PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors.

3534 Background: The BRAF activating mutation is present in up to 10% of metastatic colorectal carcinomas (mCRC) and is associated with unique clinical and pathologic features with a very poor prognosis. PLX4032 (RG7204) is an oral inhibitor of the mutant BRAF kinase, with pronounced activity in BRAF-mutant melanoma patients (pts). Methods: In this phase I study, we treated an extension cohort of mCRC pts whose tumors were positive for mutant BRAF with PLX4032 at the previously determined maximum tolerated dose of 960 mg BID. The BRAF mutation was centrally confirmed by Taqman PCR. Efficacy was evaluated by RECIST every 8 weeks. Results: 21 mCRC pts were enrolled, with a median age of 65 and ECOG performance status of 0 (35%) or 1 (65%). All but one had received prior therapy for metastatic disease. PLX4032 PK values were ∼20% lower than than those previously observed for melanoma. 19 pts were evaluable for response, with 1 confirmed partial response and 4 minor responses (≥ 10% shrinkage). 5 pts showed a mixed response pattern (i.e., with both regressing and progressing lesions). 2 of the 3 pts who underwent repeat FDG-PET imaging achieved a metabolic response, which was concordant with RECIST changes. Median progression-free survival was 3.7 months, with 2 pts still on study. PLX4032 was generally well tolerated. Three pts had dose limiting toxicities of G3 rash and G3 nausea. Other G3 or G4 drug-attributable adverse events in all cycles were seen in 6 pts, and included fatigue, diarrhea, neutropenia, elevated alkaline phosphatase, hyponatremia, hypokalemia, and hyperbilirubinemia. Five pts developed cutaneous squamous cell carcinomas consistent with keratoacanthomas, which were managed by local excision. Conclusions: The clinical activity seen with PLX4032 in previously treated mCRC pts with V600E BRAF mutations is more modest than had been seen in melanoma, but this activity does confirm mutant BRAF as a therapeutic target in this disease. The biology of BRAF activation in pts with CRC is clearly more heterogenous than in melanoma, especially as evidenced in those pts with a mixed response. Subsequent studies are planned to evaluate PLX4032 in combination regimens in an attempt to improve efficacy in this poor prognosis subset of mCRC pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Plexxikon, Roche Roche Plexxikon, Roche Plexxikon, Roche