A phase 1/2 study of CFT1946, a novel, bifunctional degradation activating compound (BIDAC) degrader, of mutant BRAF V600 as monotherapy and in combination with trametinib, in mutant BRAF V600 solid tumors

TPS3163 Background: BRAF is a protein kinase that acts as a signal transducer in the MAPK pathway. Mutant BRAF V600 is capable of uncontrolled signaling and is constitutively active and signals as a monomer, leading to hyperactivation of MEK, ERK, and dysregulation of cellular proliferation. Mutant BRAF V600 is a clinically-validated target in a variety of cancers including melanoma, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and anaplastic thyroid carcinoma (ATC). Currently approved BRAF inhibitors (BRAFi) result in paradoxical RAF activation as the mutant BRAF protein is still able to dimerize with WT BRAF, resulting in a dimeric signaling complex. CFT1946 is a novel, orally bioavailable BiDAC degrader that inhibits and degrades mutant BRAF V600 protein. Distinct from approved BRAFi, CFT1946 avoids paradoxical RAF activation as the degraded BRAF V600 mutant protein can no longer incorporate into a dimeric signaling complex. CFT1946 is selective for the mutant protein and spares WT BRAF V600. CFT1946 has demonstrated preclinical activity in BRAF V600 mutant in vitro and in vivo models, including models resistant to BRAFi. These preclinical data provide rationale for a first-in-human (FIH) study to evaluate CFT1946 in BRAF V600 mutant solid tumors. Methods: This is a FIH, open-label, multicenter, Phase 1/2 clinical trial to characterize the initial safety, tolerability, and preliminary efficacy of CFT1946 and CFT1946+trametinib in BRAF V600 mutant melanoma, NSCLC, CRC, ATC, and other non-CNS BRAF V600 mutant solid tumors. This study includes 2 phases: dose escalation Phase 1 comprising CFT1946 (Arm A) with a starting oral dose of 20 mg twice daily and CFT1946+trametinib (Arm B) as well as dose expansion Phase 2 comprising CFT1946 (Arm A1) and CFT1946+trametinib (Arms B1 and B2). Arm A1 and B1 will include BRAF V600 mutant melanoma and NSCLC with prior BRAFi therapy while Arm B2 will enroll BRAF V600 mutant NSCLC who are BRAFi-naïve. Phase 2 will be initiated once the RP2D has been identified. Eligible subjects are ≥18yo with documented BRAF V600 mutant cancers who have received ≥1 prior therapy. CFT1946 will be administered orally in 28-day cycles until disease progression or intolerable toxicity. Primary objectives include safety, tolerability, RP2D and preliminary antitumor activity of CFT1946 monotherapy and in combination with trametinib. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics. Key inclusion criteria include documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy; at least 1 prior line of standard-of-care therapy for locally advanced or metastatic disease. The study is anticipated to enroll 101-122 patients across 11 participating US and European sites and is currently open to enrollment (NCT05668585). Clinical trial information: NCT05668585 .