Pimasertib versus dacarbazine in patients with unresectable NRAS-mutated cutaneous melanoma: Phase II, randomized, controlled trial with crossover

Celeste Lebbé, Caroline Dutriaux, Thierry Lesimple, Willem Kruit, Joseph Kerger, Luc Thomas, Bernard Guillot, Filippo de Braud, Claus Garbe, Jean Jacques Grob, Carmen Loquai, Virginia Ferraresi, Caroline Robert, Paul Vasey, Robert Conry, Richard Isaacs, Enrique Espinosa, Armin Schueler, Giorgio Massimini, Brigitte Dréno

Research output: Contribution to journalArticlepeer-review

Abstract

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.

Original languageEnglish
Article number1727
Pages (from-to)1-11
Number of pages11
JournalCancers
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Adverse events
  • Dacarbazine
  • Malignant melanoma
  • N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
  • Pimasertib
  • Progression-free survival
  • Quality of life

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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