Trametinib falls short in molecularly selected advanced solid tumours, with a possible signal in RAS Q61 mutations

The final analysis of the trametinib cohort from the MegaMOST platform trial has delivered a largely negative verdict for MEK inhibition as a broad strategy in molecularly selected advanced or metastatic solid tumours. In the multicentre, open-label, biomarker-driven phase II study, trametinib failed to cross its prespecified efficacy boundary, although a small subgroup of patients whose tumours carried RAS p.Q61 mutations showed hints of benefit that the investigators say warrant further study.

MegaMOST was designed to evaluate molecular targeted therapies in patients with advanced or metastatic solid tumours using a Bayesian trial design. Rather than restricting enrolment by tumour type, the trial selected patients by the genomic alterations present in their cancers. In the trametinib cohort, eligibility required activating mutations and/or amplification of KRAS, NRAS, HRAS, MAP2K or PTPN11, biallelic inactivation of NF1, or amplification or translocation of BRAF or RAF1 — a deliberately wide net intended to capture tumours with suspected activation of the MAPK/ERK signalling pathway.

Overactivation of the MAPK/ERK pathway is frequent across many solid tumours, which made it an attractive therapeutic target. The hypothesis tested in MegaMOST was that patients whose tumours showed alterations anywhere along this signalling axis might respond to direct pharmacological MEK blockade.

Between August 2022 and February 2024, 51 patients received trametinib at a dose of 2 mg per day orally, and 50 were evaluable for efficacy. Treatment continued until loss of clinical benefit in the judgement of the investigator, unacceptable toxicity, deterioration due to disease progression, or withdrawal of consent. The median age of participants was 63 years, with a range of 29 to 83, and 26 patients, or 52 percent, were male.

The genomic landscape of the cohort reflected the breadth of the eligibility criteria. The most common alterations were KRAS mutations in 16 patients (32 percent), NRAS mutations in 11 patients (22 percent) and MAP2K mutations in 7 patients (14 percent).

The primary endpoint was the 12-week progression-free rate as assessed by RECIST 1.1, evaluated sequentially against a futility boundary of 20 percent and an efficacy boundary of 40 percent. The estimated 12-week progression-free rate was 30.8 percent, with a 95 percent credible interval of 19.1 to 43.8 percent. That estimate fell short of the efficacy boundary, and the authors conclude that trametinib did not demonstrate efficacy in this molecularly selected population overall.

Secondary endpoints reinforced the modest activity signal. The best response achieved was a partial response in 4 patients (8 percent) and stable disease in 14 patients (28 percent). Median progression-free survival was 2.6 months (95 percent confidence interval 2.5 to 2.8), and median overall survival was 6.4 months (95 percent confidence interval 4.8 to 13.4).

Safety findings were substantial and are an important part of the final analysis. The most frequent treatment-related adverse events were acneiform dermatitis in 24 patients (47.1 percent), fatigue in 16 patients (31.4 percent) and diarrhoea in 15 patients (29.4 percent). A total of 25 patients, or 49 percent, experienced grade 3 or higher related adverse events, including one fatal case involving digestive haemorrhage and pulmonary embolism.

Amid the overall negative result, one subgroup analysis stood out. Patients whose tumours carried RAS p.Q61 mutations showed a 12-week progression-free rate of 57.1 percent, with a 95 percent credible interval of 31.6 to 80.8 percent. The investigators caution that this subgroup is small, and the wide credible interval reflects the limited number of patients involved, but they suggest these patients may have benefited from treatment and deserve further investigation.

The trial is registered as ClinicalTrials.gov NCT04116541 and was first posted in October 2019. As a phase II study, MegaMOST was designed to generate signal or futility decisions rather than definitive evidence of benefit, and the subgroup observation should be read in that light.

Subject of Research: A phase II platform trial of the MEK inhibitor trametinib in patients with advanced solid tumours harbouring MAPK/ERK pathway alterations

Article Title: MEK inhibition in molecularly-selected advanced or metastatic solid tumours: final analysis of trametinib cohort from the platform phase II trial MegaMOST

Article References: Trédan, O., Cousin, S., Dalban, C., Saada-Bouzid, E., Cesne, A. L., Italiano, A., Bertucci, F., Gomez-Roca, C., Eberst, L., Ray-Coquard, I., Verlingue, L., Cassier, P. A., Attignon, V., Chabaud, S., Mayet, R., Mouillaux, J., Garin, G., Pérol, D., & Blay, J.-Y. (2026). MEK inhibition in molecularly-selected advanced or metastatic solid tumours: final analysis of trametinib cohort from the platform phase II trial MegaMOST. BMC Cancer. https://doi.org/10.1186/s12885-026-17155-z

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17155-z

Keywords: trametinib, MEK inhibition, MegaMOST, MAPK/ERK pathway, phase II trial, KRAS, NRAS, RAS p.Q61, precision oncology, progression-free survival, biomarker-driven trial, advanced solid tumours