naporafenib (ERAS-254)

Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes.

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2026 --> Oct 2026 | Trial primary completion date: Mar 2026 --> Oct 2026

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Mar 2026 | Trial primary completion date: Oct 2025 --> Mar 2026

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Mar 2026 | Trial primary completion date: Oct 2025 --> Mar 2026

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2025 --> Oct 2025 | Trial primary completion date: Jun 2025 --> Oct 2025

P1, N=86, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting

In recent years, significant clinical advancements have been achieved by targeting the NRAS-MAPK pathway, with novel therapies such as the MEK inhibitor tunlametinib and the combination therapy of the pan-RAF inhibitor naporafenib with trametinib leading the way. In this review, we will systematically summarize the recent advances in the direct targeting of mutant NRAS proteins and their downstream RAF and MEK proteins, as well as targeting the MAPK pathway in combination with other therapeutic targets, including the immunotherapy, to treat NRAS mutant melanoma. Additionally, we will further discuss the current issues and emerging countermeasures related to targeted therapy for NRAS mutant melanoma.

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2025 --> Jul 2025 | Trial primary completion date: Feb 2025 --> Jun 2025

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2025 --> Oct 2025 | Trial primary completion date: Apr 2025 --> Oct 2025

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Mar 2025

P1, N=122, Terminated, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Sep 2024; The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.

Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.