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|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||Annals of Oncology|
|Date||September 01, 2021|
|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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|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; NCT03839342).||detail...|