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

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. 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. 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: 661MOSC-A: BRAF fusion (N=15)SC-B: Point mutation (N=8)Best overall responseCR00PR9 (60.0)0SD5 (33.3)4 (50.0)PD1 (6.7)4 (50.0)ORRn (%)9 (60.0)095% CI32.29, 83.660, 36.94Disease control rate (PR+SD)n (%)14 (93.3)4 (50.0)95% CI68.05, 99.8313.70, 78.80mPFSmonth13.72.195% CI7.36, 18.231.61, 7.16 Open table in a new tab 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.