A phase 1 study of triple‐targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF‐mutated cancers

Background Aberrant PI3K/AKT signaling in BRAF‐mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF‐mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). Methods Patients with BRAF V600E/V600K–mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose‐limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8‐week intervals. Results Twenty‐seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor‐resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. Conclusions Concomitant inhibition of both the MAPK and PI3K‐AKT pathways for the treatment of BRAF‐mutated cancers was well tolerated, leading to objective responses, but higher level drug‐drug interactions affected exposure to dabrafenib and its metabolites. A phase 1 trial of triplet‐targeted therapy demonstrates that a combination of dabrafenib, trametinib, and uprosertib (BRAF, MEK, and AKT inhibitors) is well tolerated, but higher order drug‐drug interactions affect drug exposures.