TY - JOUR
T1 - Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers
AU - Janku, Filip
AU - Sakamuri, Divya
AU - Kato, Shumei
AU - Huang, Helen J.
AU - Call, S. Greg
AU - Naing, Aung
AU - Holley, Veronica R.
AU - Patel, Sapna P.
AU - Amaria, Rodabe N.
AU - Falchook, Gerald S.
AU - Piha-Paul, Sarina A.
AU - Zinner, Ralph G
AU - Tsimberidou, Apostolia M.
AU - Hong, David S.
AU - Meric-Bernstam, Funda
N1 - Funding Information:
Filip Janku reports research funding (through The University of Texas MD Anderson Cancer Center [MD Anderson]) from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol‐Myers Squibb, Asana, Ideaya Biosciences, Synthorx, FujiFilm Pharmaceuticals, Sotio, Synlogic, and Proximagen; personal fees from Guardant Health, Illumina, Ideaya Biosciences, IFM Therapeutics, Synlogic, Sotio, Puretech Health, Deciphera, Cardiff Oncology, and Immunomet; and has an ownership interest in Cardiff Oncology, all outside the submitted work. Shumei Kato reports research from ACT Genomics, Sysmex, Konica Minolta, and OmniSeq and personal fees from Foundation Medicine and Roche, all outside the submitted work. Aung Naing reports research funding (through MD Anderson) from the National Cancer Institute, EMD Serono, MedImmune, Healios Oncology Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol‐Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, Top Alliance Biosciences, Kymab, PsiOxus, and Arcus; personal fees from CytomX Therapeutics, Novartis, Kymab, and Genome; and travel and accommodation expenses from ARMO BioSciences, all outside the submitted work. Sapna P. Patel reports clinical trial support (through MD Anderson) from Bristol Myers‐Squibb, Novartis, Provectus, and InxMed; personal fees from Cardinal Health, Castle Biosciences, and Incyte; service on the Immunocore Data Safety Monitoring Board; and participation in a nonpromotional speaker's bureau for Merck, all outside the submitted work. Gerald S. Falchook reports research funding (through his institution) from 3‐V Biosciences, Abbisko, AbbVie, ADC Therapeutics, Aileron, the American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, the National Institutes of Health, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, Regeneron, Rgenix, Ribon, Sapience, Strategia, Syndax, Synthorx, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, MD Anderson, Vegenics, and Xencor; royalties from Wolters Kluwer; personal fees from Fujifilm and EMD Serono; travel compensation from Bristol‐Myers Squibb, EMD Serono, Fujifilm, Millennium, and the Sarah Cannon Research Institute; and honoraria from Total Health Conferencing and the Rocky Mountain Oncology Society, all outside the submitted work. Sarina A. Piha‐Paul reports research funding (through MD Anderson) from AbbVie Inc, ABM Therapeutics Inc, Acepodia Inc, Alkermes Inc, Aminex Therapeutics, Amphivena Therapeutics Inc, BioMarin Pharmaceutical Inc, Boehringer Ingelheim, Bristol‐Myers Squib, Chugai Pharmaceutical Company Ltd, Daichi Sankyo Inc, Eli Lilly, Five Prime Therapeutics, Gene Quantum Healthcare Company Ltd, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp, Incyte Corporation, Jacobio Pharmaceuticals Company Ltd, Medimmune LLC, Medivation Inc, Merck Sharp and Dohme Corporation, Novartis Pharmaceuticals, Pieris Pharmaceuticals Inc, Pfizer, Principia Biopharma Inc, Puma Biotechnology Inc, Rapt Therapeutics Inc, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro Inc, TransThera Bio, and the National Institutes of Health/National Cancer Institute, all outside the submitted work. Apostolia M. Tsimberidou reports clinical trial funding support (through MD Anderson) from IMMATICS, the Parker Institute for Cancer Immunotherapy, Tempus, OBI Pharma, EMD Serono, Baxalta, ONYX, Bayer, Boston Biomedical, Placon Therapeutics, Karus Therapeutics, Tvardi, and the Cancer Prevention Research Institute of Texas; travel accommodations and expenses supported by the American Society of Clinical Oncology, Genentech, Covance, and Tempus; and personal fees from Covance, Genentech, and Tempus, all outside the submitted work. David S. Hong reports grants from AbbVie, Adaptimmune, Aldi‐Norte, Amgen, AstraZeneca, Bayer, Bristol‐Myers Squibb, Daiich‐Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lily, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, the National Cancer Institute Cancer Therapy Evaluation Program, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; and travel expenses and accommodations from Bayer, LOXO, miRNA, Genmab, the American Association for Cancer Research, the American Society for Clinical Oncology, and the Society for Immunotherapy of Cancer; personal fees from Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, COG, Ecor1, Genentech, GLG Pharma, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Turning Point Therapeutics, and Molecular Match, and Presagia, all outside the submitted work; and is a founder of OncoResponse and Presagia. Funda Meric‐Bernstam reports sponsored research funding (through MD Anderson) from Aileron Therapeutics Inc, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc, Curis Inc, CytomX Therapeutics Inc, Daiichi Sankyo Company Ltd, Debiopharm International, eFFECTOR Therapeutics, Genentech Inc, Guardant Health Inc, Millennium Pharmaceuticals Inc, Novartis, Puma Biotechnology Inc, and Taiho Pharmaceutical Co; personal fees from Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; consulting fees from Aduro BioTech Inc, Alkermes, Debiopharm, eFFECTOR Therapeutics, F. Hoffman‐La Roche Ltd, Genentech Inc, IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc, Samsung Bioepis, Seattle Genetics Inc, Tyra Biosciences, Xencor, and Zymeworks; honoraria from Chugai Biopharmaceuticals, the Mayo Clinic, and the Rutgers Cancer Institute of New Jersey; and travel‐related expenses covered by the Beth Israel Deaconess Medical Center, all outside the submitted work. The remaining authors made no disclosures.
Funding Information:
This study was supported by the National Center for Advancing Translational Sciences (UL1 TR000371), the National Institutes of Health through MD Anderson's Cancer Center Support Grant (P30 CA016672) and Clinical and Translational Science Award (1UL1 TR003167), the Sidney Kimmel Foundation for Cancer Research (Filip Janku), the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy (Filip Janku), and the Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core (RP150535).
Publisher Copyright:
© 2020 American Cancer Society
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - BRAF mutation
KW - cancer
KW - crizotinib
KW - sorafenib
KW - vemurafenib
UR - http://www.scopus.com/inward/record.url?scp=85094184372&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094184372&partnerID=8YFLogxK
U2 - 10.1002/cncr.33242
DO - 10.1002/cncr.33242
M3 - Article
C2 - 33119140
AN - SCOPUS:85094184372
SN - 0008-543X
VL - 127
SP - 391
EP - 402
JO - Cancer
JF - Cancer
IS - 3
ER -