A Phase 2 Master Protocol to Assess the Efficacy and Safety of FORE8394, an Inhibitor of BRAF Class 1 and Class 2 Alterations, in Participants With Cancer Harboring BRAF Alterations

Overview

Plixorafenib (PLX-8394; FORE-8394) is an investigational, oral, selective RAF inhibitor being developed for cancers with BRAF alterations, including V600 (Class 1) mutations and certain non‑V600 (Class 2) alterations such as BRAF fusions. Early-phase clinical data suggest single‑agent antitumor activity across multiple tumor types, including primary CNS tumors, with a tolerability profile that appears to avoid “paradoxical” MAPK pathway activation seen with first‑generation BRAF inhibitors. A global, registration‑intended Phase 2 basket study (FORTE) is ongoing. (ascopubs.org)

Mechanism of action

• Next‑generation “paradox‑breaking” RAF inhibitor that inhibits BRAFV600 monomers and disrupts RAF dimers, thereby suppressing ERK signaling without inducing paradoxical MAPK activation in wild‑type BRAF cells. This design enables activity against Class 1 (V600) and certain Class 2 (e.g., fusion, splice variant) BRAF alterations. (aacrjournals.org)

• Preclinical work showed suppression of ERK signaling, tumor growth inhibition in BRAF‑mutant models, and lack of paradoxical ERK activation compared with vemurafenib. (aacrjournals.org)

Efficacy

Phase 1/2a, multi‑center study (patients ≥3 years; advanced solid and CNS tumors with BRAF alterations; monotherapy with or without cobicistat PK booster):

• Overall activity highlights (ASCO 2023 abstract; data cutoff Nov 21, 2022; n=110 treated):
• MAPK‑inhibitor–naïve, V600‑mutated tumors (excluding colorectal cancer): ORR 39% (9/23), median duration of response (DoR) ~32 months; responses observed in multiple tumor types, including gliomas. (ascopubs.org)
• MAPK‑inhibitor–pretreated, V600‑mutated tumors (excluding colorectal cancer): ORR 18% (3/17) with additional stable disease. (ascopubs.org)

• Evidence of activity in BRAF‑fusion tumors, including a complete response in AGK‑BRAF melanoma (DoR 51.8+ months) and stable disease in others. (ascopubs.org)

• CNS tumor subset updates (SNO 2023 press summary of Phase 1/2a):

• MAPK‑inhibitor–naïve adults with V600‑mutated primary recurrent CNS tumors: ORR 67% (6/9); median DoR 13.9 months. (fore.bio)

• Dose selection:

• Based on integrated PK/efficacy analyses, the recommended Phase 2 dose (RP2D) is plixorafenib 900 mg once daily with cobicistat. (ascopubs.org)

Note: Additional exploratory analyses (AACR 2025) reported pharmacodynamic effects in tumor biopsies and decreases in BRAFV600E mutant allele fraction in ctDNA for most patients; the ongoing FORTE master protocol is assessing efficacy across BRAF‑altered indications. (aacrjournals.org)

Safety

In the Phase 1/2a study (ASCO 2023 abstract):

• Most common treatment‑emergent adverse events (any grade): ALT increased (39%), AST increased (35%), fatigue (34%), nausea (27%), diarrhea (22%), vomiting (20%); majority were grade 1–2. Grade ≥3 AEs included ALT increase (9%), hyperbilirubinemia (6%), and hyponatremia (5%). Only one discontinuation was attributed to study drug. (ascopubs.org)

• Findings notable for absence of adverse events typically associated with paradoxical MAPK activation (e.g., hyperkeratosis, papillomas) and lack of significant ocular or cardiac toxicities in this dataset. (ascopubs.org)

Development status

• Registration‑intended Phase 2 FORTE master protocol is enrolling multiple baskets, including BRAF V600 recurrent primary CNS tumors, rare BRAF V600‑mutated solid tumors, and solid tumors with BRAF fusions. (fore.bio)

Further reading

• ASCO 2023 abstract (Phase 1/2a efficacy and safety): Safety and efficacy of the novel BRAF inhibitor FORE8394… J Clin Oncol 41:16_suppl, 3006 (June 2023). (ascopubs.org)
• ASCO 2023 abstract (dose optimization and RP2D): Dose optimization of novel BRAF inhibitor FORE8394… J Clin Oncol 41:16_suppl, 3106 (June 2023). (ascopubs.org)
• AACR 2025 abstract (FORTE design): Abstract CT247: FORTE: A phase 2 master protocol assessing plixorafenib for BRAF‑altered cancers. (aacrjournals.org)
• Preclinical mechanism and paradox‑breaking data: Molecular Cancer Therapeutics (2017) and Molecular Cancer (2017). (aacrjournals.org)

Disclaimer: Plixorafenib is investigational; efficacy and safety have not been established by regulatory authorities. Ongoing and future trial readouts will refine the benefit–risk profile.

Last updated: Oct 2025

Inclusion Criteria

Subprotocol A:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.

2. Histologic diagnosis of a solid tumor or primary CNS tumor.

3. Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing.

4. Have an archival tissue sample available meeting protocol requirements.

5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.

6. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.

7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Subprotocol B:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.

2. Histological diagnosis of a primary CNS tumor, including but not limited to the following:

1. Adults (≥18 years) with Grade 1-4 glioma or glioneuronal tumor (including glioblastoma, anaplastic astrocytoma, high grade astrocytoma with piloid features, pilocytic astrocytoma, gliosarcoma, anaplastic pleomorphic xanthoastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, not otherwise specified \[NOS\], ganglioglioma, or recurrent LGG). OR

2. Pediatric patients (10-17 years of age) with a Grade 3 or 4 glioma or glioneuronal tumor, including those with a prior, histologically confirmed, diagnosis of a low-grade glioma or glioneuronal tumor and now have radiographic or histopathological findings consistent with WHO \[2021\] Grade 3 or 4 primary CNS tumor.

3. Participants must have unresectable, locally advanced or metastatic disease that:

i. Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR

* Note: Participants who have a WHO Grade 3 or 4 glioma for whom chemotherapy and/or radiotherapy is not considered standard of care may remain eligible for the study.

ii. Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.

3. Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.

4. An archival tissue sample available meeting protocol requirements, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test.

5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.

6. Measurable disease based upon specified response criteria, as determined by the radiographic BICR.

7. All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline.

8. Participants who are receiving corticosteroid treatment must be on a stable or decreasing dose of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatment for 7 days prior to first dose of study treatments.

Subprotocol C:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.

2. Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.

3. Measurable disease on CT, MRI, or physical exam

4. Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test.

5. Have an archival tissue sample available meeting protocol requirements.

6. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory

7. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.

8. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Subprotocol D:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.

2. Histologic diagnosis of a metastatic melanoma or thyroid cancer harboring a BRAF V600E mutation.

3. Participants with cutaneous melanoma have previously received and not tolerated a BRAF inhibitor, while participants with thyroid cancer are MAPK inhibitor naïve.

4. Measurable disease on CT, MRI, or physical exam.

5. Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests.

6. Consent to provide a tumor biopsy.

7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Exclusion Criteria:

Subprotocol A:

1. Participants with known co-occurring NF1 alteration and/or RAS-related mutations.

2. Participants with evidence of subclonal mutations or heterogeneity that are indicative of a prior treatment effect instead of a driver mutation.

3. Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease.

4. Prior treatment with a MEK inhibitor.

5. Tyrosine kinase inhibitor(s) and/or targeted therapies are allowed (other than BRAF/MAPK pathway inhibitors per Exclusion Criteria 3 and 4) and will be restricted to no more than the number of lines of therapy that are consistent with standard treatment guidelines.

6. Malignancy with co-occurring activating RAS mutation(s) at any time.

7. Uncontrolled intercurrent illness that would limit compliance with study requirements.

8. HIV infection with exceptions; discuss with treating physician.

9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, and small bowel resection).

10. Current active liver disease from any cause, including a positive test at screening for HBV (HBsAg), or HCV (HCV antibody, confirmed by HCV RNA PCR).

11. Grade ≥2 changes in AST, ALT, GGT, or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.

Subprotocol B:

1. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).

2. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.

3. Uncontrolled intercurrent illness that would limit compliance with study requirements.

4. Active infection requiring systemic therapy.

5. HIV infection with exceptions; discuss with treating physician.

6. Have impairment of GI function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).

7. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.

Subprotocol C:

1. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).

2. Diagnosis of BRAF V600E-mutated cutaneous melanoma, thyroid cancer (ATC and PTC), or NSCLC.

3. Participant has CNS metastases.

4. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).

5. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.

6. Participants with prostate, breast, or gynecologic cancers with known activating mutations that lead to constitutive hormone receptor activation (AR-V7, ESR1).

7. Uncontrolled intercurrent illness that would limit compliance with study requirements.

8. Active infection requiring systemic therapy.

9. HIV infection with exceptions; discuss with treating physician.

Subprotocol D:

1. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.

2. Participants with known acquired driver mutations, including from prior MAPK pathway targeted therapies.

3. Participant has CNS metastases.

4. Uncontrolled intercurrent illness that would limit compliance with study requirements.

5. Active infection requiring systemic therapy.

6. HIV infection with exceptions; discuss with treating physician.