Related Experiment Video
Updated: Dec 16, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized,
Celeste Lebbé1, Caroline Dutriaux2, Thierry Lesimple3
1AP-HP Dermatology CIC Department, Saint Louis Hospital, and INSERM U976, Université de Paris, 75010 Paris, France.
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.
Insights
Pimasertib significantly improved progression-free survival in patients with NRAS-mutated melanoma compared to dacarbazine. While effective, pimasertib had more frequent serious side effects, primarily elevated creatine phosphokinase.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- NRAS-mutated melanoma represents a subset of melanoma with limited targeted treatment options.
- Dacarbazine (DTIC) is a conventional chemotherapy agent used for melanoma treatment.
- MEK1/MEK2 inhibitors offer a targeted approach for specific melanoma mutations.
Purpose of the Study:
- To compare the efficacy and safety of pimasertib, a MEK1/MEK2 inhibitor, against dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma.
- To evaluate progression-free survival (PFS), overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety profiles of both treatment arms.
Main Methods:
- A Phase II, multicenter, open-label trial randomized 194 patients with unresectable, stage IIIc/IV NRAS-mutated cutaneous melanoma.
- Patients received either pimasertib (oral twice-daily) or DTIC (intravenous) on a 21-day cycle.
- Progression-free survival (PFS) was the primary endpoint, with secondary endpoints including OS, ORR, QoL, and safety.
Main Results:
- Pimasertib significantly improved PFS compared to DTIC (median 13 vs. 7 weeks; HR 0.59, p=0.0022).
- Objective response rate (ORR) was also higher with pimasertib (p=0.0453).
- Overall survival (OS) was similar between groups, and serious adverse events were more frequent with pimasertib (57%) than DTIC (20%).
Conclusions:
- Pimasertib demonstrates significant anti-tumor activity in NRAS-mutated cutaneous melanoma, improving PFS and ORR.
- The safety profile of pimasertib is consistent with known MEK inhibitor toxicities, with higher rates of serious adverse events and specific toxicities like elevated CPK.
- Pimasertib represents a potential therapeutic option for this patient population, warranting further investigation.
