Erasca Starts Phase 3 Trial of Naporafenib Plus Trametinib for NRAS-Mutant Melanoma

Erasca, Inc., a clinical-stage precision oncology company, has initiated the global SEACRAFT-2 Phase 3 trial to evaluate the efficacy of the pan-RAF inhibitor naporafenib in combination with the MEK inhibitor trametinib (MEKINIST®) for patients with NRAS-mutant melanoma. Naporafenib is considered a promising first-in-class and best-in-class pan-RAF inhibitor designed to treat various RAS/MAPK pathway-driven tumors and has already been administered to over 500 patients.

NRAS-mutant melanoma is a particularly aggressive form of cancer with no approved targeted therapies, highlighting a significant unmet medical need. The SEACRAFT-2 trial, which features a two-stage design, aims to address this gap. Stage 1 of the trial will provide randomized data comparing the combination of naporafenib and trametinib to trametinib monotherapy, with results expected in 2025. This stage will also help determine the randomized Phase 2 dose (RP2D) for the combination. Stage 2, structured for regulatory approval based on feedback from the FDA and European health authorities, will compare the combination therapy against either chemotherapy or a single-agent MEK inhibitor. The trial will use dual primary endpoints of progression-free survival (PFS) and overall survival (OS) for its evaluation.

A pooled analysis of the Phase 1b and Phase 2 trials involving patients with NRAS-mutant melanoma who were treated with the combination of naporafenib and trametinib showed promising results. The median overall survival (mOS) was recorded at 13.0 and 14.1 months, while the median progression-free survival (mPFS) was 5.1 and 4.9 months at two different doses, respectively. These results are favorable compared to historical data.

The SEACRAFT-2 trial is a pivotal Phase 3 study that will assess the clinical efficacy of naporafenib combined with trametinib against the physician’s choice of other therapies, such as dacarbazine, temozolomide, or trametinib monotherapy, in the post-immunotherapy setting for patients with NRAS-mutant metastatic melanoma. The data from Stage 1, anticipated in 2025, will compare the combination therapy to trametinib alone.

Naporafenib, formerly known as LXH254, is a selective and potent pan-RAF inhibitor that has been tested in over 500 patients to date. Its safety, tolerability, pharmacokinetics, and pharmacodynamics have been established in both monotherapy and select combination therapies. Clinical proof-of-concept has been established for its combination with trametinib in patients with NRAS-mutant melanoma, including NRAS Q61X melanoma. Preliminary clinical proof-of-concept has also been established for its combination with trametinib in patients with RAS Q61X non-small cell lung cancer (NSCLC). Erasca's current focus is on advancing naporafenib plus trametinib for NRAS-mutant melanoma through the SEACRAFT-2 Phase 3 trial and for RAS Q61X solid tumors through the ongoing SEACRAFT-1 Phase 1b trial. Additionally, Erasca is exploring other potential combinations of naporafenib with proprietary therapeutic agents.

Naporafenib has received Fast Track Designation from the FDA for patients with advanced NRAS-mutant melanoma, underscoring its potential importance in treating this aggressive cancer type.

Erasca's mission is to "erase cancer" by developing therapies for cancers driven by the RAS/MAPK pathway. Co-founded by pioneers in precision oncology and RAS targeting, the company has developed a deep pipeline focused on this pathway. Their goal is to create novel therapies and combination regimens that can effectively shut down the RAS/MAPK pathway and provide new treatment options for cancer patients.