Company: ERAS
Filing Date: 2025-03-20
Form Type: 10-K
Source: 0000950170-25-042682
Chunk: 22

Company: Erasca, Inc.
Filing Date: 2025-03-20
Form: 10-K
Item: Item 1
Chunk 22
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 to effectively inhibit RAS mutants from signaling downstream without the paradoxical activation observed with BRAF V600E inhibitors. 

Naporafenib and trametinib are ideal combination partners since they target two vertically adjacent nodes in the RAS/MAPK pathway, RAF and MEK, and both stabilize their targeted proteins in the inactive state; naporafenib in an ATP-competitive manner and trametinib in an allosteric manner.

Clinical Overview

Novartis dosed over 500 patients with naporafenib either as monotherapy or in combination with other anti-cancer agents (investigational or approved). These agents included trametinib (MEK inhibitor), LTT462 (rineterkib; ERK inhibitor), dabrafenib (BRAF V600E inhibitor), ribociclib (CDK4/6 inhibitor), EGF816 (EGFR inhibitor), and spartalizumab (anti-PD-1). The safety, tolerability, and acceptable PK and PD have been established in both monotherapy and select combinations. Specifically, the doublet combinations of naporafenib with trametinib, rineterkib (LTT462), and ribociclib have been evaluated in both Phase 1b dose finding and Phase 2 clinical trials, and we believe PoC has been achieved for the combination of naporafenib and trametinib in patients with NRASm melanoma, the focus of our pivotal SEACRAFT-2 study.

Our initial development strategy is focused on the naporafenib combination with trametinib in patients with NRASm melanoma, an indication with high unmet medical need and no approved targeted therapy options. We will also continue to evaluate activity with other combinations in biomarker-defined populations. Our ultimate goal is to maximize the clinical benefit of naporafenib in the greatest number of patients with cancer. 

Clinical safety and tolerability

Monotherapy. A total of 87 patients were enrolled in the monotherapy dose escalation portion of the first-in-human trial (CLXH244X2101) of naporafenib in patients whose tumors had MAPK pathway alterations and progression following standard-of-care (SOC) treatment. A total of 43 patients were enrolled in six QD dosing cohorts (range 100 mg to 1200 mg QD), and 44 patients in total were enrolled in four BID dosing cohorts (200 mg to 800 mg BID).