Abstract 2689: Overcoming BRAF/MEK resistance using vemurafenib with crizotinib or sorafenib in patients with BRAF-mutant advanced cancers: phase I study
Authors: Kato Shumei , Naing Aung , Falchook Gerald , Holley Veronica R. , Velez-Bravo Vivianne M. , Patel Sapna , Zinner Ralph G. , Piha-Paul Sarina A. , Tsimberidou Apostolia M. , Hong David S. , Kurzrock Razelle , Meric-Bernstam Funda , Janku Filip 
Published: August 2015

Abstract
Background: BRAF inhibitors are effective in advanced melanoma and other cancers with BRAF V600mutations; however, patients ultimately develop therapeutic resistance through activation of alternative signaling pathways such as HGF/MET, PDGFR and CRAF. We hypothesized that combining the BRAF inhibitor vemurafenib and MET inhibitor crizotinib or PDGFR/CRAF inhibitor sorafenib can increase efficacy by overcoming intrinsic and acquired 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: To date, 29 patients (Arm A, n = 11, vemurafenib 240-960mg PO BID with crizotinib 250mg PO daily; Arm B, n = 18, vemurafenib 240-720mg PO BID with sorafenib 200 mg PO BID to 400/200 mg PO), median age of 53 (33-76) years; median number of 3 (1-5) prior therapies including 22 (76%) patients with prior BRAF or MEK inhibitors were treated. Patients (melanoma 17/29, 59%; papillary thyroid cancer 4/29, 14%; colorectal cancer 3/29, 10%; lung adenocarcinoma 2/29, 7%; other 3/29, 10%) had BRAF V600E (n = 24), V600K (n = 3) or other BRAF mutations (n = 2). The MTDs have not been reached and no DLTs have been observed. Significant drug related toxicities included grade (G) 3 thrombocytopenia (n = 1) in arm A and G3 hypertension (n = 1), G3 headache (n = 1), G3 diarrhea (n = 1) in Arm B. In Arm A, 3 of 11 (27%) patients (melanoma refractory to BRAF monotherapy, -40% for 7.9 months; melanoma refractory to BRAF monotherapy, -36% for 6.0+ months and lung adenocarcinoma, -50% for 13.9 months) attained a partial response (PR) and 1 (9%) patient (melanoma refractory to MEK inhibitor, +3% for 12.5 months) with stable disease (SD) &gt; 6 months. In Arm B, 3 of 18 (17%) patients (melanoma, -46% for 7.6 months; lung adenocarcinoma, -61% for 7.3 months and ovarian cancer refractory to MEK inhibitor, -50% for 18.7 months) attained a PR and 3 (17%) patients (papillary thyroid refractory to MEK inhibitor, -10% for 28.4 months; papillary thyroid cancer refractory to BRAF inhibitor, -6% for 7.3+ months and melanoma refractory to BRAF monotherapy -8% for 7.5 months) attained SD &gt; 6 months. In patients with longitudinal assessment of plasma cfDNA changes in the amount of BRAF mutant DNA corresponded with clinical course (data will be presented).
Conclusions: Preliminary data suggest that vemurafenib in combination with crizotinib or sorafenib are well tolerated with encouraging activity in patients previously treated with BRAF or MEK inhibitors.
Citation Format: Shumei Kato, Aung Naing, Gerald Falchook, Veronica R. Holley, Vivianne M. Velez-Bravo, Sapna Patel, Ralph G. Zinner, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, David S. Hong, Razelle Kurzrock, Funda Meric-Bernstam, Filip Janku. Overcoming BRAF/MEK resistance using vemurafenib with crizotinib or sorafenib in patients with BRAF-mutant advanced cancers: phase I study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2689. doi:10.1158/1538-7445.AM2015-2689