Purpose: No approved targeted therapy to treat patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is presently available.

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

Results: Thirty-six and 30 volunteers were signed up for escalation and expansion, correspondingly. During escalation, six patients reported grade ≥3 dose-restricting toxicities, including eczema acneiform (n = 2), maculopapular rash (n = 2), elevated lipase (n = 1), and Stevens-Manley syndrome (n = 1). The suggested doses for expansion were naporafenib 200 mg two times each day plus trametinib 1 mg once daily and naporafenib 400 mg two times each day plus trametinib .5 mg once daily. During expansion, all 30 volunteers possessed a treatment-related adverse event, the most typical being rash (80%, n = 24), bloodstream creatine phosphokinase elevated, diarrhea, and nausea (30%, n = 9 each). In expansion, the aim response rate, median time period 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 not to estimable [NE]) several weeks, and 5.52 several weeks, correspondingly, in patients given naporafenib 200 mg two times each 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) several weeks, and 4.21 several weeks, correspondingly, in patients given naporafenib 400 mg two times each day plus trametinib .5 mg once daily.
LXH254
Conclusion: Naporafenib plus trametinib demonstrated promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to reduce the incidence of skin-related occasions they are under analysis.