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

by Selleckchem | Aug 23 2023

Purpose: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available.

Patients and methods: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).

Results: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.

Conclusion: 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.

Comments:

The purpose of the study described in the given text was to evaluate the safety, tolerability, and preliminary effectiveness of a combination therapy involving naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, and trametinib in patients with advanced or metastatic non-small-cell lung cancer (NSCLC) or melanoma carrying specific genetic mutations. Specifically, the study focused on patients with KRAS- or BRAF-mutant NSCLC in the escalation arm and NRAS-mutant melanoma in both the escalation and expansion arms.

The study enrolled a total of 66 patients, with 36 patients in the escalation arm and 30 patients in the expansion arm. During the escalation phase, six patients experienced grade ≥3 dose-limiting toxicities, including dermatitis acneiform, maculopapular rash, increased lipase, and Stevens-Johnson syndrome. Based on these findings, the recommended doses for the expansion phase were determined as naporafenib 200 mg twice a day in combination with trametinib 1 mg once daily and naporafenib 400 mg twice a day in combination with trametinib 0.5 mg once daily.

In the expansion phase, all 30 patients experienced treatment-related adverse events, with the most common being rash, increased blood creatine phosphokinase, diarrhea, and nausea. The objective response rate in the expansion arm was 46.7% (95% confidence interval [CI]: 21.3 to 73.4), with a median duration of response of 3.75 months (95% CI: 1.97 to not estimable [NE]) and a median progression-free survival of 5.52 months. Among patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily, the objective response rate was 13.3% (95% CI: 1.7 to 40.5), the median duration of response was 3.75 months (95% CI: 2.04 to NE), and the median progression-free survival was 4.21 months.

In conclusion, the combination therapy of naporafenib plus trametinib demonstrated promising preliminary antitumor activity in patients with NRAS-mutant melanoma. The study also mentioned ongoing investigations into prophylactic strategies to reduce the incidence of skin-related events associated with the treatment.