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Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study
Open AccessArticle

Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

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AP-HP Dermatology CIC Department, Saint Louis Hospital, and INSERM U976, Université de Paris, 75010 Paris, France
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Dermatology, Hopital Saint-Andre—CHU, 33000 Bordeaux, France
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Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, 35000 Rennes, France
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Internal Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands
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Medical Oncology, Institut Jules Bordet, 1000 Brussels, Belgium
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Department of Dermatology, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite, France
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Department of Dermatology, Hôpital Saint Eloi, 34295 Montpellier, France
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Department of Medical Oncology, Istituto Nazionale dei Tumori, Università degli Studi di Milano, 20133 Milano, Italy
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Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany
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Department of Dermatology and Cutaneous Oncology Service, Hôpital de la Timone, 13005 Marseille, France
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Department of Dermatology, University Medical Center Mainz, 55019 Mainz, Germany
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Division of Medical Oncology 1, IRCCS “Regina Elena” National Cancer Institute, 00144 Roma, Italy
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Dermatology Department, Institut Gustave Roussy and Paris Sud University, 94800 Villejuif, France
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Icon Cancer Care, The Wesley Hospital, Auchenflower, QLD 4066, Australia
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Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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MidCentral Regional Cancer Treatment Service, Palmerston North Hospital, Palmerston North 4442, New Zealand
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Medical Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain
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Global Biostatistics Oncology, Merck KGaA, 64293 Darmstadt, Germany
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GCDU Oncology, Merck KGaA, 64293 Darmstadt, Germany
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Department of Dermato Cancerology, CIC 1413, CRCINA Inserm 1232, CHU Nantes, 44093 Nantes, France
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(7), 1727; https://doi.org/10.3390/cancers12071727 (registering DOI)
Received: 28 May 2020 / Revised: 20 June 2020 / Accepted: 22 June 2020 / Published: 29 June 2020
(This article belongs to the Special Issue Targeted Therapies for Melanoma)
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. View Full-Text
Keywords: malignant melanoma; dacarbazine; pimasertib; N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; progression-free survival; quality of life; adverse events malignant melanoma; dacarbazine; pimasertib; N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; progression-free survival; quality of life; adverse events
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Lebbé, C.; Dutriaux, C.; Lesimple, T.; Kruit, W.; Kerger, J.; Thomas, L.; Guillot, B.; de Braud, F.; Garbe, C.; Grob, J.-J.; Loquai, C.; Ferraresi, V.; Robert, C.; Vasey, P.; Conry, R.; Isaacs, R.; Espinosa, E.; Schueler, A.; Massimini, G.; Dréno, B. Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover. Cancers 2020, 12, 1727.

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