C4 Therapeutics Shows Proof of Mechanism and Concept for CFT1946 in BRAF V600 Mutant Tumors at ESMO 2024

C4 Therapeutics, Inc. (C4T) has announced initial clinical data from their ongoing trial of CFT1946, an orally bioavailable small molecule designed to degrade BRAF V600 mutations in solid tumors. These results, the first of their kind for a BRAF V600X degrader, were presented by Dr. Maria Vieito at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain.

Andrew Hirsch, president and CEO of C4 Therapeutics, expressed excitement over these findings, emphasizing the potential of CFT1946 to transform the current treatment landscape for patients with BRAF V600 mutant tumors. This new data not only addresses the needs of patients resistant to current therapies but also highlights the capabilities of C4T's TORPEDO platform to design groundbreaking small molecule degraders.

Dr. Vieito praised the early-stage data for CFT1946, noting its impressive safety and tolerability, which may facilitate further studies both as a monotherapy and in combination with other treatments. Chief Medical Officer Dr. Len Reyno echoed these sentiments, emphasizing the promising pharmacokinetic and pharmacodynamic profiles of CFT1946 and its initial anti-tumor activities.

The ongoing Phase 1 trial involves dose escalation of CFT1946 in patients with BRAF V600X solid tumors who have previously received at least one standard therapy for unresectable or metastatic disease. By the cutoff date of July 19, 2024, a total of 36 patients had received CFT1946 across five dosing cohorts. The majority of these patients had previously been treated with BRAF inhibitors, and most had advanced stages of cancer, including melanoma and colorectal cancer.

CFT1946 has demonstrated a favorable safety profile, with no dose-limiting toxicities or serious treatment-related adverse events. Adverse events reported were mostly mild to moderate, and no patients discontinued therapy due to these side effects. Additionally, the pharmacokinetics data showed dose-dependent bioavailability, with degradation of the BRAF V600E protein noted in post-treatment biopsies.

In terms of anti-tumor activity, 27 patients were evaluable at the data cutoff, with 16 showing reductions in metastatic lesions. Among these, two patients achieved a confirmed partial response. Tumor reduction was observed across various cancer types, including significant reductions in melanoma and colorectal cancer. Notably, one patient with stage IV BRAF V600K melanoma experienced a 67% decrease in target lesions, while another with stage IV BRAF V600E pancreatic cancer saw a 55% reduction.

Looking ahead, the trial will continue to enroll patients, with plans to complete the Phase 1 monotherapy dose escalation and expansion cohorts by 2025. Additional cohorts will explore the effects of CFT1946 in combination with other treatments, such as cetuximab for colorectal cancer and trametinib for melanoma. These studies aim to further elucidate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of CFT1946.

C4 Therapeutics remains committed to advancing targeted protein degradation science and aims to create a new generation of medicines that improve patient outcomes. The company continues to rely on its TORPEDO platform to design and optimize small-molecule medicines, addressing challenging diseases and potentially overcoming issues related to drug resistance and undruggable targets.

BRAF V600 mutations are prevalent in various cancers, including melanoma, colorectal cancer, and non-small cell lung cancer. These mutations account for a significant portion of BRAF mutation cancers and often lead to resistance against current FDA-approved BRAF inhibitors, resulting in limited progression-free survival.

CFT1946 is currently the only clinical-stage degrader targeting BRAF V600 mutant solid tumors, with ongoing evaluations in a global Phase 1/2 trial. Initial findings underscore its potential as a potent and selective therapeutic option for patients who have progressed on or after BRAF inhibitor treatments.

C4 Therapeutics remains dedicated to leveraging its innovative approaches to advance its clinical programs and bring transformative therapies to patients in need.