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

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 | Trial completion date: May 2026 ➔ Jun 2027 | Trial primary completion date: Dec 2025 ➔ Jun 2026

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

Feasibility of CSF and plasma ctDNA in BRAF-altered glioma during treatment with plixorafenib: trial in progress (SNO 2025) - "Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy (excluding tovorafenib) are eligible to be screened and consented for the study prior to surgery...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. The study is open and one participant has been successfully enrolled."

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

Feasibility of CSF and plasma ctDNA in BRAF-altered glioma during treatment with plixorafenib: trial in progress (WFNOS 2025) - "Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy (excluding tovorafenib) are eligible to be screened and consented for the study prior to surgery...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. The study is open and one participant has been successfully enrolled."

Circulating tumor DNA • Brain Cancer • Solid Tumor • BRAF

BGB3245-mediated RAF dimer disruption combined with MEK inhibition suppresses ERK reactivation in BRAF-mutant and ERK-dependent glioblastoma models (AACR-NCI-EORTC 2025) - "BGB3245 was evaluated alongside two mechanistically distinct BRAF inhibitors with different selectivity profiles: tovorafenib (DAY101), a type II pan-RAF inhibitor that targets both monomeric and dimeric forms of wild-type and mutant BRAF and CRAF proteins, and plixorafenib (PLX8394), a mutant-specific BRAF paradox breaker affecting monomeric and dimer-inducing mutations...To evaluate the benefits of enhanced vertical inhibition strategies, BGB3245 and other RAF inhibitors were evaluated as monotherapy or in combination with the MEK inhibitor mirdametinib... These findings support dual pan-RAF and MEK inhibition as a rational strategy for GBM subtypes addicted to ERK signaling, particularly in BRAF-mutant gliomas. Pan-RAF inhibitors may overcome some forms of resistance, though brain-penetrant RAF-dimer inhibitors are needed for optimal clinical translation."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BRAF • CDKN2A • CDKN2B • EGFR • NF1 • PTEN

Plixorafenib (PLX8394/FORE8394) treatment leads to sustained tumor regression in preclinical models of BRAF-mutated primary and brain metastatic melanoma (AACR-NCI-EORTC 2025) - P1/2 | "No emerging mutations within the MAPK pathway were found, and alternative oncogenic pathways were enriched, supporting a differentiated mechanism of resistance compared to early generation BRAFi. These data suggest that plixorafenib monotherapy would be clinically effective against both primary and CNS metastatic melanoma."

Metastases • Preclinical • Brain Cancer • CNS Tumor • Melanoma • Oncology • Solid Tumor • BRAF • NF1 • TNFA

FORE Biotherapeutics to Host Virtual Key Opinion Leader Roundtable Discussion on Plixorafenib’s Potential to Disrupt the BRAF Market to Benefit Patients (Businesswire)

Clinical • CNS Tumor

Sustained Response to Pan-BRAF Inhibitor Plixorafenib (FORE8394, PLX8394) in a Young Adult With Neurodegenerative Langerhans Cell Histiocytosis. (PubMed, JCO Precis Oncol) - No abstract available

Journal • CNS Disorders • Langerhans Cell Histiocytosis

FORE Biotherapeutics Announces Positive Outcome From a Planned Interim Efficacy Analysis for the FORTE Basket Study Evaluating Plixorafenib as a Monotherapy for Recurrent or Progressive BRAF V600 Primary CNS Tumors (Businesswire) - "The Independent Data Monitoring Committee recommends the study should proceed as planned...The interim efficacy analysis was conducted by the IDMC and was pre-specified to evaluate plixorafenib at a defined efficacy threshold after the first 25 participants treated in this basket had sufficient data for response assessment, in addition to the IDMC’s ongoing oversight for safety....'We look forward to completing enrollment and reporting topline results from this registrational CNS basket in the second half of 2026.'"

DSMB • Enrollment status • P2 data • CNS Tumor

Clinical Activity and Safety of Novel BRAF Inhibitor (BRAFi) Plixorafenib (FORE8394; PLX8394) in Advanced Thyroid Cancers (TC) Harboring BRAF Alterations (ATA 2025) - P1/2 | "Safety and efficacy of plixorafenib for participants (pts) with BRAF-altered advanced thyroid cancer from a Phase 1/2a clinical trial are described.Methods This open-label, single-arm, multicenter, dose escalation/optimization study (NCT02428712) assessed safety, pharmacokinetics (PK), and preliminary efficacy of plixorafenib 900-3600 mg/day with or without cobicistat, a PK enhancer, in pts ≥10 years of age with BRAF-altered neoplasms, including thyroid cancers. One had confirmed PR lasting 17.8 months (treated for 27.7 months); 2 had SD (treated 44.4 and 3.7 months); and 1 had PD. One pt with ATC and a BRAF fusion had SD.Discussion/Conclusion Plixorafenib treatment had an encouraging safety profile and durable disease control in pts with BRAF-altered thyroid cancer that appears very favorable compared with historical data with standard treatment options."

Clinical • Metastases • Fatigue • Gastroenterology • Gastrointestinal Disorder • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

FORE Biotherapeutics Presents Phase 1/2a Plixorafenib Data Demonstrating Prolonged Duration of Effect in BRAF Altered Thyroid Cancers at American Thyroid Association 2025 Annual Meeting (Businesswire) - "Plixorafenib demonstrated mPFS of 64 months and a clinical benefit rate of 85.7% in patients with MAPKi-naïve BRAF V600-mutated papillary thyroid cancer, a potential future development indication for plixorafenib....The data also demonstrate an encouraging safety profile consistent with previously reported results following treatment with plixorafenib."

P1/2 data • Thyroid Gland Carcinoma

Empowering the identification and validation of drug candidates targeting oncoproteins and E3 ligase functions (EACR 2025) - "The effects of several FDA-approved BRAF inhibitors on kinase activity conformations were successfully validated and compared to next-generation BRAF blockers such as Plixorafenib... The results of this study underscore the importance of understanding conformational dynamics of deregulated enzymes in the context of disease and therapy. The KinCon reporter system has proven to be a valuable tool in identifying how kinases interact with small molecule inhibitors. Our findings suggest that this technology can predict cellular factors impacting drug efficacies, thereby aiding in the design of more effective therapeutic strategies."

Late-breaking abstract • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • TP53

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