Naporafenib (LXH-254) combinations prove to exhibit favorable efficacy with a tolerable safety profile in NRAS-Mutant Unresectable/Metastatic Melanoma

Phase II study of multiple Naporafenib drug combinations in patients with unresectable/metastatic melanoma (BRAF V600 or NRAS-mutant)

Sep 11, 2022 | DelveInsight

Melanoma accounts for 1.7% of all worldwide diagnosed cancer cases and is the fifth most common cancer in the US. Melanoma rates in the United States have doubled in the last two decades, and worldwide, the number of melanoma diagnoses is expected to increase by more than 50% by 2040. Although it attributes to only 20% of all skin cancers, it is the most severe type accounting for ~80% of skin cancer deaths. Patients with melanoma who have been surgically resected and rendered free of disease, are still at high risk for relapse. Almost half of the patients are not eligible for immunotherapies, which are the mainstay treatment options. These patients have a very poor prognosis and very low survival rates creating a huge unmet need and offering a huge opportunity for these upcoming drugs. 

The combinations displayed promising efficacy among 85 patients with NRAS-mutant disease with a confirmed partial response (cPR) rate of all the combinations was 21% with 40% of patients achieving stable disease (SD). Additionally, the disease control rate (DCR) was 61%. Disease progression (PD) was reported in 28% of patients in this cohort. The overall study population (n = 134) had a median age of 60 years (range, 20-86) and most patients were males (62%). A majority of patients had an ECOG performance status of 0 (63%). In the BRAF V600–mutant arm (n = 48), the median age was 54 years (range, 20-81) and 56% of patients were males. Most patients had an ECOG performance status of 0 (60%) and received 3 or more prior treatment regimens (52%). Comparatively, in the NRAS-mutant arm (n = 86), the median age was 64 years (range, 38-86) and most patients were again males (65%). Patients primarily had an ECOG performance status of 0 (65%) and 2 was the most common number of prior lines of therapy (55%). Additional data from the trial showed that no patients with BRAF V600–mutant disease experienced a cPR; however, 13% of patients had SD. The DCR was 13%. Most patients (63%) in this group experienced PD. In terms of safety, adverse effects (AEs) of any grade were reported in 96% of the total study population. 

Conclusion- Naporafenib is an orally bioavailable small molecule, It is a type II pan-RAF inhibitor, which is selective for both BRAF wild-type and V600 and CRAF. Thereby it inhibits that kinase signalization without the risk of paradoxical activation in normal cells. For all patients with NRAS mutant melanoma, the DCR was 61%. Steady-state pharmacokinetics exposure for rineterkib, trametinib, and ribociclib combinations with naporafenib were observed in the same ranges as when administered as a single agent, indicating no apparent drug-drug interactions with naporafenib. As we already know that patients with NRAS mutation do not have any approved targeted therapy so the promising results from naporafenib can prove to be beneficial for this patient segment. Patients with NRAS mutated melanoma comprise around 30% of all melanomas which is a huge number of patients. So if further results from naporafenib prove to be efficacious then it can get the first mover advantage for this patient segment and can capture a larger market share.

Expert Opinion: “These results deserve further investigation of naporafenib combinations, particularly with ribociclib or trametinib in immuno-resistant, NRAS-mutated melanoma”

Get more detailed insights, at: Basal cell carcinoma (BCC) Market Outlook, Squamous cell carcinoma (SCC) Market Outlook, Merkel Cell Carcinoma Market Outlook and Melanoma Market Outlook

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