FDA approves Naporafenib combined with Trametinib for rapid treatment of advanced NRAS mutated melanoma

The FDA has approved naporafenib (ERAS-254; formerly LXH254) in combination with trametinib as a potential treatment option for adult patients with unresectable or metastatic melanoma and NRAS mutations who have progressed on or are intolerant to PD-1/PD-L1-based regimens. A potent and selective pan-RAF inhibitor demonstrated early activity in this population in a phase 1b trial (NCT02974725). The clinical efficacy of dual therapy versus physician's choice of single agents dacarbazine, temozolomide, or trametinib will be studied in patients with NRAS-mutated metastatic melanoma who previously received immunotherapy (IO) as part of the phase 3 SEACRAFT-2 trial.

The multicenter, open-label, Phase 1b trial enrolled patients diagnosed with advanced or metastatic NRAS-mutant cutaneous melanoma, as well as those with locally advanced or metastatic KRAS- or BRAF-mutant non-small cell lung cancer (NSCLC) who had progressed on or without standard therapy. They must be at least 18 years old, have an ECOG performance status of 0 to 2, and have at least 1 measurable lesion according to RECIST v1.1 criteria. For the expansion phase, patients cannot previously receive RAF, MEK1/2 and/or ERK1/2 inhibitors. During the escalation phase, the combination is administered under fasting conditions until the maximum tolerated dose is reached or a recommended dose for expanded dosing is determined.

The following dose level combinations were studied:1. Naporafenib 200 mg twice daily plus 1 mg trametinib once daily (Cohort 1); 2. Naporafenib 200 mg twice daily plus 0.5 mg trametinib once daily (Cohort 2a); 3. 400 mg twice daily g Naporafenib plus 1 mg trametinib once daily (cohort 2b); 4. Naporafenib 400 mg twice daily plus 0.5 mg once daily trametinib (cohort 3); 5. Naporafenib 400 mg twice daily plus 1 mg once daily trametinib, 2 weeks on/2 weeks off (cohort 4). A total of 36 patients were enrolled and treated during the step-up phase and 30 patients were enrolled and treated during the expansion phase. During these phases, the mean age of patients was 66.3 years (range, 22-83 years). In the upgrade and expansion stages, 63.9% and 50.0% of patients were male, and 91.7% and 80.0% were white, respectively.

Most patients in the upgrade stageECOG performance status was 1 (58.3%); during the expansion phase, most patients had status 0 (63.3%). In the upgrade and expansion phases, 52.8% and 33.3% of patients received 3 or more prior treatment regimens, respectively. In the upgrade phase, 13.9% of patients had BRAF-mutant NSCLC, 69.4% had KRAS-mutant NSCLC, and 16.7% had NRAS-mutant melanoma. The main aim was to examine the safety and tolerability of the combination. Secondary endpoints included objective response rate (ORR), disease control rate, duration of response (DOR), and progression-free survival (PFS) by RECIST v1.1 criteria. Researchers also evaluated pharmacokinetic and pharmacodynamic data.

The data showed that in patients receiving naporafenib 200 mg twice daily plus trametinib 1 mg once daily, dual therapy resulted in an ORR of 46.7% (95% CI, 21.3%-73.4%). In patients who received naporafenib 400 mg twice daily plus trametinib 0.5 mg once daily, the ORR was 13.3% (95% CI, 1.7%-40.5%). Among patients who received naporafenib 200 mg twice daily plus trametinib 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. Among patients treated with naporafenib 400 mg twice daily plus trametinib 0.5 mg once daily, the median DOR was 3.75 months (2.04-NE); the median disease-free survival was 4.21 months. The overall median disease-free survival was 5.03 months (95% confidence interval, 3.42-5.62).

During the expansion phase, all30 patients experienced at least 1 adverse effect (AE), including rash (80%), diarrhea (40%), anemia, elevated blood creatine kinase, and constipation (37%).