C4 Therapeutics, Inc. presented a poster at the American Association for Cancer Research (AACR) Annual Meeting 2024 highlighting new preclinical data for CFT1946 across multiple models of BRAF V600X mutant colorectal cancer (CRC) and non-small cell lung cancer (NSCLC), additional BRAF inhibitor (BRAFi)-resistant melanoma models, and an intracranial model of BRAF V600E metastatic melanoma. CFT1946 is an orally bioavailable BiDAC? degrader that selectively degrades the BRAF V600X mutant protein and prevents RAF dimer-mediated resistance.

While currently approved BRAF inhibitors are also selective for BRAF V600X mutant proteins, their activity is limited by primary or acquired resistance often mediated by mechanisms that promote RAF dimerization. Further, in a significant number of patients with BRAF V600X melanoma and NSCLC, the disease metastasizes to the brain. BRAF inhibitors have limited brain penetration, while CFT1946 demonstrates CNS activity in preclinical models.

Key findings include: Promising activity of CFT1946 as a single agent in a broad range of BRAF V600X preclinical models, including models of BRAFi resistance; CFT1946 as a single agent and in combination with cetuximab demonstrates superior activity to the standard of care combination, BRAFi with cetuximab, in all CRC models tested to date, further supporting the potential of a degrader advantage in this setting and CFT1946 demonstrates superior prolongation of survival when compared to encorafenib in an intracranial model of metastatic melanoma. Collectively, these data support the ongoing clinical evaluation of CFT1946, which is the only BRAF V600X degrader in the clinic to date. The CFT1946 Phase 1/2 trial continues to progress and data from the Phase 1 monotherapy dose escalation portion of the trial are expected to be presented in the second half of this year.

Details of the poster are as follows: Title: CFT1946, a potent, selective BRAF V600X mutant-specific degrader demonstrates superior activity as a single agent to clinically approved BRAF inhibitors and standard of care combinations in preclinical models of BRAF V600X melanoma, CRC, NSCLC, and brain metastasis; Abstract Number: 1658; Session Date and Time: April 8, 2024 9:00 AM - 12:30 PM PT; Location: Poster Section 14; Session Title: Cell Signaling Components as Therapeutic Targets; Presenter: Bridget Kreger, Ph.D., principal scientist, biology.