exarafenib (KIN-2787)

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.

P1, N=400, Active, not recruiting, Pierre Fabre Medicament | Recruiting --> Active, not recruiting

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.

P1, N=400, Recruiting, Pierre Fabre Medicament | Trial completion date: May 2027 --> Mar 2029 | Trial primary completion date: Jan 2027 --> Nov 2028

P1, N=400, Recruiting, Pierre Fabre Medicament | Trial completion date: Dec 2025 --> May 2027 | Trial primary completion date: Dec 2024 --> Jan 2027

P1, N=400, Recruiting, Pierre Fabre Medicament | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

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.

P1, N=400, Recruiting, Kinnate Biopharma | N=262 --> 400

P1, N=262, Recruiting, Kinnate Biopharma | N=155 --> 262

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).

Exarafenib achieves therapeutically meaningful drug exposures and demonstrates promising tolerability & clinical activity in BRAF or NRAS alteration-driven solid tumors. Pt enrollment & exarafenib treatment at 300 mg bid continues.

Part A1 assesses single agent KIN-2787; Part A2 assesses KIN-2787 in combination w/binimetinib. Enrollment began in August 2022. Trial is open globally.