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, 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

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.

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

Conflict of interest statement

C.L.(Celeste Lebbé) research grant and personal fees from BMS (advisory board), personal fees from MSD and Merck Serono (advisory boards and symposia), Novartis and Amgen (advisory boards), and participation in advisory boards and symposia for Pierre Fabre. C.D.: personal fees from Amgen, BMS, MSD, Novartis and Roche (advisory boards). T.L.: personal fees from Novartis, Pierre Fabre and MSD, and research funding from Roche. W.K.: No conflicts of interest. J.K.: No conflicts of interest. L.T.: Investigator funds provided to institution. B.G.: No conflicts of interest. F.d.B. personal fees from Pharm Research Associated, Daiichi Sankyo, Ignyta, Novartis, Amgen, Pfizer, Octimet Oncology, Incyte Biosciences, Teofarma, Pierre Fabre, Roche, Nerviano Medical Sciences and Sanofi. C.G. personal fees from Amgen, BMS, LEO, MSD, Novartis and Roche (advisory boards), and research funding from BMS, Novartis and Roche. J.-J.G. personal fees from BMS, MSD, Roche, Novartis, Amgen, Pierre Fabre, Merck Serono, Pfizer and Merck C.L. (Carmen Loquai): personal fees from BMS, Merck, Sanofi, Amgen, Novartis, Roche, Pierre Fabre, Sun Pharma, Biontech, Almiral Hermal and Kiowa Kirin. V.F.: No conflicts of interest. C.R.: Personal fees from Amgen, BMS, Merck, Novartis, Roche, Pierre Fabre, Biothera and MSD (advisory boards). PV No conflicts of interest. C.R.: No conflicts of interest. RI: No conflicts of interest. E.E.: Personal fees from Merck, Novartis, Pierre Fabre and BMS. A.S.: personal fees from Merck KGaA (employee). G.M.: personal fees from Merck KGaA (employee) B.D.: personal fees from BMS, GSK, Novartis and Roche (advisory boards).

Figures

Figure 1
Figure 1
Kaplan-Meier plots of PFS for pimasertib versus DTIC based on endpoints: (a) read by investigator assessment (primary endpoint); (b) independent assessment of the data (sensitivity analysis); (c) forest plot of PFS for pimasertib versus DTIC based on investigator assessment (ITT analysis set). Abbreviations: CI, confidence interval; DTIC, dacarbazine; ECOG PS, European Cooperative Oncology Group performance status; EU, European Union; HR, hazard ratio; ITT, intent-to-treat; LDH, lactate dehydrogenase; NE, not evaluable; PD, progressive disease; PFS, progression-free survival; ULN, upper limit of normal.

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