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

Overactivation of the MAPK/ERK signalling pathway is frequent across solid tumours. The selective MEK1/2 inhibitor trametinib is a potential targeted strategy in patients with MAPK/ERK pathway alterations. The multicentre, open-label, biomarker-driven phase II platform trial MegaMOST aims to evaluate molecular targeted therapies in advanced or metastatic solid tumours using a Bayesian design. In the trametinib cohort, patients with activating mutations and/or amplification of KRAS , NRAS , HRAS , MAP2K , PTPN11 , biallelic inactivation of NF1 , or amplification or translocation of BRAF or RAF1 received trametinib (2 mg/day, per os ) until loss of clinical benefit according to the investigator, unacceptable toxicity, deterioration due to disease progression or withdrawal of consent. The primary endpoint was the 12-weeks progression-free rate (12 W-PFR) as per RECIST 1.1, sequentially evaluated with a futility boundary of 20% and an efficacy boundary of 40%. Secondary endpoints included Objective Response Rate (ORR), Duration of Response (DoR), Progression-Free Survival (PFS), Overall Survival (OS), and safety. From August 2022 to February 2024, 51 patients received trametinib and 50 were evaluable for efficacy. Median age was 63 (29–83) years, 26 (52%) were males. The main alterations were KRAS ( n = 16, 32%), NRAS ( n = 11, 22%) and MAP2K ( n = 7, 14%) mutations. The estimated 12 W-PFR was 30.8% (95%CrI 19.1–43.8). Best response was PR in 4 (8%) patients and SD in 14 (28%) patients. The median PFS was 2.6 (95%CI 2.5–2.8) months and the median OS 6.4 (95%CI 4.8–13.4) months. The most frequent related adverse events (AE) were acneiform dermatitis ( n = 24, 47.1%), fatigue ( n = 16, 31.4%) and diarrhea ( n = 15, 29.4%). A total of 25 (49%) patients experienced grade ≥ 3 related AEs including one fatal case of digestive haemorrhage and pulmonary embolism. A subgroup of patients with RAS p.Q61 mutations showed a 12 W-PFR of 57.1% (95%CrI 31.6–80.8). While trametinib did not demonstrate efficacy in molecularly-selected advanced solid tumours, a small subgroup of patients with RAS p.Q61 mutations may have benefited from treatment and deserve further investigations. ClinicalTrials.gov NCT04116541, first posted: 2019-10-04.