The debate on the optimal order of the administration of immunotherapy in melanoma may have been resolved by findings from the phase II CheckMate 064 trial (NCT01783938): Twice as many patients with non-resectable melanoma showed a response by week 25 after receiving temporal administration of nivolumab followed by a forced switch to ipilimumab than patients receiving the alternate order of ipilimumab followed by nivolumab.
Additional efficacy and safety findings from the CheckMate 064 study were presented on 27 September during the Proffered Paper: Melanoma and Skin Cancer session at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September 2015.
The confirmed overall response rate (ORR) by modified RECIST v1.1 in patients with unresectable melanoma at week 25 was 41.2% (95% confidence interval [CI] 29.4%, 53.8%) in patients receiving nivolumab followed by ipilimumab induction compared to 20.0% (95% CI 11.4, 31.3) in patients receiving ipilimumab followed by nivolumab.
F. Stephen Hodi, Associate Professor, Medicine, Harvard Medical School, Assistant Professor of Medicine, Dana-Farber Cancer Institute presented findings from this phase II, randomised study that was conducted to determine which approach could provide optimal efficacy while minimising the risk of toxicity.
Patients were eligible for enrolment if they had unresectable stage III or IV melanoma and were either treatment-naive or had received one prior systemic therapy, and had an ECOG performance status of 0 or 1. In all, 140 patients from 9 US centres were enrolled, regardless of their BRAF mutational status, and randomised 1:1 to receive sequential induction treatment with nivolumab at 3 mg/kg i.v. every 2 weeks for 6 cycles followed by ipilimumab at 3 mg/kg i.v. every 4 weeks for 4 cycles (cohort A; n=68; nivo-->ipi) or to receive the reverse approach ipilimumab followed by nivolumab at the same dose and interval (cohort B; n=70; ipi-->nivo). Regardless of the week 13 response, patients were allowed to continue if clinically benefitting, i.e. during the conduct of the trial, week 13 scans showed progressive disease, stable disease, and partial response.
In those patients who completed both induction periods in either cohort, patients were eligible to receive nivolumab at 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity occurred in a continuation period.
Higher toxicity reported in cohort A during the induction periods
The trial’s primary objective was the evaluation of treatment-related grade 3 to 5 adverse events (AEs) occurring during the induction periods. Treatment-related grade 3 to 5 AEs occurred in 50.0% and 42.9% of patients in cohorts A and B, respectively. No study, drug-related deaths occurred in either cohort.
Across all study periods, including the continuation period, drug-related AEs were reported more frequently in cohort A with grade 3-4 AEs seen in 61.8% of patients versus 47.1% in cohort B, respectively. In cohort A, most high grade adverse events occurred after week 13 and before week 25, at a time after the forced switch when both drugs had been administered.
Treatment related AEs led to discontinuation of study treatment in 25 (36.8%) patients treated with nivolumab followed by ipilimumab, and in 22 (31.4%) of patients treated with the reverse sequence.
Additional efficacy evaluations favour cohort A
A lower progression rate of 38.2% (95% CI 26.7%, 50.8%) was achieved by cohort A patients versus 60.0% by cohort B (95% CI 47.6%, 71.5%) at week 25.
Although no confirmed complete responses were observed, at weeks 13 and 25 partial response was achieved by 24 (35.3%) versus 7 (10.0%) and 28 (41.2%) versus 14 (20.0%) patients in cohort A versus cohort B. In cohort A, there was 1 unconfirmed response and 2 unconfirmed responses; in cohort B, there were no unconfirmed responses.
The data from this study presented at the ECC may help inform the choice of initial treatment approaches in advanced melanoma.
Dr Caroline Robert who discussed the study said that the results are surprising as until now it was thought that the scientific data are more encouraging for ipilimumab followed by nivolumab, while clinical/safety data are more encouraging for nivolumab followed by ipilimumab. She suggested that studies of different design may add more understanding about best administration of these drugs.
Based on these findings, the authors concluded that improved efficacy outcomes were demonstrated by induction with the nivolumab followed by ipilimumab versus ipilimumab followed by nivolumab and that the incidence of treatment-related AEs was similar between the cohorts during the induction periods.
Furthermore, the frequency of AEs was consistent with previous reports for nivolumab plus ipilimumab when used concurrently, but did not appear to provide the same efficacy benefit as has been recently reported for the nivolumab plus ipilimumab combination in recent large phase II and III clinical trials
23LBA An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064)
Disclosure: The CheckMate 064 study was sponsored by Bristol-Myers Squibb.