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/m(2); 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, 95CI) 0.42-0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95.00-4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95.61-1.30); 64AEs) 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
JournalCancers
Volume12
Issue number7
DOIs
Publication statusPublished - Jun 1 2020

Keywords

  • dacarbazine
  • quality of life
  • adverse events
  • progression-free survival
  • malignant melanoma
  • N-(2
  • 3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
  • pimasertib

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