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Published on: April 22, 2019
Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials
Georgina V Long1,2, Jeffrey S Weber3,4, James Larkin5
1Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia.
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).
Insights
Selected patients receiving nivolumab (anti-programmed cell death receptor 1) may benefit from continued treatment beyond RECIST v1.1 progression. This approach demonstrated clinical benefit and maintained safety in advanced melanoma patients.
Area of Science:
- Oncology
- Immunotherapy
- Melanoma Treatment
Background:
- Immune checkpoint inhibitors (ICIs) like nivolumab can induce atypical responses not fully captured by standard criteria.
- There is a clinical need to assess the benefit of continuing ICI therapy beyond initial progression.
- Conventional response criteria may underestimate the efficacy of nivolumab in advanced melanoma.
Purpose of the Study:
- To evaluate the safety and clinical benefit of nivolumab monotherapy in patients with advanced melanoma who progressed according to RECIST v1.1 criteria.
- To assess outcomes for patients treated beyond progression (TBP) versus those who discontinued therapy at progression.
Main Methods:
- Pooled retrospective analysis of Phase 3 trial data (CheckMate 066/067) in treatment-naive advanced melanoma patients.
- Comparison of patients treated beyond progression (TBP group) with those not treated beyond progression (non-TBP group).
- Nivolumab was administered at 3 mg/kg every 2 weeks until progression or toxicity; continuation beyond progression was at investigator discretion.
Main Results:
- Of 526 patients, 306 progressed; 85 were in the TBP group and 221 in the non-TBP group.
- Twenty-eight percent of TBP patients achieved >30% target lesion reduction post-progression.
- Treatment-related grade 3-4 adverse events were similar between TBP (6%) and non-TBP (4%) groups.
Conclusions:
- Selected patients receiving frontline nivolumab can achieve clinical benefit by continuing treatment beyond RECIST v1.1 progression without compromising safety.
- Investigator assessment of clinical stability and benefit is crucial for deciding on treatment continuation.
- Further research is warranted to fully define the benefits of extended nivolumab therapy post-progression.
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