Reference Detail

Ref Type

abstract

PMID

Authors

M. Vieito, M. Mckean, A.I. Spira, E. Rosen, J. Rodon, V. Moreno Garcia, V. Gambardella, O. Saavedra, S. Cousin, P. Cassier, I. Korakis, B.A. Van Tine, V.T-L. Ma, A. Ali, E. Hinojosa, R. Lobbardi, H. Liu17 ∙ E. Hurh, L. Reyno, E. Buchbinder

Title

612O Preliminary results from a phase I study of CFT1946, a novel BIDAC degrader in mutant BRAF V600 solid tumors

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	35	Supplement 2	2024

URL

https://www.annalsofoncology.org/article/S0923-7534(24)02198-7/fulltext

Abstract Text

Background CFT1946, an oral BiDAC™ degrader that selectively degrades and inhibits mutant BRAF V600 protein, is designed to overcome RAF dimer-driven resistance and paradoxical activation of approved BRAF inhibitors (BRAFi). Methods CFT1946-1101 (NCT05668585) is an ongoing first-in-human, multicenter, phase 1/2 dose-escalation and cohort-expansion clinical trial. Phase 1 escalation monotherapy arm of CFT1946 includes patients (pts) with refractory BRAF-V600 mutant solid tumors (non-CNS), melanoma (mel), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or anaplastic thyroid cancer. Primary objectives include safety and tolerability. Secondary objectives include pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy. Blood samples were collected for PK analysis and ctDNA analysis. Tumor tissue was collected to measure BRAF V600 degradation and inhibition of the relevant pathways. Results As of April 12, 2024, 25 pts were treated with CFT1946 monotherapy at doses of 20 to 320 mg BID. Tumor types were mel (40%), CRC (40%), other (12%), and NSCLC (8%). 22/25 pts had a V600E mutation, 2 had a V600K mutation and 1 had a V600R mutation. 24/25 pts were BRAFi exposed, and all received ≥2 prior lines (median=3). No DLT occurred. Treatment-emergent adverse events (TEAEs) that occurred in >15% of pts included: anemia (any grade, 20%/grade ≥3, 4%), abdominal pain (20%/4%), and pyrexia (16%/0%). 8/25 pts experienced grade ≥3 TEAEs, none were treatment related. Plasma exposure of CFT1946 increased dose-proportionally up to 80 mg BID and less than proportionally at higher doses. Available BRAF V600E immunohistochemistry staining shows target degradation at 80mg and 160mg. BRAF V600E/K/R allele fraction decline is observed with CFT1946. At data cut, 1 pt had an unconfirmed partial response (uPR) and 7/14 (50%) efficacy evaluable pts had a best response of stable disease or better. After data cutoff, 1 recently enrolled pt (PD on BRAFi) had an uPR with a 64% reduction of target lesions. Conclusions 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. Clinical trial identification NCT05668585.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	predicted - sensitive	CFT1946	Phase I	Actionable	In a Phase I trial, CFT1946 treatment demonstrated safety and preliminary activity in patients with advanced solid tumors (n=25) including melanoma (40%), colorectal cancer (40%), non-small cell lung cancer (8%), and other non-CNS tumors harboring BRAF V600E (n=22), V600K (n=2), or V600R (n=1), with 1 unconfirmed partial response (uPR) and 7 stable diseases in efficacy evaluable patients (n=14) at data cutoff, and 1 additional uPR after data cutoff (Ann Oncol (2024) 35 (Suppl_2): S490-S491; NCT05668585).	detail...