Luis G Paz-Ares1, Suresh S Ramalingam2, Tudor-Eliade Ciuleanu3, Jong-Seok Lee4, Laszlo Urban5, Reyes Bernabe Caro6, Keunchil Park7, Hiroshi Sakai8, Yuichiro Ohe9, Makoto Nishio10, Clarisse Audigier-Valette11, Jacobus A Burgers12, Adam Pluzanski13, Randeep Sangha14, Carlos Gallardo15, Masayuki Takeda16, Helena Linardou17, Lorena Lupinacci18, Ki Hyeong Lee19, Claudia Caserta20, Mariano Provencio21, Enric Carcereny22, Gregory A Otterson23, Michael Schenker24, Bogdan Zurawski25, Aurelia Alexandru26, Alain Vergnenegre27, Judith Raimbourg28, Kynan Feeney29, Sang-We Kim30, Hossein Borghaei31, Kenneth John O'Byrne32, Matthew D Hellmann33, Arteid Memaj34, Faith Ellen Nathan34, Judith Bushong34, Phuong Tran34, Julie R Brahmer35, Martin Reck36. 1. Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit, Universidad Complutense & CiberOnc, Madrid, Spain. Electronic address: lpazaresr@seom.org. 2. Winship Cancer Institute, Emory University, Atlanta, Georgia. 3. Institutul Oncologic Prof Dr Ion Chiricuta and UMF Iuliu Hatieganu, Cluj Napoca, România. 4. Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 5. Matrai Gyogyintezet, Matrahaza, Hungary. 6. Hospital Universitario Virgen Del Rocio, Instituto de Biomedicina de Seville, Seville, Spain. 7. Samsung Medical Center at Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 8. Saitama Cancer Center, Saitama, Japan. 9. National Cancer Center Hospital, Tokyo, Japan. 10. Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 11. Hôpital Sainte Musse, Toulon, France. 12. Netherlands Cancer Institute, Amsterdam, The Netherlands. 13. Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 14. Cross Cancer Institute, Edmonton, Alberta, Canada. 15. Fundacion Arturo Lopez Perez, Santiago, Chile. 16. Kindai University Faculty of Medicine, Osaka, Japan. 17. Metropolitan Hospital, Neo Faliro, Greece. 18. Hospital Italiano De Buenos Aires, Buenos Aires, Argentina. 19. Chungbuk National University Hospital, Cheongju-si, Republic of Korea. 20. Santa Maria Hospital, Terni, Italy. 21. Hosp. Univ. Puerta De Hierro-IDIPHIM, Universidad Autónoma de Madrid, Madrid, Spain. 22. Catalan Institute of Oncology-Germans Trias i Pujol Hospital, B-ARGO group, Badalona, Spain. 23. The Ohio State University, Columbus, Ohio. 24. SF. Nectarie Oncology Center, Craiova, Romania. 25. Ambulatorium Chemioterapii, Bydgoszcz, Poland. 26. Institute of Oncology "Prof. Dr. Alexandru Trestioreanu" Bucha, Bucharest, Romania. 27. Limoges University Hospital, Limoges, France. 28. ICO Rene Gauducheau, St Herblain, France. 29. St John of God Hospital Murdoch, Perth, Australia. 30. Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 31. Fox Chase Cancer Center, Philadelphia, Pennsylvania. 32. Queensland University of Technology, Princess Alexandra Hospital, Brisbane, Australia. 33. Memorial Sloan Kettering Cancer Center, New York, New York. 34. Bristol Myers Squibb, Princeton, New Jersey. 35. Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland. 36. Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany.
Abstract
INTRODUCTION: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up. METHODS: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs). RESULTS: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population. CONCLUSIONS: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.
INTRODUCTION: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up. METHODS: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs). RESULTS: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population. CONCLUSIONS: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.
Authors: Jeffrey M Clarke; Lin Gu; Xiaofei F Wang; Thomas E Stinchcombe; Marvaretta M Stevenson; Sundhar Ramalingam; Afreen Shariff; Jennifer Garst; Andrew B Nixon; Scott J Antonia; Jeffrey Crawford; Neal E Ready Journal: JTO Clin Res Rep Date: 2022-05-17
Authors: Nick Freemantle; Yingxin Xu; Florence R Wilson; Patricia Guyot; Chieh-I Chen; Sam Keeping; Gerasimos Konidaris; Keith Chan; Andreas Kuznik; Kokuvi Atsou; Emily Glowienka; Jean-Francois Pouliot; Giuseppe Gullo; Petra Rietschel Journal: Ther Adv Med Oncol Date: 2022-06-16 Impact factor: 5.485