Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

Abstract

Background: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma.

Methods: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here.

Results: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.

Conclusions: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Figure 1. Progression-free Survival

Panel A shows the Kaplan–Meier curves for progression-free survival in the intention-to-treat population. Patients were followed for a minimum of 9 months. Panels B and C show the Kaplan–Meier curves for progression-free survival in patients with PD-L1-positive and PD-L1-negative tumors, respectively. [Please note: the KM curves shown in the graph below are based on verified PD-L1 assay data. The graphs will be updated based on validated PD-L1 data, although it is expected that there will be little difference between the verified and validated graphs.] [Please note: the KM curves shown in the graph below are based on verified PD-L1 assay data. The graphs will be updated based on validated PD-L1 data, although it is expected that there will be little difference between the verified and validated graphs.]

Figure 1. Progression-free Survival

Panel A shows the Kaplan–Meier curves for progression-free survival in the intention-to-treat population. Patients were followed for a minimum of 9 months. Panels B and C show the Kaplan–Meier curves for progression-free survival in patients with PD-L1-positive and PD-L1-negative tumors, respectively. [Please note: the KM curves shown in the graph below are based on verified PD-L1 assay data. The graphs will be updated based on validated PD-L1 data, although it is expected that there will be little difference between the verified and validated graphs.] [Please note: the KM curves shown in the graph below are based on verified PD-L1 assay data. The graphs will be updated based on validated PD-L1 data, although it is expected that there will be little difference between the verified and validated graphs.]

Figure 1. Progression-free Survival

Panel A shows the Kaplan–Meier curves for progression-free survival in the intention-to-treat population. Patients were followed for a minimum of 9 months. Panels B and C show the Kaplan–Meier curves for progression-free survival in patients with PD-L1-positive and PD-L1-negative tumors, respectively. [Please note: the KM curves shown in the graph below are based on verified PD-L1 assay data. The graphs will be updated based on validated PD-L1 data, although it is expected that there will be little difference between the verified and validated graphs.] [Please note: the KM curves shown in the graph below are based on verified PD-L1 assay data. The graphs will be updated based on validated PD-L1 data, although it is expected that there will be little difference between the verified and validated graphs.]

Figure 2. Tumor Burden Change in Target Lesions

The waterfall plots show the maximum change from baseline in the sum of the reference diameters of the target lesion in patients receiving nivolumab (Panel A), nivolumab plus ipilimumab (Panel B), and ipilimumab (Panel C). Data are shown for all the patients who had a response that could be evaluated in the target lesion at baseline and who underwent at least one tumor assessment during treatment. The percentage increase was truncated at 100% (rectangles). Symbols indicate patients who had a response to treatment according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The vertical dashed lines indicate a 30% reduction in the tumor burden in the target lesion, and the horizontal dashed line indicates the inflexion point for the nivolumab plus ipilimumab group.