C4 Therapeutics presented initial clinical data from its Phase 1 trial of CFT1946, an oral small molecule degrader targeting BRAF V600 mutations in solid tumors, at the European Society for Medical Oncology (ESMO) Congress 2024. The results, marking the first clinical data for a BRAF V600X degrader, suggest a potential new approach for patients with these mutations who have progressed on or after BRAF inhibitor therapies.
The Phase 1 dose escalation trial evaluated twice-daily oral dosing of CFT1946 in patients with BRAF V600X solid tumors who had received prior standard of care therapy. As of the July 19, 2024, data cutoff, 36 patients received CFT1946 monotherapy across five dose cohorts (20 mg BID to 640 mg BID). Patients had received a median of three prior therapies, with 97% having prior BRAF inhibitor therapy. The study included patients with melanoma (39%), colorectal cancer (39%), non-small cell lung cancer (6%), and other cancers (17%).
Safety and Tolerability
CFT1946 demonstrated a favorable safety profile, supporting further clinical development as a monotherapy and in combination with MEK and EGFR inhibitors. There were no dose-limiting toxicities or treatment-related serious adverse events. Adverse events occurring in more than 10% of patients were Grade 1 or 2. No patients discontinued therapy or experienced treatment interruptions due to treatment-related adverse events, and no Grade 3 or higher treatment-related cutaneous adverse events were reported.
Pharmacokinetics and Pharmacodynamics
Initial data showed dose-dependent bioavailability and degradation of BRAF V600E protein, supporting CFT1946's mechanism of action. Dose-dependent bioavailability was observed across the five dose levels. Degradation of BRAF V600E protein was observed in all available post-treatment biopsies collected to date.
Anti-Tumor Activity
CFT1946 demonstrated early evidence of monotherapy anti-tumor activity, supporting the degrader concept. Of the 27 patients evaluable for anti-tumor activity, 16 showed a reduction in target metastatic lesions, and two achieved a confirmed partial response. Tumor reduction was observed across various histologies. For example, one patient with Stage IV BRAF V600K melanoma achieved a 67% decrease in target lesions and remained on treatment. Another patient with Stage IV BRAF V600E pancreatic cancer achieved a 55% decrease in target lesions and also remained on treatment.
Ongoing Trial and Future Directions
The Phase 1 trial is ongoing, with multiple indication-specific cohorts advancing. Future milestones include completing the monotherapy dose escalation, completing the expansion cohort exploring CFT1946 monotherapy in melanoma, completing the dose escalation cohort exploring CFT1946 in combination with cetuximab in colorectal cancer, and initiating a dose escalation cohort exploring CFT1946 in combination with trametinib in melanoma. Data from these efforts are expected in 2025 and beyond.
According to Andrew Hirsch, president and chief executive officer of C4 Therapeutics, these clinical data reinforce the potential of their TORPEDO® platform to design innovative small molecule degraders. Dr. Vieito noted being encouraged by the safety and tolerability of CFT1946, which may allow for additional monotherapy exploration as well as combination approaches. Len Reyno, M.D., chief medical officer of C4 Therapeutics, stated that the data support the hypothesis that degradation may offer a new therapeutic option over inhibition for BRAF V600 mutant solid tumors.
BRAF mutations are found in approximately 5% of all cancers, including melanoma, colorectal cancer, and non-small cell lung cancer. Up to 90% of these mutations are BRAF V600 mutations. Resistance to FDA-approved BRAF inhibitors results in median progression-free survival rates of less than 15 months across all indications, highlighting the need for new therapeutic strategies.
