As reported in the Journal of Clinical Oncology by de Braud et al, findings in the expansion cohort of a phase Ib trial indicate activity with the combination of the BRAF/CRAF kinase inhibitor naporafenib and trametinib in patients with advanced or metastatic NRAS-mutant melanoma.
Study Details
In the international multicenter trial, 66 patients were enrolled into dose-escalation (n = 36) and -expansion (n = 30) cohorts between March 2018 and September 2020. Patients in the dose-escalation cohort had advanced/metastatic KRAS- or BRAF-mutant non–small cell lung cancer or NRAS-mutant melanoma. Patients in the expansion cohort had advanced/metastatic NRAS-mutant melanoma.
Key Findings
During dose escalation, six patients had grade ≥ 3 dose-limiting toxicities, including acneiform dermatitis in two, maculopapular rash in two, increased lipase in one, and Stevens-Johnson syndrome in one. The doses selected for the expansion phase were naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily, and naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily.
Median follow-up in the expansion cohort of patients with NRAS-mutant melanoma was 8.8 months (range = 1–21 months).
Among the 15 patients receiving naporafenib at 200 mg twice daily plus trametinib at 1 mg once daily, the objective response rate (all partial responses) was 46.7% (95% confidence interval [CI] = 21.3%–73.4%), the disease control rate was 80%, the median duration of response was 3.75 months (95% CI = 1.97 months to not estimable), and median progression-free survival was 5.52 months.
Among the 15 patients receiving naporafenib at 400 mg twice daily plus trametinib at 0.5 mg once daily, the objective response rate (all partial responses) was 13.3% (95% CI = 1.7%–40.5%), the disease control rate was 66.7%, the median duration of response was 3.75 months (95% CI = 2.04 months to not estimable), and median progression-free survival was 4.21 months.
In the expansion cohort, the most common treatment-related adverse events of any grade were rash (80%) and increased creatine phosphokinase, diarrhea, and nausea (30% each). Adverse events led to treatment discontinuation in two patients. One fatal treatment-related adverse event occurred, consisting of hypovolemic shock assessed as related to thrombocytopenia with suspected hemorrhagic cause.
The investigators concluded, “Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.”
Adil Daud, MBBS, of the Department of Medicine, University of California San Francisco, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit ascopubs.org.
