Immunogenicity and disease control induced by a multineoantigen vaccine (ADXS-503) in patients with metastatic non–small cell lung cancer who have progressed on pembrolizumab.

Abstract

9042 Background: The administration of a lung cancer-specific immunotherapy with 22 tumor-associated antigens (ADXS-503, A503), has been evaluated as an add-on therapy for patients (pts) with metastatic non-small-cell lung cancer (NSCLC) who have progressed on pembrolizumab (pembro) as last therapy [Haigentz M et al. ASCO 2021]. The present study explores the immunogenicity and potential reversal of immune resistance with A503 when added-on to pembro at the time of progressive disease (PD). Methods: A phase 2 study of A503 + pembro is being conducted in pts with metastatic squamous or non-squamous NSCLC. In Part B of the study, A503 was added-on to pembro within 12 weeks after the first scan showing disease progression following pembro therapy (per RECIST criteria v1.1). Both A503 (1x108 CFU) and pembro (200 mg) were infused by IV every 3 weeks until disease progression or dose-limiting toxicity. Immunogenicity assays included serum cytokine and chemokine levels; flow cytometry; and in-vitro stimulation FluoroSpot assay with 4 different antigen-pools represented in A503 [i.e., hot spot mutations, heteroclitic/wild-type tumor-associated antigens and other antigens not included in the A503 construct (antigen spreading)]. Results: A total of 14 pts have been treated in Part B, of which 13 are clinically evaluable and up to 11 have immune assessments. Combination therapy was well tolerated with transient increased secretion of cytokines for several hours after infusion of A503 consistent with the expected immune activation and transient ‘flu-like’ syndrome. The objective response rate (16%) and disease control rate (46%) were encouraging with 2 partial responses (PR), 4 stable diseases (SD) and 7 pts with PD. Pts with disease control, in particular, generated CD8+ T cells reactive to neoantigens in 1 or more of the 4 antigen pools tested in FluoroSpot. Also, activation of NK cells and of cytotoxic- and memory-CD8+ T cells was mainly observed in pts with PR or SD, but not in those with PD, as shown in the table. Conclusions: Adding A503 to pembro after PD appears to induce innate and adaptive immune responses that may restore or enhance sensitivity to checkpoint inhibitors in pts with clinical benefit. Clinical trial information: NCT03847519. [Table: see text]