Erasca Inc. (Nasdaq: ERAS) has announced positive clinical progress for naporafenib and preclinical advancements in its RAS targeting franchise. The updates highlight the potential of naporafenib in treating NRAS-mutant (NRASm) melanoma and the continued development of novel RAS-targeting therapies.
Naporafenib Shows Promise in NRASm Melanoma
The Phase 1b SEACRAFT-1 trial evaluating naporafenib in combination with trametinib has yielded promising initial efficacy results in patients with RAS Q61X mutations, particularly in the melanoma cohort. The data supports the ongoing Phase 3 SEACRAFT-2 trial, which has alignment with US and European regulatory agencies for a tissue-specific indication in melanoma.
"The SEACRAFT-1 trial in patients with RAS Q61X solid tumors has successfully accomplished several key objectives: delivering clinical data supporting the potential for durable efficacy in patients with NRAS-mutant (NRASm) melanoma, who currently have limited treatment options following frontline immunotherapy; identifying the most promising antitumor signal for the combination, which has been observed in melanoma patients, supporting a tissue-specific approach; and reducing the frequency and severity of dermatologic toxicities through mandatory primary prophylaxis," said Shannon R. Morris, M.D., Ph.D., Erasca’s chief medical officer.
In a post-hoc pooled analysis of Phase 1b and Phase 2 data from trials in patients with NRASm melanoma conducted by Novartis, naporafenib in combination with trametinib demonstrated favorable median overall survival (mOS) and median progression free survival (mPFS). The U.S. Food and Drug Administration has granted Fast Track Designation to naporafenib plus trametinib for the treatment of NRASm melanoma.
NRASm melanoma represents a significant unmet medical need, accounting for 25-30% of melanoma cases and associated with a worse prognosis compared to other molecular alterations. Current treatment options following frontline immunotherapy have limited efficacy, with chemotherapy demonstrating a 7% ORR and 1.5 months mPFS, and binimetinib showing a 15% ORR and 2.8 months mPFS.
In the SEACRAFT-1 melanoma cohort, a 40% response rate (4/10 patients) was observed, including three confirmed partial responses (cPR) and one unconfirmed partial response (uPR). Notably, 70% (7/10) of patients remained on treatment at the data cutoff, including all four responders. The trial also demonstrated that mandatory primary rash prophylaxis helped reduce the frequency and severity of dermatological toxicities, leading to a lower drug discontinuation rate and improved tolerability.
Randomized dose optimization data from Stage 1 of the SEACRAFT-2 Phase 3 trial is expected in 2025.
Advancing the RAS Targeting Franchise
Erasca is also making strides in its RAS targeting franchise, which includes the pan-RAS molecular glue ERAS-0015 and the pan-KRAS inhibitor ERAS-4001. Both assets have shown promising preclinical data and are on track for Investigational New Drug (IND) application submissions in the first half of 2025.
ERAS-0015 has demonstrated up to 10-fold greater potency and favorable ADME/PK properties compared to another pan-RAS molecular glue in clinical development. ERAS-4001 exhibits high potency, strong antitumor activity, and favorable ADME/PK properties, including oral bioavailability, while sparing H/NRAS and limiting resistance through KRAS wild type activation.
"We were excited to bolster our pipeline with the in-licensing of our RAS-targeting franchise in May, including the pan-RAS molecular glue ERAS-0015 and the pan-KRAS inhibitor ERAS-4001. These two assets with competitive profiles, potential for significant patient benefit, and broad application across solid tumors, have become key priorities for the company," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "Investigational new drug (IND) application submissions remain on track for the first quarter of 2025 for ERAS-4001 and the first half of 2025 for ERAS-0015."
Good Laboratory Practice (GLP) toxicology studies are progressing as anticipated, with ERAS-0015 completed and ERAS-4001 near completion.
