Pembrolizumab extends survival in advanced melanoma

Patients with advanced melanoma achieve long-term survival with the use of pembrolizumab, as shown by the results of the 10-year follow-up of the phase III KEYNOTE-006 study.

“[P]embrolizumab provides long-term survival benefits in patients with ipilimumab-naive unresectable advanced melanoma, especially in patients without disease progression after treatment with pembrolizumab,” the investigators said. “Furthermore, the results show that some patients benefit from retreatment with pembrolizumab.”

A total of 834 patients with unresectable stage III or IV melanoma were randomized to pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks for ≤2 years (n=556) or ipilimumab 3 mg/kg every 3 weeks for four cycles (n=278). Patients could then transition to KEYNOTE-586 from KEYNOTE-006 for long-term follow-up. Those who were eligible could receive second-course pembrolizumab.

Overall survival (OS) was the primary endpoint. Exploratory outcomes included modified progression-free survival (PFS; censored at date last known alive), modified PFS on second-course pembrolizumab, and melanoma-specific survival.

Of the patients in KEYNOTE-006, 333 (39.9 percent) met the eligibility criteria for KEYNOTE-587. Two hundred eleven patients (25.3 percent) transitioned to the follow-up study (pembrolizumab: n=159; ipilimumab: n=52), and 122 (14.6 percent) did not. [Ann Oncol 2024;35:1191-1199]

The median time from randomization in KEYNOTE-006 to data cutoff for KEYNOTE-587 (1 May 2024) was 123.7 months for patients who transitioned to the next phase.

Survival benefits

Median OS was 32.7 months (95 percent confidence interval [CI], 24.5‒41.6) in the pembrolizumab arm and 15.9 months (95 percent CI, 13.3‒22.0) in the ipilimumab arm (hazard ratio [HR], 0.71, 95 percent CI, 0.60‒0.85). The corresponding OS at 10 years was 34.0 percent and 23.6 percent.

The median OS from week 94 was not reached (NR) among patients who completed ≥94 weeks of pembrolizumab, while the OS rate at year 8 was 80.8 percent.

Pembrolizumab-treated patients had a median modified PFS of 9.4 months (95 percent CI, 6.7‒11.6), while those on ipilimumab had 3.8 months (95 percent CI, 2.9‒4.3; hazard ratio [HR], 0.64, 95 percent CI, 0.54‒0.75). The median PFS among those who received second-course pembrolizumab was 51.8 months (95 percent CI, 11.0‒NR), with a 6-year modified PFS of 49.2 percent.

Melanoma-specific survival was also longer with pembrolizumab at a median of 51.9 months (95 percent CI, 30.0‒114.7) compared with 17.2 months (95 percent CI, 13.9‒25.9) with ipilimumab (HR, 0.66, 95 percent CI, 0.55‒0.81).

“The findings support the continued use of pembrolizumab in this setting and further demonstrate that pembrolizumab can transform melanoma from an acute fatal disease to a long-term chronic disease in a substantial proportion of patients,” according to the investigators.

While survival has significantly improved with PD-1 inhibition, nearly three out of five patients with advanced melanoma still succumbed to the disease within 5 years after treatment with pembrolizumab.

“[T]here remains a need to address primary and acquired resistance and to optimize immunotherapy combinations,” the investigators said.

One major limitation of the current study is that not all eligible patients consented to further follow-up.

“Baseline characteristics for patients who transitioned to KEYNOTE-587, however, were similar to those for all patients enrolled in KEYNOTE-006, suggesting limited bias,” the investigators said.