 Patients with cancers driven by BRAF Class II (C II) or C III alterations and/or NRAS mutations are unlikely to benefit from approved BRAF-targeted therapies and have few other treatment options. Exarafenib is a potentially best in class orally available pan-RAF inhibitor optimized for potency & high selectivity. It has differentiated dose-dependent activity across a broad range of cell lines & models driven by BRAF C I (inc. those with acquired resistance to 1st gen RAFi), C II, C III or NRAS alterations.

 KN-8701 (NCT04913285) is an ongoing Phase 1 dose escalation & dose expansion study at 35 sites in 7 countries evaluating exarafenib monotherapy in participants (pts) with advanced solid tumors harboring oncogenic BRAF or NRAS alterations.

Preliminary results as of 13 Dec 2022 are reported for 52 pts (median age 63, 51.9% male) with a median of 3 prior therapies treated in 6 dose levels. Treated pts included those with solid tumors driven by BRAF C I (38.5%), C II (19.2%), C III (28.8%) alterations or melanoma pts with NRAS mutations (13.5%). Steady state exarafenib exposure (Cmax and AUC) increased dose proportionally. Pathway inhibition & decreases in ctDNA were observed across BRAF classes & tumor types. Dose limiting toxicities observed at the highest dose level were Grade 3 (Gr3) acneiform rash & Gr3 macular rash. The maximum tolerated dose (MTD) was determined to be 300 mg bid. Treatment-related adverse events (TRAEs) (any grade) occurred in 69.2% of pts with 13.5% of pts having Gr ≥3 events. Skin AEs (any grade) were the most common TRAEs observed in 48.1% of pts with 7.7% of pts having Gr ≥ 3 skin events. GI TRAEs occurred in 19.2% pts (Gr 1-2 only), including diarrhea (1 pt, Gr 1). Reversible, asymptomatic Gr 3 increased ALT and/or increased AST AEs in 3 pts were the only non-skin Gr ≥ 3 TRAEs reported in ≥ 2 pts. At therapeutically relevant exposures, there was no cutaneous evidence of paradoxical activation. Of the 34 pts across all dose levels with at least 1 post-baseline tumor assessment, 6 pts (17.6%) had a partial response (5 confirmed at submission date) & 16 pts (47.1%) had stable disease including 8 pts (23.5%) with objective tumor shrinkage (up to 20%). The 6 responders all continue exarafenib therapy (treatment duration up to 12 months) and include 3 pts with BRAF C I alteration-driven cancers (inc. 1 RAFi + MEKi pre-treated melanoma pt) and 1 pt each with BRAF C II, BRAF C III-driven & NRAS-mutation driven cancers. For pts who achieved or confirmed their best response at MTD, the response rate was 33% (4/12) & included responses in pts with BRAF C I, C II, C III, and NRAS mutant tumors.

 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.

Videos

Alexander I. Spira, MD, PhD, shares new dose escalation data from the first-in-human Phase 1 KIN-2787 study of the pan-RAF inhibitor exarafenib in patients with BRAF-altered solid tumors or NRAS-mutant melanoma.

A Phase 1 Clinical Trial Evaluating Monotherapy With Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF‑Altered Solid Tumors and NRAS-Mutant Melanoma

Alexander I. Spira, MD, PhD

Articles

A Phase 1 Clinical Trial Evaluating Monotherapy With Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF‑Altered Solid Tumors and NRAS-Mutant Melanoma