On April 8, 2022 Advaxis, Inc. (OTCQX: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products reported the publication of results of their KEYNOTE-46 Phase 1/2 open-label, double-arm trial of ADXS-PSA with KEYTRUDA (pembrolizumab) in patients with metastatic, castration-resistant prostate cancer (mCRPC) (Press release, Advaxis, APR 8, 2022, View Source [SID1234611717]). The paper, titled "ADXS31142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study," has been published online in The Oncologist. The article can be found online here.
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The KEYNOTE-46 trial was conducted in conjunction with Merck (known as MSD outside the U.S. and Canada) and evaluated ADXS-PSA, one of Advaxis’ Listeria monocytogenes (Lm)-based immunotherapies, alone and in combination with KEYTRUDA, Merck’s anti-PD-1 therapy.
"The published clinical and immunogenicity data demonstrate that ADXS-PSA in combination with KEYTRUDA has the potential to provide meaningful increases in median overall survival in patients with advanced, metastatic, castration-resistant prostate cancer," said Kenneth A. Berlin, President and Chief Executive Officer of Advaxis. "Furthermore, these demonstrated improvements in survival in an advanced patient population encourage us to continue researching and developing the next generation of Lm-immunotherapies such as our off-the shelf, multineoantigen drug construct, ADXS-504, currently being studied in biochemically recurrent prostate cancer. ADXS-504 is a novel treatment alternative for these earlier stage prostate cancer patients, that has the potential to delay androgen blockade therapy initiation, improve quality of life and increase life expectancy."
As of the January 28, 2020, data cut off, 50 patients with mCRPC were enrolled with evaluable responses in Advaxis’ Ph 1/2 trial of ADXS-PSA alone and ADXS-PSA in combination with KEYTRUDA. The median overall survival (OS) in 13 patients treated with ADXS-PSA alone was 7.8 months (95%CI: 4.4-18.5) with progression free survival (PFS) of 2.2 months (95%CI: 0.8–7.4). The median OS on ADXS-PSA combined with KEYTRUDA was 33.7 months (95%CI: 15.4-NR), while median PFS was 5.4 months (95%CI: 2.3–7.9; n=37). 56.8% (21/37) of patients on combination therapy and 30.8% (4/13) on monotherapy showed stable disease. Robust response was also observed with the combination therapy in patients with prior docetaxel treatment and visceral metastasis. In addition, patients in the combination arm who had prior docetaxel treatment (n=20; 17 of whom had also received 1 or 2 next generation hormonal agent (NGHA) therapies) had an OS of 16.0 months (95%CI: 6.4-34.6), while patients with prior visceral metastasis (n=11; 10 of whom had prior docetaxel and 9 whom had received 1-2 prior NGHA therapies) had an OS of 16.4 months (95%CI: 4.0-NE). Of note, 36 of the 37 patients in the combination arm were tested for microsatellite instability and were all found to be Microsatellite Stable (MSS).
The combination of ADXS-PSA and KEYTRUDA increased T-cell expansion compared to ADXS-PSA alone, suggesting broader immune stimulation. In addition, contraction of T-cell clones was observed in the combination group, which suggests that T-cell clones with lower avidity for PSA (and other prostate-related antigens) were reduced in favor of high-avidity T cells under PD-1 blockade. The combination arm also showed antigen spreading with antigen-specific T-cell responses documented against other relevant prostate cancer antigens.
Naomi B Haas, MD, Director of the Prostate and Kidney Cancer Program and Professor of Medicine at University of Pennsylvania Hospital, and senior author of this publication, said, "Altogether these data are encouraging given the prolonged survival observed in patients in the combination therapy arm regardless of prior therapy with docetaxel, NGHAs or presence of visceral metastasis. It is interesting to see increases in median overall survival to 16.4 months in patients with measurable disease/visceral metastasis as compared to historical data of ≤9.5 months with pembrolizumab alone in this population." She added, "Furthermore, one patient who completed the 2-year study-treatment with ADXS-PSA in combination with KEYTRUDA moved on to a compassionate use protocol and remained with stable disease for yet another 22 months while on combination treatment. These outcomes, delivered with a generally safe and well-tolerated treatment regimen, may warrant additional evaluation of ADXS-PSA in combination with KEYTRUDA or of new generation Lm-immunotherapies in prostate cancer."
The combined therapy was safe and well tolerated in this heavily pretreated population. All patients had more than one treatment-related adverse event, mostly transient Grade 1-2 chills/rigors, fever, hypotension, nausea and fatigue, with no additive toxicity on the combination therapy.
About KEYNOTE-046
KEYNOTE-046 (NCT02325557) was an open-label, multicenter, dose-determining, safety and tolerability Phase 1/2 trial of 50 heavily pretreated patients conducted in two parts (Part A and Part B), with a Phase 2 expansion cohort. While the objective of the study was to evaluate ADXS-PSA as a monotherapy (Part A; n=14 [13 treated]) and in combination with KEYTRUDA (Part B; n= 37) in heavily pretreated patients with progressive and refractory mCRPC, the study was not designed to compare the two treatment regimens. Primary endpoints included safety, tolerability and dosing. Secondary endpoints were anti-tumor activity, progression-free survival and overall survival, and exploratory endpoints included associations between biomarkers of immunologic response (serum PSA) with clinical outcomes.