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Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non–Small Cell Lung Cancer Treated With Nivolumab

Educational Objective: To learn about the association between nivolumab and survival in patients with advanced melanoma, renal cell carcinoma, or non–small cell lung cancer.
1 Credit CME
Key Points

Question  What is the 5-year survival, and what factors are associated with 5-year survival among patients with advanced melanoma, renal cell carcinoma, or non–small cell lung cancer receiving nivolumab?

Findings  In this secondary analysis of 270 patients from the CA209-003 clinical trial with advanced melanoma, renal cell carcinoma, or non–small cell lung cancer, 5-year survival was negatively associated with presence of bone or liver metastases and positively associated with Eastern Cooperative Oncology Group performance status of 0, objective response, degree of tumor burden reduction, and adverse event occurrence.

Meaning  Nivolumab treatment may be associated with durable survival among some heavily pretreated patients with advanced melanoma, renal cell carcinoma, or non–small cell lung cancer; characterizing factors associated with long-term survival may guide future anti–programmed cell death 1–based clinical trial design.

Abstract

Importance  Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited.

Objectives  To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS.

Design, Setting, and Participants  This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016.

Intervention  In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent.

Main Outcomes and Measures  Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months.

Results  Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios).

Conclusions and Relevance  Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development.

Trial Registration  ClinicalTrials.gov identifier: NCT00730639

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Article Information

Accepted for Publication: April 16, 2019.

Published Online: July 25, 2019. doi:10.1001/jamaoncol.2019.2187

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2019 Topalian SL et al. JAMA Oncology.

Corresponding Author: Suzanne L. Topalian, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, 1550 Orleans St, Cancer Research Bldg 2, Room 508, Baltimore, MD 21287 (stopali1@jhmi.edu).

Author Contributions: Drs Topalian and Sznol had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Topalian, Hodi, Brahmer, Atkins, Carvajal.

Acquisition, analysis, or interpretation of data: Topalian, Hodi, Gettinger, Smith, McDermott, Powderly, Sosman, Atkins, Leming, Spigel, Antonia, Drilon, Wolchok, McHenry, Hosein, Harbison, Grosso, Sznol.

Drafting of the manuscript: Topalian, Gettinger, Hosein, Harbison, Sznol.

Critical revision of the manuscript for important intellectual content: Topalian, Hodi, Brahmer, Gettinger, Smith, McDermott, Powderly, Sosman, Atkins, Leming, Spigel, Antonia, Drilon, Wolchok, Carvajal, McHenry, Harbison, Grosso, Sznol.

Statistical analysis: Gettinger, McHenry, Hosein.

Administrative, technical, or material support: Hodi, Powderly, Sosman, Carvajal, Hosein, Harbison, Grosso.

Supervision: Topalian, Hodi, Brahmer, McDermott, Leming, Drilon, Wolchok, Sznol.

Conflict of Interest Disclosures: Dr Topalian reported receiving grants from Bristol-Myers Squibb, Compugen, and Potenza Therapeutics during the conduct of the study; receiving travel reimbursements from Bristol-Myers Squibb, Dragonfly Therapeutics, Five Prime Therapeutics, and Merck; receiving consulting fees from AbbVie, Amgen, Avidity NanoMedicines, Bayer, Camden Nexus, DNAtrix, Dragonfly Therapeutics, Dynavax Technologies, Ervaxx, Five Prime Therapeutics, FLX Bio, ImaginAb, Immunomic Therapeutics, Janssen Pharmaceuticals, MedImmune/AstraZeneca, Merck, Pfizer, Rock Springs Capital, and WindMIL outside the submitted work; receiving stock or stock options from Aduro, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, FLX Bio, Jounce Therapeutics, Potenza Therapeutics, Tizona LLC, and WindMIL; having intellectual property licensed through her institution to Bristol-Myers Squibb, Aduro, Immunomic Therapeutics, NexImmune, and WindMIL; and having patents pending for cancer therapy via a combination of epigenetic modulation and immune modulation, checkpoint blockade and microsatellite instability, and biomarkers useful for determining response to PD-1 blockade therapy. Dr Hodi reported receiving other support from Bristol-Myers Squibb to his institution during the conduct of the study; receiving grants from Bristol-Myers Squibb and Novartis; receiving personal fees from Aduro, Apricity, Bayer, Bristol-Myers Squibb, Compass Therapeutics, EMD Serono, Genentech/Roche, Merck, Novartis, Partners Therapeutics, Pionyr, Pfizer, Rheos, Sanofi, Surface, Takeda, Torque, and Verastem outside the submitted work; and having a patent to Methods for Treating MIA-related Disorders (#20100111973) pending and royalties paid, a patent to Tumor Antigens and Uses Thereof (#7250291) issued, a patent to Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma Using PD-L1 Isoforms (#20160340407) pending, patents to Therapeutic Peptides (#20160046716, #20240004112, #20170022275, and #20170008962) pending, a patent to Therapeutic Peptides issued, and a patent to Methods of Using Pembrolizumab and Trebananib pending. Dr Brahmer reported receiving grants and having an uncompensated advisory committee/consulting agreement with Bristol-Myers Squibb during conduct of the study; personal fees from Amgen, AstraZeneca/MedImmune, Celgene, Genentech, Janssen Oncology, Eli Lilly, Merck, and Syndax outside the submitted work; serving on the advisory council from Amgen; consulting agreement from Celgene, Eli Lilly, and Merck; serving on the advisory board from AstraZeneca, Genentech, Janssen Oncology, Merck, and Syndax; and receiving grant support from AstraZeneca/MedImmune and Merck. Dr Gettinger reported receiving other support from Bristol-Myers Squibb outside the submitted work. Dr Smith reported receiving grant support from Bristol-Myers Squibb (Medarex) during the conduct of the study and from Astellas, Bayer, Celgene, Incyte, Eli Lilly, ESSA, F. Hoffmann-LaRoche AG, Genentech, Incyte, MedImmune, Medivation (Pfizer), Merck, Millennium, Novartis, OncoMed, and Seattle Genetics outside the submitted work. Dr McDermott reported receiving grant support and personal fees from Bristol-Myers Squibb during the conduct of the study and receiving honoraria for consulting from Array BioPharm, Bristol-Myers Squibb, Eisai, Exelixis, Genentech BioOncology, Jounce Therapeutics, Merck, Novartis, Pfizer, and Prometheus outside the submitted work. Dr Powderly reported other support from Bristol-Myers Squibb during the conduct of the study; receiving other support from Alkermes, Arcus, AstraZeneca/MedImmune, Corvus, Curis, EMD Serono, FLX Bio, Genentech, InCyte, MacroGenics, Merck, Tempest, and Top Alliance BioSciences outside the submitted work; and having a patent pending and reported being founder and owner of Carolina BioOncology Institute, PLLC, an independent Phase I Cancer Research Clinic and BioCytics Inc, a Human Applications laboratory developing cellular immunotherapies (both companies collaborate with multiple potential biopharma and biotech partners to develop future cellular immunotherapies). Dr Sosman reported receiving personal fees from Bristol-Myers Squibb, Curis, and Genentech outside the submitted work. Dr Atkins reported receiving research support (to the institution) from Bristol-Myers Squibb, Merck, Pfizer and Genentech; serving as a consultant or advisor at Bristol-Myers Squibb, Merck, Novartis, Pfizer, Genentech/Roche, Exelixis, Eisai, Aveo, Array, Arrowhead, AstraZeneca, Ideera, Aduro, ImmunoCore, Boehringer Ingelheim, Iovance, Newlink, Surface, Alexion, Acceleron, Lynx, Cota, Amgen, Galactone, Werewolf, Fathom, Pneuma, and Leads; and having stock options in Werewolf and Pyxis Oncology outside the submitted work. Dr Leming reported receiving consulting fees from Bristol-Myers Squibb for participation in an unrelated consensus panel. Dr Spigel reported receiving grants and other support from Bristol-Myers Squibb during the conduct of the study; having a leadership role at Centennial Medical Center; serving as a consultant or advisor at AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Evelo, Foundation Medicine, GlaxoSmithKline, Genentech/Roche, Illumina, Eli Lilly, Merck, Moderna Therapeutics, Nektar, Novartis, Pfizer, PharmaMar, Precision Oncology, Takeda, and TRM Oncology; receiving research funding (payments to institution) from AbbVie, Acerta Pharma, Aeglea Biotherapeutics, Amgen, ARMO Biosciences, Astellas, Boehringer Ingelheim, Celgene, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Foundation Medicine, G1 Therapeutics, Genentech/Roche, Novartis, GlaxoSmithKline, GRAIL, Ipsen, Eli Lilly, Millennium, Nektar, Neon Therapeutics, Oncogenex, Pfizer, Takeda, Tesaro, Transgene, and UT Southwestern; and receiving reimbursement for accommodations, expenses and travel from AstraZeneca, Boehringer Ingelheim, Celgene, EMD Serono, Genentech, Genzyme, Intuitive Surgical, Eli Lilly, Merck, Pfizer, Purdue Pharma, Spectrum Pharmaceuticals, and Sysmex. Dr Antonia reported receiving grants and personal fees from Bristol-Myers Squibb during the conduct of the study; receiving grants from AstraZeneca; receiving personal fees from Amgen, Boehringer Ingelheim, CBMG, Celsius, FLX Bio, Genentech, MedImmune, Memgen, Merck, Multivir, and Venn outside the submitted work; and holding a patent to p53-DC vaccine issues and license and a patent to oncolytic virus pending. Dr Drilon reported receiving personal fees from Ariad, AstraZeneca, Bayer, BeiGene, BergenBio, Blueprint Medicines, Exelixis, Genentech, Helsinn, Hengrui, Ignyta, Loxo, Millenium, MORE Health, Pfizer, Roche, Takeda, TP Therapeutics, Tyra, and Verastem during the conduct of the study; receiving other support from GlaxoSmithKline, Taiho, and Teva outside the submitted work; receiving royalties from Wolters Kluwer for Pocket Medicine; receiving research funding from Foundation Medicine; receiving food and beverage from Merck and Puma; and receiving continuing medical education honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice all outside the submitted work. Dr Wolchok reported receiving grants and personal fees from Bristol-Myers Squibb during the conduct of the study; receiving grants from Bristol-Myers Squibb, MedImmune, and Genentech; receiving personal fees from Adaptive Biotech, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Astellas, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, Esanex, F Star, Genentech, Imvaq, Janssen, Kleo Pharma, Linneaus, MedImmune, Merck, Neon Therapuetics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trieza, Sellas Life Sciences, Serametrix, Surface Oncology, and Syndax outside the submitted work; and owning equity in Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, BeiGene, Trieza, and Linneaus. Dr Carvajal reported receiving grants and personal fees from Bristol-Myers Squibb during the conduct of the study; receiving grants from Amgen, Astellis, AstraZeneca, Aura Biosciences, Bayer, Bellicum, Corvus, Incyte, Eli Lilly, Macrogenics, Merck, Mirati, Novartis, Roche/Genentech, Pfizer, and Plexxikon outside the submitted work; and receiving personal fees from Aura Biosciences, Chimeron, Incyte, Merck, PureTech, Regenix, Sanofi Genzyme, and Sorrento Therapeutics outside the submitted work. Drs McHenry, Harbison, and Hosein reported stock ownership and employment by Bristol-Myers Squibb. Dr Grosso reported employment by Bristol-Myers Squibb. Dr Sznol reported receiving other support from Bristol-Myers Squibb during the conduct of the study; receiving other support from Amphivena, Adaptive Biotechnologies, Intensity, Actym, Nextcure, and Torque; and receiving consulting fees from Bristol-Myers Squibb, Roche/Genentech, AstraZeneca/Medimmune, Pfizer, Novartis, Kyowa-Kirin, Seattle Genetics, Nektar, Pierre-Fabre, Eli Lilly, Merck US, Teravance, Biodesix, Vaccinex, Janssen, Modulate Therapeutics, Baxalta-Shire, Incyte, Newlink Genetics, Iovance, Agonox, Arbutus, Celldex, Inovio, Gritstone, Molecular Partners, Innate Pharma, AbbVie, Immunocore, Genmab, Almac, Hinge, Allakos, Anaeropharma, Array, GI Innovation, Genocea, Chugai-Roche, Symphogen, Adaptimmune, Omniox, Lycera, and Pieris outside the submitted work. No other disclosures were reported.

Funding/Support: This study was sponsored by Bristol-Myers Squibb.

Role of the Funder/Sponsor: Bristol-Myers Squibb was involved in the design and conduct of the study and the collection, management, analysis, and interpretation of the data. Authors employed by Bristol-Myers Squibb were involved in the preparation, review, and approval of the manuscript.

Additional Contributions: We thank the patients and their families, as well as the investigators and participating study teams. Joel Jiang, PhD, received compensation when formerly employed by Bristol-Myers Squibb for his help with original data analyses and early development of the manuscript. Richard Daniel, PhD, and Lawrence Hargett, BSc, of PPSI (a Parexel company), provided professional medical writing and editorial assistance; the work provided for their company (PPSI) was funded by Bristol-Myers Squibb.

Meeting Presentation: This paper was presented in part at the 32nd Annual Meeting of the Society for Immunotherapy of Cancer, National Harbor, MD; November 11, 2017.

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