Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial

Abstract

Summary Background Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6–62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1–55·3] of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4–53·8] vs 14 [20%; 11·4–31·3]). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patie...

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Although toxicity was statistically similar between the two arms throughout the entire treatment period, and broadly consistent with that observed in CheckMate 067 and CheckMate 069, efficacy outcomes were superior in the nivolumab-first arm relative to the ipilimumab-first arm 95 . In the nivolumabfirst arm, the ORR after both nivolumab and ipilimumab treatment was 56%, the median overall survival was not reached, and 12-month survival was 76% (compared with 31%, 16.9 months, and 54%, respectively in the ipilimumab-first arm) 95 . These data must be interpreted cautiously relative to those obtained with upfront combination therapy with nivolumab and ipilimumab, given the sample size limit ations and the lack of primary statistical analyses to directly address this question.…”

“…The question has arisen as to whether concurrent use of ipilimumab plus nivolumab offers benefits that are not gained with sequential singleagent anti-PD-1 and anti-CTLA-4 therapy. This question has been addressed indirectly, to some extent, by data from the randomized phase II CheckMate 064 study 95 , wherein the investigators assessed the safety of sequential administration of these agents as a primary end point, but also obtained preliminary data surrounding the efficacy of this approach. In this study, patients were treated with nivolumab induction then a forced switch to ipili mumab followed by nivolumab maintenance therapy, or with ipilimumab induction then a forced switch to nivolumab with subsequent nivolumab maintenance 95 .…”

“…This question has been addressed indirectly, to some extent, by data from the randomized phase II CheckMate 064 study 95 , wherein the investigators assessed the safety of sequential administration of these agents as a primary end point, but also obtained preliminary data surrounding the efficacy of this approach. In this study, patients were treated with nivolumab induction then a forced switch to ipili mumab followed by nivolumab maintenance therapy, or with ipilimumab induction then a forced switch to nivolumab with subsequent nivolumab maintenance 95 . Although toxicity was statistically similar between the two arms throughout the entire treatment period, and broadly consistent with that observed in CheckMate 067 and CheckMate 069, efficacy outcomes were superior in the nivolumab-first arm relative to the ipilimumab-first arm 95 .…”

“…In this study, patients were treated with nivolumab induction then a forced switch to ipili mumab followed by nivolumab maintenance therapy, or with ipilimumab induction then a forced switch to nivolumab with subsequent nivolumab maintenance 95 . Although toxicity was statistically similar between the two arms throughout the entire treatment period, and broadly consistent with that observed in CheckMate 067 and CheckMate 069, efficacy outcomes were superior in the nivolumab-first arm relative to the ipilimumab-first arm 95 . In the nivolumabfirst arm, the ORR after both nivolumab and ipilimumab treatment was 56%, the median overall survival was not reached, and 12-month survival was 76% (compared with 31%, 16.9 months, and 54%, respectively in the ipilimumab-first arm) 95 .…”

Highlights of the season 2016–2017 by the Spanish Melanoma Group (GEM)

“…Checkmate 064 was a trial designed to evaluate the optimal sequence between ipilimumab and nivolumab. Patients were randomly assigned to receive nivolumab 3 mg/kg every 2 weeks for six doses and then a planned switch to ipilimumab 3 mg/ kg every 3 weeks for four doses or the reverse sequence, both treatment arms continued after this induction with a maintenance phase of nivolumab (30). The primary objective was toxicity assessment and secondary endpoints were response and disease progression.…”