Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

Abstract

Background: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.

Methods: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety.

Results: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.

Conclusions: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

Figure 1. Kaplan–Meier Estimates of Recurrence-free Survival (RFS), Overall Survival, and Distant Metastasis– free Survival (DMFS)

Panel A shows the Kaplan–Meier estimate of recurrence-free survival according to the independent review committee. In the ipilimumab group, local or regional recurrence was reported in 96 patients, distant metastasis or death due to melanoma in 157, and death due to another cause or an unknown cause in 11. In the placebo group, local or regional recurrence was reported in 114 patients, distant metastasis or death due to melanoma in 204, and death due to another cause or an unknown cause in 5. All the statistical comparisons shown here were stratified according to the disease stage as provided at randomization. In the comparison that was stratified according to the disease stage as given on case-report forms, the hazard ratio for recurrence or death was 0.77 (95% CI, 0.65 to 0.90; P = 0.001). In a per-protocol analysis of the comparison that was stratified according to the disease stage as given at randomization, the hazard ratio was 0.77 (95% CI, 0.65 to 0.91; P = 0.002). Panel B shows the Kaplan–Meier estimate of overall survival. Because the number of patients with a follow-up of more than 7 years was too small, the estimated median overall survival was either unreliable or not reached. In the comparison that was stratified according to the disease stage as given on case-report forms, the hazard ratio for death was 0.73 (95.1% CI, 0.60 to 0.90; P = 0.003). In a per-protocol analysis of the comparison stratified according to the disease stage as given at randomization, the hazard ratio was 0.72 (95.1% CI, 0.58 to 0.89; P = 0.002). Panel C shows the Kaplan–Meier estimate of distant metastasis–free survival according to the independent review committee. In the comparison that was stratified according to the disease stage as given on the case-report forms, the hazard ratio for distant metastasis or death was 0.77 (95.8% CI, 0.65 to 0.93; P = 0.004). In a per-protocol analysis of the comparison stratified according to the disease stage as given at randomization, the hazard ratio was 0.76 (95.8% CI, 0.63 to 0.91; P = 0.003).

Figure 2. Forest Plot for Overall Survival, According to Trial Group

Results are expressed as unstratified hazard ratios for the risk of death in the ipilimumab group as compared with the placebo group with 95% confidence intervals for the analysis of the total group and with 99% confidence intervals for all the subgroup analyses. The size of the box is proportional to the total number of deaths reported in each subgroup, the diamond is centered on the overall hazard ratio for death and covers its 95% confidence interval, and the dashed line represents the overall hazard ratio for death. The P value for the univariate analysis that included all patients was provided by the unstratified log-rank test. The P value for the analysis of heterogeneity between the hazard ratios computed within the subgroups of a given variable was provided by the test of heterogeneity (see the Supplementary Appendix). The disease stage, according to the case-report forms, was determined with the use of the American Joint Committee on Cancer 2002 criteria. The number of positive lymph nodes was determined by means of pathological testing. Additional information is provided in Figure S4A in the Supplementary Appendix.