James Larkin, PhD, FRCP
The PD-1 and CTLA-4 inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was associated with a 12% reduction in the risk of death versus nivolumab monotherapy in patients with treatment-naïve advanced melanoma, according to descriptive analyses from the phase III CheckMate-067 trial presented at the 2017 AACR Annual Meeting.1
The median overall survival (OS) was not reached in the nivolumab/ipilimumab arm or for patients who received nivolumab alone, and was 20 months for those who were treated with ipilimumab. The combination showed a 2-year OS rate of 64%; the 2-year OS rates for nivolumab and ipilimumab alone were 59% and 45%, respectively.
This is the first phase III clinical trial to evaluate OS with the combination of PD-1/CTLA-4 therapies, according to lead study author James Larkin, PhD, FRCP. While the study was not powered to compare between nivolumab-containing arms, descriptive analyses were presented.
“CheckMate-067 was a positive study that met both of its co-primary endpoints,” said Larkin, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust, when reporting the findings. “Descriptively, the combination showed better overall OS, progression-free survival (PFS), and more durable response outcomes than with nivolumab alone with consistent results seen across the clinically relevant subgroups, such as those with low PD-L1 expression, elevated LDH, and those with tumors that were BRAF-mutated.”
In the randomized, double-blind phase III study, 945 patients with unresectable or metastatic previously untreated melanoma were randomized 1:1:1 to nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg bi-weekly (n = 314), nivolumab at 3 mg/kg bi-weekly plus ipilimumab-matched placebo (n = 316), or ipilimumab at 3 mg/kg every 3 weeks for 4 doses plus nivolumab-matched placebo (n = 315).
Patients were also stratified by BRAF
status, American Joint Committee on Cancer M stage, and PD-L1 expression <5% versus ≥5%. The coprimary endpoints were PFS and OS, with secondary endpoints being overall response rate (ORR) by RECIST v1.1 criteria, correlation of PD-L1 expression with efficacy, and safety. The OS analysis was conducted after all patients had 28 months of follow-up.
Additional descriptive OS findings showed that the combination was associated with a 45% reduction in the risk of death versus ipilimumab (HR, 0.55; 98% CI, 0.42-0.72; P
<.0001) and was 12% versus nivolumab (HR, 0.88; 95% CI, 0.69-1.12). There was also a 37% reduction in the risk for disease progression or death in the nivolumab monotherapy arm versus the ipilimumab arm (HR, 0.63; 95% CI, 0.48-0.81; P
Sixty-two percent of patients in the ipilimumab cohort received subsequent systemic therapies with a median time of 8 months until their next treatment, versus 44% and 27 months for those on the nivolumab arm. In the combination arm, 32% of patients went on to receive subsequent treatment, and the median time to next treatment was not reached. Furthermore, 66% of combination-treated patients remain free of treatment at 2 years, Larkin added.
wild-type tumors, the OS benefit was less significant, with the 2-year OS rates 61%, 57%, and 42% for nivolumab/ipilimumab, nivolumab, and ipilimumab, respectively. The median OS was not reached in the combination arm (95% CI, 27.6-NR) and the nivolumab arm (95% CI, 25.8-NR) and was 18.5 months in the ipilimumab arm (95% CI, 14.8-23.0). The hazard ratio for the combination when compared with nivolumab was 0.97 (95% CI, 0.74-1.28).
-mutant tumors, the median OS was not reached in the combination or nivolumab arm and was 24.6 months in the ipilimumab cohort (95% CI, 17.9-31.0), with a descriptive hazard ratio between nivolumab and nivolumab/ipilimumab of 0.71 (95% CI, 0.45-1.13). The 2-year OS rate was 71% with the combination, 62% with nivolumab alone, and 51% with ipilimumab alone.
When stratified for PD-L1 expression with a 5% cutoff, OS was improved with the combination versus nivolumab (HR, 0.84; 95% CI, 0.63-1.12) in patients with PD-L1 <5%, as well as the ORR (56.2% vs 42.3%). The 2-year OS rates were 63%, 55%, and 41% for nivolumab/ipilimumab, nivolumab, and ipilimumab, respectively.
However, in patients with ≥5% PD-L1 expression, the 2-year OS rate was higher in the nivolumab arm (72%) than the combination (68%); it was 54% with ipilimumab. The median OS was not reached in either the combination or nivolumab arm (HR, 1.05; 95% CI, 0.61-1.83) and was 28.9% in the ipilimumab cohort (95% CI, 18.1-NR). The ORR was 73.5% for nivolumab/ipilimumab and 58.8% for nivolumab, regardless of PD-L1 expression.
“In the roughly one-quarter of patients with PD-L1 expression greater than or equal to 5%, both nivolumab and nivolumab plus ipilimumab results in a similar prolongation of survival, although the response rate remains significantly higher with the combination,” explained Larkin.