360 A phase 1 study of an Off-the-Shelf, multi-neoantigen vector (ADXS-503) alone and in combination with pembrolizumab in subjects with metastatic non-small cell lung cancer (NSCLC)

Background ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programed death receptor-1 (PD-1)- blocking antibody approved for the treatment of advanced lung cancer. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods We conducted a phase 1 study of A503 ± Pembro in patients (pts) with metastatic squamous or non-squamous NSCLC. In Part A, A503 alone has been tested at two dose levels (i.e., 1 × 108 and 5 × 108 CFU) in pts refractory or intolerant to prior systemic therapy. In dose escalation Part B, A503 has been evaluated at the lower dose level (DL) in combination with Pembro within 6 weeks of presenting with disease progression per RECIST criteria v1.1. Part C dose expansion cohort with A503 + Pembro has started for first-line treatment in the metastatic setting. A503 ± Pembro (200 mg) are infused by IV every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data. Results Twelve patients have been treated: 7 in Part A, 4 in Part B-DL1 and 1 in Part C. No pts in Part A experienced dose-limiting toxicities at the 2 DLs tested. A503+ Pembro has also been well tolerated in 4 pts treated in Part B-DL1 and in one in Part C. No immune related AEs have been reported in Part B or Part C. Three evaluable pts in Part A achieved stable disease (SD). Of the three evaluable pts in Part B-DL1 one has achieved SD for 8 months and the second one a partial response for over 6 months; both of these patients had been on Pembro therapy for 2 years before enrollment. The 3rd pt showed progressive disease. ADXS-503 induced transient release of pro-inflammatory cytokines, activation of cytotoxic- and memory-CD8+ T cells against antigens in the construct and antigen spreading in peripheral blood across all cohorts. Preliminary data in on-therapy biopsies showed increased PD-L1 expression and decreased Treg cell counts. Part B -DL1 cohort has thus been expanded to further explore the potential reversal of Pembro resistance with ADXS-503 in these pts. Conclusions ADXS-503 alone and in combination with Pembro has demonstrated a manageable safety profile and induction of antigen specific T cell responses. The potential effect of A503 to reverse resistance to Pembro is now being studied in an expansion cohort and this combination approach is also being evaluated in the first line treatment setting (Part C). Ethics Approval This study was approved by all Institution’s Ethics Board participating in the trial. Acknowledgements Dr.S Miglani and Dr.M Chopra (AWINSA group) for PV review, Precision for Medicine for immune-correlative work and Abhay Sheeri for data analyses. Trial Registration NCT03847519