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

Determinants of response and rational combination strategies for plixorafenib (PLX8394/FORE8394) in models of BRAF-altered colorectal cancer (EORTC-NCI-AACR 2026) - "Abstract will be available as of 4 November (with consent of the author)"

Colorectal Cancer • Oncology • Solid Tumor • BRAF

Long-term safety and efficacy of plixorafenib in patients with BRAF-altered CNS neoplasms from the phase 1/2a PLX120-03 study (SNO 2026) - No abstract available

Clinical • P1/2 data • Brain Cancer • CNS Tumor • BRAF

Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study. (ASCO 2023) - P1/2 | " In a phase 1/2a study, patients (pts) aged ≥3 years with BRAF-altered, advanced solid or CNS tumors received FORE8394 (900-3600 mg/day or mg/m2 dosing) with or without a pharmacokinetic booster (cobicistat 150 mg/day). As single agent anticancer therapy, FORE8394 had antitumor activity in various tumors with BRAF alterations, including pts previously treated with MAPKi and pts with BRAF fusions. Durable tolerability was observed, and TEAEs indicative of paradoxical MAPK activation were not observed, consistent with the novel mechanism of action of FORE8394. These results support further evaluation of FORE8394."

Clinical • Metastases • P1/2 data • Brain Cancer • Cardiovascular • CNS Disorders • CNS Tumor • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Glioma • Heart Failure • Langerhans Cell Histiocytosis • Melanoma • Ocular Inflammation • Oncology • Ophthalmology • Ovarian Cancer • Retinal Disorders • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Uveitis • AGK • BRAF

FORE Biotherapeutics Announces Positive Outcome from First Planned Interim Efficacy Analysis from FORTE Basket Study Evaluating Plixorafenib Monotherapy in Advanced Solid Tumors with BRAF Fusions (Businesswire) - "Independent Data Monitoring Committee recommends study should proceed as planned...This first interim efficacy analysis for the BRAF fusion basket 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 of the FORTE study had sufficient data for response assessment, in addition to the IDMC’s ongoing oversight for safety. A second interim efficacy analysis is anticipated once sufficient data is available from 50 participants in this basket....'we expect to achieve several important milestones, including reporting topline results from the BRAF V600E CNS basket around the end of 2026, submitting an NDA for the treatment of BRAF V600E CNS tumors during the first half of 2027, and reporting topline results from the BRAF fusion basket during the second half of 2027.'"

DSMB • FDA filing • P2 data • Anaplastic Astrocytoma • Anaplastic Oligoastrocytoma • Glioblastoma • Glioneuronal Tumor • Gliosarcoma • Low Grade Glioma • Oligodendroglioma • Pleomorphic Xanthoastrocytoma

FORTE: A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations (clinicaltrials.gov) - P2 | N=254 | Recruiting | Sponsor: Fore Biotherapeutics | Trial completion date: Dec 2026 ➔ Dec 2028 | Trial primary completion date: Jun 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oligodendroglioma • Oncology • Solid Tumor • BRAF

SOS1-RAS-RAF signaling sensitizes platelet responsiveness via GPVI and PAR-1 (ISTH 2026) - "At high convulxin and TRAP-6 concentrations, inhibition of SOS1-RAS interaction, (Bay-293), BRAF (PLX4032) or BRAF dimerization (PLX8394) partially reduced platelet αIIbβ3 integrin activation, P-selectin/CD63 surface expression, aggregation and phosphatidylserine exposure in a dose dependent manner...Synergistic inhibition of convulxin-induced platelet activation and MEK1/2 S217/221 phosphorylation was observed by combined blocking of BRAF and PKC isoforms (GF109203X), P2Y 12 receptor (AR-C69931), PI3K-p110β (TGX-221) and ASK1 (selonsertib), respectively...This project was supported by the German Research Foundation (DFG). DOI*10.1016/j.rpth.2026.105258"

ARAF • CD63 • MAP2K1

FORE Biotherapeutics Announces Closing of Upsized $67.4 Million Series D-2 Extension Financing and Highlights Recent Plixorafenib Achievements (Businesswire) - "Target enrollment reached in BRAF V600E primary CNS tumor basket of FORTE study; topline results from this registrational basket anticipated around the end of 2026...The company anticipates that the primary analysis of data from this basket, if positive, would enable the submission of a New Drug Application to the U.S. Food and Drug Administration under the Accelerated Approval pathway...The company anticipates advancing through multiple clinical and regulatory milestones across the plixorafenib development program throughout 2026 and into 2027."

Financing • P2 data • Anaplastic Astrocytoma • Anaplastic Oligoastrocytoma • Ganglioglioma • Glioma • Glioneuronal Tumor • Oligodendroglioma • Pilocytic Astrocytoma • Pleomorphic Xanthoastrocytoma

FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers (ISPNO 2026) - P2 | "Assessment at cycle 1 day 1, every 9 weeks for 48 weeks, then every 12 weeks. (D)Plasma ctDNA assessed for all participants; plasma, CSF assessed for primary CNS tumors."

Clinical • P2 data • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

A trial to evaluate CSF ctDNA and safety of plixorafenib alone or with retifanlimab in patients with BRAF-altered glioma. (ASCO 2026) - P1 | "The trial is IRB approved and enrollment is ongoing (10 patients per arm). Clinical trial identifier NCT06610682."

Circulating tumor DNA • Clinical • IO biomarker • Brain Cancer • Glioma • Solid Tumor • BRAF

FORTE: A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations (clinicaltrials.gov) - P2 | N=254 | Recruiting | Sponsor: Fore Biotherapeutics | N=134 ➔ 254

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

FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers (AACR 2026) - P2 | "To date, over 100 patients are enrolled. Clinical trial registry number: NCT05503797."

Clinical • P2 data • Oncology • Solid Tumor • BRAF

Clinical activity and safety of novel BRAF inhibitor plixorafenib (FORE8394) in BRAF V600-mutated advanced colorectal cancers (CRC) (AACR 2026) - "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."

Clinical • Metastases • Colorectal Cancer • Oncology • Solid Tumor • AKT2 • AR • CDKN2A • CDKN2B • KRAS • MAP2K1 • NF1 • NRAS • PIK3CA • PTEN

A Trial to Evaluate CSF ctDNA and Safety of Plixorafenib Alone or With Retifanlimab in Patients With BRAF-altered Glioma (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=15 ➔ 24 | Trial completion date: Jun 2027 ➔ Jun 2028 | Trial primary completion date: Jun 2026 ➔ Jun 2027

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

BRAF mutations in primary central nervous system tumors (AACR 2024) - "For 5 patients treated at recurrence with BDI, median PFS was 15 months (3-27).5 patients were treated with plixorafenib (PLX8394) on clinical trial achieving disease control (PR +SD) in 4 cases. Upon progression, 4 were rechallenged with dabrafenib + trametinib and 1 with another BDI... BRAF mutant CNS tumors are a heterogeneous disease. Longer survival was observed in the small group of HGG patients treated with BDI compared to SoC (56 months vs 22months). BDI rechallenge showed durable responses in heavily pretreated patients."

Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • High Grade Glioma • Oncology • Pleomorphic Xanthoastrocytoma • Solid Tumor • BRAF • CDKN2A • CDKN2B • IDH1 • KIAA1549 • MTAP • TERT • TMB

Plixorafenib (plixo) synergizes with MEK inhibitors (MEKi) in MAPK pathway inhibition in BRAF V600 and non V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi (AACR 2024) - "Using ForeSight assay, a unique platform for testing MAPK signaling, we tested the efficacy of plixo and 4 MEKi (trametinib, cobimetinib, binimetinib and mirdametinib) across a cohort 18 BRAF alterations (V600E, 2 class II and 15 fusions) as single agents and in combinations...Furthermore, we compared the potency of a combination of plixo with binimetinib (bini) to that of another BRAFi (vemurafenib) or pan-RAFi's (tovorafenib and lifirafenib) with bini in 2 class I, 3 class II and 7 BRAF fusions using the foresight assay...These results indicate the improved efficacy of plixo + bini combination in inhibiting MAPK signaling and cancer cell proliferation. Overall results support that maximal suppression of the MAPK pathway with plixo is more potent in combination with a MEK inhibitor in BRAF V600 and non-V600 nonclinical models compared to BRAF or pan-RAF combinations."

Melanoma • Oncology • Solid Tumor • BRAF

Comprehensive cell line profiling of monomer- and dimer-selective small molecule RAF inhibitors uncovers determinants of cellular responses (AACR 2024) - "Additionally, the primary mechanism of cellular inhibitor activity was determined by relating cell line responses to gene dependency data from large CRISPR knockout screens.Our results showed striking similarity in the overall inhibitory profile of BRAF-monomer inhibitors and the vemurafenib-derivative and paradox breaker plixorafenib, which all selectively targeted BRAF-mutant cell lines. Lastly, correlation analyses of cell line profiling data with CRISPR knockout data revealed the preferential targeting of RAF1-dependent cell lines by the dual RAF/MEK inhibitor avutometinib. The results of our analyses shed light on the intricacies of cellular targeting by RAF inhibitors and provide insights to guide the development of new RAF inhibitors."

Preclinical • Oncology • ARAF • KRAS • NRAS

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 • High Grade Glioma • Lung Cancer • Melanoma • Neuroendocrine Carcinoma • 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

Inhibition of FASN postpones development of resistance to BRAF inhibitors in colorectal cancer (AACR 2024) - "Therefore, our hypothesis is that inhibition lipid metabolism via FASN will postpone development of resistance to BRAFi. We established CRC cells resistant to PLX8394, a novel BRAFi... Our study demonstrates that resistance to BRAFi is associated with a significant increase in proliferation, metastasis, and lipid metabolism. We demonstrate that combination of FASN inhibitors and BRAFi postpones development of resistance in BRAFV600E cells. However, FASN inhibition does not sensitize cells to BRAFi in already resistance cells, suggesting that this approach cannot be used to overcome acquired resistance to BRAFi."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BIRC5 • CDH1 • FASN

FORE Biotherapeutics…announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to plixorafenib for the treatment of adult patients with BRAF V600E-mutated high-grade glioma (HGG) (Businesswire) - "The FDA granted this BTD based on data from approximately 25 patients treated in the completed Phase 1/2a clinical trial and ongoing Phase 2 FORTE basket evaluating plixorafenib in BRAF V600E-mutated central nervous system (CNS) tumors....Topline results from Fore Bio’s FORTE Basket evaluating plixorafenib monotherapy for recurrent or progressive BRAF V600 primary CNS tumors by the end of 2026."

Breakthrough therapy • P2 data • High Grade Glioma

Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer. (PubMed, Neoplasia) - "Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance...Importantly, we demonstrate that addition of TVB3664 to the PLX8394 or encorafenib regimen significantly postpones development of resistance to BRAF-targeted therapy by inhibiting the cell cycle progression via a decrease in pRb (Ser780) and downregulation of E2F transcription factor and Cyclin D1 expression. Consistently, clinical data show that patients with BRAFV600E CRC who have high FASN expression in tumor tissues have higher expression of cell cycle-associated genes, including CDKs, E2F, CCDN1 (Cyclin D1), survivin, and MKI67. Collectively, these findings identify FASN-driven lipid metabolism as a critical mediator of resistance to BRAF-targeted therapy and suggest that incorporation of FASN inhibitors may enhance therapeutic efficacy and delay acquired resistance in BRAFV600E CRC."

Journal • Preclinical • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • BIRC5 • BRAF • CCND1 • FASN

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