Abstract CT106: A phase 1b/2 trial of dupilumab given in conjunction with PD-1 or PD-L1 blockade and anakinra in the treatment of relapsed/refractory metastatic NSCLC

Abstract Introduction: Chronic inflammation can contribute to growth and immune evasion of solid tumors, with multiple cytokines and chemokines implicated in this process. We previously showed that disrupting the Th2 immune response systemically by blocking IL-4 signaling can activate dendritic cells and T effector cells to generate a robust immune response against tumor antigens in pre-clinical lung cancer models (Maier, B., et al., A conserved dendritic-cell regulatory program limits anti-tumour immunity. Nature, 2020.580[7802]:257-262). Further analysis of our pre-clinical lung cancer model has indicated that IL-1 signaling contributes to pathogenic emergency myelopoiesis and progression of lung cancer. Dual disruption of IL-1alpha and IL-1beta using anakinra inhibits tumor growth. In humans, we have demonstrated that dupilumab, an IL-4 receptor alpha antagonist, can rescue response to PD-(L)1 blockade in a subset of patients. Based on our pre-clinical data, we have now initiated a Phase 1b/2 trial of dupilumab and anakinra combined with PD-(L)1 blockade in patients with NSCLC who have progressed on previous PD-(L)1 inhibitors. (Park M.D., et al., Hematopoietic aging promotes cancer by fueling IL-1alpha-driven emergency myelopoiesis. Science 386, eadn0327(2024). DOI:10.1126/science.adn0327) Methods: This is a Phase 1b/2 trial in patients with relapsed/refractory NSCLC who have previously received PD-(L)1 blockade are eligible for enrollment. Patients with progressive disease on PD-(L)1 agents continue PD-(L)1 targeted therapy, and three doses of dupilumab are added, administered every three weeks, as was performed in the study we recently completed. In this new trial cohort, alongside continued PD-(L)1 blockade and q3w dupilumab, daily injections of anakinra are administered for the first four weeks. Patients undergo pre- and on-treatment biopsies and blood collection throughout, with cryopreservation of PBMCs and plasma at each collection timepoint. The primary endpoint of Phase 1b is the occurrence of dose limiting toxicities, while the primary endpoint of phase 2 is overall response rate. Secondary objectives include best overall response rate, progression free survival, overall survival, and duration of response. Exploratory objectives include characterization of the immunodynamic changes that occur in patients’ tumor microenvironment and systemic immune milieu. Citation Format: Jacob A. Lowy, Matthew D. Park, Nicholas C. Rohs, Pamela Vaiskauskas, Fionnuala Crowley, Nicholas Venturini, Stephanie Chang, Nelson LaMarche, Clotilde Hennequin, Jessica Le Berichel, Pauline Hamon, Meriem Belabed, Nader Yatim, Jesse Boumelha, Alexis Saffon, Frederika Rentzeperis, Brian Y. Soong, Leanna Troncoso, Laszlo Halasz, Christina Noel, Theodore Chin, Earnest P. Chen, Amanda Reid, Maria Casanova-Acebes, Matthew Su, Ashley Reid, Shira Wood-Isenberg, Darwin D’souza, Travis Dawson, Kai Nie, Zhihong Chen, Jorge E. Gomez, Seunghee Kim-Schulze, Filip K. Swirski, Nicolas Vabret, Udit Chaddha, Dan Feng, Mary B. Beasley, David F. Yankelevitz, Deborah B. Doroshow, Rajwanth Veluswamy, Robert Samstein, Brian D. Brown, Fred R. Hirsch, Sacha Gnjatic, Miriam Merad, Thomas U. Marron. A phase 1b/2 trial of dupilumab given in conjunction with PD-1 or PD-L1 blockade and anakinra in the treatment of relapsed/refractory metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT106.