PMID- 32610581
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 7
DP  - 2020 Jun 29
TI  - Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated 
      Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover.
LID - 10.3390/cancers12071727 [doi]
LID - 1727
AB  - 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, 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.
FAU - Lebbe, Celeste
AU  - Lebbe C
AD  - AP-HP Dermatology CIC Department, Saint Louis Hospital, and INSERM U976, 
      Universite de Paris, 75010 Paris, France.
FAU - Dutriaux, Caroline
AU  - Dutriaux C
AD  - Dermatology, Hopital Saint-Andre-CHU, 33000 Bordeaux, France.
FAU - Lesimple, Thierry
AU  - Lesimple T
AD  - Medical Oncology Department, Comprehensive Cancer Center Eugene Marquis, 35000 
      Rennes, France.
FAU - Kruit, Willem
AU  - Kruit W
AD  - Internal Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The 
      Netherlands.
FAU - Kerger, Joseph
AU  - Kerger J
AD  - Medical Oncology, Institut Jules Bordet, 1000 Brussels, Belgium.
FAU - Thomas, Luc
AU  - Thomas L
AD  - Department of Dermatology, Centre Hospitalier Lyon Sud, 69310 Pierre Benite, 
      France.
FAU - Guillot, Bernard
AU  - Guillot B
AD  - Department of Dermatology, Hopital Saint Eloi, 34295 Montpellier, France.
FAU - Braud, Filippo de
AU  - Braud F
AD  - Department of Medical Oncology, Istituto Nazionale dei Tumori, Universita degli 
      Studi di Milano, 20133 Milano, Italy.
FAU - Garbe, Claus
AU  - Garbe C
AD  - Department of Dermatology, University Hospital Tubingen, 72076 Tubingen, Germany.
FAU - Grob, Jean-Jacques
AU  - Grob JJ
AD  - Department of Dermatology and Cutaneous Oncology Service, Hopital de la Timone, 
      13005 Marseille, France.
FAU - Loquai, Carmen
AU  - Loquai C
AD  - Department of Dermatology, University Medical Center Mainz, 55019 Mainz, Germany.
FAU - Ferraresi, Virginia
AU  - Ferraresi V
AD  - Division of Medical Oncology 1, IRCCS "Regina Elena" National Cancer Institute, 
      00144 Roma, Italy.
FAU - Robert, Caroline
AU  - Robert C
AD  - Dermatology Department, Institut Gustave Roussy and Paris Sud University, 94800 
      Villejuif, France.
FAU - Vasey, Paul
AU  - Vasey P
AD  - Icon Cancer Care, The Wesley Hospital, Auchenflower, QLD 4066, Australia.
FAU - Conry, Robert
AU  - Conry R
AD  - Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 
      35233, USA.
FAU - Isaacs, Richard
AU  - Isaacs R
AD  - MidCentral Regional Cancer Treatment Service, Palmerston North Hospital, 
      Palmerston North 4442, New Zealand.
FAU - Espinosa, Enrique
AU  - Espinosa E
AD  - Medical Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain.
FAU - Schueler, Armin
AU  - Schueler A
AUID- ORCID: 0000-0003-3833-5757
AD  - Global Biostatistics Oncology, Merck KGaA, 64293 Darmstadt, Germany.
FAU - Massimini, Giorgio
AU  - Massimini G
AD  - GCDU Oncology, Merck KGaA, 64293 Darmstadt, Germany.
FAU - Dreno, Brigitte
AU  - Dreno B
AD  - Department of Dermato Cancerology, CIC 1413, CRCINA Inserm 1232, CHU Nantes, 
      44093 Nantes, France.
LA  - eng
SI  - ClinicalTrials.gov/NCT01693068
PT  - Journal Article
DEP - 20200629
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7408351
OTO - NOTNLM
OT  - N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
OT  - adverse events
OT  - dacarbazine
OT  - malignant melanoma
OT  - pimasertib
OT  - progression-free survival
OT  - quality of life
COIS- C.L.(Celeste Lebbe) 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).
EDAT- 2020/07/03 06:00
MHDA- 2020/07/03 06:01
PMCR- 2020/06/29
CRDT- 2020/07/03 06:00
PHST- 2020/05/28 00:00 [received]
PHST- 2020/06/20 00:00 [revised]
PHST- 2020/06/22 00:00 [accepted]
PHST- 2020/07/03 06:00 [entrez]
PHST- 2020/07/03 06:00 [pubmed]
PHST- 2020/07/03 06:01 [medline]
PHST- 2020/06/29 00:00 [pmc-release]
AID - cancers12071727 [pii]
AID - cancers-12-01727 [pii]
AID - 10.3390/cancers12071727 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Jun 29;12(7):1727. doi: 10.3390/cancers12071727.