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Pembrolizumab Triplet Shows Activity in BRAF-Mutant Melanoma


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AS FIRST-LINE treatment of advanced BRAF-mutant melanoma, pembrolizumab (Keytruda) added to dabrafenib (Tafinlar) and trametinib (Mekinist) produced a nonsignificant improvement in progression-free survival. It also increased the rate of grade 3 to 5 treatment-related adverse events in the phase II KEYNOTE-022 trial.1

Paolo A. Ascierto, MD

Paolo A. Ascierto, MD

“Pembrolizumab and dabrafenib plus trametinib showed promising efficacy and manageable toxicity,” said Paolo A. Ascierto, MD, who presented the findings at the European Society for Medical Oncology (ESMO) 2018 Congress. Dr. Ascierto is Director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, at the National Tumor Institute Fondazione G. Pascale in Naples.

Dr. Ascierto presented Part 3 (phase II) of this randomized study of first-line treatment of BRAF-mutant advanced melanoma with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, with or without the addition of pembrolizumab. In the phase I part of the study, promising antitumor activity was observed.

KEYNOTE-022 Outcomes

THE KEYNOTE-022 trial randomly assigned 120 patients with treatment-naive unresectable stage III or IV melanoma harboring a BRAF V600E/K mutation to receive dabrafenib/trametinib plus either pembrolizumab or placebo. Patients received dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily with pembrolizumab at 2 mg/kg every 3 weeks or placebo. The primary endpoint was progression-free survival. With the addition of pembrolizumab, the following outcomes were seen:

  • Numerically higher progression-free survival (not statistically significant as per study design)
  • Numerically longer duration of response
  • Higher rate of grade 3 or 4 treatment-related adverse events and one treatment-related death
  • More discontinuations of at least one study drug due to treatment-related adverse events.

The objective response rate was 63% with the triplet compared with 72% with dabrafenib/trametinib alone, with complete response rates of 18% and 13%, respectively. After a median follow-up of 9.6 months, the progression-free survival endpoint did not meet the prespecified significance parameter requiring a hazard ratio (HR) of 0.62 or less, although a trend favoring pembrolizumab was seen. The median progression-free survival for the pembrolizumab combination was 16.0 months compared with 10.3 months with dabrafenib plus trametinib, resulting in a hazard ratio of 0.66 (P = .043). The 12-month progression-free survival was 59% and 45%, respectively. The median duration of response was longer with the pembrolizumab combination—18.7 months vs 12.5 months—and responses lasting at least 18 months occurred in 60% compared with 28% of patients treated with the standard of care.

“Pembrolizumab and dabrafenib plus trametinib showed promising efficacy and manageable toxicity.”
— Paolo A. Ascierto, MD

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The median overall survival was not reached in the pembrolizumab arm and was 23.4 months in the placebo arm. At 12 months, 79% and 73% of patients, respectively, were alive. After discontinuing study treatment, 15% of the pembrolizumab arm received immunotherapy, compared with 48% of the placebo arm.

Although the rates of any treatment-related adverse events were similar, grades 3 to 5 adverse events occurred in 58% of the pembrolizumab arm compared with 27% of the dabrafenib and trametinib arm, leading to drug discontinuations in 40% and 20%, respectively.

DISCLOSURE: The KEYNOTE-022 trial was funded by Merck. Dr. Ascierto has served as an advisor to Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Amgen, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, MedImmune, Syndax, AstraZeneca, Sun Pharma, Sanofi, Idera, and Ultimovacs; has received research funding from Bristol-Myers Squibb, Roche-Genentech, and Array; and has received travel support from MSD.

REFERENCE

1. Ascierto PA, et al: KEYNOTE-022 Part 3: Phase 2 randomized study of 1L dabrafenib and trametinib plus pembrolizumab or placebo for BRAF-mutant advanced melanoma. 2018 ESMO Congress. Abstract 1244O. Presented October 22, 2018.


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