FDA Grants Fast Track Status to Naporafenib Plus Trametinib for Advanced NRAS-Mutated Melanoma

The FDA has granted fast track designation to naporafenib (ERAS-254; formerly LXH254) plus trametinib (Mekinist) for use as a potential therapeutic option in adult patients with unresectable or metastatic melanoma with an NRAS mutation who progressed on or are intolerant to a PD-1/PD-L1–based regimen.¹

The potent and selective pan-RAF inhibitor demonstrated early activity in this population in a phase 1b trial (NCT02974725).² The clinical efficacy of the doublet vs physician’s choice of single-agent dacarbazine, temozolomide, or trametinib will be explored in patients with NRAS-mutated metastatic melanoma who previously received immunotherapy (IO) as part of the phase 3 SEACRAFT-2 trial.¹

“We are now rapidly advancing clinical development of naporafenib in combination with trametinib in the post-IO setting in patients with NRAS-mutant melanoma with initiation of our pivotal phase 3 SEACRAFT-2 trial expected in the first half of 2024,” Jonathan E. Lim, MD, chairman, chief executive officer, and co-founder of Erasca, Inc., stated in a press release. “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.”

The multicenter, open-label, phase 1b trial enrolled patients with confirmed advanced or metastatic NRAS-mutated cutaneous melanoma and those with locally advanced or metastatic KRAS- or BRAF-mutated non–small cell lung cancer (NSCLC) who progressed following standard treatment or who did not have standard therapy available.2 They were required to be at least 18 years of age, an ECOG performance status of 0 to 2, and at least 1 measurable lesion by RECIST v1.1 criteria. For the expansion phase, patients could not have previously received a RAF, MEK1/2, and/or ERK1/2 inhibitor.

In the escalation phase, the combination was given under fasted condition until the maximum tolerated dose was reached or the recommended dose for expansion was identified. The combination was explored at the following dose levels:

• Naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily (cohort 1)
• Naporafenib at 200 mg twice daily plus trametinib at 0.5 mg once daily (cohort 2a)
• Naporafenib at 400 mg twice daily plus trametinib at 1 mg once daily (cohort 2 b)
• Naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily (cohort 3)
• Naporafenib at 400 mg twice daily plus trametinib at 1 mg once daily 2 weeks on/2 weeks off (cohort 4)

A total of 36 patients were enrolled and treated in the escalation phase and 30 patients were enrolled and treated in the expansion phase. Across the phases, the median patient age was 66.3 years (range, 22-83). In the escalation and expansion phases, 63.9% and 50.0% of patients, respectively, were male and 91.7% vs 80.0% were White. Most patients in the escalation phase had an ECOG performance status of 1 (58.3%); in the expansion phase, most patients had a status of 0 (63.3%). In the escalation and expansion phases, 52.8% and 33.3% of patients, respectively, received 3 or more prior regimens. In the escalation phase, 13.9% of patients had BRAF-mutant NSCLC, 69.4% had KRAS-mutant NSCLC, and 16.7% had NRAS-mutated melanoma.

The primary objective was to examine safety and tolerability of the combination. Secondary end points included objective response rate (ORR), disease control rate, duration of response (DOR), and progression-free survival (PFS) by RECIST v1.1 criteria. Investigators also evaluated pharmacokinetic and pharmacodynamic data.

Data showed that the doublet elicited an ORR of 46.7% (95% CI, 21.3%-73.4%) in those who received naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily. In those who received naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily, the ORR was 13.3% (95% CI, 1.7%-40.5%).

In those who received naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily, the median DOR was 3.75 months (1.97-not estimable [NE]); the median PFS in this group was 5.52 months. In those treated with naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily, the median DOR was 3.75 months (2.04-NE); the median PFS was 4.21 months. The overall median PFS was 5.03 months (95% CI, 3.42-5.62).

In the expansion phase, all 30 patients experienced at least 1 adverse effect (AE), which included rash (80%), diarrhea (40%), and anemia, increased blood creatine phosphokinase, and constipation (37%).

The drug developer, Erasca, recently reported that end-of-phase 2 meetings with the FDA and European health authorities confirmed the trial design of SEACRAFT-2 and “provided clarity on the registrational pathway.”

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 13, 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