Phase II trial of trametinib in patients with advanced solid tumors harboring genomic alterations in the MAPK pathway: Results from the BELIEVE trial (NCCH1901).

Abstract

3111 Background: The MAPK pathway is one of the most mutated oncogenic pathways in solid tumors. However, effective treatments targeting this pathway have not been well-established. The BELIEVE trial aimed to evaluate the efficacy of trametinib, a selective MEK inhibitor, in patients with solid tumors harboring genomic alterations in the MAPK pathway. Methods: The BELIEVE trial is a multi-cohort, tumor agnostic phase II trial. Eligibility criteria included patients with solid tumors for which no standard treatment was available or those who had shown resistance or intolerance to standard therapies. In the trametinib arm, participants received 2 mg/day of trametinib continuously until disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR) within 16 weeks, and secondary endpoints were overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and safety. The clinical hypothesis was that patients would respond to the genotype-matched drugs. Bayesian analysis was performed using a prior distribution with an expected response rate of 30% [Beta (0.6, 1.4)]. Results: Between October 2019 and October 2023, 60 patients with measurable disease and 9 without measurable disease were enrolled. The top three primary tumor sites were the central nervous system (n=20), pancreas (n=7), and ovary (n=6). The targeted genes for trametinib included non- BRAF V600 (n=26), NF1 (n=18), MAP2K1 (n=10), NRAS (n=6), KRAS (n=5), and RAF1 (n=4). Among the full analysis set of 49 patients with measurable disease, the confirmed ORR was 12.2% (95% CI, 4.6% to 24.8%), and the expected value of posterior distribution [Beta (6.6, 44.4)] was 12.9%. Partial responses were observed in patients with genomic alterations in non BRAF V600 (n=3), KRAS (n=2), and NF1 (n=1). However, the confirmed ORR of 12.2% fell below the prespecified threshold of 20%, therefore the primary endpoint was not achieved. The median OS was 11.9 months (95% CI, 8.5 to 22.9 months), and median PFS was 3.9 months (95% CI, 2.4 to 44 months). The DCR was 46.9% (95% CI, 32.5% to 61.7%). Among 59 patients in the safety analysis, severe adverse events (Grade ≥3) were observed in 55.9% of patients. The most frequent adverse effects were acneiform dermatitis (22%), blood creatine phosphokinase increased (20%), and stomatitis (15%). Conclusions: The BELIEVE trial demonstrated limited efficacy of trametinib in patients with advanced solid tumors harboring genomic alterations in the MAPK pathway. While the confirmed ORR did not meet the primary endpoint, the outcomes for OS, PFS, and DCR were consistent with the clinical hypothesis, suggesting potential benefit in a subset of patients. Clinical trial information: jRCTs031190104 .