FDA Fast Tracks Naporafenib for Unresectable, Metastatic Melanoma

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Erasca’s naporafenib (ERAS-254) has been granted FDA Fast Track Designation for the treatment of adults with unresectable or metastatic melanoma with an NRAS mutation who progressed on or who are intolerant to a programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1)–based regimen.¹ Naporafenib, a selective pan-RAF inhibitor, was found to produce early activity in a multicenter, open-label, Phase Ib trial (NCT02974725) for metastatic melanoma.²

“We are now rapidly advancing clinical development of naporafenib in combination with trametinib in the post-[immunotherapy] setting in patients with NRAS-mutant melanoma with initiation of our pivotal phase 3 SEACRAFT-2 trial expected in the first half of 2024,” said Jonathan E. Lim, MD, chairman, chief executive officer, and co-founder of Erasca, Inc., in a press release.¹ “Receiving fast track designation further strengthens our ability to work closely with the FDA toward our goal of bringing this new therapy for difficult-to-treat melanoma to patients as soon as possible.”

As part of the Phase III SEACRAFT-2 trial, investigators will analyze the clinical efficacy of the doublet compared with physician’s choice of single-agent dacarbazine, temozolomide, or trametinib among patients with NRAS-mutated metastatic melanoma who received prior treatment with an immunotherapy.¹

In the multicenter, open-label, Phase Ib trial, investigators enrolled patients with confirmed advanced or metastatic NRAS-mutated cutaneous melanoma and patients with locally advanced or metastatic KRAS- or BRAF-mutated non–small cell lung cancer (NSCLC) who progressed after standard treatment or who did not have standard therapy available.² Enrollment criteria included being at least 18 years of age, an ECOG performance status of 0 to 2, and at least one measurable lesion by RECIST v1.1 criteria.

For the expansion phase of the trial, patients could not have received prior treatment with a RAF, MEK1/2, and/or ERK1/2 inhibitor. For the escalation phase, the treatment combination was administered under fasted condition until the maximum tolerated dose was reached or the recommended dose for expansion was identified. Thirty-six patients were treated in the escalation phase and 30 patients were treated in the expansion phase, with a median patient age of 66.3 years (range, 22-83).

The trial’s primary objective was to analyze the safety and tolerability of the combination, with secondary endpoints that included objective response rate (ORR), disease control rate, duration of response (DOR), and progression-free survival (PFS) by RECIST v1.1 criteria.

The doublet produced an ORR of 46.7% in the trial among patients administered naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily. ORR was 13.3% among patients administered naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily.

Median DOR was 3.75 months (1.97-not estimable [NE]) and median PFS was 5.52 months among patients administered naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily. In the naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily cohort, median DOR was 3.75 months (2.04-NE) and median PFS was 4.21 months. The overall median PFS across dosing groups was 5.03 months.

In terms of safety, all 30 patients experienced at least one adverse effect (AE) in the expansion phase, including rash (80%), diarrhea (40%), and anemia, increased blood creatine phosphokinase, and constipation (37%).

References

1. Erasca granted FDA fast track designation for PAN-RAF inhibitor naporafenib in patients with advanced NRAS-mutated melanoma. News release. Erasca, Inc. December 11, 2023. Accessed December 15, 2023. https://investors.erasca.com/news-releases/news-release-details/erasca-granted-fda-fast-track-designation-pan-raf-inhibitor

2. de Braud F, Dooms C, Heist RS, et al. Initial evidence for the efficacy of naporafenib in combination with trametinib in NRAS-mutant melanoma: results from the expansion arm of a phase Ib, open-label study. J Clin Oncol. 2018;41(14):2651-2660. doi:10.1200/JCO.22.02018. Accessed December 15, 2023.