A phase 1 study of an off-the shelf, multi-neoantigen vector (ADXS-503) in subjects with metastatic non-small cell lung cancer (NSCLC) progressing on pembrolizumab as last therapy.

2616 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 programmed 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: A phase 1 study of A503 ± Pembro has been conducted in patients (pts) with metastatic squamous or non-squamous NSCLC. In dose-escalation part B, A503 was added-on to Pembro within 12 weeks of the first scan showing disease progression per RECIST criteria v1.1. Both, A503 (1 x108 CFU) and Pembro (200 mg) were infused by IV every 3 weeks until disease progression or limiting toxicity. The dose-escalation cohort has established safety, tolerability and immunogenicity of the combination therapy and it has been further expanded to evaluate efficacy (Goldman JW et.al., SITC 2020). Results: Nine pts have been treated and evaluated in Part B. Pembro + A503 combo has been well tolerated and without immune related AEs. Of the nine evaluable pts, one has achieved partial response (PR) and 3 stable disease (SD), yielding an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Two patients have had clinical benefit for over 12 months (i.e., one PR and one SD) and both of them had been on Pembro therapy for 2 years before enrollment. The two other pts with SD have sustained it for almost 6 months thus far. Seven pts have been evaluated for immunogenicity. In all pts there was a transient release of pro-inflammatory cytokines and proliferation of cytotoxic- and memory-CD8+ T cells. Seven evaluable pts had antigen-specific T cells within 1-2 weeks after starting therapy and 4/7 showed antigen spreading. Conclusions: ADXS-503 as an add-on therapy to Pembro at disease progression has been well tolerated and it has induced antigen specific-T cell responses and durable disease control in 44% of pts. Part B cohort is currently enrolling additional pts to further explore the potential reversal of Pembro resistance with ADXS-503. Clinical trial information: NCT03847519.