Abstract CT199: Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade
Authors: Marron Thomas Urban , LaMarche Nelson M. , Park Matthew D. , Hegde Samarth , Fitzgerald Bailey , Hennequin Clotilde , Mattiuz Raphael , Belabed Meriem , Berichel Jessica Le , Maier Barbara , Hall Nicole , Miller Justin , Doroshow Deborah B. , Rohs Nicholas , Veluswamy Rajwanth , Venturini Nicholas , Gomez Jorge E. , Rolfo Christian , Yankelevitz David , Chaddha Udit , Harkin Timothy , Beasley Mary B. , Kim-schulze Seunghee , Gnjatic Sacha , Hirsch Fred R. , Merad Miriam 
Published: April 2023

Abstract
Type-2 cytokines are hypothesized to promote an immune-permissive milieu for cancer to grow. Through scRNAseq and CITEseq on human non-small cell lung cancer (NSCLC) and the krasG12Dp53−/− lung cancer model we previously described a tumor-enriched dendritic cell program of concomitant immunosuppression and activation which we termed the “mregDC,” that was also notable for a strong Th2 immune signature. We subsequently blocked the canonical Th2 cytokine IL-4 in vivo in tumor-bearing mice, and found that this significantly decreased lung tumor burden, which was recapitulated in multiple other tumor models. Furthermore, this effect synergized with PD-L1 blockade. Based on this data, we designed a clinical trial to assess if the addition of dupilumab, an anti-IL-4Ra antibody widely used for treatment of atopic diseases, may rescue responses to checkpoint blockade (NCT05013450).
In this Phase 1b/2 trial, up to 21 patients with NSCLC that have progressed on prior anti-PD-(L)1 therapy will be enrolled. Patients continue PD-(L)1 blockade while receiving three doses of dupilumab, administered every three weeks, with initial radiographic assessment of response at 9 weeks. Patients without progression of disease then continue anti-PD-(L)1 alone. The primary endpoint of Phase 1b is safety and tolerability, while the primary endpoint of Phase 2, inclusive of patients from Phase 1b, is efficacy as per RECIST. Patients undergo pre- and on-treatment biopsies, pre-treatment stool collection for microbiome analysis, as well as blood collection at 6 timepoints for PBMCs, plasma and ctDNA. Here we report the Phase 1b portion that has completed accrual in which 6 patients were enrolled in a Phase 1b run-in to confirm safety and tolerability.
There were no adverse events attributable to study treatment during Phase 1b in any of the 6 patients treated. Serum proteomic analysis of this cohort revealed that dupilumab treatment induced a profound increase in proinflammatory/tumoricidal immune effector molecules, and reversed a systemic Th2 cytokine signature. Furthermore, mass cytometry of circulating immune populations showed an expansion of cytotoxic lymphocyte populations and a reduction in immunosuppressive myeloid cells. The fourth patient treated on trial who had progressive disease after 9 cycles of consolidation checkpoint blockade following concurrent chemoradiation for squamous NSCLC was enrolled, and had a partial response at 9 weeks, with deepening of the PR at 25 weeks. This patient’s on-treatment biopsy showed a major increase in CD8 T cell tumor infiltration. Histological analysis using spatial transcriptomics and multiplexed imaging from these patients is ongoing, and will be reported at the conference.
Based on this promising signal in the initial lead-in, the trial will proceed through Simon’s Two Stage design and enroll a full 21 patients as part of the Phase 2 expansion cohort. This clinical trial is funded entirely through philanthropy support through the Tisch Cancer Institute.
Citation Format: Thomas Urban Marron, Nelson M. LaMarche, Matthew D. Park, Samarth Hegde, Bailey Fitzgerald, Clotilde Hennequin, Raphael Mattiuz, Meriem Belabed, Jessica Le Berichel, Barbara Maier, Nicole Hall, Justin Miller, Deborah B. Doroshow, Nicholas Rohs, Rajwanth Veluswamy, Nicholas Venturini, Jorge E. Gomez, Christian Rolfo, David Yankelevitz, Udit Chaddha, Timothy Harkin, Mary B. Beasley, Seunghee Kim-schulze, Sacha Gnjatic, Fred R. Hirsch, Miriam Merad. Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT199.