Erasca, Inc. (Nasdaq: ERAS) announced positive preliminary Phase 1b SEACRAFT-1 trial data for naporafenib plus trametinib in NRAS-mutant (NRASm) melanoma, showcasing a 40% response rate (4 out of 10 patients). The company also reported that its RAS targeting franchise, including pan-RAS molecular glue ERAS-0015 and pan-KRAS inhibitor ERAS-4001, remains on track for Investigational New Drug (IND) submissions. These advancements highlight Erasca's focus on developing therapies for RAS/MAPK pathway-driven cancers.
Naporafenib Clinical Progress
The Phase 1b SEACRAFT-1 trial evaluated naporafenib in combination with trametinib in patients with RAS Q61X mutations. The observed 40% response rate in the melanoma cohort included three confirmed partial responses and one unconfirmed partial response. Notably, 70% of patients (7 out of 10) remained on treatment at the time of the data cutoff, including all four responders. These results build upon previous data from Phase 1b and Phase 2 trials conducted by Novartis, which indicated favorable median overall survival (mOS) and median progression-free survival (mPFS) with the naporafenib and trametinib combination.
Shannon R. Morris, M.D., Ph.D., Erasca’s chief medical officer, stated that the SEACRAFT-1 trial successfully delivered clinical data supporting the potential for durable efficacy in patients with NRASm melanoma, identified the most promising antitumor signal in melanoma patients, and reduced the frequency and severity of dermatologic toxicities through mandatory primary prophylaxis.
The U.S. Food and Drug Administration (FDA) has granted Fast Track Designation to naporafenib plus trametinib for the treatment of NRASm melanoma, underscoring the unmet medical need in this patient population. The Phase 3 SEACRAFT-2 trial is underway, with randomized dose optimization data from Stage 1 expected in 2025. Erasca has achieved regulatory alignment with US and European agencies for potential approval based on a tissue-specific indication in melanoma.
Addressing Unmet Needs in NRAS-Mutant Melanoma
NRASm melanoma accounts for 25-30% of all melanoma cases and is associated with a worse prognosis compared to other molecular alterations. Current treatment options following frontline immunotherapy are limited. Chemotherapy, the approved standard of care, has demonstrated a 7% objective response rate (ORR) and 1.5 months median progression-free survival (mPFS). Binimetinib has shown a 15% ORR and 2.8 months mPFS. The promising initial Phase 1b efficacy results in the SEACRAFT-1 melanoma cohort further support the rationale for pursuing the NRASm melanoma indication.
The implementation of mandatory primary rash prophylaxis has improved the tolerability profile of naporafenib plus trametinib, reducing the frequency and severity of dermatological toxicities and decreasing the drug discontinuation rate due to adverse events.
RAS Targeting Franchise: ERAS-0015 and ERAS-4001
Erasca is also advancing its RAS targeting franchise, which includes ERAS-0015, a pan-RAS molecular glue, and ERAS-4001, a pan-KRAS inhibitor. ERAS-0015 has demonstrated up to 10-fold greater potency and favorable ADME (absorption, distribution, metabolism, and excretion) properties in preclinical studies compared to another pan-RAS molecular glue currently in clinical development. ERAS-4001 has shown high potency, strong antitumor activity, favorable ADME and PK (pharmacokinetics) properties, including oral bioavailability, and the ability to spare H/NRAS while limiting resistance through KRAS wild type activation.
Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder, noted that the company bolstered its pipeline with the in-licensing of the RAS-targeting franchise. He added that 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. These programs are on track to achieve the previously articulated guidance of IND filing in H1 2025 for ERAS-0015 and Q1 2025 for ERAS-4001.
