Nivolumab + Pexmetinib

The combination of nivolumab and pexmetinib represents an investigational therapeutic approach being studied for various advanced solid tumors. Nivolumab is a well-established immune checkpoint inhibitor, while pexmetinib (also known as ARRY-614) is a small molecule inhibitor targeting p38 MAPK and Tie2 kinases. According to the search results, this combination has been investigated in clinical trials, particularly in a Phase 1b/2 study (NCT04074967) for patients with advanced solid tumors, including those who had progressed on prior anti-PD1 therapy. The study aimed to establish safety and tolerability of pexmetinib with nivolumab and to determine a recommended phase two dose. The clinical trial data indicates that pexmetinib at 200mg in combination with nivolumab was well tolerated and showed promising efficacy, with some patients achieving partial responses and stable disease. The combination demonstrated activity in high-risk, PD-(L)1-refractory patients with advanced solid tumors. Mechanistically, this combination appears to target both immune checkpoint inhibition (via nivolumab) and p38 MAPK pathway inhibition (via pexmetinib). Research suggests that p38 activation in tumor cells may drive immune exclusion, and inhibiting p38 with pexmetinib while simultaneously using nivolumab could potentially overcome immunotherapy resistance. The combination has been studied in various cancer types including non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma, and other solid tumors. The development status appears to be in Phase 1/2 clinical trials as of the search results provided. Pexmetinib itself is an orally bioavailable small-molecule inhibitor with potential antineoplastic, anti-inflammatory, and antiangiogenic activities. It inhibits both p38 and Tie2 kinases, which may reduce proinflammatory cytokine production and decrease tumor angiogenesis. This combination represents an innovative approach to potentially overcome resistance to immune checkpoint inhibitor therapy by targeting complementary pathways involved in tumor immune evasion.

Brand names

Opdivo

Other names

ARRY-614 + nivolumabpexmetinib + nivolumab