exarafenib (KIN-2787) / Pierre Fabre - LARVOL DELTA

Targeting BRAF Fusions with Pan-RAF Inhibitors Highlights Fusion Type–Associated Heterogeneity in Drug Responses and the Need for Combination Therapy with MEK/ERK Inhibitors (IASLC-TTLC 2026) - P1 | "These cell lines were also resistant to the pan-RAS inhibitor RMC-6236 and showed differential sensitivity to pan-RAF inhibitors, with BRAF ex8/9 fusions being the most responsive compared to ex10/11: specifically, average IC50 values for growth inhibition by exarafenib were AGK::BRAFex8: 66nM; AGAP3::BRAFex9: 60nM; TRIM24::BRAFex10: 321nM; SND1::BRAFex11: 1921nM. Similar patterns of sensitivity were observed with other pan-RAF inhibitors (LY3009120, belvarefinib, encorafenib). All CRISPR lines were exquisitely sensitive to MEK1/2 (binimetinib, cobimetinib) and ERK1/2 (ulixertinib) inhibitors, compared to isogenic control cells...We also found that the combination of exarafenib and osimertinib is effective in vivo for EGFR-mutated NSCLC with acquired BRAF fusion. Exarafenib is currently in clinical trials for BRAF- and NRAS-mutant solid tumors (NCT04913285)."

Combination therapy • Heterogeneity • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • AGK • BRAF • EML4 • KIAA1549 • MAP2K1 • NRAS • TRIM24

Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies. (PubMed, Nat Commun) - "RAS or MEK inhibition co-targeting is effective against this resistance mechanism. This study provides preclinical rationale for clinical testing of exarafenib in BRAF Class II/III cancers and unveils RAS-mediated ARAF-KSR1 complex formation as a resistance mechanism and rational co-therapy strategies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ARAF • BRAF

Novel syngeneic cell lines for studying high-risk BRAFV600E-driven colorectal cancer in vivo. (PubMed, Cancer Res Commun) - "Interestingly, these so-called NaJa lines displayed distinct differentiation states and responses to the clinically relevant RAF inhibitors (RAFi) encorafenib and exarafenib, thereby resembling the clinical heterogeneity of BRAFV600E-driven CRC. RAFi resistance was overcome by the EGFR-family inhibitor afatinib...Upon re-transplantation into syngeneic mice, all NaJa lines established aggressive tumors with distinct tumor microenvironments matching to their differentiation states. Thus, the NaJa lines provide a unique tool to study tumor heterogeneity, drug resistance and the interplay between tumor, stroma and immune cells in BRAFV600E-driven CRC."

IO biomarker • Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • Transplantation • APC • BRAF

KN-8701: A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov) - P1 | N=400 | Active, not recruiting | Sponsor: Pierre Fabre Medicament | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

Targeting BRAF Class II and III Mutations in NSCLC with the pan-RAF inhibitor Exarafenib Reveals ARAF-KSR1-Mediated Resistance and Rational Combination Strategies. (PubMed, Res Sq) - "The exarafenib plus binimetinib combination demonstrated superior efficacy in diverse preclinical models. This study establishes ARAF-KSR1 complex formation as a novel resistance mechanism to pan-RAF inhibition and provides mechanistic rationale for combination strategies with potential to address the unmet clinical need for BRAF Class II and III-mutated NSCLC."

Journal • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ARAF • BRAF

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (AACR 2025) - P3 | "The combination of avutometinib with the focal adhesion kinase (FAK) inhibitor defactinib has shown clinical activity for patients with low-grade serous ovarian cancer and is currently being investigated in a Phase 3 confirmatory study (RAMP 301; NCT06072781)...In contrast to the tumor regressions induced by avutometinib plus exarafenib in this ME9518 model, the combination of the MEK-only inhibitor binimetinib with exarafenib caused substantial body weight loss and failed to show tumor regression. Strong tumor regressions in all mice were also observed with the combination of avutometinib and the pan-RAFi belvarafenib in an NRAS mutant xenograft model (SKMEL2). Mechanistically, the deep tumor regressions observed with the combination of avutometinib plus exarafenib corresponded with virtually complete elimination of MAPK pathway markers such as pMEK, DUSP4 and pS6 in the tumors relative to avutometinib or exarafenib alone which conferred less complete inhibition...."

Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • DUSP4 • KRAS • NRAS

Unveiling the potent anti-tumor activity and underlying mechanism of action of the novel pan-RAF inhibitor exarafenib in BRAF-mutated NSCLC (AACR 2025) - P1 | "Based on this mechanism, we evaluated combination strategies and found that co-targeting MEK with binimetinib provided synergistic anti-tumor effects both in vitro and in vivo, while maintaining tolerability. These mechanistic insights provide strong biological rationale for the ongoing Phase 1 trial (KN-8701; NCT04913285) evaluating exarafenib as monotherapy and in combination with binimetinib in BRAF-altered solid tumors including NSCLC and NRAS-mutant melanoma, offering a potential therapeutic strategy for patients that currently lack effective targeted treatment options."

Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (Businesswire) - "Verastem Oncology announces multiple presentations focused on RAS/MAPK pathway inhibition at AACR Annual Meeting 2025....Abstract #: 4393....Combining avutometinib with a pan-RAF inhibitor (exarafenib or belvarafenib) led to strong tumor regressions in multiple NRAS- and BRAF-driven tumor models corresponding with nearly complete inhibition of RAS/MAPK pathway signaling."

Preclinical • Solid Tumor

KN-8701: A Study to Evaluate KIN-2787 in Participants with BRAF And/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov) - P1 | N=400 | Recruiting | Sponsor: Pierre Fabre Medicament | Trial completion date: May 2027 ➔ Mar 2029 | Trial primary completion date: Jan 2027 ➔ Nov 2028

Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

KN-8701: A Study to Evaluate KIN-2787 in Participants with BRAF And/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov) - P1 | N=400 | Recruiting | Sponsor: Pierre Fabre Medicament | Trial completion date: Dec 2025 ➔ May 2027 | Trial primary completion date: Dec 2024 ➔ Jan 2027

Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

Results from a Phase I trial evaluating exarafenib in NRAS-mutant melanoma (YouTube) - "Janice Mehnert, MD...shares the results from a Phase I KN-8701 trial (NCT04913285) of exarafenib, a selective pan-RAF inhibitor, as monotherapy and in combination with binimetinib in NRAS-mutant melanoma. Promising responses were reported in patients receiving exarafenib, which was also tolerable when combined with binimetinib in most patients with NRAS-mutant melanoma. This interview took place at the Society for Melanoma Research (SMR) 2024 Annual Meeting in New Orleans, LA."

Interview • Video

A Phase 1 Clinical Trial Evaluating Exarafenib, a Selective Pan-RAF lnhibitor, as monotherapy and in combination with Binimetinib in NRAS-mutant (NRASMut) Melanoma (Mel) (SMR 2024) - No abstract available

Clinical • Combination therapy • Late-breaking abstract • Monotherapy • P1 data • Melanoma • Oncology • Solid Tumor

A phase I clinical trial evaluating exarafenib, a selective pan-RAF inhibitor in combination with binimetinib in NRAS-mutant (NRASMut) melanoma (Mel) & BRAF-altered solid tumors (ESMO 2024) - P1 | "Ex + B can be safely administered, achieve meaningful drug exposures & show promising activity in NRASMut Mel & BRAF Cl. II fusion-driven cancer pts. Pt enrollment continues under Pierre Fabre sponsorship ahead of a planned expansion phase."

Clinical • Combination therapy • P1 data • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

Exarafenib in NRAS mutant solid tumors -33% ORR. Remains an unmet need, especially in melanoma. Glad to see progress in this area.

A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov) - P1 | N=400 | Recruiting | Sponsor: Pierre Fabre Medicament | Trial completion date: Jun 2024 ➔ Dec 2025 | Trial primary completion date: Mar 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

Kinnate Biopharma Inc. Sells Its Investigational Pan-RAF Inhibitor, Exarafenib, to Pierre Fabre Laboratories (GlobeNewswire) - "Kinnate Biopharma Inc...and Pierre Fabre Médicament, SAS (“Pierre Fabre Laboratories”), a global player in oncology, today announced their agreement to the sale of the Company’s investigational pan-RAF inhibitor, exarafenib, and other pan-RAF program assets pursuant to the APA entered into by the parties. The sale of global rights is in furtherance of the Company’s previously announced exploration of strategic alternatives...Under the terms of the APA, Pierre Fabre Laboratories has purchased exarafenib and other pan-RAF assets and will assume 100% of the ongoing program and costs associated with these assets. In consideration, Kinnate will receive a total consideration of up to $31 million, consisting of $500,000 at closing, and a $30.5 million payment, contingent upon the earlier of the dosing of the first patient in the first pivotal trial for exarafenib or any other acquired asset..."

Licensing / partnership • Oncology • Solid Tumor

Kinnate Biopharma Inc. Enters into Agreement to be Acquired by XOMA Corporation for Between $2.3352 and $2.5879 Per Share in Cash, Plus One Contingent Value Right per Share (GlobeNewswire) - "Kinnate Biopharma...announced it has entered into a definitive merger agreement...whereby XOMA Corporation ('XOMA') will acquire Kinnate for a price per share of Kinnate common stock...of between $2.3352 and $2.5879 in cash, consisting of (i) a base cash price of $2.3352 per share and (ii) an additional cash amount of up to $0.2527 per share, plus one non-transferable contingent value right per share, representing the right to receive (a) 100% of the net proceeds payable from any disposition of the Company’s investigational pan-RAF inhibitor, exarafenib, and/or any other pan-RAF inhibitors prior to the closing of the merger transaction and (b) 85% of the net proceeds payable from any disposition of other Kinnate assets entered into prior to, or within one year from, closing and received within five years of closing pursuant to a definitive contingent value rights agreement....The merger transaction is expected to close in the first half of 2024."

M&A • Solid Tumor

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition. (PubMed, J Med Chem) - "However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov) - P1 | N=400 | Recruiting | Sponsor: Kinnate Biopharma | N=262 ➔ 400

Enrollment change • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

Kinnate Biopharma Inc. Announces Pipeline Updates, Strategic Reprioritization and Workforce Restructuring (GlobeNewswire) - P1/1b | N=262 | NCT04913285 | Sponsor: Kinnate Biopharma | "As of September 11, 2023, the data cutoff, a total of 107 patients were enrolled in the monotherapy arm....Out of 8 patients with Class II fusion-driven solid tumors who received exarafenib at 300 mg bid, 3 showed radiographic tumor reductions, 2 of the 6 efficacy-evaluable patients achieved confirmed PRs, resulting in a 33% ORR, and the remaining 4 efficacy-evaluable patients achieved SD as their best response, yielding a 100% DCR. Among 13 patients with Class II non-fusion driven solid tumors treated with exarafenib at 300 mg bid, 7 patients experienced radiographic tumor reductions and 6 patients experienced SD as their best response, yielding a DCR of 60%. In addition, 1 patient treated at the 200 mg bid dose experienced a confirmed PR....Kinnate will not proceed with further clinical development of exarafenib as a monotherapy agent and will explore strategic alternatives."

Discontinued • P1 data • Oncology • Solid Tumor

Kinnate Biopharma Inc. Announces Pipeline Updates, Strategic Reprioritization and Workforce Restructuring (GlobeNewswire) - P1/1b | N=262 | NCT04913285 | Sponsor: Kinnate Biopharma | "As of September 11, 2023, the data cutoff, 44 patients with NRAS mutant melanoma and BRAF-altered solid tumors were enrolled across 6 exarafenib plus binimetinib combination dose cohorts, including 24 patients who continue on therapy....Among 16 efficacy-evaluable patients with NRAS mutant melanoma who had not received prior RAF, MEK, or ERK inhibitors, 6 achieved confirmed and unconfirmed partial responses (PRs), resulting in a 38% overall response rate (ORR), with 5 additional patients experiencing stable disease (SD) as their best response, yielding a 69% disease control rate (DCR)....In the fourth quarter of 2023, the Company intends to select two doses for further development."

P1 data • Melanoma • Oncology • Skin Cancer • Solid Tumor

Kinnate Biopharma Inc. Reports First Quarter 2023 Financial Results and Recent Corporate Updates (GlobeNewswire) - "Pipeline Updates:...(i) The company expects to provide an update in the second half of 2023 on the dose selection and additional escalation data for exarafenib plus binimetinib, and initial exarafenib monotherapy dose expansion data in the first half of 2024; (ii) A brain penetrant mitogen-activated protein kinase (MEK) inhibitor (KIN-7136), expected to enter the clinic in the second half of 2023."

New trial • P1 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Skin Cancer • Solid Tumor • Thoracic Cancer

First Report of Positive Dose Escalation Data Supports Best-in-Class Profile for Investigational Exarafenib as a Single Agent and in Combination with Binimetinib in BRAF-altered Cancers and NRAS Mutant Melanoma (GlobeNewswire) - P1 | N=155 | NCT04913285 | Sponsor: Kinnate Biopharma | "Kinnate Biopharma...announced positive monotherapy dose escalation data for its investigational, highly selective and potent pan-RAF inhibitor, exarafenib, from Part A1 of its ongoing global Phase 1 KN-8701 clinical trial....'The exarafenib dose escalation data provide striking proof of concept for a monotherapy pan-RAF inhibitor,' said Alexander Spira..."

P1 data • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov) - P1 | N=262 | Recruiting | Sponsor: Kinnate Biopharma | N=155 ➔ 262

Enrollment change • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • NRAS

Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma (AACR 2023) - P1 | "The superior kinome selectivity of exarafenib and its activity across multiple RAF-dependent melanoma models position it as a potentially class-leading pan-RAF inhibitor. In addition to efficacy in BRAF mutant tumors, these data support use of exarafenib in combination therapy with MEK inhibitors in NRAS mutant melanoma. A Ph I dose escalation clinical trial evaluating the safety and efficacy of exarafenib in monotherapy and in combination with binimetinib is ongoing (NCT04913285)."

Preclinical • Melanoma • Oncology • Solid Tumor • BRAF • NRAS