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.
Highlights
Dacarbazine (DTIC) was the standard of care (SOC) for metastatic melanoma [1] until agents, such as ipilimumab, nivolumab, and pembrolizumab [2,3,4,5], as well as the oncolytic virus therapy talimogene laherparepvec [6], were approved
This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma
This study demonstrated a significant improvement in progression-free survival (PFS) with pimasertib at the RP2D, compared with DTIC, in patients with NRAS-mutated cutaneous melanoma, whether assessed by investigators or independently
Summary
Dacarbazine (DTIC) was the standard of care (SOC) for metastatic melanoma [1] until agents, such as ipilimumab, nivolumab, and pembrolizumab [2,3,4,5], as well as the oncolytic virus therapy talimogene laherparepvec [6], were approved. BRAF and NRAS mutations occur in approximately 40% and. For BRAF-mutated metastatic melanoma, targeted therapies—such as the BRAF inhibitors dabrafenib, vemurafenib, and encorafenib—are available, which in combination with MEK inhibitors—such as trametinib, cobimetinib, and binimetinib—can help overcome acquired resistance and improve survival and response outcomes [9,10,11,12]. For the more aggressive NRAS-mutated melanomas [13,14], there are no targeted therapies available; a significant unmet need remains for new treatment options. At the recommended phase II dose (RP2D) of 60 mg twice-daily (bid) it has an acceptable safety profile in patients with solid tumors and potential efficacy in patients with BRAF- and/or NRAS-mutated melanoma tumors [15]
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