plixorafenib (FORE-8394) / Daiichi Sankyo, Fore Biotherap - LARVOL DELTA

Trial in progress: Feasibility of CSF and plasma ctDNA in BRAF-altered glioma during treatment with plixorafenib. (ASCO 2025) - P1 | "Patients will initiate oral plixorafenib 900mg daily with cobicistat, a CYP3A inhibitor and PK enhancer, when clinically recovered from surgery. The trial is IRB approved and currently open to enrollment. Clinical trial identifier NCT06610682."

Circulating tumor DNA • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • BRAF

FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers. (ASCO 2025) - P2 | "All patients receive plixorafenib continuous dosing, in some cohorts coadministered with cobicistat, a pharmacokinetic (PK) booster. Tumors assessed at cycle 1 day 1, every 9 weeks for 48 weeks, then every 12 weeks. 4Plasma for all patients; plasma and CSF for patients with primary CNS tumors."

Clinical • P2 data • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Colorectal Adenocarcinoma • Colorectal Cancer • Endocrine Cancer • Fatigue • Gastrointestinal Cancer • Gynecologic Cancers • Melanoma • Neuroendocrine Tumor • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF

BRAF oncogenic mutants evade autoinhibition through a common mechanism. (PubMed, Science) - "This structural change likely results from helix αC displacement. PLX8394, a BRAF inhibitor that stabilizes helix αC in an inactive conformation, restored the autoinhibited conformation of oncogenic BRAF, explaining the properties of this class of compounds."

Journal • Oncology • Sarcoma • Solid Tumor • BRAF

FORE Biotherapeutics Raises $38 Million in Series D-2 Financing for the Continued Advancement of Plixorafenib (Businesswire) - "Financing extends Company’s cash runway beyond important clinical milestones anticipated beginning in 2H25, supporting the ongoing execution of the FORTE Master Protocol evaluating plixorafenib as a monotherapy in three distinct patient populations...An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the third quarter of 2025. Pending a positive recommendation from the data monitoring committee, topline data from this trial would be anticipated in the second half of 2026...At the upcoming 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30 - June 3 in Chicago, Fore will present the master protocol design of the ongoing global Phase 2 FORTE clinical trial."

Clinical protocol • Financing • P2 data • CNS Tumor • Solid Tumor

FORE Biotherapeutics to Present Plixorafenib Abstract at the 2025 American Society of Clinical Oncology Annual Meeting (Businesswire) - "FORE Biotherapeutics...announced that a plixorafenib abstract has been selected for poster presentation at the 2025 American Society of Clinical Oncology Annual Meeting (ASCO), taking place May 30-June 3, 2025 in Chicago....At ASCO 2025, Karisa Schreck, M.D., Ph.D., from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, will present a trials-in-progress poster highlighting the study design of the global registration-intended FORTE Master Protocol, which includes four sub-protocol baskets evaluating plixorafenib in distinct patient populations. The three monotherapy indications currently under evaluation are BRAF V600 Recurrent Primary Central Nervous System Tumors, Rare BRAF V600 Mutated Solid Tumors and Solid Tumors with BRAF Fusions."

Trial status • CNS Tumor • Solid Tumor

FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers (AACR 2025) - P2 | "All patients receive plixorafenib continuous dosing, in some cohorts coadministered with cobicistat, a pharmacokinetic booster. Tumors assessed at cycle 1 day 1, every 9 weeks for 48 weeks, then every 12 weeks. 4Plasma ctDNA assessments for all patients; plasma and CSF assessments for patients with primary CNS tumors.BICR, blinded independent central review; BOP2, Bayesian optimal phase 2; CSF, cerebrospinal fluid; ctDNA, circulating tumor DNA; DCR, disease control rate; DOR, duration of response; HGG, high-grade glioma; LGG, low-grade glioma; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; RANO, Response Assessment in Neuro-oncology; RECIST, Response Evaluation Criteria in Solid Tumors."

Clinical • P2 data • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Colorectal Adenocarcinoma • Colorectal Cancer • Cutaneous Melanoma • Endocrine Cancer • Gastrointestinal Cancer • Glioma • Gynecologic Cancers • Lung Cancer • Malignant Glioma • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Small Intestinal Carcinoma • Solid Tumor • Thyroid Gland Carcinoma • BRAF

Inhibition of FASN postpones development of resistance to PLX8394 in colorectal cancer (AACR 2025) - "While the FDA-approved encorafenib plus cetuximab therapy for BRAF-mutant CRC provides a significant benefit, only 22% of patients respond to this therapeutic approach and resistance ultimately develops in the majority of patients. Collectively, these data show that combination of PLX8394 with FASN-targeted therapy at treatment initiation reduces BRAFV600E CRC cell proliferation via inhibition of their cell cycle progression. These findings suggest that targeting FASN could enhance the efficacy and delay the development of resistance to PLX8394 in BRAF-mutant CRC."

Colorectal Cancer • Oncology • Solid Tumor • FASN

Circulating tumor DNA analysis of patients with BRAF-mutated advanced unresectable solid tumors treated with plixorafenib (FORE8394/PLX8394) in phase 1/2a study (AACR 2025) - P1/2 | "Response to plixorafenib was observed through declines in ctDNA BRAF VAF and pERK. Furthermore, the "paradox breaking" property of plixorafenib was confirmed, as no new MAPK mutations emerged after treatment."

Circulating tumor DNA • Clinical • Metastases • P1/2 data • Endocrine Cancer • Melanoma • Oncology • Ovarian Cancer • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF • NF1

FORE Biotherapeutics Presents New Plixorafenib Results at AACR 2025 Demonstrating Pharmacodynamic Effect in Clinical Tumor Biopsies and Decreased V600E Mutant Allele Frequency in ctDNA of 85% of Patients (Businesswire) - "Also being presented at AACR 2025 is a trial in progress poster showcasing the global FORTE master protocol with a basket design, including three monotherapy sub-protocols in patients with BRAF fusions, rare BRAF V600-mutated tumors, and BRAF V600 primary recurrent central nervous system tumors. An interim analysis is planned for each of the monotherapy baskets during 2025. A fourth, exploratory sub-protocol will assess preliminary activity of plixorafenib in BRAF V600-mutated select solid tumors. Alongside primary and key secondary endpoints of overall response rate, duration of response, safety, progression-free survival, overall survival, and pharmacokinetics, key exploratory endpoint of each of the four sub-protocols is a longitudinal ctDNA assessment."

Trial status • Solid Tumor

FORE Biotherapeutics Presents New Plixorafenib Results at AACR 2025 Demonstrating Pharmacodynamic Effect in Clinical Tumor Biopsies and Decreased V600E Mutant Allele Frequency in ctDNA of 85% of Patients (Businesswire) - P1/2a | N=113 | NCT02428712 | Sponsor: Fore Biotherapeutics | "The ctDNA results are from over 70 plixorafenib-treated patients and were an exploratory endpoint from a previously completed Phase 1/2a study. Utilizing next-generation sequencing (NGS), the plasma ctDNA results demonstrated high concordance with tissue biopsy at baseline across tumor types and mutations. Declines of V600 VAF% were observed in 85% of study participants after one cycle of plixorafenib treatment. Declines of class 2 and class 3 BRAF alterations in ctDNA were also observed. In participants with available paired tumor biopsies, decreases in pERK validated ctDNA results and demonstrated the suppression of the MAPK pathway at clinically relevant exposures. In addition, participants with V600E-mutated advanced solid tumors, early changes in V600E VAF% may predict response to plixorafenib, as responders had larger decreases in VAF% from baseline to cycle 2."

P1/2 data • Solid Tumor

A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations (clinicaltrials.gov) - P2 | N=250 | Recruiting | Sponsor: Fore Biotherapeutics | Trial completion date: Aug 2026 ➔ Dec 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Brain Cancer • Endocrine Cancer • Glioblastoma • Melanoma • Oligodendroglioma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

Feasibility of CSF and Plasma ctDNA in BRAF-altered Glioma During Treatment With Plixorafenib (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Circulating tumor DNA • Enrollment open • Brain Cancer • CNS Tumor • Glioma • Oncology • Sarcoma • Solid Tumor • BRAF

FORE Biotherapeutics to Present Two Plixorafenib Abstracts at the American Association for Cancer Research Annual Meeting 2025 (Businesswire) - "The first poster features important results showing that circulating tumor DNA (ctDNA) accurately detects BRAF mutations from tumor biopsies and may be a surrogate marker for monitoring disease. The ctDNA results are from plixorafenib-treated patients and were an exploratory endpoint from a previously completed Phase 1/2a study. The second poster highlights the study design for the recently commenced Phase 2 FORTE basket study evaluating plixorafenib in patients with various types of BRAF-mutated tumors."

Clinical protocol • P1/2 data • Solid Tumor

A Study of the Effects of Food and Cobicistat on Plixorafenib Pharmacokinetics in Healthy Volunteers. (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Fore Biotherapeutics | Recruiting ➔ Completed

Trial completion

Feasibility of CSF and Plasma ctDNA in BRAF-altered Glioma During Treatment With Plixorafenib (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting ➔ Recruiting | Trial completion date: May 2027 ➔ May 2026 | Trial primary completion date: Dec 2026 ➔ Dec 2025

Circulating tumor DNA • Enrollment open • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Oncology • Sarcoma • Solid Tumor • BRAF

Oncogenic non-V600 mutations evade the regulatory machinery of RAF including the Cdc37/Hsp90 chaperone and the 14-3-3 scaffold. (PubMed, Theranostics) - "These BRAF mutants with high dimer propensity sustained a prolonged ERK signaling, and were effectively targeted by RAF dimer breaker plx8394 in vitro and in vivo... Cdc37/Hsp90 chaperones and 14-3-3 scaffolds cooperatively facilitate the switch of RAF proteins from open active dimers to close inactive monomers. Non-V600 mutations disrupt this regulatory machinery, and trap RAF in dimers, which could be targeted by RAF dimer breakers."

Journal • Oncology • ARAF • BRAF • CDC37 • HSP90AA1

Feasibility of CSF and Plasma ctDNA in BRAF-altered Glioma During Treatment With Plixorafenib (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • CNS Tumor • Glioma • Oncology • Sarcoma • Solid Tumor • BRAF

FORE Biotherapeutics Highlights Recent Pipeline Achievements for its Targeted-Oncology Program and Provides Strategic Objectives for 2025 (Businesswire) - "2025 Strategic Objectives and Anticipated Milestones - Continued Execution of the FORTE Master Protocol with Interim Analyses in Three Monotherapy Indications Anticipated in 2025: (i) BRAF V600 Primary Recurrent Central Nervous System Tumors: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the third quarter of 2025. Pending a positive recommendation from the data monitoring committee, topline data from this trial would be anticipated in the second half of 2026...; (ii) Rare BRAF V600 Mutated Solid Tumors: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the fourth quarter of 2025; (iii) Advanced Solid Tumors with BRAF Fusions: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the fourth quarter of 2025."

P2 data • CNS Tumor

A Study of the Effects of Food and Cobicistat on Plixorafenib Pharmacokinetics in Healthy Volunteers. (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: Fore Biotherapeutics | N=12 ➔ 28

Enrollment change

Evaluation of safer-SeqS ctDNA assay optimized for detecting low ctDNA counts from CSF and plasma: assessing sensitivity and feasibility for clinical implementation (SNO 2024) - "Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery. MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. Enrollment is planned to begin November, 2024."

Circulating tumor DNA • Clinical • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

Feasibility of CSF and Plasma ctDNA in BRAF-altered Glioma During Treatment With Plixorafenib (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

New P1 trial • Brain Cancer • CNS Tumor • Glioma • Oncology • Sarcoma • Solid Tumor • BRAF

A Study to Assess the Efficacy and Safety of FORE8394 in Participants with Cancer Harboring BRAF Alterations (clinicaltrials.gov) - P2 | N=250 | Recruiting | Sponsor: Fore Biotherapeutics | N=135 ➔ 250

Enrollment change • Brain Cancer • Glioblastoma • Oligodendroglioma • Oncology • BRAF

PLX120-03: A Study of FORE8394 as a Single Agent in Patients With Advanced Unresectable Solid Tumors (clinicaltrials.gov) - P1/2 | N=113 | Completed | Sponsor: Fore Biotherapeutics | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Jul 2024

Metastases • Trial completion • Trial completion date • Brain Cancer • Oncology • Solid Tumor • BRAF

Safety and efficacy of BRAF inhibitor plixorafenib (FORE8394; PLX8394) in children and adults with recurrent, BRAF-altered primary central nervous system tumors (PCNST) (ISPNO 2024) - P1/2 | NCT02428712 | Sponsor: PharmaPolaris | "Plixorafenib had low rates of symptomatic TEAEs with a manageable safety profile, and high ORR in MAPKi-naive BRAFV600 PCNST. A phase 2 study in children and adults is ongoing (NCT05503797)."

P1/2 data

Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function. (PubMed, Life Sci Alliance) - "Endothelial barrier function and junction integrity were impaired upon treatment with vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with dabrafenib or encorafenib. Together, these findings provide insights into the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma."

Journal • Melanoma • Oncology • Solid Tumor