Melanomas account for less than 5% of all skin cancers, but they claim the most lives. How to optimize the therapy? The CheckMate-069 trial, published in the New England Journal of Medicine in late April 2015, is the first randomized trial of the first-line combination of nivolumab and ipilimumab versus ipilimumab monotherapy in patients with advanced malignant melanoma. The results are promising. However, special attention must be paid to patient selection.
Already in the phase Ib dose-finding study CheckMate-004, combined inhibition of T-cell checkpoint signaling pathways by nivolumab and ipilimumab had shown good response rates in advanced melanoma (including complete response). The CTLA-4 and PD-1 checkpoints are used by cancer cells to override the cancer-specific immune response. By inhibiting these, nivolumab and ipilimumab activate the immune system, thus increasing T-cell activity.
In the follow-up study, CheckMate-069 (phase II), 142 untreated patients with stage III or IV metastatic melanoma were now randomized 2:1 to a combination (n=95) and a monotherapy group (n=47). Either patients received 3 mg/kg ipilimumab plus 1 mg/kg nivolumab for four cycles (once every three weeks), followed by nivolumab 3 mg/kg every two weeks until the onset of progression or until unacceptable toxicities occurred. Patients in the second group received the same dosing regimen with placebo instead of nivolumab in each case. The primary endpoint was objective response in patients with BRAF V600 wild-type tumors.
Response from 61
44 of 72 patients with BRAF wild-type responded to treatment in the combination group, for an objective response rate of 61%. In the monotherapy group, only 11% responded (4 of 37 patients). The difference reached statistical significance. 22% showed a complete response under dual therapy – under monotherapy the rate was 0%. The hazard ratio for progression or death was 0.4 (95% CI 0.23-0.68; p<0.001). Thus, the combination reduced the risk of mortality/progression by 60%. Similar response and survival results were also observed in the 33 patients with positive BRAF mutation status.
Toxicity also increased
The increased effectiveness is impressive. It is at a level not previously achieved with immuno-oncology agents. However, the higher sustained response rates and the significant decrease in tumor burden were only bought with an increase in side effects: While under combination 54% of patients suffered a grade 3-4 side effect (e.g. colitis, diarrhea, elevation of alanine aminotransferase), this was only 24% under ipilimumab monotherapy. Events with potential immunologic causes were consistent with observations from phase 1, and most adverse events resolved with immunomodulatory medication. Overall, 47% of those treated with the combination discontinued therapy due to adverse events (vs. 17% with monotherapy). Three treatment-associated deaths occurred in the combination group.
Given the increased toxicity, patient selection for combination therapy will be quite critical. Further investigations of the safety profile as well as close monitoring of the combined treated patients are indicated in any case.
Source: Postow MA, et al: Nivolumab and ipilimumab versus ipilimumab in Untreated Melanoma. N Engl J Med 2015 Apr 20 [Epub ahead of print].
InFo ONCOLOGY & HEMATOLOGY 2015; 3(6): 2-4.
