Phase II trial of dabrafenib and trametinib in patients with BRAFV600E/R or non-BRAFV600 mutated advanced solid tumors: Results from the BELIEVE trial (NCCH1901).

Abstract

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Background: BRAF V600 mutations are prevalent in melanoma, thyroid cancer, non-small cell lung cancer, and other malignancies to a lesser degree. The BELIEVE study, a Japanese equivalent of the NCI-MATCH trial, assessed the efficacy of the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors harboring BRAFV600E/R or non- BRAFV600 mutations. Methods: The BELIEVE study was a single-arm, open-label clinical trial. Eligible patients were those with solid tumors, with the exception of those with colorectal cancer who were subsequently excluded through amendment. Participants received dabrafenib 150 mg twice daily and trametinib 2 mg/day continuously until disease progression or intolerable toxicity occurred. The primary endpoint was objective response rate (ORR; investigator assessed, RECIST criteria, CR+PR) and secondary endpoints were progression-free survival (PFS), 6-month PFS, and overall survival. The clinical hypothesis was that patients would respond to the matched drug. Bayesian analysis using a prior distribution with an expected response rate of 30% [Beta(0.6, 1.4)] was carried out. If the posterior distribution provided unexpectedly high probability (i.e. > 95%) of response rate exceeding 60% or being inferior to 20%, early termination would be considered during the trial. Otherwise, the efficacy of the drug would be concluded as promising in terms of the clinical hypothesis. Results: Fifty patients who had target lesions were included as primary endpoints. The median age was 56.5 years. The three most prevalent primary sites among the main cohort were the thyroid, the central nervous system and biliary tract. The confirmed ORR was 28.0% (95% CI, 16.2% to 42.5%), which met the pre-determined hypothesis, and disease control rate (DCR; CR+PR+SD) was 84.0% (95% CI, 70.9% to 92.8%); PFS was 6.5 months (95% CI, 4.2 to 7.2 months) and responses were observed across seven different types of tumors; the PFS rate at 6 months was 87.8%. Data regarding overall survival was premature, with a median of 9.7 months at the time of analysis. Furthermore, the median PFS was 4.5 months (95% CI, 0.8 to 8.6 months) for the seven patients without target lesions in the exploratory analysis. Adverse events reported among 57 safety analysis population were consistent with those previously reported for dabrafenib and trametinib. Patients who had grade ≥3 adverse events were 45.6%. The most frequent AEs were pyrexia (26.3%), anemia (12.3%), anorexia (8.8%), aspartate aminotransferase elevation (8.8%) and hypoalbuminemia (8.8%). Conclusions: The study met its primary endpoint with an ORR of 28.0% in this mixed histology pre-treatment cohort, furthermore, the DCR was 84.0%, which is encouraging for efficacy in BRAFV600-mutant tumors across solid tumors. jRCTs031190104. Clinical trial information: Clinical trial information: jRCTs031190104 .