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Dose‐escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF ‐mutated advanced cancers
Author(s) -
Janku Filip,
Sakamuri Divya,
Kato Shumei,
Huang Helen J.,
Call S. Greg,
Naing Aung,
Holley Veronica R.,
Patel Sapna P.,
Amaria Rodabe N.,
Falchook Gerald S.,
PihaPaul Sarina A.,
Zinner Ralph G.,
Tsimberidou Apostolia M.,
Hong David S.,
MericBernstam Funda
Publication year - 2021
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.33242
Subject(s) - vemurafenib , medicine , crizotinib , sorafenib , rash , melanoma , oncology , lung cancer , mek inhibitor , cancer research , mapk/erk pathway , pharmacology , metastatic melanoma , kinase , biology , hepatocellular carcinoma , malignant pleural effusion , microbiology and biotechnology
Background BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance. METHODS Patients with advanced cancers and BRAF mutations were enrolled in a dose‐escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose‐limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC). Results In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am /200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF ‐mutant DNA from plasma during therapy ( P = .005). Conclusions Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.