Dose escalation study of vemurafenib with crizotinib or sorafenib in patient with BRAF-mutated advance cancers

Abstract

Background: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through activation of alternative signaling pathways such as MET, PDGFR and CRAF. We hypothesized that combining the BRAF inhibitor vemurafenib and MET inhibitor crizotinib or PDGFR/CRAF inhibitor sorafenib can overcome resistance. Methods: We designed a phase I study (3+3 design) to determine the safety of vemurafenib (240-960 mg PO BID q 28 days) with crizotinib (250 mg PO daily or BID q 28 days) in arm A or sorafenib (200 mg PO daily to 400mg PO BID q 28 days) in Arm B in patients with BRAF-mutant advanced cancers. Endpoints included maximum tolerated dose (MTD), dose limiting toxicities (DLT), safety, response (RECIST 1.1) and plasma cell-free DNA mutation analysis. Results: Thirty-six patients (arm A, 13; arm B, 23), median number of 3 prior therapies (29 [81%] had prior BRAF/MEK inhibitors) were treated. Patients (melanoma 17/36, 47%; papillary thyroid cancer 5/36, 14%; colorectal cancer 3/36, 8%; lung adenocarcinoma 2/36, 6%; other 9/36, 25%) had BRAF V600E (30), V600K (3) or other BRAF mutations (3). Vemurafenib 720mg BID with crizotinib 250mg daily and vemurafenib 720 mg BID with sorafenib 400mg/200mg were identified as MTDs. DLTs included grade (G) 3 rash (2) in arm A and G3 rash and G3 hypertension in arm B. Other G3 treatment related toxicities were G3 fatigue (2), G3 anemia (1), G3 thrombocytopenia (1), G3 neutropenia (1), G3 thromboembolic event (1) in arm A and G3 hypertension (1), G3 headache (1), G3 diarrhea (2), G3 intraocular inflammation (1) in arm B. In Arm A, 3 of 13 (23%) patients (melanoma refractory to BRAF monotherapy [2] and lung adenocarcinoma) attained a partial response (PR). In Arm B, 4 of 23 (17%) patients (ovarian cancer refractory to MEK inhibitor, melanoma, lung adenocarcinoma, papillary thyroid cancer) attained a PR. Optional longitudinal collection of plasma cfDNA to assess clonal evolution was performed and will be presented at the meeting. Conclusions: Vemurafenib in combination with crizotinib or sorafenib is well tolerated with encouraging activity including patients previously treated with BRAF/MEK inhibitors.