Final KEYNOTE-006 OS analysis confirms efficacy of pembrolizumab in advanced melanoma
Individuals with advanced melanoma treated with pembrolizumab had better overall survival (OS) compared with those treated with ipilimumab regardless of pembrolizumab dosing schedule, results of the final survival analysis of the KEYNOTE-006* trial showed.
“Pembrolizumab provides a favourable benefit-risk profile in comparison with ipilimumab, supporting pembrolizumab as a standard of care for advanced melanoma,” said the researchers.
Median OS was 16.0 months in patients on ipilimumab compared with those on pembrolizumab Q2W and Q3W in whom median OS was not reached (hazard ratio [HR], 0.68, 95 percent confidence interval [CI], 0.53–0.87; p=0.0009 for pembrolizumab Q2W vs ipilimumab and HR, 0.68, 95 percent CI, 0.53–0.86; p=0.0008 for pembrolizumab Q3W vs ipilimumab). [Lancet 2017;doi:10.1016/S0140-6736(17)31601-X]
OS at 24 months was comparable in the pembrolizumab groups (55 percent each) vs 43 percent in the ipilimumab group.
Patients on pembrolizumab also had better progression-free survival (PFS) compared with those on ipilimumab (median PFS, 5.6, 4.1, and 2.8 months for patients on pembrolizumab Q2W, Q3W, and ipilimumab, respectively; HR, 0.61, 95 percent CI, 0.50–0.75; p<0.0001), with no difference between pembrolizumab dosing schedules (HR, 0.95; p=0.62).
After treatment discontinuation, more patients on ipilimumab initiated new oncologic therapy (52 percent) compared with those on pembrolizumab Q2W (40 percent) and Q3W (39 percent).
In this multinational (16 countries), open-label, phase III trial, 834 adults (median age 62 years, 60 percent male) with ECOG status 0 or 1, unresectable stage III or IV melanoma previously treated with ≤1 systemic therapy were randomized to receive intravenous doses (10 mg/kg) of pembrolizumab Q2W (n=279, median time on therapy 28.1 weeks) or Q3W (n=277, median time on therapy 24.0 weeks) for 2 years or ipilimumab Q3W (four doses, each 3 mg/kg, n=278, median time on therapy 9.0 weeks). There were 383 deaths after a median follow-up of 22.9 months.
Patients with ocular melanoma, active brain metastasis or autoimmune disease requiring systemic steroid therapy, and those previously treated with anti-CTLA-4, PD-1, or PD-L1 agents were excluded.
Of the 811 patients who received ≥1 dose of treatment, treatment-related adverse events (AEs) of any grade occurred in 82, 77, and 74 percent of patients on pembrolizumab Q2W, Q3W, and ipilimumab, respectively, with fatigue, pruritus, diarrhoea, and rash being the most commonly reported AEs, while thyroid disorders and colitis were the most frequent immune-mediated AEs.
Incidence of grade 3–5 treatment-related AEs was comparable between groups (17, 17, and 20 percent of patients on pembrolizumab Q2W, Q3W, and ipilimumab, respectively), and resulted in treatment discontinuation in 7, 11, and 9 percent of patients in these respective groups.
“The tolerability profile of pembrolizumab makes it a promising candidate for combination therapy, which has the potential to further improve outcomes for patients with advanced melanoma,” said the researchers.
“Although first-line therapy with anti-PD-1 antibodies has shown superiority to ipilimumab, and combination therapy with anti-PD-1 and anti-CTLA-4 antibodies appears to improve antitumour efficacy, optimal sequencing of these agents has not been established,” they said.
“The main task for the future will be to better understand the mechanisms that underlie checkpoint inhibition with different antibodies against other targets, and to predict which patients will respond best to each regimen,” said Dr Kilian Wistuba-Hamprecht and Professor Graham Pawelec from the University Medical Centre Tuebingen in Tuebingen, Germany, in a commentary. [Lancet 2017;doi:10.1016/S0140-6736(17)31816-0]