CFT1946 / C4 Therap - LARVOL DELTA

CFT1946-1101: A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 as Monotherapy and Combination Therapy in Subjects With BRAF V600 Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=89 | Completed | Sponsor: C4 Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Apr 2027 ➔ Nov 2025 | Trial primary completion date: Mar 2027 ➔ Nov 2025

Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MSI

CFT1946 is an Orally Available Brain-Penetrant BRAFV600-Mutant Degrader that Overcomes BRAF Inhibitor Resistance. (PubMed, Cancer Res) - "CFT1946 was efficacious in an intracranial BRAFV600E melanoma tumor model and demonstrated robust activity in multiple cellular and patient-derived BRAFV600-mutant melanoma and CRC models of acquired and adaptive RAF-dimer driven BRAFi-resistance. CFT1946 therefore represents an effective therapeutic modality with the potential to overcome the key limitations of current BRAFV600-mutant targeted therapies."

Journal • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • CRBN

CFT1946 is an Orally Available Brain-Penetrant BRAFV600-Mutant Degrader that Overcomes BRAF Inhibitor Resistance (Cancer Res) - "CFT1946 was efficacious in an intracranial BRAFV600E melanoma tumor model and demonstrated robust activity in multiple cellular and patient-derived BRAFV600-mutant melanoma and CRC models of acquired and adaptive RAF-dimer driven BRAFi-resistance."

Preclinical • Colorectal Cancer • Melanoma

CFT1946-1101: A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 as Monotherapy and Combination Therapy in Subjects With BRAF V600 Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=89 | Active, not recruiting | Sponsor: C4 Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P1/2 ➔ P1 | N=206 ➔ 89

Enrollment change • Enrollment closed • Monotherapy • Phase classification • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MSI

C4 Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Recent Business Highlights (GlobeNewswire) - "KEY UPCOMING MILESTONES: CFT1946: Complete monotherapy Phase 1 dose escalation in BRAF V600 mutant solid tumors in the first half of 2025; Present Phase 1 data in the second half of 2025, which will include: (1) CFT1946 monotherapy in BRAF V600 mutant solid tumors, (2) CFT1946 monotherapy expansion in melanoma and (3) CFT1946 in combination with cetuximab in CRC."

P1 data • Trial status • Colorectal Cancer • Melanoma • Solid Tumor

C4 Therapeutics Announces 2025 Milestones Across Clinical Portfolio of Degrader Medicines Pursuing Targets of High Unmet Need in Oncology (GlobeNewswire) - "ANTICIPATED 2025 MILESTONES - CFT1946: Complete monotherapy Phase 1 dose escalation in BRAF V600 mutant solid tumors in the first half of 2025. Generate data from the Phase 1 cohorts exploring monotherapy CFT1946 in melanoma, CFT1946 in combination with cetuximab in CRC and CFT1946 in combination with trametinib in melanoma. Data from these cohorts will define and enable the next phase of development. Present Phase 1 data in the second half of 2025. These presentations will include: (1) monotherapy in BRAF V600 mutant solid tumors, (2) monotherapy expansion cohorts in melanoma, and (3) in combination with cetuximab in CRC. CFT8919: Evaluate data from the Phase 1 dose escalation study in Greater China, which is led by partner Betta Pharmaceuticals, in patients with locally or advanced metastatic NSCLC harboring an EGFR L858R mutation. These data will be used to determine the next phase of development."

P1 data • Trial status • Colorectal Cancer • Melanoma • Non Small Cell Lung Cancer • Solid Tumor

PD-1 refractory melanoma: BRAF MEK vs IPI/NIVO (YouTube) - "After patients get single agent anti-PD1, what is better if they progress to give them anti-PD1 anti-CTLA-4 ipilimumab or if the patients' tumor is BRAF V600 to give them targeted therapy? We asked Jeffrey Sosman...about his position after the Great Debate about the issue at Melanoma Bridge 2024."

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A 3D graph like the one above & here looks cool, but 3D effect serves to distort the data. Due to 3D perspective in this fig, notice how EGFR (12.7%) & KRAS nonG12C groups (23.1%) look ~same, as do BRAF V600E (1.8%) v non-V600E (3.9%). 3D effect adds confusion >> value. (3/7)

Current treatment options for brain metastases in advanced melanoma (YouTube) - "Allison Betof Warner, MD...discusses current treatments available for the management of brain metastases in patients with advanced melanoma, which occur in 30 to 40% of patients at the time of diagnosis. Results from the CheckMate 204 (NCT02320058) and ABC (NCT02374242) trials have indicated ipilimumab and nivolumab as frontline treatments. Patients with BRAF V600 mutations undergo targeted therapy with either a combination of dabrafenib and trametinib or encorafenib and binimetinib. Ensuring its efficacy as a long-term treatment option remain a challenge in this area. This interview took place at the Society for Melanoma Research (SMR) 2024 Annual Meeting in New Orleans, LA."

Interview • Video

C4 Therapeutics Reports Third Quarter 2024 Financial Results and Recent Business Highlights (GlobeNewswire) - "CFT1946: Initiate the Phase 1b dose escalation cohort evaluating CFT1946 in combination with trametinib in melanoma by year-end; Present data from multiple anticipated readouts in 2025, including: Full monotherapy CFT1946 dose escalation cohorts in BRAF V600 mutant solid tumors; Expansion cohorts evaluating CFT1946 as a monotherapy in melanoma; Phase 1b dose escalation cohort evaluating CFT1946 in combination with cetuximab in CRC."

P1 data • Trial status • Colorectal Cancer • Melanoma • Oncology • Solid Tumor

Improving clinical outcomes for BRAF V600 colorectal cancer (YouTube) - "Dr. Ryan Corcoran of MGH discusses BRAF crc and clinical trial options."

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Promising results for BRAFV600E mCRC patients. Breakwater SLI cohort 3 results @TaberneroJosep #ESMO24 @myESMO

Preliminary results from a phase I study of CFT1946, a novel BIDAC degrader in mutant BRAF V600 solid tumors (ESMO 2024) - P1/2 | "CFT1946 was well tolerated with evidence of BRAF V600E degradation and relevant pathway inhibition. Early evidence of monotherapy efficacy was observed; further dose exploration is ongoing. Updated data will be presented at the conference."

P1 data • CNS Tumor • Colorectal Cancer • Endocrine Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF

Next Steps and Future Milestones for CFT1946 (GlobeNewswire) - "Complete dose escalation cohort exploring CFT1946 in combination with cetuximab in colorectal cancer....These data are expected in 2025; Initiate dose escalation cohort exploring CFT1946 in combination with trametinib in melanoma....C4T expects to initiate this cohort by year-end 2024."

P1 data • Trial status • Colorectal Cancer • Melanoma • Oncology • Solid Tumor

C4 Therapeutics 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 the European Society for Medical Oncology (ESMO) Congress 2024 (GlobeNewswire) - P1/2 | N=206 | NCT05668585 | Sponsor; C4 Therapeutics, Inc. | "CFT1946 Is Well-Tolerated at All Dose Levels; No Dose-Limiting Toxicities; CFT1946 Achieves Dose Proportional Pharmacokinetic Exposure; Successfully Degrades BRAF V600 Mutant Protein; Early Evidence of CFT1946 Monotherapy Anti-Tumor Activity in Patients Who Have Progressed on or After BRAF Inhibitor Therapies; Majority of Patients Demonstrated Tumor Reduction Across V600 Mutation Types; CFT1946 Global Phase 1 Trial Continues to Enroll; Monotherapy and Combination Expansion Cohorts Advancing With Additional Data Expected in 2025."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Next Steps and Future Milestones for CFT1946 (GlobeNewswire) - "Complete Phase 1 monotherapy dose escalation – This portion of the trial is enrolling patients with BRAF V600X mutations across solid tumor indications....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....Data from these dose levels are expected in 2025."

P1 data • Trial status • Melanoma • Solid Tumor

C4 Therapeutics to Present Preliminary CFT1946 Monotherapy Phase 1 Clinical Data at the European Society for Medical Oncology (ESMO) Congress 2024 (GlobeNewswire) - "C4 Therapeutics...announced the abstract sharing clinical data from its ongoing Phase 1 clinical trial of CFT1946, a novel BiDAC degrader, in mutant BRAF V600 solid tumors, was released in conjunction with the ESMO Congress 2024....Data on 36 patients, with a data cut-off date of July 19, 2024, will be presented as a proffered paper in an oral presentation scheduled for Friday, September 13, 2024 at 4:10 pm CEST (10:10 am ET) at the ESMO Congress 2024. This oral presentation will include patient demographics, safety, pharmacokinetic, pharmacodynamic and anti-tumor activity data as measured by RECIST 1.1 criteria."

P1 data • Solid Tumor

Dr Long on Unmet Needs in BRAF-Mutant Melanoma (YouTube) - "Georgina V. Long, MBBS, PhD...discusses the remaining unmet needs for patients with BRAF-mutant melanoma and how data from the phase 3 NADINA trial (NCT04949113) could help address some of these needs."

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C4 Therapeutics Announces European Society for Medical Oncology (ESMO) Changed the Previously Accepted CFT1946 Preliminary Phase 1 Abstract to a Proffered Paper Presentation (GlobeNewswire) - "C4 Therapeutics, Inc...announced the ESMO Congress decided to move C4T’s previously accepted preliminary monotherapy Phase 1 abstract for CFT1946, a novel BiDAC degrader in mutant BRAF V600 solid tumors, to an oral presentation....C4T will host an investor webcast on Friday, September 13, 2024 to discuss the CFT1946 monotherapy data from ongoing CFT1946 Phase 1 trial in BRAF V600 solid tumors."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Skin Cancer • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

Adjuvant Dabrafenib Plus Trametinib for Stage III BRAF V600–Mutated Melanoma: Final Results of the COMBI-AD Trial (THE ASCO POST) - "Georgina V. Long, MD, PhD...reported the final follow-up analysis of the phase III COMBI-AD trial at the 2024 ASCO Annual Meeting (Abstract 9500) and published their findings in The New England Journal of Medicine.1 With a maximum follow-up of more than 10 years, and a median follow-up of 8 years, continued improvements were seen in relapse-free and distant metastasis–free survival, as well as a 20% lower risk of death, with the adjuvant combination of the BRAF-targeted agent dabrafenib plus the MEK inhibitor trametinib in patients with resected stage III melanoma and BRAF V600E or V600K mutations."

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C4 Therapeutics Reports Second Quarter 2024 Financial Results and Recent Business Highlights (GlobeNewswire) - "KEY UPCOMING MILESTONES: (i) Cemsidomide: Present updated data from at least three dose levels from the dose escalation and expansion cohorts of the ongoing Phase 1/2 clinical trial in R/R MM in Q4 2024; Present data from at least four dose levels from the dose escalation portion of the ongoing Phase 1/2 clinical trial in R/R NHL in Q4 2024; Complete Phase 1 dose exploration in R/R MM and R/R NHL by year-end 2024; (ii) CFT1946: Present data from at least five dose levels from the ongoing Phase 1 monotherapy dose escalation trial in BRAF V600X solid tumors as a mini oral presentation on Saturday, September 14, 2024 from 2:45 – 2:50 CEST at the ESMO Congress 2024 in Barcelona, Spain."

P1 data • P1/2 data • Trial status • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Solid Tumor

Drug Combinations Improve Survival in Melanoma (Medscape) - "If you look at melanoma-specific survival, there were similar data to the overall group, at 76% at 100 months vs 70%, which I think clearly establishes that dabrafenib-trametinib is an impressive standard-of-care adjuvant therapy in patients with stage IIIA/B/C disease by AJCC Seventh Edition criteria who are candidates for adjuvant therapy and are BRAF mutated, whether BRAF V600E or BRAF V600K."

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Adjuvant Dabrafenib Plus Trametinib Improved Long-Term Survival Among Patients With Advanced-Stage Melanoma Harboring BRAF V600 Mutations (THE ASCO POST) - "As previously reported, 'Five-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis–free survival than placebo among patients with BRAF V600–mutated stage III melanoma,' stated Georgina Long, MD, PhD...and coauthors. However, 'longer-term data were needed, including data regarding overall survival.'"

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C4 Therapeutics to Present Preliminary Monotherapy Data from the Ongoing Phase 1 Trial of CFT1946 as a Mini Oral Presentation at the ESMO Congress 2024 (GlobeNewswire) - "C4 Therapeutics...announced that preliminary data from the monotherapy dose escalation portion of the ongoing Phase 1/2 clinical trial of CFT1946, a novel BiDAC degrader in mutant BRAF V600 solid tumors, will be presented as a mini oral presentation at the European Society for Medical Oncology (ESMO) Congress 2024 taking place September 13 - 17, 2024 in Barcelona, Spain."

P1 data • Solid Tumor

Targeted induction before immunotherapy shows limited benefit in advanced melanoma (Healio) - "'I think these studies show quite clearly although our patients do seem to benefit significantly when we start them on combination immunotherapy, but there is a subset of patients for whom immunotherapy may not be possible or reasonable at the outset,' Chandra said....Multiple treatments exist for patients with advanced BRAF V600E or V600K melanoma, including various immunotherapies or targeted therapy with BRAF plus MEK in inhibitors, according to background information Robert presented."

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