Long-term data from the phase 3 KEYNOTE-006 study demonstrate that pembrolizumab (Keytruda) continues to provide a significant survival advantage compared to ipilimumab (Yervoy) in patients with unresectable stage III or IV melanoma. The 10-year follow-up results, presented at the 2024 ESMO Congress, reinforce pembrolizumab as a standard-of-care treatment for this patient population.
The KEYNOTE-006 trial, designed to compare the efficacy and safety of these immunotherapy agents, has now reached a median follow-up of 123.7 months. Patients who participated were also eligible to transition to the KEYNOTE-587 extension study to continue long-term efficacy monitoring.
Overall Survival and Progression-Free Survival
The study revealed a median overall survival (OS) of 32.7 months (95% CI, 24.5-41.6) for patients treated with pembrolizumab (n = 159) compared to 15.9 months (95% CI, 13.3-22.0) for those treated with ipilimumab (n = 52), with a hazard ratio of 0.71 (95% CI, 0.60-0.85). The 8- and 10-year OS rates in the pembrolizumab arm were 36.9% and 34.0%, respectively, while the ipilimumab arm showed rates of 24.8% and 23.6%.
Modified median progression-free survival (PFS) was 9.4 months (95% CI, 6.7-11.6) with pembrolizumab versus 3.8 months (95% CI, 2.9-4.3) with ipilimumab (HR, 0.64; 95% CI, 0.54-0.75). The PFS rates at 8 and 10 years in the pembrolizumab arm were 23.4% and 22.0%, respectively, compared to 12.8% at both time points in the ipilimumab arm.
Melanoma-Specific Survival
Pembrolizumab also demonstrated a superior median melanoma-specific survival (MSS) of 51.9 months (95% CI, 30.0-114.7) compared to 17.2 months (95% CI, 13.9-25.9) with ipilimumab (HR, 0.66; 95% CI, 0.55-0.81). The 8- and 10-year MSS rates in the pembrolizumab arm were 46.5% and 45.2%, respectively, versus 32.1% and 31.3% in the ipilimumab arm.
Insights from Lead Investigator
According to Dr. Caroline Robert of Gustave Roussy and Paris-Saclay University, "With this 10-year follow-up, we have an OS rate of 34% but a MSS rate of 45.2%. We have a very good outcome for patients who responded or who had the benefit to the first course, and again, it shows that response is actually the best marker for long-term outcome."
Study Design and Patient Population
KEYNOTE-006 enrolled patients with unresectable stage III or IV melanoma who had not received prior anti-CTLA-4, PD-1, or PD-L1 therapy. Participants were randomized to receive pembrolizumab at 10 mg/kg every 2 weeks, pembrolizumab at 10 mg/kg every 3 weeks, or ipilimumab at 3 mg/kg every 3 weeks for 4 cycles.
Second Course of Pembrolizumab
Patients who experienced stable disease or better during the first course of pembrolizumab were eligible for a second course at 200 mg every 3 weeks for up to 1 year if they experienced progressive disease after discontinuing therapy. Among those who received a second course (n = 16), 5 achieved a complete response, 5 experienced a partial response, and 4 had stable disease. The median modified PFS from the start of the second course was 51.8 months (95% CI, 11.0-NR).
Subgroup Analysis
Pembrolizumab consistently showed superiority over ipilimumab across various subgroups, including those with elevated lactate dehydrogenase levels (HR, 0.60; 95% CI, 0.44-0.80), large tumors (HR, 0.64; 95% CI, 0.45-0.91), and brain metastases (HR, 0.56; 95% CI, 0.32-0.98).
Conclusion
The study authors conclude that these long-term results confirm the sustained benefit of pembrolizumab in patients with advanced melanoma, solidifying its role as a standard of care in this setting.
