COVALENT-102: A phase 1/1b dose finding study of BMF-219, an oral covalent menin inhibitor, in adults with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC) and colorectal cancer (CRC) with activating KRAS mutations.
Authors: Fountzilas Christos , Cohen Stacey A. , Duvivier Herbert Leon , Hong David S. , Pedersen Katrina Sophia , Pisick Evan P. , Sommerhalder David , Cacovean Alex , Follit Courtney , Kowalczyk Nicole , Munneke Brian , Tong Tracy , Morris Steve , Butler Thomas , Spira Alexander I. 
Published: January 2024

TPS716 Background: BMF-219 is a selective covalent inhibitor of menin, a transcriptional regulator of oncogenic signaling pathways in multiple cancers, that inhibits the menin/MYC interaction and downregulates the expression of MYC and MYC target genes, including KRAS. In addition, inhibition of the menin complex by BMF-219 alters function of the AP-1 transcription factor, JunD, a crucial factor for KRAS-driven tumorigenesis. Further, inhibition of the menin-MLL complex suppresses expression of Rasgrf1, a guanine nucleotide exchange factor essential for generation of the active RAS-GTP conformation of KRAS, activation of downstream pathways, and tumorigenesis. Preclinically, BMF-219 shows potent abrogation of menin-dependent oncogenic signaling and exerts pan-mutant KRAS anticancer activity independent of the specific KRAS-activating mutation. Methods: COVALENT-102 (NCT05631574) is a prospective, open-label, dose-finding study evaluating the safety, tolerability, and clinical activity of BMF-219 administered daily in adults with unresectable, locally advanced, or metastatic NSCLC (Cohort 1), PDAC (Cohort 2) and CRC (Cohort 3) with activating KRAS mutations who have received standard therapy. All indications as a group follow a 3+3 dose escalation design. BMF-219 is orally administered once or twice daily as continuous therapy in 28-day cycles until progression or intolerability/unacceptable toxicity. Following dose-escalation, each indication will enroll patients in expansion cohorts independently to obtain further safety and efficacy data. Eligible patients include those with any KRAS mutation and (Cohort 1) stage IIIB/IV NSCLC with 2-4 prior lines of therapy including immune checkpoint inhibitors (ICI) &/or platinum-based chemo ± bevacizumab with ECOG 0-2; (Cohort 2) stage III/IV PDAC with ≥ 1 prior line of therapy including either FOLFIRINOX or gemcitabine/nab-paclitaxel, ECOG 0-1; or (Cohort 3) stage III/IV CRC with ≥ 1 prior line of therapy including FOLFOX or FOLFIRI ± bevacizumab (prior ICI if MSI-H/dMMR), ECOG 0-2. Patients must have documented progression and measurable disease as defined by RECIST 1.1. Patients with prior KRAS inhibitor exposure are eligible. Key exclusion criteria include untreated CNS metastasis, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine the optimal biological dose/ recommended Phase 2 dose of BMF-219 monotherapy. Secondary objectives include further evaluation of safety and tolerability, characterization of the PK/PD of BMF-219, and efficacy based on duration of response and disease control rate. PFS, OS, and time to response are exploratory endpoints. Accrual began in January 2023 and is ongoing. Clinical trial information: NCT05631574 .