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Ref Type Abstract
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
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...