A phase 2 study of an off-the-shelf, multi-neoantigen vector (ADXS-503) in patients with metastatic non–small cell lung cancer either progressing on prior pembrolizumab or in the first-line setting.
Authors: Gerstner Gregory James , Ramalingam Suresh S. , Lisberg Aaron E. , Farber Charles Michael , Morganstein Neil , Sanborn Rachel E. , Halmos Balazs , Spira Alexander I. , Pathak Ranjan , Huang Chao Hui , Vangala Surya , Parsi Megan , Metran Cristiane , Gutierrez Andres A. , Goldman Jonathan W. 
Published: June 2022

9038 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 non-small-cell lung cancer (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 2 study of A503 ± pembro is being conducted in patients with metastatic squamous or non-squamous NSCLC. In Part B of the study, A503 was added-on to pembro within 12 weeks of the first scan showing disease progression following pembro (per RECIST criteria v1.1). In Part C of the study, A503 and pembro were administered to previously untreated patients. Both A503 (1x108 CFU) and pembro (200 mg) were infused by IV every 3 weeks until disease progression or limiting toxicity. Results: A total of 17 patients have been treated/evaluated from Part B (n = 14/13) and Part C (n = 3/3). Pembro + A503 was well tolerated in both parts of the study, with mostly grade 1–2, transient and reversible treatment-related adverse events, the most common being fever (47%), chills (35%), fatigue (29%) and nausea (21%). There have been no added immune-related toxicities associated with the combination. Of the 13 evaluable patients in Part B, 2 achieved partial response (PR) and 4 achieved stable disease (SD), yielding an objective response rate (ORR) of 15.4% and a disease control rate (DCR) of 46.2%. Two patients from Part C also achieved SD (DCR 67%). The 2 PRs in Part B have been durable (i.e. 710 and 189 days) as were 5 of the SDs: 3 in Part B (i.e. 448, 175, 117 days) and 2 in Part C (i.e. 322 and 175 days). Both patients with PR in Part B are still undergoing therapy in addition to the other patients who achieved SD. Patients who seem to achieve clinical benefit in both parts of the study include those with PD-L1 expression ≥ 50% and those who show proliferation and/or activation of NK and CD8+ T cells within the first weeks of therapy. In addition, patients with prior pembro exposure ≥ 6 months and DCR > 6 months seem to have clinical benefit when A503 is added to pembro (Part B). Conclusions: The addition of A503 to pembro after disease progression on pembro appears to be well tolerated and induced antigen-specific T-cell responses and durable disease control in 46% of patients in Part B and 67% of patients in Part C. Additional patients are currently being enrolled into both parts of the study to further explore the potential of A503 to restore or enhance sensitivity to checkpoint inhibitors. Clinical trial information: NCT03847519.