C4 Therapeutics (CCCC) Study Update summary

Study overview and objectives

• Phase 1/2 trial of CFT1946, an oral BiDAC degrader targeting BRAF V600X mutations in advanced/metastatic solid tumors, including melanoma, colorectal cancer, NSCLC, and others, refractory to BRAF inhibitors.

• 36 patients enrolled across multiple tumor types, most with prior BRAF inhibitor therapy and advanced/metastatic disease.

• Primary endpoints: safety, tolerability, and recommended phase II dose; secondary endpoints: anti-tumor activity, pharmacokinetics, and pharmacodynamics.

• Dose escalation from 20 to 640 mg BID using a Bayesian model; expansion cohorts ongoing at 320 and 640 mg for melanoma and 160 mg for CRC in combination.

• Combination cohorts with cetuximab (CRC) and trametinib (melanoma/NSCLC) are planned or ongoing.

Safety and tolerability

• CFT1946 was well tolerated at all dose levels, with no protocol-defined dose-limiting toxicities or treatment-related serious adverse events.

• Only one grade 3 or higher treatment-related event (hypertension at 640 mg) was reported, with the patient continuing therapy.

• No severe cutaneous adverse events or wild-type BRAF inhibition toxicities observed, a notable improvement over approved BRAF inhibitors.

• Most adverse events were mild to moderate (grade 1 or 2), and no events led to discontinuation, interruption, or dose reduction.

• Most common TEAEs included anemia, abdominal pain, peripheral edema, and pyrexia, each in less than 20% of patients.

Pharmacokinetics and pharmacodynamics

• CFT1946 showed dose-dependent oral bioavailability and plasma exposure, with no significant drug accumulation, supporting BID dosing.

• Post-treatment biopsies confirmed robust degradation of BRAF V600E protein, with median H-score dropping from 200 to 100 by day 15, supporting proof of mechanism.

• All tested exposures were associated with degradation, though more data are needed to correlate dose, degradation, and outcomes.