Reference Detail

Ref Type

Abstract

PMID

Authors

T.W. Kim J. Lee T.M. Kim S.J. Shin S-W. Han J-S. Kim Y.J. Kim C. Yoo Y.S. Hong J.W. Kim D.H. Lee C.B. Ahn S.T. Kim J-W. Kim Y-H. Hong J. Kim E. Baek B. Choi V. Malhi S. Baek

Title

A phase Ib trial of belvarafenib in combination with cobimetinib in patients (pts) with RAS- or RAF- mutated (m) solid tumors: Updated safety data and indication-specific efficacy results

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	32	SUPPLEMENT 5	September 01, 2021

URL

https://www.annalsofoncology.org/article/S0923-7534(21)03280-4/fulltext#relatedArticles

Abstract Text

Background Belvarafenib (belva), a potent and selective RAF dimer (type II) inhibitor, has shown a favorable clinical safety profile and anti-tumor activity as a single agent or in combination with low dose of cobimetinib (cobi) in pts with RAS or RAF-mutated tumors, especially in non-canonical and canonical BRAF mutation. Here, the overall safety profiles and efficacy data will be presented. Methods As of the data cutoff date of 31 Jan 2021, a total of 118 pts (escalation: 19, expansion: 99 pts) with metastatic solid tumors harboring RAS or RAF mutations were enrolled and analyzed for safety, pharmacokinetics and anti-tumor activity of belva in combination with cobi. Belva was dosed twice daily (BID) for 28-day cycle, cobi was dosed for the 21 days of 28-day cycle. The doses for expansion cohorts (Cohort I: Belva 200mg BID + Cobi 20mg QD, Cohort II: Belva 300mg BID + Cobi 20mg QOD (3 times a week)) were based on safety results from the dose escalation cohorts. Results The most common treatment-emergent adverse events (TEAEs) were dermatitis acneiform (52.5%), diarrhea (28.0%), rash (27.1%), and increased CPK level (25.4%). TEAEs were largely grade 1/2 across all dosing regimens. The incidence of these TEAEs, excluding dermatitis acneiform, was lower in cohort II compared to cohort I. There was no apparent drug-drug interaction observed between belva and cobi. Anti-tumor activity was analyzed by cancer and mutation type across all dose levels. Overall 17 out of 118 (14.4%) pts responded. Among 19 pts with NRASm melanoma, 5 (26.3%) pts had a confirmed partial response (cPR) and 8 (42.1%) pts reached stable disease. For BRAFm melanoma, 3 out of 9 pts (33.3%) with a canonical V600 mutation and 3 out of 6 pts (50.0%) with non-canonical mutations achieved cPR. Two out of 2 pts (100.0%) with non-canonical BRAFm NSCLC achieved PR (one unconfirmed). Three additional PR occurred: 2 KRAS G13-mutant CRCs and 1 HRAS melanoma. Conclusions Belva in combination with cobi was tolerable and the safety profile was consistent with that of each agent. In this study, belva and cobi exhibited encouraging anti-tumor activity in NRASm and BRAFm (canonical and non-canonical) melanoma, and non-canonical BRAFm NSCLC. Clinical trial identification NCT03284502.

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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 V600X	Advanced Solid Tumor	predicted - sensitive	Belvarafenib + Cobimetinib	Phase I	Actionable	In a Phase Ib trial, combination treatment with Belvarafenib (HM95573) and Cotellic (cobimetinib) was well-tolerated and demonstrated safety, and led to a confirmed partial response in 33.3% (3/9) solid tumor patients harboring BRAF V600 mutations (Annals of Oncology 32 (2021): S595; NCT03284502).	detail...