Abstract
Abstract There has been significant interest in combining anti-PD-1/PD-L1 agents with other clinically active anticancer agents. Gefitinib, a first-generation inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. Durvalumab has demonstrated clinical activity in NSCLC and is approved for Stage III, unresectable NSCLC that has not progressed following platinum-based chemotherapy and radiotherapy. A phase I trial (NCT02088112) combining gefitinib and durvalumab was initiated to establish the safety profile of this combination in tyrosine-kinase inhibitor (TKI)-naive patients with NSCLC containing EGFR-positive sensitizing mutations. As part of this trial, paired tumor biopsies and multiple blood samples were collected for biomarker evaluation. Peripheral blood samples were analyzed for gene expression, cytokine production, immunophenotyping, and circulating DNA (ctDNA). Paired tumor biopsies were evaluated for expression of multiple proteins by immunohistochemistry, including phosphorylated EGFR (pEGFR), PD-L1, CD73, and CD8. We saw ≥50% inhibition of pEGFR in 8 of 17 paired biopsies but no consistent directional changes with PD-L1. We observed known durvalumab-mediated effects such as increases in tumor CD8+ cells (3.7 fold, p=0.011), proliferating CD8+ cells in circulation (2.4 fold, p=0.074), and increased interferon gamma (10.3 fold, p=0.01). A cohort of patients (n=10) was treated with a 28-day gefitinib run-in prior to addition of durvalumab. Sample collection during this period allowed us to evaluate the effects of gefitinib alone on immunologic readouts. While treatment with gefitinib alone resulted in ≥50% reduction of pEGFR in 5 of 8 paired tumor biopsies, its effect on expression of immune-related genes, interferon-related cytokines, and immune subpopulations was minimal. Interestingly, we saw an association between higher baseline tumor PD-L1, pEGFR or CD73 expression and a numerical trend for longer progression-free survival. Finally, analysis of ctDNA showed robust decreases in mutant EGFR could be observed as early as Day 5 of gefitinib treatment, either alone or in combination with durvalumab. Altogether, these results demonstrate that each agent had its expected downstream biologic effects and there was no antagonism between the two agents. We did not observe any novel biologic effects nor any striking synergy for known readouts. New hypotheses (i.e., high PD-L1/pEGFR/CD73) for patient selection biomarkers were identified, although more follow-up is required to determine whether they reflect combination or single-agent treatment. These studies highlight the utility of collecting biomarker samples to confirm target engagement, understand downstream effects, identify patient selection biomarkers, and explore ctDNA biomarkers. Citation Format: Tammie C. Yeh, Helen K. Angell, Vicky Rowlands, Emma V. Jones, Vidalba Rocher Ros, Alison Pritchard, Martine P. Roudier, Nathan Standifer, Mike Kuziora, Philip Martin, Kirill Peskov, Rosie Taylor, J. Carl Barrett, Ben Sidders. Exploratory biomarker analyses of tumor and peripheral blood samples from the phase I durvalumab plus gefitinib trial in EGFR-mutated NSCLC [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B55.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call