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

Abstract

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.

BRAF Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

“…7, A to F). Notably, the sorafenib/trametinib combination has already been applied in the context of BRAF class III mutations ( 83 ) and advanced hepatocellular carcinoma ( 84 ), while first clinical data on naporafenib/trametinib combinations have recently been published for NRAS-driven melanoma ( 85 ). We also tested whether the efficacy of naporafenib could be further improved by the HSP90i XL888, which shows clinical activity in combination with vemurafenib in melanoma ( 49 , 86 ).…”

TargetingNRASMutations in Advanced Melanoma

“…31 Similar findings were seen in other Ras-mutant tumors when the BRAF/CRAF inhibitor naporafenib was combined with the MEKi trametinib. 32 In the phase Ib study of naporafenib + trametinib, reported here by de Braud et al, 8 the evidence of antitumor activity was seen in > 46% of patients with heavily pretreated NRAS-mutant melanoma. These encouraging findings suggest that targeted therapies could be developed for NRAS-mutant melanoma.…”

“…Ras proteins have proven difficult to target, and although inhibitors of KRAS have recently been developed with promising clinical activity reported, 5-7 equivalent inhibitors of mutant NRAS are lacking. In the accompanying article, de Braud et al 8 report encouraging results from the expansion arm of a phase Ib dose escalation trial of the BRAF/CRAF kinase inhibitor naporafenib (LXH254) in combination with the MEK inhibitor trametinib in NRAS-mutant melanoma. In this understanding the pathway article, we review the biology of mutant NRAS in melanoma and discuss strategies for targeting this pathway.…”

“…19 Other studies have demonstrated that upfront anti–programmed cell death protein 1 therapy can improve responses to the BRAF-MEKi combination by potentially priming the immune response. 25,33 Although much remains to be done, the results of de Braud et al 8 offer the possibility of developing effective targeted therapies for patients with NRAS-mutant melanoma.…”

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition

“…As such, the discovery of pan-RAF inhibitors that can block RAF dimer-dependent signaling has received significant attention from the scientific community . Naporafenib ( 3 ) and belvarafenib ( 4 ) are clinical stage inhibitors that have shown promising preclinical activity against RAF homo- and heterodimers, and both inhibitors are currently advancing in the clinic in combination with MEK inhibitors in patients harboring NRAS-driven cancers. , However, both compounds carry challenging physical and chemical properties that may constrain their effectiveness for robust alteration coverage as monotherapy. For example, the low thermodynamic solubility of compound 3 required a thermomechanical solid dispersion formulation to improve oral bioavailability…”