A long-term follow-up analysis of the phase III KEYNOTE-006 clinical trial, published in Annals of Oncology on September 15, 2024, provides important insights into the efficacy of pembrolizumab versus ipilimumab for advanced melanoma over a 10-year period. This multicenter, open-label, randomized study was conducted at 87 sites across 16 countries and funded by Merck Sharp & Dohme LLC.
The primary purpose of this analysis was to evaluate the long-term survival outcomes of patients with unresectable stage III or IV melanoma treated with either pembrolizumab or ipilimumab. The study included 834 patients who were initially randomized in a 1:1:1 ratio to receive pembrolizumab 10 mg/kg every 2 weeks, pembrolizumab 10 mg/kg every 3 weeks (both for up to 2 years), or ipilimumab 3 mg/kg every 3 weeks for four cycles.
Eligible patients were 18 years or older with unresectable stage III or IV melanoma not amenable to local therapy. They had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per RECIST v1.1 criteria, and known BRAF mutation status. Patients could have received up to one prior systemic therapy, but those who had received prior anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 agents were excluded. Additionally, patients with uveal melanoma, ocular melanoma, or known active central nervous system metastases were not eligible, although those with previously treated stable brain metastases could participate.
The study population had a median age of 62 years, with 59.6% being male. Notably, 32.4% of patients had elevated lactate dehydrogenase (LDH) levels, 36.2% had BRAF-mutant melanoma, 22.3% had a baseline tumor size ≥110 cm, and 9.6% had brain metastases. The majority (65.8%) received study treatment as first-line therapy.
After the completion of KEYNOTE-006, eligible patients could transition to the KEYNOTE-587 extension study for long-term follow-up. Of the 834 original patients, 211 (25.3%) transitioned to KEYNOTE-587, with a median follow-up duration of 123.7 months from randomization to the data cut-off date of May 1, 2024.
The results of this extended follow-up are striking. The median overall survival (OS) was 32.7 months for pembrolizumab compared to 15.9 months for ipilimumab, with a hazard ratio of 0.71 (95% CI: 0.60-0.85). The 10-year OS rates were 34.0% for pembrolizumab and 23.6% for ipilimumab. Progression-free survival (PFS) also favored pembrolizumab, with a median of 9.4 months versus 3.8 months for ipilimumab (HR: 0.64; 95% CI: 0.54-0.75). The 10-year PFS rates were 22.0% and 12.8% for pembrolizumab and ipilimumab, respectively.
Subgroup analyses demonstrated consistent benefits of pembrolizumab across various patient characteristics, including BRAF mutation status, LDH levels, tumor size, and presence of brain metastases. Notably, patients who completed ≥94 weeks of pembrolizumab treatment showed particularly favorable outcomes, with an 8-year OS rate of 80.8% from week 94.
The study also evaluated melanoma-specific survival (MSS), finding a median MSS of 51.9 months for pembrolizumab versus 17.2 months for ipilimumab (HR: 0.66; 95% CI: 0.55-0.81). This analysis provides valuable insight into the long-term disease control achieved with pembrolizumab.
An interesting aspect of the study was the evaluation of second-course pembrolizumab in patients who had achieved stable disease or better during initial treatment and later experienced disease progression. Among 16 patients who received second-course pembrolizumab, the median PFS from the start of the second course was 51.8 months, with a 6-year PFS rate of 49.2%.
While these results are impressive, it's important to note the limitations of the study. Not all patients eligible for transition to KEYNOTE-587 consented to further follow-up, which could introduce some bias. However, the baseline characteristics of those who transitioned were similar to the overall KEYNOTE-006 population, suggesting limited impact on the results.
The authors conclude that these 10-year follow-up data confirm the long-term survival benefits of pembrolizumab in advanced melanoma, supporting its role as a standard of care in this setting. They highlight that pembrolizumab can transform melanoma from an acute fatal disease to a long-term chronic condition for a substantial proportion of patients.
The potential clinical impact of these findings is significant. The durable responses and long-term survival rates observed with pembrolizumab provide valuable information for clinicians when discussing treatment options and prognosis with patients. The data on second-course pembrolizumab also suggest that re-treatment can be an effective strategy for some patients who experience disease progression after initial response.
However, the authors note that despite these improvements, approximately 60% of patients with advanced melanoma still died within 5 years of pembrolizumab treatment. This underscores the ongoing need for research to address primary and acquired resistance to immunotherapy and to optimize combination strategies.
In conclusion, this long-term follow-up study provides robust evidence supporting the use of pembrolizumab in advanced melanoma, demonstrating durable responses and significant survival benefits compared to ipilimumab. These results will likely reinforce current treatment guidelines and may inform future clinical trial designs in the evolving landscape of melanoma immunotherapy.
References
Long GV, Carlino MS, McNeil C, et al. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study. Ann Oncol. 2024;35(12):1191-1199. doi:10.1016/j.annonc.2024.08.2330
