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

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) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8-25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7-not reached), whereas over a median follow-up of 14·7 months (IQR 5·6-23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2-26·5; HR 0·48 [95% CI 0·29-0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64-85 vs 54%; 42-65).

Interpretation: Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events.

Funding: Bristol-Myers Squibb.

Figure 1. Trial profile

Figure 2. Treatment-related grade 3-5 adverse events by study period No treatment-related deaths were reported during any study period

*95% CI 37·6-62·4%. †95% CI 31·1–55·3%. ‡Adverse events were counted only once for both induction periods. Error bars are 95% CIs.

Figure 3. Tumour burden change from baseline (A) at week 13 and (B) at week 25, and (C) best tumour burden change during the entire study period

*Patients with target lesion at baseline and at least one tumour assessment (A) at week 13 or (B) at week 25 or (C) on treatment. †Negative/positive value means maximum tumour reduction/minimum tumour increase. Reduction is based on evaluable target lesion measurements up to the start of subsequent therapy. Horizontal dotted reference line indicates the 30% reduction consistent with a Response Evaluation Criteria in Solid Tumors version 1.1 response. ‡Responders (A) at week 13 or (B) at week 25 or (C) during the entire study period. Square symbol represents percentage change truncated to 100%.

Figure 4. Overall survival

HR=hazard ratio. NR=not reached. *Median follow-up in the nivolumab followed by ipilimumab group was 19·8 months (IQR 12·8–257). †Median follow-up in the ipilimumab followed by nivolumab group was 147 months (56–23·9).

Figure 5. Subgroup survival analysis

NR=not reached. ECOG=Eastern Cooperative Oncology Group. PD-L1=programmed death-ligand 1. LDH=lactate dehydrogenase. ULN=upper limit of normal.