FDA Awards Orphan Drug Designation to Avutometinib Plus Defactinib for Pancreatic Cancer Treatment
The FDA has granted an orphan drug designation to the combination of avutometinib and defactinib for use as a potential therapeutic option in patients with pancreatic cancer. This combination, paired with standard-of-care gemcitabine and nab-paclitaxel, is under investigation as a first-line treatment in the phase 1b/2 RAMP 205 study (NCT05669482).
Data presented at the 2024 ASCO Annual Meeting revealed that the combination elicited an objective response rate (ORR) of 83%, with five out of six patients experiencing a partial response and one achieving stable disease. The median time to response was 4.6 months. One dose-limiting toxicity, febrile neutropenia, was reported, but the maximum tolerated dose has not yet been reached.
Avutometinib, a first-in-class oral RAF/MEK clamp, inhibits MEK kinase activity and blocks reactivation of MEK by upstream RAF, while defactinib is a FAK inhibitor. Preclinical data suggest that combining avutometinib with FAK inhibition and chemotherapy leads to tumor regression and prolonged survival in pancreatic ductal adenocarcinoma models.
The RAMP 205 study enrolled patients with metastatic pancreatic ductal adenocarcinoma who had not received prior systemic treatment. The study's Part A evaluated varying doses to determine the maximum tolerated dose and recommended phase 2 dose, with Part B focusing on ORR as the primary endpoint.
Preliminary efficacy data showed a reduction in CA19-9 levels by at least 60% in all patients with elevated baseline levels. Treatment-emergent serious adverse effects occurred in 19 patients, with 11 experiencing grade 3 or higher effects. Common treatment-emergent adverse events included nausea, fatigue, and decreased neutrophil count.
Avutometinib, with and without defactinib, is also being investigated in low-grade serous ovarian cancer, showing promising ORR results in the phase 2 RAMP 201 study.