exarafenib (KIN-2787)

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.

In contrast to vemurafenib, an approved BRAF inhibitor with activity limited to Class I BRAF alterations, KIN-2787 was active across all classes of BRAF mutant melanoma cells (EC50 values < 100 nM)...Additionally, KIN-2787 was efficacious in a pre-/post-treatment melanoma PDX pair in which the original tumor was Class I BRAF V600E but acquired a Class II BRAF kinase domain duplication upon progression on dabrafenib + trametinib... KIN-2787 is a next-generation, pan-RAF inhibitor with in vitro and in vivo activity against human melanoma driven by BRAF and/or NRAS mutations. Data supports KIN-2787 use in acquired BRAF dimer-dependent resistance to BRAF+MEK inhibitor therapy. A Phase I dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285).

While the RAF inhibitor dabrafenib is approved for treatment of BRAF Class I-altered NSCLC (in combination with trametinib), there are no RAF targeted therapies for treatment of NSCLC patients with tumors driven by BRAF Class II or Class III dimer-dependent alterations, likely contributing to the inferior clinical outcomes of these patients (Dagogo-Jack et al...In contrast to dabrafenib or vemurafenib, approved BRAF inhibitors with activity limited to Class I BRAF alterations, KIN-2787 was most active in Class II and Class III BRAF mutant NSCLC cells (EC50 median values 264 nM and 24 nM, respectively)...A Phase I dose-escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is actively enrolling (NCT04913285). Patients with advanced and metastatic solid tumors, including NSCLC patients, whose cancers are driven by BRAF Class I, II, or III alterations will receive KIN-2787 treatment on this study.

P1, N=155, Recruiting, Kinnate Biopharma | N=115 --> 155

No abstract available

P1, N=115, Recruiting, Kinnate Biopharma | Not yet recruiting --> Recruiting

P1, N=115, Not yet recruiting, Kinnate Biopharma