Company: ERAS
Filing Date: 2025-03-20
Form Type: 10-K
Source: 0000950170-25-042682
Chunk: 26

Company: Erasca, Inc.
Filing Date: 2025-03-20
Form: 10-K
Item: Item 1
Chunk 26
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 with a variety of mechanisms of action (e.g., trametinib, LTT462, spartalizumab) without clinically relevant drug-drug interactions suggesting that naporafenib may be a potential partner for combination approaches.

As would be expected for combination therapies, the combination of naporafenib and trametinib in the Novartis clinical trials demonstrated an increased frequency and severity of AEs, the most common of which were skin toxicities, as compared to either naporafenib or trametinib administered as a monotherapy. However, more recent results from our SEACRAFT-1 trial suggest that mandatory primary rash prophylaxis improved the tolerability results as measured by reduced frequency and severity of dermatological toxicities, reduced drug discontinuation rate due to adverse events, and increased RDI as compared to the historical Novartis trials which did not include the use of mandatory primary rash prophylaxis. We believe this approach increases the potential for improvement in long-term tolerability and consequently increased efficacy.

Clinical Pharmacology 

Monotherapy naporafenib showed a relatively rapid absorption with a median time to reach peak plasma concentration (Tmax) ranging from approximately 2 to 4 hours. Similar median Tmax ranges were observed when naporafenib was administered in combination with trametinib, LTT462, and ribociclib. The effective half-life is approximately 20-25 hours. The clinical exposure was approximately dose proportional across the dose range tested between 100 mg and 1200 mg QD as well as 200 mg and 600 mg BID. No significant drug-drug interactions have been observed between naporafenib and trametinib, LTT462, or ribociclib in the dose ranges tested. Other clinical pharmacology studies are ongoing.

Clinical Efficacy

Monotherapy. In the first-in-human dose escalation trial CLXH254X2101, two patients achieved confirmed partial responses (PRs): a patient with KRAS G12V-mutated ovarian cancer was treated with naporafenib 300 mg QD, and a patient with HRAS G13R-mutated head and neck cancer was treated with naporafenib 400 mg QD.

Naporafenib plus trametinib. A total of 71 patients with NRASm melanoma were dosed with the combination of naporafenib and trametinib at two different doses across two different trials (Phase 1b CLX