Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover
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||malignant melanoma, dacarbazine, pimasertib, N-(2, 3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide, progression-free survival, quality of life, adverse events|
|Persistent URL||dx.doi.org/10.3390/cancers12071727, hdl.handle.net/1765/130572|
Lebbe, C, Dutriaux, C., Lesimple, T, Kruit, W, Kerger, J., Thomas, L, … Dreno, B. (2020). Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover. Cancers, 12(7). doi:10.3390/cancers12071727