Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials

Abstract

Importance: Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.

Objective: To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.

Design, setting, and participants: Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.

Interventions: Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion.

Main outcomes and measures: Tumor response and safety in TBP and non-TBP patients.

Results: Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).

Conclusions and relevance: A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.

Trial registration: clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067).

Conflict of interest statement

Conflict of Interest Disclosures: Prof Long is a consultant advisor to the following and reports receiving personal fees from Bristol-Myers Squibb, Amgen, Novartis, Merck, GlaxoSmithKline, and Roche. She has also received honoraria from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Roche. Dr Weber has stock or other ownership in Celldex, Altor, and cCAM. He has received honoraria from and is a paid consultant advisor for Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, and Genentech. He has also received research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, Genentech, and MacroGenics. Dr Larkin has received research funding from Pfizer, Bristol-Myers Squibb, Novartis, and Merck Sharp & Dohme. Dr Atkinson has received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, and Merck Sharp & Dohme. She is a consultant advisor for Bristol-Myers Squibb and Merck Sharp & Dohme. She has also received travel, accommodation, and expenses from Bristol-Myers Squibb and Roche. Prof Grob is a consultant advisor for Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Amgen, Merck, and Roche. He has participated in speakers’ bureaus for Bristol-Myers Squibb, GlaxoSmithKline, and Roche. He has also received research funding from Bristol-Myers Squibb and Roche, as well as travel, accommodation, and expenses from Roche. Prof Schadendorf is a consultant advisor for and has received honoraria from Roche, GlaxoSmithKline, Amgen, Novartis, Bristol-Myers Squibb, and Merck Sharp & Dohme. He has also participated in speakers’ bureaus for and has received travel support from Roche, GlaxoSmithKline, Amgen, Novartis, Bristol-Myers Squibb, and Merck Sharp & Dohme. His institution has received research funding from Merck Sharp & Dohme. Prof Dummer is a consultant advisor for and has received honoraria and research funding from Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis. Dr Robert is a consultant advisor for and has received honoraria from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, Novartis, and Amgen. Dr Márquez-Rodas is a consultant advisor for Bristol-Myers Squibb, Novartis, Roche, Amgen, and Merck Sharp & Dohme. He has participated in speakers’ bureaus for Bristol-Myers Squibb, Novartis, and Amgen. He has also received travel, accommodation, and expenses from Bristol-Myers Squibb, Novartis, and Merck Sharp & Dohme. Dr McNeil reports travel grants from Bristol-Myers Squibb for her research fellow and nurse. Dr Briscoe reports conference travel support from Bristol-Myers Squibb. Dr Hodi is a nonpaid consultant advisor for Bristol-Myers Squibb. His institution has received research funding from Bristol-Myers Squibb and has a patent pending (immune target). Dr Wolchok is a consultant for and reports grants from Bristol-Myers Squibb and Merck. No other disclosures are reported.

Figures

Figure 1.. Consolidated Standards of Reporting Trials Flow Diagram for Patient Disposition, Showing Patient Subgroups for Analysis

Patients were assessed for eligibility and randomized in 2 separate phase 3 trials, CheckMate 066 and CheckMate 067. Other treatments (in addition to nivolumab monotherapy) to which patients were randomized comprised dacarbazine (n = 208) in CheckMate 066 and nivolumab plus ipilimumab (n = 314) or ipilimumab monotherapy (n = 315) in CheckMate 067. TBP indicates treatment beyond progression.

Figure 2.. Duration of Treatment and Survival

A, All patients treated beyond progression. B, Patients treated beyond progression with greater than 30% tumor reduction in target lesion after progression when compared with baseline. TBP indicates treatment beyond progression.

Figure 3.. Tumor Burden Change Over Time in 24 Patients Treated Beyond Progression With Greater Than 30% Tumor Reduction in Target Lesion After Progression Compared With Baseline

The horizontal dashed reference line indicates the 30% reduction consistent with a Response Evaluation Criteria in Solid Tumors v1.1 response.