661MO - Anti-tumor activity of belvarafenib in combination with cobimetinib in patients with metastatic solid tumors harboring BRAF fusions or BRAF class II/III mutation

Background

Belvarafenib (Belva) is a type II selective RAF dimer inhibitor that, in combination with Cobimetinib (Cobi) has shown clinical activity in patients with NRAS-mutant melanoma ( ASCO 2021 , ESMO 2021 ). One cohort in this phase I trial evaluated BRAF fusions (including indel/rearrangement) or class II/III point mutations, which are considered potential therapeutic targets for Belva +/- Cobi. Here, we present findings on activity and safety of Belva and Cobi in patients with BRAF fusion including indel/rearrangement.

Methods

A total of 23 patients harboring BRAF non-canonical aberration were enrolled and treated with Belva 300mg PO BID and Cobi 20mg PO TIW (3 times a week) in the HM-RAFI-103 study (NCT03284502). Sub-cohort A (SC-A) enrolled patients with BRAF fusions and sub-cohort B (SC-B) enrolled patients with BRAF class II/III point mutations. Safety results were updated based on 133 patients who were treated with Belva and Cobi as of Jan 31, 2023.

Results

In SC-A, a total of 15 patients harboring BRAF fusions (Melanoma (10), NSCLC (3), CRC (1), Pancreatic cancer (1)) and 8 patients with BRAF class II/III point mutation were in SC-B (Biliary tract cancer (3), CRC (3), SCLC (1), Glioblastoma (1)) were enrolled. The confirmed objective response rate (ORR), assessed by investigators’ assessment, for SC-A was 60.0%, median progression-free survival (mPFS) was 13.7 months, and median duration of response was 12.0 months (95% CI: 7.43 to 22.34) with median follow-up time 12.9 months, while patients in SC-B showed best response of stable disease. As of cut-off date, the most common treatment related adverse events from 133 patients is dermatitis acneiform (54.1%), rash (28.6%), and blood creatine phosphokinase increased (24.1%). No new safety signals were found.

Table: 661MO

Conclusions

The combination of Belva with Cobi showed promising anti-tumor activity as well as durable responses in patients with BRAF fusions regardless of cancer type.

Clinical trial identification

NCT03284502.

Editorial acknowledgement

Legal entity responsible for the study

Hanmi Pharmaceutical.

Funding

Hanmi Pharmaceurical.

Disclosure

T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech. J. Lee: Financial Interests, Steering Committee Member: Seattle Genetics, AZ; Non-Financial Interests, Principal Investigator: AstraZeneca, Daiichi Sankyo, Merck MSD, BMS, Leaptherapeutics; Non-Financial Interests, Project Lead: Samsung Bioepis, Genome and Company, Oncxerna; Non-Financial Interests, Advisory Role: Mirati Therapeutics; Non-Financial Interests, Member: KSMO; Non-Financial Interests, Other, AP Council: ASCO. S. Han: Financial Interests, Institutional, Local PI: Hanmi, Genentech, Roche, Loxo, Mirati, MSD, Janssen, Lilly, Seagen, Arcus. J. Kim: Financial Interests, Personal, Invited Speaker: CJ Healthcare, AstraZeneca, GeneCKer, Sanofi/Aventis, Gencurix, Boryung; Financial Interests, Personal, Advisory Board: ABION, CJ Healthcare; Financial Interests, Personal, Member of Board of Directors: IMBdx; Financial Interests, Local PI: AstraZeneca, Boehringer Ingelheim, Sanofi, Lilly, CJ Healthcare, Hanmi, Ono Pharmaceutical, Pfizer, Novotech, Astellas Pharma, Merck, Alpha Biopharma, Yuhan, MSD, IL-Yang Pharm, AbbVie, Boryung, ChongKeunDang Healthcare, Daiichi Sankyo, BeiGene. D.H. Lee: Financial Interests, Personal, Advisory Board, honoraria for lectures and consulting: AstraZeneca, Roche; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Mundipharma, Ono, Pfizer, AbbVie, Takeda, BluePrint Medicine, BC Pharma; Financial Interests, Personal, Advisory Board, honoraria for lectures: Novartis; Financial Interests, Personal, Advisory Board, honoraria for consulting: ST Cube, Menarini, BMS, Bayer; Financial Interests, Personal, Advisory Board: Eli Lilly, ChongKeunDang; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Stocks/Shares: STCube. Y. Hong: Financial Interests, Personal, Full or part-time Employment: Hanmi. S. Kim, T. Kim: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharm. B. Lee: Financial Interests, Personal, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. J. Eng-Wong, Y. Yan: Financial Interests, Personal, Full or part-time Employment: Genentech. C. Chou: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. Y.S. Noh: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Company. All other authors have declared no conflicts of interest.