Abstract 529P
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.
Editorial acknowledgement
Legal entity responsible for the study
Hanmi Pharm. Co., Ltd.
Funding
Hanmi Pharm. Co., Ltd.
Disclosure
T.W. Kim: Financial Interests, Institutional, Research Grant, null: AstraZeneca; Financial Interests, Institutional, Research Grant, null: SanofiAventis. J. Lee: Financial Interests, Personal, Advisory Role: Mirati; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Oncologie; Financial Interests, Personal, Advisory Role: AstraZeneca. T.M. Kim: Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Role: Boryung; Financial Interests, Personal and Institutional, Advisory Role: F. Hoffmann-La Roche Ltd/Genentech, Inc; Financial Interests, Personal and Institutional, Advisory Role: Hanmi; Financial Interests, Personal and Institutional, Advisory Role: Novartis; Financial Interests, Personal and Institutional, Advisory Role: Takeda; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Korea Health Industry Development Institute. C. Yoo: Financial Interests, Personal and Institutional, Other, Honoraria: Bayer; Financial Interests, Personal and Institutional, Other, Honoraria: Eisai; Financial Interests, Personal and Institutional, Other, Honoraria: MSD; Financial Interests, Personal and Institutional, Other, Honoraria: Ipsen; Financial Interests, Personal and Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria: Celgene; Financial Interests, Personal and Institutional, Other, Honoraria: BMS; Financial Interests, Personal and Institutional, Other, Honoraria: Hanmi; Financial Interests, Personal and Institutional, Other, Honoraria: Kyowa Kirin; Financial Interests, Personal and Institutional, Other, Honoraria: Boryung pharmaceuticals; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Ipsen; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Celgene; Financial Interests, Personal, Research Grant: Boryung pharmaceuticals; Financial Interests, Personal, Research Grant: eil pharmaceuticals; Financial Interests, Personal, Research Grant: Ildong pharmaceuticals; Financial Interests, Personal, Research Grant: HK inno.N. D.H. Lee: Financial Interests, Personal, Invited Speaker, honoraria for lectures: Abbvie; Financial Interests, Personal, Advisory Board, honoraria for lectures and consulting: AstraZeneca; Financial Interests, Personal, Advisory Board, honoraria for consulting: Bayer; Financial Interests, Personal, Invited Speaker, honoraria for lectures: BC Pharma; Financial Interests, Personal, Invited Speaker, honoraria for lectures: BluePrint Medicine; Financial Interests, Personal, Advisory Board, honoraria for consulting: BMS; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Genexine; Financial Interests, Personal, Advisory Board, honoraria for consulting: Menarini; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Mundipharma; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Novartis; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Ono; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Pfizer; Financial Interests, Personal, Advisory Board, honoraria for lectures and consulting: Roche; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Samyang; Financial Interests, Personal, Advisory Board, honoraria for consulting: ST Cube; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Takeda. Y. Hong: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. J. Kim: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. E. Baek: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. B. Choi: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. V. Malhi: Financial Interests, Institutional, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. S. Baek: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.