お知らせ • Sep 13
C4 Therapeutics, Inc. Presents Monotherapy Data Demonstrating Proof of Mechanism and Early Evidence of Proof of Concept from Ongoing CFT1946 Phase 1 Trial in BRAF V600 Mutant Solid Tumors at European Society for Medical Oncology Congress 2024
C4 Therapeutics, Inc. (C4T) announced initial clinical data from the ongoing clinical trial of CFT1946, an orally bioavailable small molecule degrader of BRAF V600 mutations in solid tumors. These data, the first clinical results for a BRAF V600X degrader, were shared as a proffered paper in an oral presentation by Maria Vieito, M.D., MSc, medical oncologist at Vall d’Hebron University Hospital, Barcelona, Spain, at the European Society for Medical Oncology (ESMO) Congress 2024, being held September 13 – 17 in Barcelona, Spain. At the ESMO Congress 2024, C4T reported initial monotherapy data from the ongoing dose escalation Phase 1 clinical trial evaluating twice daily oral dosing of CFT1946, a degrader of BRAF V600 mutants, in patients with BRAF V600X solid tumors who have received at least one prior standard of care therapy for unresectable locally advanced or metastatic disease. Prior therapy must include a BRAF inhibitor, unless access is limited by regional regulatory approvals or reimbursement. As of the data cutoff date of July 19, 2024, a total of 36 patients received CFT1946 monotherapy across five dose escalation cohorts (20 mg BID, 80 mg BID, 160 mg BID, 320 mg BID and 640 mg BID). Patients received a median of three prior therapies; 35 patients (97%) had received prior BRAF inhibitor therapy. Thirty-three patients (92%) had a BRAF V600E mutation, two patients (6%) had a BRAF V600K mutation and one patient (2%) had a BRAF V600R mutation. Fourteen patients (39%) had melanoma, 14 patients (39%) had colorectal cancer, two patients (6%) had non-small cell lung cancer and six patients (17%) had other cancers. All patients had unresectable, locally advanced or metastatic disease, and 32 patients (89%) entered the study with Stage IV cancer. Safety and Tolerability: CFT1946 has a well-tolerated safety profile that supports further clinical development as monotherapy and in combination with MEK and EGFR inhibitors. There were no dose-limiting toxicities and no treatment-related serious adverse events. Adverse events occurring in more than 10% of patients were all Grade 1 or Grade 2. No patients discontinued therapy or experienced treatment interruptions due to treatment-related adverse events. No patients receiving CFT1946 monotherapy experienced a Grade 3 or higher treatment-related cutaneous adverse event. These cutaneous adverse events, which are related to BRAF wild-type inhibition, are commonly seen with BRAF inhibitors. Pharmacokinetics (PK) and Pharmacodynamics (PD): Initial data demonstrating dose-dependent bioavailability and degradation of BRAF V600E protein support CFT1946 proof of mechanism. CFT1946 exhibits dose-dependent bioavailability in the five dose levels explored to date. In all available post-treatment biopsies collected to date, degradation of BRAF V600E protein is observed. Anti-Tumor Activity: CFT1946 demonstrates evidence of monotherapy anti-tumor activity, supportive of early proof of degrader concept. At data cutoff, 27 patients were evaluable for anti-tumor activity, which is measured by RECIST 1.1 criteria. 16 patients demonstrated reduction of target metastatic lesions. Two patients achieved a confirmed Partial Response. Reduction of target lesion tumors was observed across histologies. Of the 27 patients evaluable for anti-tumor activity: Eleven patients had melanoma, eight of whom had evidence of tumor reduction. One patient with Stage IV BRAF V600K melanoma enrolled in the 320 mg BID cohort achieved a 67% decrease in target lesions as measured by RECIST 1.1 criteria. This patient remains on CFT1946 treatment and in response. Nine patients had colorectal cancer, three of whom had evidence of tumor reduction. Seven patients have other tumor histologies, three of whom had evidence of tumor reduction. One patient with Stage IV BRAF V600E pancreatic cancer, who has liver metastases, enrolled in the 640 mg BID cohort achieved a 55% decrease in target lesion as measured by RECIST 1.1 criteria. This patient remains on CFT1946 treatment and in response. As of data cutoff, 11 of the patients who were evaluable for anti-tumor activity remain on therapy. Next Steps and Future Milestones for CFT1946: The CFT1946 Phase 1 trial is ongoing and multiple indication-specific cohorts are advancing. Next steps and related milestones for CFT1946 include: Complete Phase 1 monotherapy dose escalation – This portion of the trial is enrolling patients with BRAF V600X mutations across solid tumor indications. Patients are currently enrolling in the 640 mg BID PD backfill cohort as this dose level was recently declared safe. The full monotherapy dose escalation data are expected in 2025. Complete expansion cohort exploring CFT1946 monotherapy in melanoma – This Phase 1 exploratory expansion cohort is evaluating the potential of CFT1946 monotherapy for melanoma patients refractory to BRAF inhibitor therapies. Enrollment for the 320 mg BID dose level is complete, and enrollment is ongoing for the 640 mg BID dose level. Data from these dose levels are expected in 2025. Complete dose escalation cohort exploring CFT1946 in combination with cetuximab in colorectal cancer – This Phase 1b dose escalation cohort is enrolling patients at the 160 mg BID dose level to explore safety and tolerability, PK, PD and anti-tumor activity of CFT1946 in combination with cetuximab. These data are expected in 2025. Initiate dose escalation cohort exploring CFT1946 in combination with trametinib in melanoma – This Phase 1b dose escalation cohort will explore safety and tolerability, PK, PD and anti-tumor activity of CFT1946 in combination with trametinib. C4T expects to initiate this cohort by year-end 2024.