First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations
Background: We explored the use of naporafenib (LXH254), a pan-RAF kinase inhibitor, either alone or in combination with spartalizumab, in patients with advanced solid tumors exhibiting MAPK pathway alterations.
Methods: This phase 1 study, the first of its kind in humans, consisted of two dose-escalation arms: one for naporafenib alone (starting at 100 mg once-daily) and another for naporafenib (at the recommended dose/regimen) in combination with spartalizumab (400 mg every 4 weeks). The dose-expansion phase for the naporafenib/spartalizumab arm included patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to determine the maximum tolerated doses (MTD) and recommended doses for expansion (RDE), as well as assess tolerability and safety.
Results: A total of 142 patients participated across the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12), and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE for naporafenib was determined to be 600 mg twice-daily. In the naporafenib escalation arm, five patients experienced seven dose-limiting toxicities (DLTs), including decreased platelet count (1200 mg QD), neuralgia, maculopapular rash, pruritus (600 mg BID), and increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs were observed in the naporafenib/spartalizumab arm, where the RDE was established at 400 mg BID. The most common treatment-related adverse events included rash and dermatitis acneiform (24.1% each) for naporafenib, and nausea and pruritus (33.3% each) for naporafenib/spartalizumab in the escalation phase. In the expansion phase, rash was observed in 39.5% of patients. Naporafenib also reduced DUSP6 expression in tumors. Clinical responses included two partial responses (PRs) in the naporafenib escalation arm and one complete response and three PRs in the naporafenib/spartalizumab arm for NRAS-mutated melanoma and KRAS-mutated NSCLC, respectively.
Conclusions: Naporafenib, either alone or in combination with spartalizumab, demonstrated an acceptable safety profile, pharmacodynamic activity, and limited antitumor efficacy. Ongoing studies are exploring additional combination therapies with naporafenib.