poorer PFS. CONCLUSION PPIs therapy has a negative impact on the clinical outcomes of advanced SCLC patients treated with PD-L1 inhibitors.
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Affiliation(s)
- Sisi Zhang
- Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250062, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Jing Tian
- Department of Radiation Oncology, Jinan Zhangqiu District People's Hospital, Jinan, Shandong, 250200, China
| | - Xinwei Wang
- Department of Intensive Care Medical Center, Shandong Public Health Clinical Center, Shandong University, Jinan, Shandong, 250013, China
| | - Chengxin Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Academy of Medical Sciences, Jinan, Shandong, 250117, China.
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He J, Hu Q. Progress in the clinical application of immune checkpoint inhibitors in small cell lung cancer. Front Immunol 2023; 14:1126582. [PMID: 37063927 PMCID: PMC10090448 DOI: 10.3389/fimmu.2023.1126582] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Small cell lung cancer (SCLC) is a refractory cancer with poor prognosis due to its aggressive malignancy and high rates of metastasis, recurrence and drug resistance. These characteristics have also greatly impeded the identification of new treatment methods and drugs. The traditional model of SCLC treatment that has been reliant on platinum combined with etoposide for decades has been superseded by the emergence of immune checkpoint inhibitors (ICIs), which have shown significant therapeutic effects and broad application prospects as a monotherapy. This has led to the evaluation of ICIs with different mechanisms of action and their use in combination with radiotherapy or a variety of molecular targeted drugs to achieve synergy, complementary advantages, and reduce adverse reactions. Here, we review the progress in the use of ICIs as a monotherapy or in combination therapy for SCLC and consider the current limitations of these approaches as well as prospects for future developments.
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Cozzi S, Bruni A, Ruggieri MP, Borghetti P, Scotti V, Franceschini D, Fiore M, Taraborrelli M, Salvi F, Galaverni M, Savoldi L, Braglia L, Botti A, Finocchi Ghersi S, Niccolò GL, Lohr F, Iotti C, Ciammella P. Thoracic Radiotherapy in Extensive Disease Small Cell Lung Cancer: Multicenter Prospective Observational TRENDS Study. Cancers (Basel) 2023; 15:cancers15020434. [PMID: 36672383 PMCID: PMC9857193 DOI: 10.3390/cancers15020434] [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: 11/09/2022] [Revised: 12/19/2022] [Accepted: 01/06/2023] [Indexed: 01/12/2023] Open
Abstract
(1) Introduction: Small cell lung cancer (SCLC) is an aggressive tumor type, accounting for about 15% of all lung cancers. Radiotherapy (RT) plays a fundamental role in both early and advanced stages. Currently, in advanced disease, the use of consolidative chest RT should be recommended for patients with good response to platinum-based first-line chemotherapy, but its use has not yet been standardized. The present prospective study aims to evaluate the pattern of care of consolidative chest RT in patients with advanced stage SCLC, and its effectiveness in terms of disease control and tolerability. (2) Materials and methods: This study was a multicenter prospective observational trial, proposed and conducted within the AIRO lung study group to evaluate the pattern of care of consolidative chest RT after first-line chemotherapy in patients with advanced SCLC. The patient and tumor characteristics, doses, fractionation and volumes of thoracic RT and prophylactic cranial irradiation (PCI), as well as the thoracic and extrathoracic response to the treatment, toxicity and clinical outcomes, were collected and analyzed. (3) Results: From January 2017 to December 2019, sixty-four patients were enrolled. Median follow-up was 33 months. The median age was 68 years (range 42-81); 38 patients (59%) were male and 26 (41%) female. Carboplatin + etoposide for 6 cycles was the most commonly used first-line therapeutic scheme (42%). With regard to consolidative chest RT, 56% of patients (35) received 30 Gy in 10 factions and 16 patients (26%) received 45 Gy in 15 sessions. The modulated intensity technique was used in 84.5% of cases, and post-chemotherapy macroscopic residual disease was the target volume in 87.5% of patients. Forty-four patients (69%) also underwent PCI. At the last follow-up, over 60% of patients did not experience chest disease progression, while 67% showed extrathoracic progression. At the first radiological evaluation after RT, complete response and stable disease were recorded in 6% and 46% of the cases, respectively. Two patients had a long-term complete response to the combined treatment. The brain was the first site of extrathoracic progression in 28%. 1y and 2y OS and PFS were 67%, 19%, 28% and 6%, respectively. Consolidative chest RT was well-tolerated in the majority of patients; it was interrupted in three cases (due to G2 pulmonary toxicity, disease progression and clinical decay, respectively). Only 1 patient developed G3 asthenia. (4) Conclusions: Consolidative chest RT has been shown to be useful in reducing the risk of thoracic disease progression and is absolutely well-tolerated in patients with advanced stage SCLC with good response after first-line chemotherapy. Among the Italian centers that participated in this study, there is still variability in the choice of fractionation and target volumes, although the guidelines contain clear recommendations. The aim of future research should be to clarify the role and modalities of chest RT in the era of immunotherapy in advanced-stage SCLC.
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Affiliation(s)
- Salvatore Cozzi
- Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
- Radiation Oncology Department, Centre Lèon Bèrard, 693736 Lyon, France
- Correspondence:
| | - Alessio Bruni
- Radiation Therapy Unit, Department of Oncology and Hematology, University Hospital of Modena, 41125 Modena, Italy
| | - Maria Paola Ruggieri
- Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Paolo Borghetti
- Radiation Oncology Department, ASST Spedali Civili and University of Brescia, 25123 Brescia, Italy
| | - Vieri Scotti
- Radiation Oncology Unit, Oncology Department AOU Careggi Firenze, 50134 Florence, Italy
| | | | - Michele Fiore
- Radiation Oncology, Campus Bio-Medico University, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Maria Taraborrelli
- Radiation Oncology Unit, “SS Annunziata” Hospital, “G. D’Annunzio” University, 66100 Chieti, Italy
| | - Fabrizio Salvi
- Radiation Oncology Unit, Bellaria Hospital, 40139 Bologna, Italy
| | - Marco Galaverni
- Radiotherapy Unit, Azienda Ospedaliera Universitaria, 43126 Parma, Italy
| | - Luisa Savoldi
- Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale–IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Luca Braglia
- Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale–IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Andrea Botti
- Medical Physics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Sebastiano Finocchi Ghersi
- Radiation Oncolgy Unit, AOU Sant’Andrea, Facoltà di Medicina e Psicologia, Università La Sapienza, 00185 Rome, Italy
| | - Giaj-Levra Niccolò
- Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, 37024 Verona, Italy
| | - Frank Lohr
- Radiation Oncology Department, Centre Lèon Bèrard, 693736 Lyon, France
- Department of Medical and Surgical Science, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Cinzia Iotti
- Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Patrizia Ciammella
- Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
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Darvishi M, Tosan F, Nakhaei P, Manjili DA, Kharkouei SA, Alizadeh A, Ilkhani S, Khalafi F, Zadeh FA, Shafagh SG. Recent progress in cancer immunotherapy: Overview of current status and challenges. Pathol Res Pract 2023; 241:154241. [PMID: 36543080 DOI: 10.1016/j.prp.2022.154241] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022]
Abstract
Cancer treatment is presently one of the most important challenges in medical science. Surgery, chemotherapy, radiotherapy, or combining these methods is used to eliminate the tumor. Hormone therapy, bone marrow transplantation, stem cell therapy as well as immunotherapy are other well-known therapeutic modalities. Immunotherapy, as the most important complementary method, uses the immune system for treating cancer followed by surgery, chemotherapy, and radiotherapy. This method is systematically used to prevent malignancies development mainly via potentiating antitumor immune cells activation and conversely compromising their exhaustion with the lowest negative effects on healthy cells. Active immunotherapy can be employed for cancer immunotherapy by directly using the ingredients of the immune system and activating immune responses. On the other hand, inactive immunotherapy is utilized by indirect induction and using immune cell-based products consisting of monoclonal antibodies. It has strongly been proved that combination therapy with immunotherapies and other therapeutic means, such as anti-angiogenic agents, could be a rational plan to treat cancer. Herein, we have focused on recent findings concerning the therapeutic merits of cancer therapy using immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and cancer vaccine alone or in combination with other approaches. Also, we offer a glimpse into the current challenges in this context.
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Affiliation(s)
- Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medicinal Sciences, Tehran, Iran.
| | - Foad Tosan
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran.
| | - Pooria Nakhaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Danial Amiri Manjili
- Department of Infectious Disease, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
| | | | - Ali Alizadeh
- Department of Digital Health, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Saba Ilkhani
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farima Khalafi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Efficacy and Safety of PD-L1 Inhibitors plus Chemotherapy versus Chemotherapy Alone in First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer: A Retrospective Real-World Study. JOURNAL OF ONCOLOGY 2022; 2022:3645489. [PMID: 36199793 PMCID: PMC9529407 DOI: 10.1155/2022/3645489] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/15/2022] [Accepted: 07/29/2022] [Indexed: 12/02/2022]
Abstract
Background Most patients with small-cell lung cancer (SCLC) have extensive-stage (ES) disease with a poor prognosis. Immunotherapy has shown good therapeutic effects in the treatment of ES-SCLC. We performed a real-world retrospective study to evaluate the safety and efficacy of PD-L1 inhibitors plus chemotherapy in patients with ES-SCLC. Method A total of 224 patients diagnosed with ES-SCLC between March 2017 and April 2021 were included, of which 115 received only etoposide-platinum (EP) chemotherapy,and 109 received programmed cell-death ligand 1 (PD-L1) inhibitors and EP. Results Immune checkpoint inhibitors (ICIs) plus platinum were associated with a significant improvement in overall survival (OS), with a hazard ratio (HR) of 0.60 (95% CI, 0.42–0.85; P=0.0054); median OS was 19 months in the ICIs plus EP group vs. 12 months in the EP group. The median progression-free survival (PFS) was 8.5 and 5.0 months, respectively (HR for disease progression or death, 0.42; 95% CI, 0.31–0.57; P < 0.0001). Male patients <65 years old, Stage IV, PS 0-1, without liver and brain metastasis had a better OS in the ICIs plus EP group than the EP group. The PFS and OS in the durvalumab plus chemotherapy group were insignificantly longer than that of the atezolizumab plus chemotherapy group. Any adverse effects (AEs) of grade 3 or 4 occurred in 50 patients (45.9%) in the ICIs plus EP group and 48 patients (41.7%) in the EP alone group. The most common immune-related AEs (irAEs) were immune hypothyroidism events (17.1%, 7/41), immune dermatitis (9.8%, 4/41), and immune pneumonia (9.8%, 4/41) in the durvalumab plus platinum-etoposide group. Immune liver insufficiency (10.3%, 7/68) and immune hypothyroidism (8.8%, 6/68) were the most common irAEs in the atezolizumab plus platinum-etoposide group. Conclusion This study shows that adding PD-L1 inhibitors to chemotherapy can significantly improve PFS and OS in patients with ES-SCLC and demonstrates its safety without additional AEs.
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14
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Real-world evidence for immunotherapy in the first line setting in small cell lung cancer. Lung Cancer 2022; 172:136-141. [DOI: 10.1016/j.lungcan.2022.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/14/2022] [Accepted: 08/24/2022] [Indexed: 11/20/2022]
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15
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Tang N, Li Z, Han X, Zhao C, Guo J, Wang H. Whole-Exome Sequencing Uncovers Specific Genetic Variation Difference Based on Different Modes of Drug Resistance in Small Cell Lung Cancer. Front Oncol 2022; 12:891938. [PMID: 35847960 PMCID: PMC9280676 DOI: 10.3389/fonc.2022.891938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/17/2022] [Indexed: 11/17/2022] Open
Abstract
The poor survival rate of small cell lung cancer (SCLC) is mainly related to the condition that patients with SCLC often have good responses to first-line chemotherapy initially, but later on, most of these patients relapse rapidly due to resistance to further treatment. In this study, we attempted to analyze whole-exome sequencing data based on the largest sample size to date, to develop a classifier to predict whether a patient will be chemorefractory or chemosensitive and to explicate the risk of recurrence that affects the prognosis of patients. We showed the different characteristics of somatic mutational signatures, somatic mutation genes, and distinct genome instability between chemorefractory and chemosensitive SCLC patients. Amplified mutations in the chemosensitive group inhibited the regulation of the cell cycle process, transcription factor binding, and B-cell differentiation. Analysis of deletion mutation also suggested that detection of the chromosomal-level variation might influence our treatment decisions. Higher PD-L1 expressions (based on TPS methods) were mostly present among chemosensitive patients (p = 0.026), while there were no differences in PD-L1 expressions (based on CPS methods) and CD8+ TILs between the two groups. According to the model determined by logistic regression, each sample was endowed with a predictive probability value (PV). The samples were divided into a high-risk group (>0.55) and a low-risk group (≤0.55), and the survival analysis showed obvious differences between the two groups. This study provides a reference basis to translate this knowledge into practice, such as formulating personalized treatment plans, which may benefit Chinese patients with SCLC.
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Affiliation(s)
- Ning Tang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | | | - Xiao Han
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chenglong Zhao
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jun Guo
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Jun Guo, ; Haiyong Wang,
| | - Haiyong Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Jun Guo, ; Haiyong Wang,
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16
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Pangua C, Rogado J, Serrano-Montero G, Belda-Sanchís J, Álvarez Rodríguez B, Torrado L, Rodríguez De Dios N, Mielgo-Rubio X, Trujillo JC, Couñago F. New perspectives in the management of small cell lung cancer. World J Clin Oncol 2022; 13:429-447. [PMID: 35949427 PMCID: PMC9244973 DOI: 10.5306/wjco.v13.i6.429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 09/05/2021] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
The treatment of small cell lung cancer (SCLC) is a challenge for all specialists involved. New treatments have been added to the therapeutic armamentarium in recent months, but efforts must continue to improve both survival and quality of life. Advances in surgery and radiotherapy have resulted in prolonged survival times and fewer complications, while more careful patient selection has led to increased staging accuracy. Developments in the field of systemic therapy have resulted in changes to clinical guidelines and the management of patients with advanced disease, mainly with the introduction of immunotherapy. In this article, we describe recent improvements in the management of patients with SCLC, review current treatments, and discuss future lines of research.
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Affiliation(s)
- Cristina Pangua
- Department of Medical Oncology, Hospital Universitario Infanta Leonor, Madrid 28031, Spain
| | - Jacobo Rogado
- Department of Medical Oncology, Hospital Universitario Infanta Leonor, Madrid 28031, Spain
| | - Gloria Serrano-Montero
- Department of Medical Oncology, Hospital Universitario Infanta Leonor, Madrid 28031, Spain
| | - José Belda-Sanchís
- Department of Thoracic Surgery, Hospital de la Santa Creu i Sant Pau & Hospital de Mar, Universitat Autònoma de Barcelona, Barcelona 08041, Catalonia, Spain
| | - Beatriz Álvarez Rodríguez
- Department of Radiation Oncology, Hospital Universitario HM Sanchinarro, HM Hospitales, HM CIOCC Centro Integral Oncológico Clara Campal, Madrid 28050, Spain
| | - Laura Torrado
- Department of Radiation Oncology, Hospital Universitario Lucus Augusti & Instituto de Investigación Sanitaria Santiago de Compostela (IDIS), Lugo 27003, Spain
| | - Nuria Rodríguez De Dios
- Department of Radiation Oncology, Hospital Del Mar & Hospital Del Mar Medical Research Institute (IMIM) & Pompeu Fabra University, Barcelona 08003, Catalonia, Spain
| | - Xabier Mielgo-Rubio
- Department of Medical Oncology, Alcorcón Foundation University Hospital, Alcorcón 28922, Madrid, Spain
| | - Juan Carlos Trujillo
- Department of Thoracic Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona 08029, Spain
| | - Felipe Couñago
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Hospital La Luz, Universidad Europea de Madrid, Madrid 28223, Spain
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17
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Govindan R, Aggarwal C, Antonia SJ, Davies M, Dubinett SM, Ferris A, Forde PM, Garon EB, Goldberg SB, Hassan R, Hellmann MD, Hirsch FR, Johnson ML, Malik S, Morgensztern D, Neal JW, Patel JD, Rimm DL, Sagorsky S, Schwartz LH, Sepesi B, Herbst RS. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma. J Immunother Cancer 2022; 10:jitc-2021-003956. [PMID: 35640927 PMCID: PMC9157337 DOI: 10.1136/jitc-2021-003956] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2022] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)— either as monotherapy or in combination with other ICIs or chemotherapy—have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC’s 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma.
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Affiliation(s)
- Ramaswamy Govindan
- Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in Saint Louis, St Louis, Missouri, USA
| | - Charu Aggarwal
- Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Scott J Antonia
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute Center for Cancer Immunotherapy, Durham, North Carolina, USA
| | - Marianne Davies
- Yale School of Nursing, Yale Cancer Center, New Haven, Connecticut, USA
| | - Steven M Dubinett
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
| | | | - Patrick M Forde
- Upper Aerodigestive Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Edward B Garon
- Division of Hematology/Oncology, Department of Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
| | - Sarah B Goldberg
- Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut, USA
| | - Raffit Hassan
- Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Fred R Hirsch
- Center for Thoracic Oncology, Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Melissa L Johnson
- Sarah Cannon Research Institute, Nashville, Tennessee, USA
- Tennessee Oncology/One Oncology, Nashville, Tennessee, USA
| | - Shakun Malik
- Division of Cancer Treatment & Diagnosis, CTEP, National Cancer Institute, Rockville, Maryland, USA
| | - Daniel Morgensztern
- Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in Saint Louis, St Louis, Missouri, USA
| | - Joel W Neal
- Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Jyoti D Patel
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, USA
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Sarah Sagorsky
- Upper Aerodigestive Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lawrence H Schwartz
- Department of Radiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
| | - Boris Sepesi
- Department of Thoracic and Cardiovascular Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Roy S Herbst
- Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut, USA
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18
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Li YC. Durable response to durvalumab-based immunochemotherapy in small-cell lung carcinoma transformation from EGFR-mutant non-small cell lung cancer: A case report. Thorac Cancer 2022; 13:775-779. [PMID: 35088537 PMCID: PMC8888151 DOI: 10.1111/1759-7714.14325] [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: 09/28/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 11/30/2022] Open
Abstract
Combined small‐cell lung carcinoma (C‐SCLC) is small‐cell lung carcinoma (SCLC) with added non–small‐cell morphology. We report a case of epidermal growth factor receptor (EGFR) mutation‐positive C‐SCLC in an 84‐year‐old patient with metastatic brain lesions who developed intrinsic resistance to osimertinib, a tyrosine kinase inhibitor (TKI). The patient was diagnosed with small‐cell transformation of non–small‐cell lung carcinoma (NSCLC) and received 6 cycles of dose‐adjusted durvalumab with etoposide and carboplatin. In December 2021, the patient received the seventeenth cycle of maintenance durvalumab 19 months after diagnosis and showed continued treatment response and disease control. Comprehensive molecular profiling and repeated biopsies are recommended in NSCLC patients who progress on first‐line EGFR‐TKIs. Durvalumab in combination with chemotherapy appears to be beneficial for EGFR mutation‐positive C‐SCLC patients that are resistant to TKIs.
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Affiliation(s)
- Yu-Chung Li
- Hong Kong United Oncology Centre, Hong Kong, China
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19
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Arriola E, González-Cao M, Domine M, De Castro J, Cobo M, Bernabé R, Navarro A, Sullivan I, Trigo JM, Mosquera J, Crama L, Isla D. Addition of Immune Checkpoint Inhibitors to Chemotherapy vs Chemotherapy Alone as First-Line Treatment in Extensive-Stage Small-Cell Lung Carcinoma: A Systematic Review and Meta-Analysis. Oncol Ther 2022; 10:167-184. [PMID: 35032007 PMCID: PMC9098752 DOI: 10.1007/s40487-021-00182-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/23/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction The addition of immune checkpoint inhibitors (ICIs) to conventional chemotherapy (CT) as first-line treatment improves survival in extensive-stage small-cell lung cancer (ES-SCLC). The aim of this meta-analysis was to determine the relative efficacy of first-line ICIs compared with CT in patients with ES-SCLC. Methods Two independent reviewers extracted relevant data according to PRISMA guidelines and assessed the risk of bias using the Cochrane Collaboration's risk-of-bias tool. Meta-analysis was conducted using random-effects models to calculate an average effect size for overall survival (OS), progression-free survival (PFS), and safety outcomes in the overall populations and clinically relevant subgroups. Results A literature search of PubMed and Embase was performed. Six randomized controlled clinical trials (IMpower133, CHECKMATE-451, CASPIAN, KEYNOTE-604, and phase II and III ipilimumab plus CT trials) with a total of 3757 patients were included. Compared with CT alone, ICIs plus CT showed a favourable effect on OS (hazard ratio [HR] 0.85; 95% confidence intervals [CI] 0.79–0.96) and PFS (HR 0.78; 95% CI 0.72–0.83) but a non-significant increase in the risk of experiencing any adverse event (relative risk, 1.05; 95% CI 0.99–1.11). The estimated HR for OS favoured ICI combinations in all planned subgroups according to age (< 65 years/≥ 65 years), sex (men/women), and ECOG performance status (0/1). Analysis by specific ICI revealed significant improvements in OS only for atezolizumab + CT (HR 1.36; 95% CI 1.09–1.69) and durvalumab + CT (HR 1.35; 95% CI 1.12–1.62) compared with CT alone. Conclusion Combining anti-programmed cell death ligand 1 antibodies with platinum/etoposide is a superior therapeutic approach compared to CT alone for the first-line treatment of patients with ES-SCLC. Graphic abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1007/s40487-021-00182-0.
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Affiliation(s)
- Edurne Arriola
- Medical Oncology Department, Hospital Universitari del Mar-CIBERONC, Passeig Marítim 25-29, 08003 Barcelona, Spain
| | | | - Manuel Domine
- Medical Oncology Department, Fundación Jiménez Díaz, Madrid, Spain
| | - Javier De Castro
- Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Manuel Cobo
- Inter-Center Medical Oncology Clinical Management Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain
| | - Reyes Bernabé
- Medical Oncology Department, Hospital Virgen del Rocío, Sevilla, Spain
| | - Alejandro Navarro
- Medical Oncology Department, Vall d’Hebron University Hospital & Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ivana Sullivan
- Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - José Manuel Trigo
- Medical Oncology Department, Hospital Virgen de la Victoria, Málaga, Spain
| | - Joaquín Mosquera
- Medical Oncology Department, Hospital Universitario A Coruña, A Coruña, Spain
| | | | - Dolores Isla
- Medical Oncology Department, Hospital Universitario Lozano Blesa, Zaragoza, Spain
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Vafaei S, Zekiy AO, Khanamir RA, Zaman BA, Ghayourvahdat A, Azimizonuzi H, Zamani M. Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier. Cancer Cell Int 2022; 22:2. [PMID: 34980128 PMCID: PMC8725311 DOI: 10.1186/s12935-021-02407-8] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 12/10/2021] [Indexed: 12/15/2022] Open
Abstract
Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60-70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.
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Affiliation(s)
- Somayeh Vafaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Angelina O. Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ramadhan Ado Khanamir
- Internal Medicine and Surgery Department, College of Veterinary Medicine, University of Duhok, Kurdistan Region, Iraq
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Kurdistan Region, Iraq
| | | | | | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
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21
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Plaja A, Moran T, Carcereny E, Saigi M, Hernández A, Cucurull M, Domènech M. Small-Cell Lung Cancer Long-Term Survivor Patients: How to Find a Needle in a Haystack? Int J Mol Sci 2021; 22:ijms222413508. [PMID: 34948300 PMCID: PMC8707503 DOI: 10.3390/ijms222413508] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 12/28/2022] Open
Abstract
Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by a rapid progression and a high resistance to treatments. Unlike other solid tumors, there has been a scarce improvement in emerging treatments and survival during the last years. A better understanding of SCLC biology has allowed for the establishment of a molecular classification based on four transcription factors, and certain therapeutic vulnerabilities have been proposed. The universal inactivation of TP53 and RB1, along with the absence of mutations in known targetable oncogenes, has hampered the development of targeted therapies. On the other hand, the immunosuppressive microenvironment makes the success of immune checkpoint inhibitors (ICIs), which have achieved a modest improvement in overall survival in patients with extensive disease, difficult. Currently, atezolizumab or durvalumab, in combination with platinum–etoposide chemotherapy, is the standard of care in first-line setting. However, the magnitude of the benefit is scarce and no predictive biomarkers of response have yet been established. In this review, we describe SCLC biology and molecular classification, examine the SCLC tumor microenvironment and the challenges of predictive biomarkers of response to new treatments, and, finally, assess clinical and molecular characteristics of long-term survivor patients in order to identify possible prognostic factors and treatment vulnerabilities.
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22
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Rugo HS, Loi S, Adams S, Schmid P, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Winer EP, Kockx MM, Peeters D, Chui SY, Lin JC, Nguyen-Duc A, Viale G, Molinero L, Emens LA. PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer. J Natl Cancer Inst 2021; 113:1733-1743. [PMID: 34097070 PMCID: PMC8634452 DOI: 10.1093/jnci/djab108] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 01/07/2021] [Accepted: 05/14/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND In the phase III IMpassion130 study, atezolizumab plus nab-paclitaxel (A+nP) showed clinical benefit in advanced or metastatic triple-negative breast cancer patients who were programmed death-ligand 1 (PD-L1)+ (tumor-infiltrating immune cells [IC] ≥1%) using the SP142 immunohistochemistry assay. Here we evaluate 2 other PD-L1 assays for analytical concordance with SP142 and patient-associated clinical outcomes. METHODS Samples from 614 patients (68.1% of intention-to-treat population) were centrally evaluated by immunohistochemistry for PD-L1 status on IC (VENTANA SP142, SP263, Dako 22C3) or as a combined positive score (CPS; 22C3). RESULTS Using SP142, SP263, and 22C3 assays, PD-L1 IC ≥1% prevalence was 46.4% (95% confidence interval [CI] = 42.5% to 50.4%), 74.9% (95% CI = 71.5% to 78.3%), and 73.1% (95% CI = 69.6% to 76.6%), respectively; 80.9% were 22C3 CPS ≥1. At IC ≥1% (+), the analytical concordance between SP142 and SP263 and 22C3 was 69.2% and 68.7%, respectively. Almost all SP142+ cases were captured by other assays (double positive), but several SP263+ (29.6%) or 22C3+ (29.0%) cases were SP142- (single positive). A+nP clinical activity vs placebo+nP in SP263+ and 22C3+ patients (progression-free survival [PFS] hazard ratios [HRs] = 0.64 to 0.68; overall survival [OS] HRs = 0.75 to 0.79) was driven by double-positive cases (PFS HRs = 0.60 to 0.61; OS HRs = 0.71 to 0.75) rather than single-positive cases (PFS HRs = 0.68 to 0.81; OS HRs = 0.87 to 0.95). Concordance for harmonized cutoffs for SP263 (IC ≥4%) and 22C3 (CPS ≥10) to SP142 (IC ≥1%) was subpar (approximately 75%). CONCLUSIONS 22C3 and SP263 assays identified more patients as PD-L1+ (IC ≥1%) than SP142. No inter-assay analytical equivalency was observed. Consistent improved A+nP efficacy was captured by the SP142 PD-L1 IC ≥1% subgroup nested within 22C3 and SP263 PD-L1+ (IC ≥1%) populations.
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Affiliation(s)
- Hope S Rugo
- Department of Medicine (Hematology/Oncology), University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Sherene Loi
- Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia
| | - Sylvia Adams
- New York University Langone Health, Perlmutter Cancer Center, New York, NY, USA
| | - Peter Schmid
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Andreas Schneeweiss
- National Center for Tumor Diseases (NCT), Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Carlos H Barrios
- Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Véronique Diéras
- Department of Medical Oncology, Institut Curie, Paris, and Centre Eugène Marquis, Rennes, France
| | | | | | | | | | | | | | - Giuseppe Viale
- Post-graduate Medical School in Pathology, University of Milan, Milan, Italy
- Division of Pathology and Laboratory Medicine, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Leisha A Emens
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
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23
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Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet 2021; 398:535-554. [PMID: 34273294 DOI: 10.1016/s0140-6736(21)00312-3] [Citation(s) in RCA: 1343] [Impact Index Per Article: 335.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 01/14/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023]
Abstract
Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide with an estimated 2 million new cases and 1·76 million deaths per year. Substantial improvements in our understanding of disease biology, application of predictive biomarkers, and refinements in treatment have led to remarkable progress in the past two decades and transformed outcomes for many patients. This seminar provides an overview of advances in the screening, diagnosis, and treatment of non-small-cell lung cancer and small-cell lung cancer, with a particular focus on targeted therapies and immune checkpoint inhibitors.
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Affiliation(s)
- Alesha A Thai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
| | - Benjamin J Solomon
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
| | - Lecia V Sequist
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Justin F Gainor
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Rebecca S Heist
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
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Gan J, Huang Y, Fang W, Zhang L. Research progress in immune checkpoint inhibitors for lung cancer in China. Ther Adv Med Oncol 2021; 13:17588359211029826. [PMID: 34349843 PMCID: PMC8295948 DOI: 10.1177/17588359211029826] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 06/14/2021] [Indexed: 01/11/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have come to play an increasingly prominent role in the treatment of lung cancer, and some are recommended as a first-line treatment for late-stage non-small-cell lung cancer, either as a monotherapy or in combination with chemotherapy. Accordingly, the indications of Food and Drug Administration-approved ICIs have increased. In this background, China has implemented various policies to encourage and accelerate the marketing of domestic and imported innovative antitumor drugs. Eight ICIs have been approved in China. Among these, four imported programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have received approval for six indications, and one domestic PD-1 inhibitor has received approval for one indication for lung cancer in 2018. Numerous clinical trials of ICIs for lung cancer are underway in China. This review aims to summarize the recent advances and future directions of ICIs, including PD-1 inhibitors, PD-L1 inhibitors, cytotoxic T lymphocyte-associated antigen-4 inhibitors, bi-specific antibodies, and a novel inhibitor of T-cell immune-receptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains in immunotherapies for lung cancer in China.
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Affiliation(s)
- Jiadi Gan
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yihua Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Wenfeng Fang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Li Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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25
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Ai X, Pan Y, Shi J, Yang N, Liu C, Zhou J, Zhang X, Dong X, He J, Li X, Chen G, Li X, Zhang H, Liao W, Zhang Y, Ma Z, Jiang L, Cui J, Hu C, Wang W, Huang C, Zhao J, Ding C, Hu X, Wang K, Gao B, Song Y, Liu X, Xiong J, Liu A, Li J, Liu Z, Li Y, Wang M, Zhang B, Zhang D, Lu S. Efficacy and Safety of Niraparib as Maintenance Treatment in Patients With Extensive-Stage SCLC After First-Line Chemotherapy: A Randomized, Double-Blind, Phase 3 Study. J Thorac Oncol 2021; 16:1403-1414. [PMID: 33915252 DOI: 10.1016/j.jtho.2021.04.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/01/2021] [Accepted: 04/04/2021] [Indexed: 01/12/2023]
Abstract
INTRODUCTION ZL-2306-005 is a randomized, double-blind, multicenter phase 3 study evaluating the efficacy and safety of niraparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, as first-line maintenance therapy in Chinese patients with platinum-responsive, extensive-stage SCLC (ES-SCLC). METHODS Patients with complete response (CR) or partial response (PR) to standardized, platinum-based first-line chemotherapy were randomized 2:1 to receive niraparib or placebo (300 mg [baseline body weight ≥ 77 kg, platelet count ≥ 150,000/μL] or 200 mg) once daily until progression or unacceptable toxicity. Primary end points were progression-free survival (PFS) (blinded independent central review) and overall survival (sample size planned: 591 patients). Secondary end points included investigator-evaluated PFS and safety. RESULTS ZL-2306-005 was terminated early owing to ES-SCLC treatment landscape changes (data cutoff: March 20, 2020). During July 2018-February 2020, a total of 185 of 272 patients screened were randomized (niraparib: n = 125 [CR = 1, PR = 124]; placebo: n = 60 [CR = 1, PR = 59]). Median (95% confidence interval [CI]) PFS (blinded independent central review) was 1.54 months (1.41-2.69, niraparib) and 1.36 months (1.31-1.48, placebo); hazard ratio (HR) = 0.66 (95% CI: 0.46-0.95, p = 0.0242). Median overall survival was 9.92 months (9.33-13.54, niraparib) and 11.43 months (9.53-not estimable, placebo); HR = 1.03 (95% CI: 0.62-1.73, p = 0.9052). Median investigator-evaluated PFS was 1.48 months (1.41-2.56, niraparib) and 1.41 months (1.31-2.00, placebo); HR = 0.88 (95% CI: 0.61-1.26; p = 0.4653). Grade greater than or equal to 3 adverse events occurred in 34.4% (niraparib) and 25.0% (placebo) of patients. CONCLUSIONS ZL-2306-005 did not reach primary end points. Nevertheless, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability profile and no new safety signal.
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Affiliation(s)
- Xinghao Ai
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Yueyin Pan
- Department of Chemotherapy, Anhui Provincial Hospital, Hefei, People's Republic of China
| | - Jianhua Shi
- Department of Medical Oncology, Linyi Cancer Hospital, Linyi, People's Republic of China
| | - Nong Yang
- Lung & Gastrointestinal Oncology Department, Hunan Cancer Hospital, Changsha, People's Republic of China
| | - Chunling Liu
- Department of Pulmonary Medicine, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi, People's Republic of China
| | - Jianying Zhou
- Department of Respiratory Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, People's Republic of China
| | - Xiaodong Zhang
- Department of Medical Oncology, Nantong Tumor Hospital, Nantong, People's Republic of China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Jianxing He
- Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xiaoling Li
- Department of Thoracic Medicine, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Gongyan Chen
- Department of Respiratory Medicine, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China
| | - Xingya Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Helong Zhang
- Department of Oncology, Tangdu Hospital, Xi'an, People's Republic of China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Guangzhou, People's Republic of China
| | - Yiping Zhang
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, People's Republic of China
| | - Zhiyong Ma
- Department of Respiratory Medicine, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, People's Republic of China
| | - Liyan Jiang
- Department of Respiration, Shanghai Chest Hospital, Shanghai, People's Republic of China
| | - Jiuwei Cui
- Department of Oncology, The First Bethune Hospital of Jilin University, Changchun, People's Republic of China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Wei Wang
- Department of Oncology, Jinzhou Central Hospital, Jinzhou, People's Republic of China
| | - Cheng Huang
- Department of Oncology, Fujian Cancer Hospital, Fuzhou, People's Republic of China
| | - Jun Zhao
- Department of Thoracic Oncology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Cuimin Ding
- Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University and Hebei Cancer Hospital, Shijiazhuang, People's Republic of China
| | - Xiaohua Hu
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Kai Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Beili Gao
- Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yong Song
- Department of Respiratory Medicine, Nanjing General Hospital of Nanjing Military Command, Nanjing, People's Republic of China
| | - Xiaoqing Liu
- Department of Pulmonary Oncology, The 307th Hospital of the Chinese People's Liberation Army, Beijing, People's Republic of China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Anwen Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Junling Li
- Department of Internal Medicine, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Zhe Liu
- Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yinyin Li
- Department of Oncology, Shenyang the Tenth People's Hospital, Shenyang, People's Republic of China
| | - Mengzhao Wang
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, People's Republic of China
| | - Biao Zhang
- R&D Department, Zai Lab (Shanghai) Co., Ltd., Shanghai, People's Republic of China
| | - Dan Zhang
- R&D Department, Zai Lab (Shanghai) Co., Ltd., Shanghai, People's Republic of China
| | - Shun Lu
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
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Yap TA, Parkes EE, Peng W, Moyers JT, Curran MA, Tawbi HA. Development of Immunotherapy Combination Strategies in Cancer. Cancer Discov 2021; 11:1368-1397. [PMID: 33811048 DOI: 10.1158/2159-8290.cd-20-1209] [Citation(s) in RCA: 207] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/03/2021] [Accepted: 02/01/2021] [Indexed: 12/11/2022]
Abstract
Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies.
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Affiliation(s)
- Timothy A Yap
- Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eileen E Parkes
- Oxford Institute of Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Weiyi Peng
- Department of Biology and Biochemistry, University of Houston, Houston, Texas
| | - Justin T Moyers
- Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael A Curran
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hussein A Tawbi
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Utility of Prophylactic Cranial Irradiation for Extensive-Stage Small-Cell Lung Cancer in the MRI Screening Era. Clin Lung Cancer 2021; 22:e808-e816. [PMID: 33966983 DOI: 10.1016/j.cllc.2021.03.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Conflicting data exists regarding the benefit of prophylactic cranial irradiation (PCI) in patients with extensive-stage small-cell lung cancer (ES-SCLC). We sought to retrospectively review outcomes of patients within our network with ES-SCLC treated with and without PCI between 2009 and 2020. METHODS Endpoints assessed using the Kaplan-Meier estimator were overall survival (OS), freedom from death with uncontrolled intracranial disease (UI-DFS), brain metastasis-free survival (BMFS), and symptomatic BMFS (SBMFS). Log-rank test was performed for univariate comparison of outcomes, with Cox regression performed for univariate and multivariable analysis of OS and UI-DFS. RESULTS Some 250 patients were determined to be eligible for PCI based on any response to upfront chemotherapy, with 46 patients excluded owing to lack of negative staging brain magnetic resonance imaging (MRI). Brain MRI was performed both at diagnosis and near completion of chemotherapy in 108 patients, with brain metastases identified near completion of chemotherapy in 17 patients (15.7%), excluding them from further analysis. Median OS in remaining eligible 187 patients was 9.0 months, with 2-year Kaplan-Meier estimate of OS of 21.9%. PCI was associated with improved UI-DFS, BMFS, and SBMFS. However, PCI was not associated with improved OS in the entire cohort or the propensity matched cohort. CONCLUSION Our study suggests screening with MRI following chemotherapy is important because of the identification of unsuspected brain metastases in nearly 16% of patients with response to chemotherapy. PCI is associated with reduction in brain metastases, without a demonstrable impact on OS in the era of MRI screening.
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Senan S. The elusive pursuit of progress in limited stage small-cell lung cancer. Lancet Oncol 2021; 22:290-291. [DOI: 10.1016/s1470-2045(21)00018-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 11/29/2022]
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Ortega-Franco A, Ackermann C, Paz-Ares L, Califano R. First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions. ESMO Open 2021; 6:100003. [PMID: 33450659 PMCID: PMC7811117 DOI: 10.1016/j.esmoop.2020.100003] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
Small-cell lung cancer (SCLC) is an aggressive and rapidly growing disease with poor prognosis. Despite intense efforts to improve clinical outcomes, platinum/etoposide chemotherapy has remained the most effective regimen for first-line extensive disease SCLC for decades. The addition of immune checkpoint inhibitors, and specifically programmed death-ligand 1 inhibitors, to standard platinum/etoposide, significantly improves survival and represents a promising advance in this field. However, identification of a predictive biomarker to refine patient selection is an area of unmet need. Further understanding of tumour immunity and mechanism of resistance is required to design novel strategies that improve survival. In this review, we describe recent developments and future directions on first-line immune checkpoint blockade for extensive disease-SCLC.
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Affiliation(s)
- A Ortega-Franco
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - C Ackermann
- Department of Medical Oncology, Onkologie und Hämatologiezentrum Thun Berner Oberland, Spital, Switzerland
| | - L Paz-Ares
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - R Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
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Wong SK, Iams WT. Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer. Cancers (Basel) 2021; 13:506. [PMID: 33572705 PMCID: PMC7865814 DOI: 10.3390/cancers13030506] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/20/2021] [Accepted: 01/26/2021] [Indexed: 12/25/2022] Open
Abstract
After being stagnant for decades, there has finally been a paradigm shift in the treatment of small-cell lung cancer (SCLC) with the emergence and application of immune checkpoint inhibitors (ICIs). Multiple trials of first-line ICI-chemotherapy combinations have demonstrated survival benefit compared to chemotherapy alone in patients with extensive-stage SCLC, establishing this as the new standard of care. ICIs are now being applied in the potentially curative limited-stage setting, actively being investigated as concurrent treatment with chemoradiation and as adjuvant treatment following completion of chemoradiation. This review highlights the evidence behind the practice-changing addition of ICIs in the first-line setting of extensive-stage SCLC, the potentially practice-changing immunotherapy trials that are currently underway in the limited-stage setting, and alternate immunotherapeutic strategies being studied in the treatment of SCLC.
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Affiliation(s)
- Selina K. Wong
- Department of Medicine, Division of Hematology and Oncology, Nashville, TN 37232, USA;
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Wade T. Iams
- Department of Medicine, Division of Hematology and Oncology, Nashville, TN 37232, USA;
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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31
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Hann CL. Small Cell Lung Cancer: Biology Advances. Lung Cancer 2021. [DOI: 10.1007/978-3-030-74028-3_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Farid S, Liu SV. Chemo-immunotherapy as first-line treatment for small-cell lung cancer. Ther Adv Med Oncol 2020; 12:1758835920980365. [PMID: 33414848 PMCID: PMC7750570 DOI: 10.1177/1758835920980365] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022] Open
Abstract
Small-cell lung cancer (SCLC) is a highly lethal subtype of lung cancer. Despite concerted efforts over the past several decades, there have been limited therapeutic advances. Traditional chemotherapy offers a high response rate and rapid symptomatic improvement, but its benefit is fleeting, and relapse is quick and unforgiving. Immunotherapy has delivered improved outcomes for patients with many cancers and there was compelling rationale for development in SCLC. While initial efforts with cytotoxic T-lymphocyte protein-4 inhibitors failed to improve upon chemotherapy alone, the addition of programmed death ligand-1 (PD-L1) inhibitors to first-line chemotherapy finally provided long-awaited gains in survival. Atezolizumab, when added to carboplatin and etoposide, improved both progression-free survival and overall survival. Durvalumab, when added to platinum plus etoposide, similarly improved OS. Biomarker development has stalled as PD-L1 expression and tumor mutational burden have not been useful predictive biomarkers. However, based on the significant survival improvements, both atezolizumab and durvalumab were approved by the US Food and Drug Administration to be given with first-line chemotherapy, and these regimens represent the new standards of care for SCLC.
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Affiliation(s)
- Saira Farid
- Department of Internal Medicine, MedStar Washington Hospital Center, Washington, DC, USA
| | - Stephen V Liu
- Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
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Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Özgüroğlu M, Ji JH, Garassino MC, Voitko O, Poltoratskiy A, Ponce S, Verderame F, Havel L, Bondarenko I, Każarnowicz A, Losonczy G, Conev NV, Armstrong J, Byrne N, Thiyagarajah P, Jiang H, Paz-Ares L. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2020; 22:51-65. [PMID: 33285097 DOI: 10.1016/s1470-2045(20)30539-8] [Citation(s) in RCA: 414] [Impact Index Per Article: 82.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/14/2020] [Accepted: 09/02/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone. METHODS CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. FINDINGS Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]). INTERPRETATION First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC. FUNDING AstraZeneca.
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Affiliation(s)
- Jonathan W Goldman
- David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
| | - Mikhail Dvorkin
- BHI of Omsk Region Clinical Oncology Dispensary, Omsk, Russia
| | - Yuanbin Chen
- Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA
| | | | | | | | | | - Maximilian J Hochmair
- Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria
| | - Mustafa Özgüroğlu
- Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey
| | - Jun Ho Ji
- Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
| | | | | | | | - Santiago Ponce
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain
| | | | - Libor Havel
- Thomayer Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | | | | | - György Losonczy
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Nikolay V Conev
- Clinic of Medical Oncology, University Multiprofile Hospital for Active Treatment St Marina, Varna, Bulgaria
| | | | | | | | | | - Luis Paz-Ares
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain.
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Acheampong E, Abed A, Morici M, Bowyer S, Amanuel B, Lin W, Millward M, S. Gray E. Tumour PD-L1 Expression in Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Cells 2020; 9:cells9112393. [PMID: 33142852 PMCID: PMC7693331 DOI: 10.3390/cells9112393] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/22/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Antibodies against programmed death-1 (PD-1), and its ligand, (PD-L1) have been approved recently for the treatment of small-cell lung cancer (SCLC). Although there are previous reports that addressed PD-L1 detection on tumour cells in SCLC, there is no comprehensive meta-analysis on the prevalence of PD-L1 expression in SCLC. We performed a systematic search of the PubMed, Cochrane Library and EMBASE databases to assess reports on the prevalence of PD-L1 expression and the association between PD-L1 expression and overall survival (OS). This meta-analysis included 27 studies enrolling a total of 2792 patients. The pooled estimate of PD-L1 expression was 26.0% (95% CI 17.0–37.0), (22.0% after removing outlying studies). The effect size was significantly heterogeneous (I2 = 97.4, 95% CI: 95.5–98.5, p < 0.0001).Positive PD-L1 expression was a favourable prognostic factor for SCLC but not statistically significant (HR = 0.86 (95% CI (0.49–1.50), p = 0.5880; I2 = 88.7%, p < 0.0001). Begg’s funnel plots and Egger’s tests indicated no publication bias across included studies (p > 0.05). Overall, there is heterogeneity in the prevalence of PD-L1 expression in SCLC tumour cells across studies. This is significantly moderated by factors such as immunohistochemistry (IHC) evaluation cut-off values, and assessment of PD-L1 staining patterns as membranous and/or cytoplasmic. There is the need for large size, prospective and multicentre studies with well-defined protocols and endpoints to advance the clinical value of PD-L1 expression in SCLC.
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Affiliation(s)
- Emmanuel Acheampong
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (E.A.); (A.A.); (M.M.); (B.A.); (W.L.)
| | - Afaf Abed
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (E.A.); (A.A.); (M.M.); (B.A.); (W.L.)
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009, Australia; (S.B.); (M.M.)
| | - Michael Morici
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (E.A.); (A.A.); (M.M.); (B.A.); (W.L.)
| | - Samantha Bowyer
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009, Australia; (S.B.); (M.M.)
- School of Medicine, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
| | - Benhur Amanuel
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (E.A.); (A.A.); (M.M.); (B.A.); (W.L.)
- Department of Anatomical Pathology, PathWest, Hospital Avenue, Nedlands, WA 6009, Australia
| | - Weitao Lin
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (E.A.); (A.A.); (M.M.); (B.A.); (W.L.)
| | - Michael Millward
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009, Australia; (S.B.); (M.M.)
- School of Medicine, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
| | - Elin S. Gray
- School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027, Australia; (E.A.); (A.A.); (M.M.); (B.A.); (W.L.)
- Correspondence: ; Tel.: +61-(0)8-6304-2756
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Fu X, Liu Z, Xiang L, Liu M, Zheng X, Wang J, Liu N, Gao H, Jiang A, Yang Y, Liang X, Ruan Z, Tian T, Yao Y. PD-L1 Predicts Poor Prognosis in Surgically Resected Limited Stage Small-Cell Lung Cancer. Cancer Manag Res 2020; 12:10939-10948. [PMID: 33154673 PMCID: PMC7608588 DOI: 10.2147/cmar.s260599] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine tumor with limited treatment strategies. Programmed death 1 (PD-1) and its ligand (PD-L1), delta-like ligand-3 (DLL-3), and poly ADP-ribose polymerase (PARP) inhibitors have shed light on the treatment of extensive stage-SCLC. However, the expression and prognostic role of PD-L1, DLL-3, and PARP are barely explored in surgically resected limited stage-SCLC (LS-SCLC). Methods We retrospectively reviewed 404 SCLC patients from 2011 to 2018 in the First Affiliated Hospital of Xi’an Jiaotong University and collected 43 surgically resected LS-SCLC samples with adequate materials and histological specimens containing abundant tumor cells. Immunohistochemistry staining of PD-L1, DLL-3, and PAPR1 was performed by anti-PD-L1 (22C3/Dako), anti-DLL-3, and anti-PAPR1 antibodies, respectively. Positive expression of PD-L1 was characterized as >5% tumor cells and/or tumor-infiltrating immune cells expressing PD-L1. The correlation between PD-L1, DLL-3, PARP1, and clinicopathological characteristics of surgically resected LS-SCLC patients was performed by χ2 test. The survival curves were calculated by the Kaplan–Meier method and analyzed by the Log rank test and Cox proportional hazards model. Results and Conclusion 63.04% patients were positive for PD-L1, 65.12% were positive for DLL-3, and 20.93% were positive for PARP1. DLL-3 was significantly overexpressed in SCLC tissues, compared with matched para-noncancerous tissues. Male, elder than 60 years old, advanced TNM stage, smoking, and positive PD-L1 expression predicted shorter DFS, while patients received adjuvant therapy performed better DFS. Further multivariate analysis revealed that TNM stage (HR=2.51, 95% CI=1.31–4.78, P=0.005) was an individual prognostic factor for DFS in LS-SCLC. Moreover, advanced TNM stage and positive PD-L1 expression also indicated worse OS, but adjuvant therapy improved OS in LS-SCLC. Multivariate analysis demonstrated that PD-L1 and TNM stage were independent and significant negative predictive factors for OS (HR=2.89, 95% CI=1.21–6.93, P=0.017; HR=2.49, 95% CI=1.25–4.94, P=0.009 for PD-L1 and TNM stage, respectively), while adjuvant treatment was an independent positive prognostic factor for OS (HR=0.37, 95% CI=0.17–0.81, P=0.012).
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Affiliation(s)
- Xiao Fu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Zhiyan Liu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Northwest University, Xi'an No. 3 Hospital, Xi'an, Shaanxi Province, 710018, People's Republic of China
| | - Luochengling Xiang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Mengjie Liu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Xiaoqiang Zheng
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Jingjing Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Na Liu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Huan Gao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Aimin Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yujuan Yang
- The Third Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, 710068, People's Republic of China
| | - Xuan Liang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Zhiping Ruan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Tao Tian
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yu Yao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
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Zhang S, Li S, Cheng Y. Efficacy and safety of PD-1/PD-L1 inhibitor plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small cell lung cancer: A systematic review and meta-analysis. Thorac Cancer 2020; 11:3536-3546. [PMID: 33058504 PMCID: PMC7705912 DOI: 10.1111/1759-7714.13698] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Immunotherapy has afforded new treatment options for extensive small cell lung cancer (ES-SCLC). However, reports on the effectiveness of immune checkpoint inhibitors (ICIs) combined with chemotherapy on survival in ES-SCLC patients are inconsistent. Therefore, we conducted a meta-analysis on the efficacy and safety of ICI combined with chemotherapy for ES-SCLC. METHODS We searched for randomized controlled clinical trials related to first-line treatment of ES-SCLC with ICI combined with chemotherapy in PUBMED, ESMO, ASCO, and WCLC since 2018. The primary outcome was overall survival (OS). RESULTS Four studies were included. Compared to chemotherapy alone, ICI in combination with chemotherapy as first-line treatment reduced the risk of death (hazard ratio [HR]: 0.76; 95% CI: 0.68-0.86; P < 0.00001) and disease progression (HR: 0.76; 95% CI: 0.68-0.84; P < 0.00001). The objective response rate (ORR) with ICI plus chemotherapy was significantly higher than that with chemotherapy alone (HR: 1.10; 95% CI: 1.02-1.19, P = 0.01). The duration of response (DoR) rate at one year was also better with ICI plus chemotherapy (HR: 3.46; 95% CI: 2.24-5.33; P < 0.00001). Security analysis revealed that the incidence of immune-mediated adverse events (imAEs) (HR: 3.77; 95% CI: 1.99-7.15, P < 0.0001) and grade 3/4 imAEs (HR: 7.01; 95% CI: 2.48-19.81; P = 0.0002) increased significantly with ICI plus chemotherapy. CONCLUSIONS ICI combined with chemotherapy as first-line treatment can significantly improve the OS and progression-free survival (PFS) of ES-SCLC patients, but the toxicity caused by immunotherapy should be carefully considered. KEY POINTS Significant findings of the studyOur meta-analysis shows that PD-L1/PD-1 plus chemotherapy can significantly improve the OS and PFS of ES-SCLC patients when used as first-line therapy. WHAT THIS STUDY ADDS This study fills gaps regarding the efficacy of immunotherapy combined with chemotherapy as first-line treatment for ES-SCLC, and provides better evidence for the use of PD-L1/PD-1 immunotherapy plus chemotherapy for patients with ES-SCLC.
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Affiliation(s)
- Shuang Zhang
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China
| | - Shuang Li
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China
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Abstract
Small-cell lung cancer has defied our scientific community for decades. Chemotherapy has been the mainstay treatment for small-cell lung cancer (SCLC) and unlike its counterpart, non-small cell lung cancer, no significant therapeutic breakthroughs have been made since the 1970s. Among the reasons for this slow-paced therapeutic development, one that stands out is the distinctive and almost universal loss of function of the tumour suppressor genes TP53 and RB1 in this disease, for which pharmacological activation has yet to be achieved, despite having been highly sought after. Although no molecularly targeted approach has been approved for clinical practice thus far, several strategies are currently exploring the potential to drug the tumour's "Achilles heel" that stems from essential pathways regulating DNA-damage response. Most recently, we have witnessed newfound reasons to hope, as the combination of immunotherapy and systemic chemotherapy has improved survival outcomes, representing the first landmark achievement in decades and a new standard of care for patients with extensive disease SCLC. However, continuous efforts are still needed towards a better understanding of the molecular pathways that singularise this tumour to eventually identify the predictive biomarkers that might result in the development of a more rational therapeutic approach, including the use of immunotherapy combinations. In this review we aim to uncover critical aspects of the immune microenvironment and biology of SCLC and provide an overview of the current and future landscape of promising therapeutic opportunities. The challenge still stands, but regardless, we are living in exciting times to finally check SCLC off the "bucket list" of our scientific community.
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Facchinetti F, Di Maio M, Tiseo M. Adding PD-1/PD-L1 Inhibitors to Chemotherapy for the First-Line Treatment of Extensive Stage Small Cell Lung Cancer (SCLC): A Meta-Analysis of Randomized Trials. Cancers (Basel) 2020; 12:cancers12092645. [PMID: 32947924 PMCID: PMC7565587 DOI: 10.3390/cancers12092645] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/23/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Treatment strategies in advanced, metastatic small cell lung cancer have been recently implemented by the combination of chemotherapy and immunotherapy. Nevertheless, the magnitude of survival benefit observed in clinical trials does not reproduce the major improvements observed in non-small cell lung cancer and other malignant diseases. By performing a systematic review and gathering the available data in a meta-analysis, we aim to compare the outcomes of patients treated with standard chemotherapy alone or with PD-1/PD-L1 inhibitors immunotherapy across clinical trials, in order to sustain treatment decisions. The addition of PD-1/PD-L1 inhibitors to standard chemotherapy improves all activity and efficacy outcomes, with a manageable safety profile. The benefit in overall survival is more evident if considering long-term analysis, compared to median estimations. Abstract Survival outcomes in extensive-stage small cell lung cancer (ES SCLC) are dismal, with median overall survival (OS) less than 12 months. The combination of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with first-line platinum-etoposide chemotherapy has been recently evaluated in randomized clinical trials. We performed a systematic literature review through PubMed and conference proceedings. Randomized trials evaluating chemotherapy +/− PD-1/PD-L1 ICIs were included in the meta-analysis. Efficacy (OS), activity [progression-free survival (PFS) and objective response rate (ORR)] outcomes and toxicities were analyzed. For selected endpoints, we focused on patients’ subgroups (OS) and on landmark analyses (OS, PFS). Four randomized trials were identified; globally, 1553 patients were randomized to receive chemotherapy +/− PD-1/PD-L1 ICIs. Adding a PD-1/PD-L1 ICI to chemotherapy led to a significant benefit in OS [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.68–0.85, p < 0.00001), PFS [HR 0.75, 95% CI 0.68–0.84, p < 0.00001] and ORR [odds ratio 1.28, 95% CI 1.04–1.57, p = 0.02]. No unexpected toxicity emerged. At 12, 18, 24 months for OS, and at 12, 18 months for PFS, experimental arms retained significant improvement in event-free rates, with absolute gain of approximately 10% compared with standard treatment. Albeit the magnitude of the benefit is less impacting compared to other settings of immunotherapy, the addition of PD-1/PD-L1 ICIs to chemotherapy in ES SCLC provided significant improvements in survival outcomes with the known toxicity profile. Biomarkers predicting which patients are suitable to derive long-term benefits are eagerly awaited.
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Affiliation(s)
- Francesco Facchinetti
- Predictive Biomarkers and Novel Therapeutc Strategies in Oncology, Inserm U981, Gustave Roussy Cancer Campus, Paris-Saclay University, 94800 Villejuif, France;
| | - Massimo Di Maio
- Department of Oncology, University of Turin, at Ordine Mauriziano Hospital, 10128 Torino, Italy
- Correspondence:
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy;
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
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Immunotherapy in Small Cell Lung Cancer. Cancers (Basel) 2020; 12:cancers12092522. [PMID: 32899891 PMCID: PMC7565004 DOI: 10.3390/cancers12092522] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/03/2020] [Accepted: 09/03/2020] [Indexed: 01/20/2023] Open
Abstract
Simple Summary Small cell lung cancer (SCLC) accounts for about 15% of lung cancers and it has limited therapeutic options and poor prognosis. There has been no real progress for over 30 years in the treatment of this aggressive tumor type and platinum based chemotherapy represented the cornerstone of therapy. Immune checkpoint inhibitors are the first agents in the last decades to determine an improvement in outcomes of patients with extensive stage (ES) SCLC patients. In the IMpower 133 and CASPIAN studies, the addition of atezolizumab or durvalumab, respectively, to first-line chemotherapy produced a significant improvement in overall survival with an acceptable safety profile in previously untreated patients with ES-SCLC, leading to a new standard of care. This review summarizes the main results observed with checkpoint inhibitors in SCLC, discussing the critical issues related to the use of novel checkpoint inhibitors and the future research with immunotherapy agents in SCLC. Abstract Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.
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Friedlaender A, Liu SV, Passaro A, Metro G, Banna G, Addeo A. The Role of Performance Status in Small-Cell Lung Cancer in the Era of Immune Checkpoint Inhibitors. Clin Lung Cancer 2020; 21:e539-e543. [PMID: 32499210 DOI: 10.1016/j.cllc.2020.04.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/17/2020] [Accepted: 04/03/2020] [Indexed: 10/24/2022]
Abstract
After decades of platinum-based chemotherapy for advanced small-cell lung cancer, there has finally been a therapeutic advance. The combination of a platinum chemotherapy, etoposide, and an immune checkpoint inhibitor has yielded overall survival benefits in two successive phase 3 trials. Unfortunately, these trials only included fit patients, namely those with an Eastern Cooperative Oncology Group performance status of 0-1. In the real-world setting, roughly a third of patients with advanced small-cell lung cancer has a performance status of 2, and an additional 15% have a performance status of 3 or 4, meaning that approximately half of all patients are excluded from chemoimmunotherapy trials. Poor performance status is a known negative prognostic factor, with a dismal prognosis among patients with disease that does not respond to the first cycle of chemotherapy.We review current data on immunotherapy in advanced small-cell lung cancer and discuss how we integrate the new therapeutic options into daily practice.
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Affiliation(s)
- Alex Friedlaender
- Oncology Department, University Hospital of Geneva, Geneva, Switzerland
| | - Stephen V Liu
- Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Antonio Passaro
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Giulio Metro
- Department of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy
| | - Giuseppe Banna
- Deparment of Oncology, United Lincolnshire NHS Hospital Trust, Lincoln, UK
| | - Alfredo Addeo
- Oncology Department, University Hospital of Geneva, Geneva, Switzerland.
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SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019). Clin Transl Oncol 2020; 22:245-255. [DOI: 10.1007/s12094-020-02295-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 01/07/2020] [Indexed: 01/18/2023]
Abstract
AbstractSmall-cell lung cancer (SCLC) accounts for 15% of lung cancers. Only one-third of patients are diagnosed at limited stage. The median survival remains to be around 15–20 months without significative changes in the strategies of treatment for many years. In stage I and IIA, the standard treatment is the surgery followed by adjuvant therapy with platinum–etoposide. In stage IIB–IIIC, the recommended treatment is early concurrent chemotherapy with platinum–etoposide plus thoracic radiotherapy followed by prophylactic cranial irradiation in patients without progression. However, in the extensive stage, significant advances have been observed adding immunotherapy to platinum–etoposide chemotherapy to obtain a significant increase in overall survival, constituting the new recommended standard of care. In the second-line treatment, topotecan remains as the standard treatment. Reinduction with platinum–etoposide is the recommended regimen in patients with sensitive relapse (≥ 3 months) and new drugs such as lurbinectedin and immunotherapy are new treatment options. New biomarkers and new clinical trials designed according to the new classification of SCLC subtypes defined by distinct gene expression profiles are necessary.
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Dashing Decades of Defeat: Long Anticipated Advances in the First-line Treatment of Extensive-Stage Small Cell Lung Cancer. Curr Oncol Rep 2020; 22:20. [PMID: 32034529 DOI: 10.1007/s11912-020-0887-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Small cell lung cancer (SCLC) is an exceptionally lethal subtype of lung cancer. For patients with extensive-stage (ES) disease, which is the majority of patients, platinum-doublet chemotherapy has been the standard of care for decades. Dozens of phase III trials have failed to improve survival over standard platinum plus etoposide. Recent results, however, have met with long-overdue success. This manuscript reviews the new standards of care for ES-SCLC. RECENT FINDINGS Two recent phase III trials have shown an improvement in overall survival with concurrent immunotherapy and chemotherapy. In IMpower 133, the addition of the anti-PD-L1 antibody atezolizumab to carboplatin plus etoposide significantly improved both progression-free survival (PFS) and overall survival (OS). This was the first trial in over 30 years to improve survival. In CASPIAN, concurrent durvalumab, another anti-PD-L1 antibody, also led to an improvement in survival. While there is clearly a need to further improve outcomes, the improvement in survival with the addition of atezolizumab or durvalumab to platinum-doublet chemotherapy is a major advance. We now have new standards of care and the potential of a more meaningful benefit for patients with advanced SCLC.
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Ahmed Y, Calvert P, Dennehy C, Lee J. Immune checkpoint inhibitors in the driver’s seat: Evaluating the evolving evidence in the treatment of extensive-stage small-cell lung cancer. ACTA ACUST UNITED AC 2019. [DOI: 10.4103/jco.jco_12_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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