Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial

Abstract

Importance: Response patterns with immunotherapy may differ from those of other treatments. This warrants further investigation because some patients may benefit from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progression.

Objective: To evaluate the safety and potential benefit of treatment with nivolumab, a programmed cell death 1 immune checkpoint inhibitor, beyond investigator-assessed first progression in patients with metastatic renal cell carcinoma (mRCC).

Design, setting, and participants: Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging trial initiated May 31, 2011, including patients with clear-cell mRCC previously treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were May 15, 2013, for progression-free survival and objective response rate and March 5, 2014, for overall survival and duration of response. In this analysis, patients treated beyond first progression received their last dose of nivolumab more than 6 weeks after RECIST-defined progression, and patients not treated beyond first progression discontinued nivolumab before or at RECIST-defined progression.

Interventions: Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3 weeks.

Main outcomes and measures: Safety and efficacy of nivolumab treatment.

Results: Of 168 patients (median [range] age, 61 [37-81] years; 72% male) randomized to nivolumab, 154 experienced progression (36 were treated beyond first progression, 26 were treated beyond first progression for ≤6 weeks, and 92 were not treated beyond first progression), 13 were treated and did not experience progression, and 1 was not treated. Prior to first progression, the RECIST-defined objective response rate was 14% (5 patients) and 16% (15 patients), and median progression-free survival was 4.2 (95% CI, 2.8-5.5) and 2.6 (95% CI, 1.5-3.9) months in patients treated and not treated beyond progression, respectively. Following initial progression, 25 (69%) patients treated beyond progression experienced subsequent tumor reduction or stabilization in target lesion size. The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression).

Conclusions and relevance: In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help define the clinical benefit for patients with mRCC treated with nivolumab beyond progression.

Trial registration: clinicaltrials.gov Identifier: NCT01354431.

Conflict of interest statement

Conflict of Interest Disclosures: Dr George has received grants from Acceleron, Agensys, Bayer, Bristol-Myers Squibb, Merck, Novartis, and Pfizer; and personal fees from Astellas, Bayer, Bristol-Myers Squibb, Novartis, Onclive, Sanofi, and Xcenda. Dr Motzer has received grants from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck, Novartis, and Pfizer; and personal fees from Bristol-Myers Squibb, Eisai, Novartis, and Pfizer. Dr Hammers has received grants from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Exelixis; and personal fees from Bristol-Myers Squibb and Ono Pharmaceutical Company. Dr Redman has received grants and personal fees from Bristol-Myers Squibb. Dr Kuzel has received grants from Bayer, Bristol-Myers Squibb, CureTech, Eisai, Genentech, MedImmune, Merck, and Millennium Takeda; and personal fees from Amgen, Argos Therapeutics, Astellas, Bayer, Bionomics, Celgene, Eisai, Genentech, and Janssen Pharmaceuticals. Dr Tykodi has received grants from Argos Therapeutics, Bristol-Myers Squibb, Exelixis, Immatics Biotechnologies, Novartis, and Prometheus; and personal fees from Amgen and Prometheus. Dr Plimack has received grants from Acceleron Pharma, AstraZeneca, Bristol-Myers Squibb, Dendreon, Eli Lilly, GlaxoSmithKline, Merck, and Pfizer; and personal fees from Acceleron Pharma, Bristol-Myers Squibb, Genentech, Novartis, Pfizer, and Roche. Drs Jiang and Waxman are employees/stockholders of Bristol-Myers Squibb. Dr Rini has received grants from Bristol-Myers Squibb, GlaxoSmithKline, Immatics Biotechnologies, Millennium Pharmaceuticals, Pfizer, and Roche/Genentech; and personal fees from Bristol-Myers Squibb. No other disclosures are reported.

Figures

Figure 1

Patient Disposition (as of May 15, 2013, Data Cutoff)

Figure 2. Duration of Treatment and Survival in Patients Treated Beyond Progression

Patients were censored for progression-free survival if they received subsequent anticancer therapy, radiotherapy, or surgery, without progression being reported prior to this or on the same day. One patient had only 1 day of tumor progression so is not visible in the Figure.

Figure 3. Tumor Burden Change From First Progression

Tumor burden change in target lesions from first progression in patients treated beyond progression. The horizontal dashed reference line indicates the 30% reduction consistent with a Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response. Plus signs indicate patients who had at least 20% increase in target lesions at time of first progression. One patient did not have tumor sum of diameters values available prior to progression because 1 of the target lesions became nonmeasurable, and therefore is not shown in the Figure.