Abstract CT154: Clinical activity and safety of novel BRAF inhibitor plixorafenib (FORE8394) in BRAF V600-mutated advanced colorectal cancers (CRC)

Abstract BRAF V600 mutant CRC is an aggressive subset with shorter survival. Current BRAF inhibitors (BRAFis) are limited by rapid resistance and side effects. There is a high unmet need in patients who progress on BRAFi-containing regimens. Plixorafenib is a paradox breaker designed to disrupt RAF dimers, selectively inhibiting V600 and non-V600 BRAF alterations without activating the MAPK pathway. PLX120-03, a completed single-arm phase 1/2a study assessed optimal dose, safety, and efficacy of plixorafenib monotherapy in BRAF-altered solid tumors. Preliminary data for the total population were reported previously. In this first disclosure of a prespecified efficacy analysis for BRAF V600 mutated CRC (N=14), median age was 60 years, 57% were female, and 100% were White. Participants (pts) received a median of 2 prior lines of treatment, and one received a prior MAPK inhibitor (MAPKi) -containing regimen. For 13 pts with no prior MAPKi, disease control rate with plixorafenib monotherapy was 62% and median PFS was 3. 5 months (mos). There was confirmed PR (ORR 8%) lasting 3. 7 mos (treatment duration 6 mos) ; the MAPKi pretreated pt had PD. Seven pts had SD (treatment duration range: 3. 7-28. 7 mos) with 4 remaining on treatment ≥6 mos. Clinical benefit correlated with fewer lines of prior therapy. Safety was encouraging and consistent with the total population; TEAEs were primarily low-grade LFT elevations, GI disorders, and fatigue. There were 11 grade 3 TEAEs in 5 pts, 8 unrelated and 3 related (decreased appetite, diarrhea, hyperglycemia), and no discontinuations due to TEAEs. Plasma ctDNA alterations at baseline and subsequent timepoints were analyzed (n=12). Decreases in BRAF variant allele frequency (VAF) and intratumor ERK phosphorylation after administration of plixorafenib were observed, confirming direct PD effects. BRAF VAF decreased throughout treatment and rebounded at PD, matching the dynamics of tumor volume changes. At the end of treatment, we identified lower rates of acquired mutations within the MAPK (KRAS, MAP2K1, MET AMP) and PI3K (PIK3CA, AKT2, AKT3) pathways compared to that for approved BRAFis. NRAS mutations or BRAF exon deletions were not observed. Other acquired mutations found in 2 pt were NF1 (n=2), androgen receptor (AR; n=2), and CDKN2A/B CNV (n=3). In pts who did not respond to plixorafenib, baseline mutations in RTKs, NF1, and PI3K pathway (PTEN, PIK3CA, AKT) were identified and may have contributed to resistance. Plixorafenib monotherapy in heavily pre-treated pts with BRAF V600 mutated CRC demonstrated activity comparable to approved BRAFi monotherapy with a markedly improved safety profile. ctDNA data showed a pattern of resistance distinct from that of approved BRAFis, with lower acquired MAPK pathway and PI3K pathway mutations. These data warrant exploration of combination approaches of plixorafenib with targeted drugs or chemotherapy. Citation Format: Rona Yaeger, Sunil Sharma, Aparna Parikh, Stacie Peacock Shepherd, Manish Monga, Ping Jiang, Jessica Jang, Michael Paz, Frank Tsai, Ulka Vaishampayan, Jordi Rodon. Clinical activity and safety of novel BRAF inhibitor plixorafenib (FORE8394) in BRAF V600-mutated advanced colorectal cancers (CRC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT154.