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Coschi CH, Ding K, Tong J, Tu D, O’Callaghan C, Leighl NB, Vera-Badillo F, Juergens RA, Hao D, Seymour L, Renouf DJ, Chen E, Gaudreau PO, Fung AS. Effects of cannabinoids on immune checkpoint inhibitor response: CCTG pooled analysis of individual patient data. Immunotherapy 2025; 17:257-268. [PMID: 40184324 PMCID: PMC12036482 DOI: 10.1080/1750743x.2025.2485012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/24/2025] [Indexed: 04/06/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) benefit patients across various tumor types. ICIs block cancer and T-cell interactions whereas cannabinoids may inhibit T-cell activation, reducing lysis of tumor cells. Interactions between cannabinoid use and dual ICI treatment remain unknown. METHODS Individual patient data from 4 Canadian Cancer Trials Group (CCTG) trials of patients treated with dual ICI ± chemotherapy (n = 684) were pooled. Cochran - Mantel - Haenszel and log-rank tests (stratified by trial/treatment arms) correlated cannabinoid use with clinicopathologic characteristics, Best Overall Response (BOR)/iBOR per RECIST 1.1/iRECIST, Progression-Free Survival (PFS)/iPFS, Overall Survival (OS) and immune-related adverse events (irAEs). RESULTS Sixty-five (9.5%) patients took cannabinoids at any time on trial, 32 (4.7%) of which were using cannabinoids at baseline. By multivariate analysis, cannabinoid use at baseline was significantly associated with improved iPFS (0.05), but not iBOR (p = 0.15), PFS (p = 0.12), OS (p = 0.35) or incidence of grade 1/2 or 3/4 irAEs (p = 0.96 and 0.65 respectively). Results were not significantly different with cannabinoid use at any time on trial. CONCLUSION Improved iPFS with cannabinoid use in patients treated with durvalumab plus tremelimumab ± chemotherapy did not translate into OS benefits. This study supports the safe use of cannabinoids in the context of combination ICI therapy.
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Affiliation(s)
| | - Keyue Ding
- Canadian Cancer Trials Group, Kingston, ON, Canada
| | - Justin Tong
- Kingston Health Sciences Centre, Kingston, ON, Canada
| | - Dongsheng Tu
- Canadian Cancer Trials Group, Kingston, ON, Canada
| | | | | | | | | | - Desiree Hao
- Arthur J.E. Child Comprehensive Cancer Centre and Cumming School of Medicine, Calgary, AB, Canada
| | | | | | - Eric Chen
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | | | - Andrea S. Fung
- Arthur J.E. Child Comprehensive Cancer Centre, University of Calgary, Calgary, AB, Canada
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Liu J, Farrow M, Seymour L, Desai J, Loong HH, Ivy P, Koyoma T, Cook N, Blagden S, Garralda E, Massard C, Tolcher AW, Adashek JJ, Zhang L, Zhao S, Shen L, Kurzrock R, El-Deiry WS, Subbiah V, Joshua AM. Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials. J Clin Oncol 2025; 43:735-747. [PMID: 39808749 DOI: 10.1200/jco-24-01534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/15/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
PURPOSE Over the past 15 years, the landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation of sites, trials, sponsors, and contract research organizations has surged exponentially, marking a significant shift in research conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety and the recommended phase II dose need to be established in a timely manner. Networks and consortia may overcome some of these challenges of enrolling suitable patients and streamlining start-up, particularly when distance and disease trajectory come into play. DESIGN In this article, we provide an overview of EPCT consortia in adult oncology across different continents assembled through systematic review of the literature and snowball sampling methodology. We illustrate their scope, structure, funding, and achievements. RESULTS Fifteen EPCT consortia were identified including two in the United States, three in Europe, five in Asia-Pacific, two intercontinental consortia, and three within private oncology networks. These consortia vary in their scope, funding, and structure from government-funded models such as the National Cancer Institute Experimental Therapeutics Clinical Trials Networks through charitably funded and private research organizations. EPCT consortia play a role in collaborative research, molecular tumor boards to provide patient-centric biomarker-matched treatments, and streamlining trial conduct to improve timelines and cost efficiency. CONCLUSION The growth in EPCT activity and complexity has resulted in expansion in the number of EPCT consortia globally. By actively engaging with regulatory bodies and pharmaceutical and contract research organization industries, consortia have an opportunity to address the evolving challenges faced in this field and to accelerate the translation of scientific discoveries into clinical practice.
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Affiliation(s)
- Jia Liu
- The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia
- Faculty of Medicine & Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Max Farrow
- Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Lesley Seymour
- Canadian Cancer Trials Group, Queens University, Kingston, ON, Canada
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Herbert H Loong
- The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Percy Ivy
- National Cancer Institute, Bethesda, MD
| | | | - Natalie Cook
- The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom
| | - Sarah Blagden
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Elena Garralda
- Research Unit for Molecular Therapy of Cancer (UITM), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Oncology Department, Hospital Universitario Vall d'Hebron (HUVH), Barcelona, Spain
- Phase I Unit-NEXT Oncology, Hospital Quirón Salud, Barcelona, Spain
| | - Christophe Massard
- Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
| | | | - Jacob J Adashek
- START Center for Cancer Research, San Antonio, TX
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD
| | - Li Zhang
- Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Provincial Clinical Research Centre for Cancer, Guangzhou, China
| | - Shen Zhao
- Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Provincial Clinical Research Centre for Cancer, Guangzhou, China
| | - Lin Shen
- Peking University Cancer Hospital & Institute, Beijing, China
| | - Razelle Kurzrock
- Medical College of Wisconsin, Milwaukie, WI
- Worldwide Innovative Network (WIN) Consortium in Cancer Personalized Medicine, Paris, France
| | - Wafik S El-Deiry
- Medical College of Wisconsin, Milwaukie, WI
- Worldwide Innovative Network (WIN) Consortium in Cancer Personalized Medicine, Paris, France
- The Legorreta Cancer Center at Brown University, Providence, RI
| | | | - Anthony M Joshua
- The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia
- Faculty of Medicine & Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
- Garvan Institute of Medical Research, Sydney, NSW, Australia
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Ngo HX, Oh E, Li C, Yu J. Oncology Dose Selection in Subsequent Indications: What Can We Learn From FDA-approved Oncology Drugs? Clin Ther 2024; 46:927-937. [PMID: 39304367 DOI: 10.1016/j.clinthera.2024.08.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/08/2024] [Accepted: 08/22/2024] [Indexed: 09/22/2024]
Abstract
PURPOSE The modern oncology drug development landscape has shifted away from traditional cytotoxic chemotherapies. Following their initial approvals, many oncology drugs have been approved in subsequent indications either as monotherapy or in combination to benefit a broader patient population. To date, dose selection strategies for subsequent indications have not been systematically reviewed. This review examines how approved dosing regimens were selected in subsequent indications for FDA-approved oncology drugs. METHODS The Drugs@FDA database was used to identify FDA-approved new molecular entities (NMEs) between 2010 and 2023. NMEs with more than 1 approved indication were included in the analysis. In total, the dosing regimens for 67 novel oncology drugs that obtained FDA approvals for multiple indications were evaluated. FINDINGS Overall, in subsequent indications, 72% of NMEs used the same or clinically equivalent alternative dosing regimens to those approved in the initial indications. Amongst the 28% of NMEs that used different dosing regimens, safety/tolerability was the leading cause of a dosing regimen changes in both monotherapy and combination therapy settings. Other factors leading to changes in dosing regimens include differences in tumor biology, disease burden, pharmacokinetics, and overall benefit-risk profiles obtained from dose-finding studies. IMPLICATIONS Our analysis highlighted the importance of selecting a safe, tolerable, and yet efficacious dosing regimen for the initial indication as a suboptimal initially approved regimen could lead to dosing regimen changes in later indications. Preclinical and clinical data could be leveraged to understand the pharmacology, pharmacokinetic, and pharmacodynamic differences between indications and thus support dose selection in subsequent indications.
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Affiliation(s)
- Huy X Ngo
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA
| | - Elise Oh
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA
| | - Chunze Li
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA
| | - Jiajie Yu
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA.
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Dehar N, Meem M, Aggarwal I, Hopman W, Gaudreau PO, Robinson A, Fung AS. Brief Report: Real-World Eligibility for Clinical Trials in Patients With Extensive-Stage SCLC at a Tertiary Care Center. JTO Clin Res Rep 2024; 5:100696. [PMID: 39091596 PMCID: PMC11293570 DOI: 10.1016/j.jtocrr.2024.100696] [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: 01/23/2024] [Revised: 04/22/2024] [Accepted: 06/02/2024] [Indexed: 08/04/2024] Open
Abstract
Introduction The CASPIAN and IMpower133 trials revealed a significant survival benefit of chemotherapy plus immunotherapy in patients with extensive-stage SCLC. The current study characterizes the proportion of real-world patients who would have met eligibility for these trials and highlights factors influencing eligibility in the real-world setting. Methods A retrospective analysis of patient data was conducted for stage IV patients with SCLC treated at the Cancer Centre of Southeastern Ontario, Canada. Trial eligibility was based on criteria used in the IMpower133 and CASPIAN trials. Data were summarized using descriptive statistics. Overall survival was assessed using the Kaplan-Meier method. Results Of the 116 patients included, only 12.1% met the overall eligibility criteria for the IMpower133 trial, and 14.7% for the CASPIAN trial. The most common reasons for ineligibility included: Eastern Cooperative Oncology Group (ECOG) 2 or greater (77.5%), inadequate organ function (48%), and the presence of brain metastases at diagnosis (37.3%). Sixty-one patients (59.8%) met two or more major ineligibility criteria. If trial eligibility was expanded to include ECOG 2 patients, an additional 10.3% would have met eligibility. The median overall survival for all-comers was 6.5 months. Conclusions Only a small minority of real-world patients with extensive-stage SCLC would have met eligibility for the IMpower133 and CASPIAN trials, with ECOG greater than or equal to 2, inadequate organ function, and brain metastases comprising the most common reasons for trial ineligibility. Future clinical trials should expand the inclusion criteria to better represent real-world patient populations.
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Affiliation(s)
- Navdeep Dehar
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
- Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Mahbuba Meem
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
- Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Ishita Aggarwal
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
- Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Wilma Hopman
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
| | - Pierre-Olivier Gaudreau
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
- Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Andrew Robinson
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
- Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Andrea S. Fung
- Department of Oncology, Queen’s School of Medicine, Queen’s University, Kingston, Ontario, Canada
- Cancer Centre of Southeastern Ontario, Kingston Health Sciences Centre, Kingston, Ontario, Canada
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Zhang XT, Ge N, Xiang ZJ, Liu T. Immune checkpoint inhibitor-related adverse cardiac events in patients with lung cancer: a systematic review and meta-analysis. Cancer Cell Int 2022; 22:363. [PMCID: PMC9675058 DOI: 10.1186/s12935-022-02760-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/25/2022] [Indexed: 11/21/2022] Open
Abstract
Background Although people are more and more aware of the cardiotoxicity caused by immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, its incidence rate has not been systematically analyzed. This study aims to evaluate the incidence of cardiotoxicity related to the ICI therapies for lung cancer, so as to enhance clinicians' attention to cardiotoxicity, implement proper prevention and intervention for high-risk patients, and minimize the risk of cardiac dysfunction during and after completion of therapy. Methods We conducted a systematic literature search for relevant publications in PubMed and Scopus from inception to 19 April 2022. Pooled incidence and risk ratios with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated. Results A total of 37 studies covering 38 trials, including 14,342 patients, were identified. The pooled risk ratios of incidence of any cardiac AEs were 1.944 [95% CI 0.8–4.725] (Single ICI versus chemotherapy), 1.677 [95% CI 1.065–2.64] (Single ICI plus chemotherapy versus chemotherapy), and 0.478 [95% CI 0.127–1.798] (Single ICI versus Dual ICI). The incidence of myocarditis and arrhythmia were 0.003[95%CI 0.002–0.006] and 0.014[95%CI 0–0.037], respectively. Conclusion Single ICI did not increase the risk of cardiotoxicity compared with chemotherapy, and single ICI plus chemotherapy increased the risk of cardiotoxicity by 67% compared with chemotherapy alone. Combination immunotherapy did not increase the risk of cardiotoxicity compared with single ICI. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02760-2.
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Affiliation(s)
- Xiao-Tong Zhang
- grid.506261.60000 0001 0706 7839Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730 China
| | - Nan Ge
- grid.506261.60000 0001 0706 7839Department of Geriatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zi-Jian Xiang
- Beijing Zhiyun Data Technology Co. LTD, Beijing, China
| | - Tao Liu
- grid.506261.60000 0001 0706 7839Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730 China
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Cozma A, Sporis ND, Lazar AL, Buruiana A, Ganea AM, Malinescu TV, Berechet BM, Fodor A, Sitar-Taut AV, Vlad VC, Negrean V, Orasan OH. Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review. Int J Mol Sci 2022; 23:ijms231810948. [PMID: 36142866 PMCID: PMC9502843 DOI: 10.3390/ijms231810948] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body's own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016-2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.
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Affiliation(s)
- Angela Cozma
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Nicolae Dan Sporis
- Department of Medical Oncology, Prof. Dr. I. Chiricuta Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Andrada Luciana Lazar
- Department of Dermatology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Andrei Buruiana
- Department of Medical Oncology, Prof. Dr. I. Chiricuta Oncology Institute, 400015 Cluj-Napoca, Romania
- Correspondence:
| | - Andreea Maria Ganea
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Toma Vlad Malinescu
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Bianca Mihaela Berechet
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Adriana Fodor
- Clinical Centre of Diabetes, Nutrition and Metabolic Disease, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Adela Viviana Sitar-Taut
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Vasile Calin Vlad
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Vasile Negrean
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Olga Hilda Orasan
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
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Akamatsu H, Teraoka S, Takamori S, Miura S, Hayashi H, Hata A, Toi Y, Shiraishi Y, Mamesaya N, Sato Y, Furuya N, Oyanagi J, Koh Y, Misumi T, Yamamoto N, Nakagawa K. Nivolumab Retreatment in Non-Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L). Clin Cancer Res 2022; 28:OF1-OF7. [PMID: 35762926 PMCID: PMC9662947 DOI: 10.1158/1078-0432.ccr-22-0602] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/23/2022] [Accepted: 05/24/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE To explore the efficacy of retreatment with immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC) who responded to prior ICI and had adequate ICI-free interval. PATIENTS AND METHODS Patients with advanced NSCLC who had achieved complete response (CR), partial response (PR), or stable disease for ≥6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval ≥60 days before registration. Patients were treated with nivolumab (240 mg) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561). RESULTS Sixty-one patients were enrolled during October 2017 to February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAE) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% [95% confidence interval (CI), 2.8-18.7%] and median PFS of 2.6 months (95% CI, 1.6-2.8 months) while 5 responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (HR, 2.02; P = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%). CONCLUSIONS Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
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Affiliation(s)
- Hiroaki Akamatsu
- Internal Medicine III, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Shunsuke Teraoka
- Internal Medicine III, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Shinkichi Takamori
- Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Notame, Minami-Ku, Fukuoka, Japan
| | - Satoru Miura
- Department of Internal Medicine, Niigata Cancer Center Hospital, Kawagishi-cho, Chuo-Ku, Niigata, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Onohigashi, Osakasayama, Japan
| | - Akito Hata
- Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Minatojima-Nakamachi, Chuo-Ku, Kobe, Japan
| | - Yukihiro Toi
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Hirosemachi, Aoba-Ku, Sendai, Japan
| | - Yoshimasa Shiraishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan
| | - Nobuaki Mamesaya
- Department of Thoracic Oncology, Shizuoka Cancer Center, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
| | - Yuki Sato
- Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Minatojimaminami-Machi, Chuo-Ku, Kobe, Japan
| | - Naoki Furuya
- Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Japan
| | - Jun Oyanagi
- Internal Medicine III, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Yasuhiro Koh
- Internal Medicine III, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Toshihiro Misumi
- Department of Biostatistics, Yokohama City University Graduate School of Medicine, Fukuura, Kanazawa-Ku, Yokohama, Japan
| | - Nobuyuki Yamamoto
- Internal Medicine III, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Onohigashi, Osakasayama, Japan
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8
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Hecht M, Eckstein M, Rutzner S, von der Grün J, Illmer T, Klautke G, Laban S, Hautmann MG, Brunner TB, Tamaskovics B, Hinke A, Zhou JG, Frey B, Donaubauer AJ, Becker I, Semrau S, Hartmann A, Balermpas P, Budach W, Gaipl US, Iro H, Gostian AO, Fietkau R. Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer. J Immunother Cancer 2022; 10:e003747. [PMID: 35078923 PMCID: PMC8796267 DOI: 10.1136/jitc-2021-003747] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2021] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed. METHODS Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%. RESULTS Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%). CONCLUSIONS The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS. TRIAL REGISTRATION NUMBER The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST).
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Affiliation(s)
- Markus Hecht
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Markus Eckstein
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sandra Rutzner
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Jens von der Grün
- Department of Radiation Oncology, University Hospital Frankfurt, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
| | - Thomas Illmer
- Private Praxis Oncology, Arnoldstraße, Dresden, Germany
| | - Gunther Klautke
- Department of Radiation Oncology, Chemnitz Hospital, Chemnitz, Germany
| | - Simon Laban
- Department of Otolaryngology - Head & Neck Surgery, Universität Ulm, Ulm, Germany
| | - Matthias G Hautmann
- Department of Radiotherapy, University Hospital Regensburg, Universität Regensburg, Regensburg, Germany
| | - Thomas B Brunner
- Department of Radiation Oncology, University Hospital Magdeburg, Otto von Guericke Universität Magdeburg, Magdeburg, Germany
| | - Bálint Tamaskovics
- Department of Radiation Oncology, University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Dusseldorf, Germany
| | - Axel Hinke
- Clinical Cancer Research Consulting (CCRC), Düsseldorf, Germany
| | - Jian-Guo Zhou
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Benjamin Frey
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Anna-Jasmina Donaubauer
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Ina Becker
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Sabine Semrau
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Arndt Hartmann
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Panagiotis Balermpas
- Department of Radiation Oncology, University Hospital Frankfurt, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
| | - Wilfried Budach
- Department of Radiation Oncology, University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Dusseldorf, Germany
| | - Udo S Gaipl
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Heinrich Iro
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Department of Otolaryngology - Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Antoniu-Oreste Gostian
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Department of Otolaryngology - Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Rainer Fietkau
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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9
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CCTG BR34: A randomized phase II trial of durvalumab and tremelimumab +/- platinum-based chemotherapy in patients with metastatic non-small cell lung cancer. J Thorac Oncol 2021; 17:434-445. [PMID: 34800700 DOI: 10.1016/j.jtho.2021.10.023] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/18/2021] [Accepted: 10/31/2021] [Indexed: 11/21/2022]
Abstract
INTRODUCTION First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition or in combination with chemotherapy. We compared outcomes with combination chemo-immunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naïve, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum doublet chemotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. RESULTS 301 patients were randomized. Median OS was 16.6 months (95%CI, 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95%CI, 10.6-18.3) with immunotherapy, (HR 0.88, 90%CI, 0.67-1.16; P=0.46). Median PFS with chemotherapy plus immunotherapy was 7.7 months (95%CI, 5.5-8.5) and 3.2 months (95%CI, 2.7-5.1) with immunotherapy, (HR 0.67, 95%CI, 0.52-0.88). The ORR with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy, (adjusted odds ratio 1.69, 95%CI, 1.04-2.76). The percentage of patients with grade ≥3 adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of PD-L1 expression and bTMB revealed no differential treatment effect on OS. CONCLUSIONS The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared to durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.
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10
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Ma L, Diao B, Huang Z, Wang B, Yu J, Meng X. The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Commun (Lond) 2021; 41:1314-1330. [PMID: 34699691 PMCID: PMC8696228 DOI: 10.1002/cac2.12229] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/20/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Over the past few years, immune checkpoint inhibitors (ICIs) have greatly improved the survival for patients with non‐small cell lung cancer (NSCLC) without driver mutations. Compared with wild‐type tumors, tumors with epidermal growth factor receptor (EGFR) mutations show more heterogeneity in the expression level of programmed cell death‐ligand 1 (PD‐L1), tumor mutational burden (TMB), and other immune microenvironment characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In previous studies, no significantly improved benefits were observed with immunotherapy monotherapy in NSCLC patients with EGFR mutation. Here, we summarized and analyzed data from the clinical trials of ICIs or combined therapy in NSCLC patients with EGFR mutations. We also focused on the mechanisms affecting the efficacy of ICIs in NSCLC patients with EGFR mutations, the characteristics of potential responders, and provided insights into areas worth further investigations in future studies.
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Affiliation(s)
- Lin Ma
- Cheeloo College of Medicine, Shandong University, Jinan 250117, Shandong, P. R. China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, P. R. China
| | - Bowen Diao
- Department of Gynecology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi 832061, Xinjiang, P. R. China
| | - Zhaoqin Huang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250117, Shandong, P. R. China
| | - Bin Wang
- Cheeloo College of Medicine, Shandong University, Jinan 250117, Shandong, P. R. China
| | - Jinming Yu
- Cheeloo College of Medicine, Shandong University, Jinan 250117, Shandong, P. R. China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, P. R. China
| | - Xiangjiao Meng
- Cheeloo College of Medicine, Shandong University, Jinan 250117, Shandong, P. R. China.,Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, P. R. China
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11
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Wang B, Guo H, Xu H, Yu H, Chen Y, Zhao G. Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer. Cells 2021; 10:2620. [PMID: 34685600 PMCID: PMC8533870 DOI: 10.3390/cells10102620] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/06/2021] [Accepted: 09/25/2021] [Indexed: 12/26/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1-3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.
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Affiliation(s)
- Bin Wang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Hanfei Guo
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, China;
| | - Haiyang Xu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Hongquan Yu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Yong Chen
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Gang Zhao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
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12
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Giustozzi M, Becattini C, Roila F, Agnelli G, Mandalà M. Vascular events with immune checkpoint inhibitors in melanoma or non-small cell lung cancer: A systematic review and meta-analysis. Cancer Treat Rev 2021; 100:102280. [PMID: 34438237 DOI: 10.1016/j.ctrv.2021.102280] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/17/2022]
Abstract
The incidence of venous and arterial thromboembolic events in advanced cancer patients treated with immune checkpoint inhibitors (ICIs) has been sporadically reported. We performed a systematic review and meta-analysis to assess the rate of vascular events in patients with melanoma and non-small cell lung cancer (NSCLC) treated with ICIs. A systematic search of MEDLINE and EMBASE was performed to identify randomized clinical trials and prospective studies. The main outcomes were venous thromboembolism (VTE), stroke or systemic embolism (SE) and myocardial infarction (MI). Secondary outcomes were fatal VTE, fatal stroke or SE and fatal MI. Pooled proportions with 95% confidence intervals (CI) were calculated using random-effects models. A total of 59 trials, 25 in 5,578 patients with melanoma and 34 in 6,543 patients with NSCLC were included. In patients with melanoma, rates of VTE, stroke or SE and MI were 1.5% (95% CI 0.8-2.8), 1.7% (95% CI 0.8-3.7) and 0.4% (95% CI 0.2-0.9), respectively. In patients with NSCLC, corresponding rates were 1.9% (95% CI 1.2-3.2), 1.2% (95% CI 0.6-2.5), and 1.1% (95% CI 0.5-2.1), respectively. Rates of fatal VTE and MI were similar in melanoma and NSCLC patients. Rates of fatal stroke or SE were 1.9% (95% CI 0.4-9.5) and 0.7% (95% CI 0.2-2.3) in melanoma and NSCLC patients, respectively. Rates of VTE (3.1% vs. 1.1%) and myocardial infarction (3.4% Vs. 0.5%) were numerically higher in NSCLC patients treated with combined-ICIs vs mono-ICIs. Our study shows a not negligible rate of vascular events in patients with melanoma or NSCLC treated with ICIs.
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Affiliation(s)
- Michela Giustozzi
- Internal, Vascular and Emergency Medicine - Stroke Unit, University of Perugia, Perugia, Italy.
| | - Cecilia Becattini
- Internal, Vascular and Emergency Medicine - Stroke Unit, University of Perugia, Perugia, Italy
| | - Fausto Roila
- Unit of Medical Oncology, University of Perugia, Perugia, Italy
| | - Giancarlo Agnelli
- Internal, Vascular and Emergency Medicine - Stroke Unit, University of Perugia, Perugia, Italy
| | - Mario Mandalà
- Unit of Medical Oncology, University of Perugia, Perugia, Italy
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13
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Arru C, De Miglio MR, Cossu A, Muroni MR, Carru C, Zinellu A, Paliogiannis P. Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Adv Ther 2021; 38:3674-3693. [PMID: 34105088 PMCID: PMC8279985 DOI: 10.1007/s12325-021-01796-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/15/2021] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Cancer immunotherapy represents one of the most important innovations in modern medicine. Durvalumab is an anti-programmed cell death ligand 1 (PDL-1) agent which is currently under investigation in several studies in combination with the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drug tremelimumab. The aim of this review was to systematically identify and revise the current scientific literature investigating the combination of these two drugs in solid tumors. METHODS A digital search on the Medline (PubMed interface) and Scopus databases for articles published from inception to 26 February 2021 was performed. The terms used for the search were durvalumab AND tremelimumab. Trials reported in English involving adult patients with solid cancers treated with the combination durvalumab plus tremelimumab were retrieved; the references of the articles were cross-checked to identify missing papers. RESULTS The electronic search produced 267 results; after exclusion of duplicates, irrelevant articles, reviews, and papers not in English or missing data, 19 articles were included for revision. The total number of patients treated with the combination of durvalumab and tremelimumab in the studies retrieved was 2052. CONCLUSION The combination of durvalumab plus tremelimumab showed some oncological advantages in comparison with traditional chemotherapies in some subsets of tumors, but generally has not shown consistent advantages in comparison with the employment of durvalumab monotherapy. A number of the studies examined had intrinsic methodological limitations; therefore, future well-designed studies involving larger cohorts are warranted.
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Affiliation(s)
- Caterina Arru
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Maria Rosaria De Miglio
- Department of Medical, Clinical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy.
| | - Antonio Cossu
- Department of Medical, Clinical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Maria Rosaria Muroni
- Department of Medical, Clinical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
- Laboratory Quality Control Unit, University Hospital Sassari (AOU-SS), 07100, Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Panagiotis Paliogiannis
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
- Laboratory Quality Control Unit, University Hospital Sassari (AOU-SS), 07100, Sassari, Italy
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14
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Lv P, Man S, Xie L, Ma L, Gao W. Pathogenesis and therapeutic strategy in platinum resistance lung cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188577. [PMID: 34098035 DOI: 10.1016/j.bbcan.2021.188577] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/25/2021] [Accepted: 05/30/2021] [Indexed: 12/20/2022]
Abstract
Platinum compounds (cisplatin and carboplatin) represent the most active anticancer agents in clinical use both of lung cancer in mono-and combination therapies. However, platinum resistance limits its clinical application. It is necessary to understand the molecular mechanism of platinum resistance, identify predictive markers, and develop newer, more effective and less toxic agents to treat platinum resistance in lung cancer. Here, it summarizes the main molecular mechanisms associated with platinum resistance in lung cancer and the development of new approaches to tackle this clinically relevant problem. Moreover, it could lead to the development of more effective treatment for refractory lung cancer in future.
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Affiliation(s)
- Panpan Lv
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Lu Xie
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
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15
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Nso N, Antwi-Amoabeng D, Beutler BD, Ulanja MB, Ghuman J, Hanfy A, Nimo-Boampong J, Atanga S, Doshi R, Enoru S, Gullapalli N. Cardiac adverse events of immune checkpoint inhibitors in oncology patients: A systematic review and meta-analysis. World J Cardiol 2020; 12:584-598. [PMID: 33312443 PMCID: PMC7701899 DOI: 10.4330/wjc.v12.i11.584] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/12/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are novel therapeutic agents used for various types of cancer. ICIs have revolutionized cancer treatment and improved clinical outcomes among cancer patients. However, immune-related adverse effects of ICI therapy are common. Cardiovascular immune-related adverse events (irAEs) are rare but potentially life-threatening complications.
AIM To estimate the incidence of cardiovascular irAEs among patients undergoing ICI therapy for various malignancies.
METHODS We conducted this systematic review and meta-analysis by searching PubMed, Cochrane CENTRAL, Web of Science, and SCOPUS databases for relevant interventional trials reporting cardiovascular irAEs. We performed a single-arm meta-analysis using OpenMeta [Analyst] software of the following outcomes: Myocarditis, pericardial effusion, heart failure, cardiomyopathy, atrial fibrillation, myocardial infarction, and cardiac arrest. We assessed the heterogeneity using the I2 test and managed to solve it with Cochrane’s leave-one-out method. The risk of bias was performed with the Cochrane’s risk of bias tool.
RESULTS A total of 26 studies were included. The incidence of irAEs follows: Myocarditis: 0.5% [95% confidence interval (CI): 0.1%-0.9%]; Pericardial effusion: 0.5% (95%CI: 0.1%-1.0%); Heart failure: 0.3% (95%CI: 0.0%-0.5%); Cardiomyopathy: 0.3% (95%CI: -0.1%-0.6%); atrial fibrillation: 4.6% (95%CI: 1.0%-14.1%); Myocardial infarction: 0.4% (95%CI: 0.0%-0.7%); and Cardiac arrest: 0.4% (95%CI: 0.1%-0.8%).
CONCLUSION The most common cardiovascular irAEs were atrial fibrillation, myocarditis, and pericardial effusion. Although rare, data from post market surveillance will provide estimates of the long-term prevalence and prognosis in patients with ICI-associated cardiovascular complications.
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Affiliation(s)
- Nso Nso
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Queens, NY 10029, United States
| | - Daniel Antwi-Amoabeng
- Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89502, United States
| | - Bryce D Beutler
- Department of Radiology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, United States
| | - Mark B Ulanja
- Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89502, United States
| | - Jasmine Ghuman
- Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89502, United States
| | - Ahmed Hanfy
- Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89502, United States
| | - Joyce Nimo-Boampong
- Department of Internal Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
| | - Sirri Atanga
- Department of Medicine, United Health Services Wilson Medical Center, Johnson City, NY 13790, United States
| | - Rajkumar Doshi
- Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89502, United States
| | - Sostanie Enoru
- Department of Cardiovascular Disease, SUNY Downstate Health Science University, Brooklyn, NY 11203, United States
| | - Nageshwara Gullapalli
- Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89502, United States
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16
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Hecht M, Gostian AO, Eckstein M, Rutzner S, von der Grün J, Illmer T, Hautmann MG, Klautke G, Laban S, Brunner T, Hinke A, Becker I, Frey B, Semrau S, Geppert CI, Hartmann A, Balermpas P, Budach W, Gaipl US, Iro H, Fietkau R. Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8. J Immunother Cancer 2020; 8:jitc-2020-001378. [PMID: 33023982 PMCID: PMC7539609 DOI: 10.1136/jitc-2020-001378] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2020] [Indexed: 12/31/2022] Open
Abstract
Background To determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer. Methods Patients received a single cycle of cisplatin 30 mg/m² on days 1–3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy. Results A total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3–4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3–4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR. Conclusions Single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.
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Affiliation(s)
- Markus Hecht
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany .,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
| | - Antoniu Oreste Gostian
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany.,Department of Otolaryngology - Head & Neck Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Markus Eckstein
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany.,Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Sandra Rutzner
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
| | - Jens von der Grün
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Thomas Illmer
- Medical Oncology Clinic Dresden Freiberg, Dresden, Saxony, Germany
| | - Matthias G Hautmann
- Department of Radiation Oncology, Universität Regensburg, Regensburg, Bayern, Germany
| | - Gunther Klautke
- Department of Radiation Oncology, Chemnitz Hospital, Chemnitz, Sachsen, Germany
| | - Simon Laban
- Department of Otolaryngology - Head & Neck Surgery, Universität Ulm, Ulm, Baden-Württemberg, Germany
| | - Thomas Brunner
- Department of Radiation Oncology, Otto von Guericke Universität Magdeburg, Magdeburg, Sachsen-Anhalt, Germany
| | - Axel Hinke
- Clinical Cancer Research Consulting (CCRC), Düsseldorf, Nordrhein-Westfalen, Germany
| | - Ina Becker
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
| | - Benjamin Frey
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
| | - Sabine Semrau
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
| | - Carol I Geppert
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany.,Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Arndt Hartmann
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany.,Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Panagiotis Balermpas
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Wilfried Budach
- Department of Radiation Oncology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Nordrhein-Westfalen, Germany
| | - Udo S Gaipl
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
| | - Heinrich Iro
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany.,Department of Otolaryngology - Head & Neck Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Rainer Fietkau
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany
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17
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Wu Z, Man S, Sun R, Li Z, Wu Y, Zuo D. Recent advances and challenges of immune checkpoint inhibitors in immunotherapy of non-small cell lung cancer. Int Immunopharmacol 2020; 85:106613. [DOI: 10.1016/j.intimp.2020.106613] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/14/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023]
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18
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Gullapalli S, Remon J, Hendriks LEL, Lopes G. Update on Targeted Therapies for Advanced Non-Small Cell Lung Cancer: Durvalumab in Context. Onco Targets Ther 2020; 13:6885-6896. [PMID: 32764980 PMCID: PMC7369644 DOI: 10.2147/ott.s259308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/25/2020] [Indexed: 12/25/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the therapeutic strategy and prognosis of advanced non-small cell lung cancer (NSCLC) patients. Nowadays, ICIs as monotherapy or in combination with chemotherapy are the standard of care treatment in advanced NSCLC, and in stage III, durvalumab (a programmed death ligand 1 inhibitor) is the unique drug approved as consolidation treatment after chemo-radiotherapy. This article reviews the pharmacological properties, clinical activity and safety of durvalumab as monotherapy or in combination with chemotherapy or other ICIs in the therapeutic strategy of NSCLC patients.
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Affiliation(s)
- Sneha Gullapalli
- Division of Pulmonary and Critical Care, University of Miami, Jackson Memorial Hospital, Miami, FL, USA
| | - Jordi Remon
- Department of Medical Oncology, Centro Integral Oncológico Clara Campal (HM-CIOCC), Hospital HM Delfos, HM Hospitales, Barcelona, Spain
| | - Lizza E L Hendriks
- Department of Pulmonary Diseases GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Gilberto Lopes
- Divisions of Hematology and Medical Oncology, Departments of Medicine, Miller School of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA
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19
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Ashrafizadeh M, Zarrabi A, Hashemi F, Moghadam ER, Hashemi F, Entezari M, Hushmandi K, Mohammadinejad R, Najafi M. Curcumin in cancer therapy: A novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects. Life Sci 2020; 256:117984. [PMID: 32593707 DOI: 10.1016/j.lfs.2020.117984] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/14/2020] [Accepted: 06/15/2020] [Indexed: 12/15/2022]
Abstract
Dealing with cancer is of importance due to enhanced incidence rate of this life-threatening disorder. Chemotherapy is an ideal candidate in overcoming and eradication of cancer. To date, various chemotherapeutic agents have been applied in cancer therapy and paclitaxel (PTX) is one of them. PTX is a key member of taxane family with potential anti-tumor activity against different cancers. Notably, PTX has demonstrated excellent proficiency in elimination of cancer in clinical trials. This chemotherapeutic agent is isolated from Taxus brevifolia, and is a tricyclic diterpenoid. However, resistance of cancer cells into PTX chemotherapy has endangered its efficacy. Besides, administration of PTX is associated with a number of side effects such as neurotoxicity, hepatotoxicity, cardiotoxicity and so on, demanding novel strategies in obviating PTX issues. Curcumin is a pharmacological compound with diverse therapeutic effects including anti-tumor, anti-oxidant, anti-inflammatory, anti-diabetic and so on. In the current review, we demonstrate that curcumin, a naturally occurring nutraceutical compound is able to enhance anti-tumor activity of PTX against different cancers. Besides, curcumin administration reduces adverse effects of PTX due to its excellent pharmacological activities. These topics are discussed with an emphasis on molecular pathways to provide direction for further studies in revealing other signaling networks.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey; Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, Tuzia, Istanbul 34956, Turkey
| | - Farid Hashemi
- DVM, Graduated, Young Researcher and Elite Club, Kazerun Branch, Islamic Azad University, Kazeroon, Iran
| | - Ebrahim Rahmani Moghadam
- Department of Anatomical Sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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20
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Mariniello A, Novello S, Scagliotti GV, Ramalingam SS. Double immune checkpoint blockade in advanced NSCLC. Crit Rev Oncol Hematol 2020; 152:102980. [PMID: 32516722 DOI: 10.1016/j.critrevonc.2020.102980] [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] [Received: 02/07/2020] [Revised: 04/28/2020] [Accepted: 05/04/2020] [Indexed: 12/25/2022] Open
Abstract
Immunotherapy-based options for patients with advanced non-small cell lung cancer (NSCLC) are increasing at an unprecedented pace, carrying the promise to prolong survival of this deadly disease. To maximize responses and extend benefit to a larger portion of patients, immunotherapy combination strategies are currently under investigation, with chemo-immunotherapy already in use. Combinations of programmed death-1/ligand-1 (PD-1/L1) and cytotoxic T lymphocytes antigen-4 (CTLA-4) were developed with the rationale of targeting complementary pathways involved in T cell activation, and already showed to be highly active in other malignancies. Recently, the phase III Checkmate 227 trial showed that combination of nivolumab and ipilimumab provided survival benefit in untreated advanced NSCLC patients. However, accurate patients' selection and appropriate sequencing of different immunotherapy-based approaches remain unsolved. In this review, we provide an overview of the currently available evidence on double immune checkpoint inhibition (ICI) for NSCLC treatment and discuss current issues and future perspectives.
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Affiliation(s)
- Annapaola Mariniello
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
| | - Silvia Novello
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Giorgio V Scagliotti
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Suresh S Ramalingam
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
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