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Ref Type Journal Article
PMID (38096472)
Authors Meric-Bernstam F, Rothe M, Mangat PK, Garrett-Mayer E, Gutierrez R, Ahn ER, Cannon TL, Powell S, Krauss JC, Reynolds CM, von Mehren M, Behl D, Calfa CJ, Duvivier HL, Kaplan HG, Livingston MB, Sharma MR, Urba WJ, Grantham GN, Hinshaw DC, Gregory A, Halabi S, Schilsky RL
Title Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 7 2023 Sep e2300385 JCO Precis Oncol
URL
Abstract Text The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. The results in a cohort of patients with solid tumors with BRAF mutations treated with cobimetinib plus vemurafenib are reported.Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as complete response (CR) or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low-accruing histology-specific cohorts with BRAF mutations treated with cobimetinib plus vemurafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, .82; α, .10). The secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety.Thirty-one patients with solid tumors with BRAF mutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a DC rate of 68% (P < .0001; one-sided 90% CI, 54 to 100) and an OR rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury.Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E pancreatic endocrine carcinoma predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in a patient with pancreatic neuroendocrine carcinoma harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E cholangiocarcinoma predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in a patient with cholangiocarcinoma harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E clear cell sarcoma predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in a patient with clear cell sarcoma harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E pancreatic cancer predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in 2 patients with pancreatic cancer harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E Advanced Solid Tumor sensitive Cobimetinib + Vemurafenib Phase II Actionable In a Phase II trial (TAPUR), treatment with the combination of Zelboraf (vemurafenib) and Cotellic (cobimetinib) resulted in an objective response rate of 57% (16/28, 2 complete responses (CR), 14 partial responses (PR)) and a disease control rate (CR + PR + stable disease at 16 wks (SD16+)) of 68% in patients with advanced solid tumors harboring BRAF mutations, with 2 CR, 13 PR, and 2 SD16+ in a total of 26 patients harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF N581I neuroendocrine carcinoma predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in a patient with neuroendocrine carcinoma harboring BRAF N581I (PMID: 38096472; NCT02693535). 38096472
BRAF V600E colon neuroendocrine neoplasm predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in a patient with neuroendocrine carcinoma of the colon harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E breast cancer predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a complete response that lasted 170 days and 2 partial responses out of 4 patients with advanced breast cancer harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E ovarian cancer predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in one complete response lasting 5 weeks, 2 partial responses, and 1 with stable disease lasting more than 16 weeks out of 6 patients with advanced ovarian cancer harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472
BRAF V600E breast malignant phyllodes tumor predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (TAPUR), Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy resulted in a partial response in a patient with a phyllodes tumor of the breast harboring BRAF V600E (PMID: 38096472; NCT02693535). 38096472