PURPOSE Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC. METHODS Eligible patients had metastatic PDAC and at least one, but no more than two prior lines of systemic therapy. A safety lead-in evaluating the combination was conducted and the maximum tolerated dose level of LY3214996 was identified. Patients were then randomly assigned in a 1:1 fashion to receive either LY3214996 200 mg orally (PO) once daily + HCQ 600 mg PO twice a day (arm 1) or LY3214996 400 mg PO once daily (arm 2). The primary end point for this study was disease control rate (DCR). Secondary end points included overall survival (OS) and progression-free survival (PFS). RESULTS Thirty-nine patients enrolled (20 in arm 1, 19 in arm 2). The DCR rates were 5% in arm 1 and 5.3% in arm 2. The median OS was 2.4 months in arm 1 (95% CI, 1.3 to 5.8) and 4.6 months in arm 2 (95% CI, 3.1 to 5.7). The median PFS was 1.3 months in arm 1 (95% CI, 0.8 to 1.8) and 1.9 months in arm 2 (95% CI, 1.644 to 2.4). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase, anorexia, and cytopenias. Exploratory analysis using patient-derived PDAC organoids did not show evidence of synergistic antiproliferative activity of LY3214996 in combination with chloroquine. CONCLUSION LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC.
Surana et al. (2025) studied this question.