With 10 years of follow-up, pembrolizumab continued to show improved overall survival versus ipilimumab in the KEYNOTE-006 study. These results confirm that pembrolizumab provides long-term benefit for advanced melanoma, supporting it as a standard of care in this setting.
The phase III KEYNOTE-006 study was designed to evaluate the efficacy and safety of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma. Results from the primary analysis showed that pembrolizumab significantly improved overall survival (OS) and progression-free survival (PFS) compared with ipilimumab in patients with ipilimumab-naive disease. Given the clinical interest in long-term outcomes with immune checkpoint inhibitors, the phase III KEYNOTE-587 extension study was initiated to collect long-term data on the efficacy and safety of pembrolizumab in patients with solid tumours. At ESMO 2024, Prof. Caroline Robert presented an analysis of the efficacy of pembrolizumab and ipilimumab after 10 years of follow-up in ipilimumab-naive advanced melanoma from the KEYNOTE-006 and KEYNOTE-587 studies, including those patients who received a second course of pembrolizumab.
KEYNOTE-006 was a randomised, open-label, phase III study. Adult patients with unresectable stage III or IV melanoma for whom local therapy was not possible were eligible for participation if they had an ECOG performance status of 0 or 1 and known BRAF mutation status. Patients could not be previously treated with ipilimumab and could not have received more than one systemic therapy.
Participants were randomised 1:1:1 between treatment with: (a) pembrolizumab (10 mg/kg IV every 2 weeks); (b) pembrolizumab (10 mg/kg IV every 3 weeks); or (c) ipilimumab (3 mg/kg IV every 3 weeks in 4 cycles). Treatment with pembrolizumab lasted up to 2 years. After KEYNOTE-006 ended,
patients could transition to the KEYNOTE-587 extension study. Eligible patients could receive a second course of pembrolizumab for maximum one year in KEYNOTE-006 or KEYNOTE-587. The primary endpoint of KEYNOTE-587 was OS, with exploratory endpoints being modified PFS (mPFS) and melanoma-specific survival (MSS). Data from patients in the 2 pembrolizumab groups were analysed together.
Of the 834 patients randomly assigned in KEYNOTE-006, 39.9% were eligible for KEYNOTE-587, of which 25.3% transitioned to KEYNOTE-587 and 14.6% did not. The median time from randomisation in KEYNOTE-006 to the data collection cut-off date in KEYNOTE-587 was 123.7 months. Median OS was 32.7 months in the pembrolizumab group and 15.9 months in the ipilimumab group (HR[95% CI]: 0.71[0.60-0.85]), with a 10-year OS of 34.0% and 23.6% respectively. This OS benefit was consistent across subgroups, including patients with unfavourable prognostic features, such as elevated LDH concentration (HR[95%CI]: 0.60[0.44-0.80]), tumour size ≥10 cm in diameter (HR [95%CI]: 0.57[0.39-0.83]) and brain metastases (HR[95%CI]: 0.56[0.32-0.98]). Among patients who completed ≥94 weeks of pembrolizumab, median OS was not reached (NR; 95%CI NR-NR), with an 8-year OS rate of 80.8%.
The median mPFS was 9.4 months in the pembrolizumab group versus 3.8 months in the ipilimumab group (HR[95%CI]: 0.64[0.54-0.75]), with a 10-year mPFS of 22.0% and 12.8% respectively. In the group of patients who received a second course of pembrolizumab, the median mPFS from start of second course was 51.8 months and the 6-year mPFS was 49.2%. PFS was particularly favourable in patients who received at least 94 weeks of pembrolizumab (8-years mPFS of 64.8%). Finally, the median MSS was statistically significantly longer in the pembrolizumab group compared to the ipilimumab group (median: 51.9 vs. 17.2 months; HR[95%CI]: 0.66[0.55-0.81]), with a 10-year MSS of 45.2% and 31.3%, respectively.
With 10 years of follow-up of patients enrolled in KEYNOTE-587, pembrolizumab continued to show improved survival versus ipilimumab. OS and PFS were particularly favourable in patients who received at least 94 weeks of pembrolizumab. Furthermore, additional antitumour activity was observed in patients who received second-course pembrolizumab with no new safety signals. These results confirm that pembrolizumab provides long-term benefit in patients with advanced melanoma, supporting it as a standard of care in this setting.
Reference
Robert C, et al. Pembrolizumab vs ipilimumab in advanced melanoma: 10-year follow-up of the phase 3 KEYNOTE-006 study. Presented at ESMO 2024; Abstract LBA44.
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