Long-term follow-up data from the phase 3 KEYNOTE-006 study demonstrates that pembrolizumab (Keytruda) continues to provide sustained survival benefits compared to ipilimumab (Yervoy) in patients with unresectable stage III or IV melanoma. The 10-year data, presented at the 2024 ESMO Congress, reinforce pembrolizumab as a standard of care for advanced melanoma.
The KEYNOTE-006 trial (NCT01866319) was designed to compare the safety and efficacy of pembrolizumab and ipilimumab in patients with advanced melanoma. Patients who participated in KEYNOTE-006 were eligible to transition to the open-label phase 3 KEYNOTE-587 extension study (NCT03486873) to continue long-term efficacy monitoring. The median time from KEYNOTE-006 entry to the KEYNOTE-587 data cutoff was 123.7 months (range, 122.0-127.3).
Overall Survival and Progression-Free Survival
Patients treated with pembrolizumab (n = 159) had a median overall survival (OS) of 32.7 months (95% CI, 24.5-41.6) compared to 15.9 months (95% CI, 13.3-22.0) for those treated with ipilimumab (n = 52; HR, 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 in the ipilimumab arm, the rates were 24.8% and 23.6%.
The median progression-free survival (PFS) with pembrolizumab was 9.4 months (95% CI, 6.7-11.6) compared to 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% for both 8 and 10 years in the ipilimumab arm. The median melanoma-specific survival (MSS) with pembrolizumab was 51.9 months (95% CI, 30.0-114.7) vs 17.2 months (95% CI, 13.9-25.9) with ipilimumab (HR, 0.66; 95% CI, 0.55-0.81).
Insights from Expert
According to Caroline Robert, MD, PhD, 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 at least 1 measurable lesion by RECIST 1.1 criteria and an ECOG performance status of 0 or 1. Patients could have received up to 1 prior systemic treatment, excluding anti–CTLA-4, PD-1, PD-L1, or PD-L1 agents. Participants were randomly assigned 1:1:1 to receive pembrolizumab at 10 mg/kg every 2 weeks, pembrolizumab 10 mg/kg every 3 weeks, or ipilimumab at 3 mg/kg every 3 weeks for 4 cycles.
Outcomes in Specific Subgroups
Pembrolizumab demonstrated superiority over ipilimumab across various subgroups, including those with elevated lactate dehydrogenase levels (HR, 0.60; 95% CI, 0.44-0.80), large tumors (≥10 cm; HR, 0.64; 95% CI, 0.45-0.91), and brain metastases (HR, 0.56; 95% CI, 0.32-0.98).
In patients who completed at least 94 weeks of pembrolizumab treatment (n = 103), the median OS from week 94 was not reached (95% CI, NR-NR), with 6- and 8-year OS rates from week 94 of 91.8% and 80.8%, respectively. The median modified PFS in this group was also not reached (95% CI, NR-NR), with 6- and 8-year modified PFS rates from week 94 of 73.2% and 64.8%, respectively.
Second Course of Pembrolizumab
Of the patients who received a second course of pembrolizumab (n = 16), 5 achieved a complete response (CR), 5 experienced a partial response, and 4 had stable disease (SD). The median modified PFS from the start of the second course was 51.8 months (95% CI, 11.0-NR), with 4- and 6-year modified PFS rates of 56.3% and 49.2%, respectively.
First-Line Treatment Analysis
In the first-line setting, the median OS with pembrolizumab was 38.7 months (95% CI, 27.3-50.9) compared to 17.2 months (95% CI, 13.8-26.2) with ipilimumab (HR, 0.68; 95% CI, 0.55-0.86). The 8-year OS rates were 40.1% and 27.0%, and the 10-year OS rates were 36.9% and 25.0%, respectively. The median modified PFS was 12.0 months (95% CI, 8.3-16.6) with pembrolizumab and 4.1 months (95% CI, 2.9-5.2) with ipilimumab (HR, 0.62; 95% CI, 0.50-0.76).
The study authors conclude that these results confirm the long-term benefit of pembrolizumab in patients with advanced melanoma, supporting its role as a standard of care.
