ADXS-503 Plus Pembrolizumab Shows Early Clinical Benefit, Safety in Metastatic NSCLC

Pipeline Report | <b>Pipeline Report: January 2022</b>

The addition of ADXS-503 to the treatment of patients with metastatic non–small cell lung cancer who were progressing on pembrolizumab (Keytruda) resulted in encouraging responses and durable disease control, according to findings from the phase 1/2 trial.

The addition of ADXS-503 to the treatment of patients with metastatic non–small cell lung cancer (NSCLC) who were progressing on pembrolizumab (Keytruda) resulted in encouraging responses and durable disease control, according to findings from the phase 1/2 trial (NCT03847519).1 The combination also showed activity in those with newly diagnosed disease.

Findings from part B of the trial showed that among 13 evaluable patients, the combination elicited an overall response rate of 15.4% (n = 2) and a disease control rate (DCR) of 46% (n = 6). Moreover, 2 partial responses were noted to continue for 702 and 189 days, respectively, underscoring the durability of the clinical benefit achieved with the regimen. Three patients had stable disease (SD) with the doublet, and this was sustained for 448, 175, and 117 days, respectively. An additional patient with SD is still under assessment.

Early data from part C of the study showed that among 3 evaluable patients with newly diagnosed NSCLC who received the combination, the DCR to date is 67%. Two patients sustained SD for 332 and 94 days, respectively.

“[Patients with] NSCLC [who are] resistant to PD-1/PD-L1 checkpoint inhibitors [CPI] have limited treatment options. Current treatment guidelines allow for CPI rechallenge, but the ORR seen with this approach is below 10% and a DCR of up to 45%,” Jonathan W. Goldman, MD, associate professor of UCLA Medical Center, stated in a press release. “Thus, it is encouraging to report that in part B of the study, the documented ORR has now increased to 15.4% and the DCR has reached 46% in the first 13 evaluable patients treated with ADXS-503 as an add-on therapy at progression with pembrolizumab…The durable nature of disease control is also encouraging.”

An off-the-shelf, attenuated Listeria monocytogenes–based immunotherapy, ADXS-503, was designed to produce potent T-cell responses against 22 tumor antigens that are frequently found in NSCLC, including 11 hotspot mutations and 11 tumor-associated antigens.2

The open-label trial enrolled patients with histologically or cytologically confirmed, stage IV squamous or nonsquamous NSCLC who were at least 18 years of age, had measurable disease per RECIST v1.1 criteria and investigator assessment, an ECOG performance status of 0 to 1, and a life expectancy of at least 3 months.3

To be included in part A of the trial, which examined ADX-503 as a monotherapy, patients needed to have progressed or been intolerant to up to 3 lines of previous therapy in the metastatic setting. Patients were enrolled regardless of PD-L1 expression and EGFR or ALK mutational status.

For part B, patients must have been undergoing treatment with single-agent pembrolizumab for metastatic NSCLC. Additionally, their most recent tumor assessment had to showcase progressive disease per RECIST v1.1 criteria; investigators had to confirm disease progression within 4 to 8 weeks. Participants must have been willing to undergo a confirmatory scan 4 to 8 weeks after the previous scan that demonstrated progression. Moreover, there could be no rapid disease progression or clinical deterioration evident.

To be eligible to participate in part C of the research, patients could not have previously received systemic therapy in the metastatic setting. Participants needed to be able to provide a formalin-fixed tumor sample from a biopsy of a lesion at the time of, or following, a metastatic disease diagnosis and from a site that had not had prior irradiation. Moreover, the tumor had to have a PD-L1 expression of 50% or higher and could not have harbored an EGFR-sensitizing mutation or an ALK translocation.

For part A, dose-escalation with ADXS-503 monotherapy was evaluated in patients who were refractory or intolerant to previous systemic therapy, at the following 2 dose levels (DLs): 1 x 108 CFU and 5 x 108 CFU. This portion of the research has been completed.

Earlier results from part A presented during the 2020 ASCO Virtual Scientific Program showed that among 7 patients who received ADXS-503 monotherapy, 3 patients achieved a best overall response of SD.2 Moreover, the agent was found to induce immune responses in those evaluated. Notably, no patients in part A reported dose-limiting toxicities (DLTs) at the 2 DLs evaluated.

In part B, ADXS-503 was examined at the same DLs in combination with pembrolizumab at 200 mg every 3 weeks in those who had progressed on the immunotherapy. Data on 2 patients enrolled to part B were also reported at 2020 ASCO and showed that 1 patient had a best overall response of SD, and the combination was well tolerated in both patients.

Additional updated data from part B showed that patients who derived clinical benefit from the combination included those with a PD-L1 expression of 50% or higher, those with secondary resistance to pembrolizumab, and those who demonstrated proliferation and/or activation of natural killer and CD8-positive T cells within the first weeks of treatment.

The combination was also found to be well tolerated without DLTs or any added toxicity. Approximately half of patients experienced chills, fever, and fatigue with the combination that were grade 1 and 2 in severity and determined to be transient and reversible.

Investigators are currently enrolling the efficacy expansion in part B for up to 18 patients at ADXS-503 DL1 plus pembrolizumab with the potential to proceed to ADXS-503 DL2 at a later date. Part C will comprise a dose-expansion cohort with ADXS-503 DL1 and pembrolizumab in the frontline treatment of patients with NSCLC and a PD-L1 expression of 1% or higher or who are not eligible for chemotherapy.

“The enrollment of part C of the study, evaluating [patients with] NSCLC treated in first line with ADXS-503 in combination with pembrolizumab, has also started,” Andres A. Gutierrez, MD, PhD, chief medical officer of Advaxis, Inc., stated in a press release. “Given that the median progression-free survival achieved with CPIs alone in first-line NSCLC is 7 to 10 months, and the encouraging results from part B in this study, it is expected that the addition of ADXS-503 to pembrolizumab may achieve meaningful improvements in PFS above standard of care with a target of greater than or equal to 9 months.”

Data from additional translational studies, such as flow cytometry, ELISPOT, cytokines/chemokine levels, and mutational analysis, along with microsatellite instability, tumor mutational burden, and cell-free DNA and their clinical correlates, are anticipated to be shared at an upcoming medical conference.


  1. Advaxis presents updated clinical data from ongoing phase 1/2 trial of ADXS-503 in NSCLC and upcoming milestones. News release. Advaxis, Inc.; January 11, 2022. Accessed January 13, 2022.
  2. Ramalingam SS, Stinchcombe T, Gerstner GJ, et al. A phase I study of ADXS-503 alone and in combination with pembrolizumab in subjects with metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl15):e21682. doi:10.1200/JCO.2020.38.15_suppl.e21682
  3. Study of ADXS-503 with or without pembro in subjects with metastatic non-small cell lung cancer. Updated July 14, 2021. Accessed January 13, 2022.