Results from the quick efficacy seeking trial (QuEST1) arm combining BN-brachyury (BNVax) + bintrafusp alfa (BA) + nogapendekin alfa inbakicept-pmln (N-803) in castration-resistant prostate cancer (CRPC)

BackgroundImmune checkpoint blockade (ICB) is minimally active in unselected CRPC patients (pts). We tested a combination regimen designed to generate a tumor-directed immune response (vaccine) and facilitate anti-tumor activity (checkpoint blockade, cytokine): BNVax (a poxviral vaccine targeting brachyury, a transcription factor involved in invasion and metastasis) + BA (a bifunctional fusion protein: anti-PD-L1 monoclonal antibody fused to the TGF-β-RII receptor extracellular domain [a TGF-β trap]) + N-803 (Anktiva),an IL-15 superagonist FDA-approved for BCG-unresponsive non-muscle invasive bladder cancer. Here we report results from this fully enrolled arm of the QuEST1 trial.MethodsCRPC pts received BNVax (2 prime doses followed by boosts) and both BA (1,200 mg intravenously) and Anktiva (15 μg/kg subcutaneously) every 2 weeks on Arm 2.2A or Arm 2.2B (Simon two-stage design). Efficacy is defined as objective response by RECISTv1.1 or PSA decrease ≥ 30% for > 21 days. Safety was a secondary endpoint.ResultsAs of April 2024, 25 pts (median age 66 years old; median PSA 17.6 ng/dL) enrolled and had 0.25-54 months follow up. 15 pts had prior androgen receptor pathway inhibitor (ARPI), 4 had both ARPI and chemotherapy, and 6 had neither. 6 pts continued ARPI. 1 pt withdrew at 1 week to start a newly available standard therapy and is not included in efficacy analysis. 6-month PFS was 35.0% (95% CI: 16.4-54.3%) and 36-month OS was 66.9% (95% CI: 39.9-83.9%). 7/24 pts (29.2%) had PSA responses (1 had dMMR disease); 2 responders (pMMR) had confirmed PR. 5 pts had grade ≥3 treatment-related adverse events: hematuria (G3), non-infective cystitis (G3), anemia (G3), and eosinophilia (G3). 1 pt developed diabetes (G3) and neutropenia (G4) requiring steroids. 3 pts (all PSA responders) developed G3 central adrenal insufficiency (cAI) manageable with physiologic replacement.ConclusionsBNVax + BA + Anktiva shows activity in CRPC. As expected, immunotoxicities occurred in several pts but we observed an unexpectedly high incidence of cAI only occurring in responders. This supports further study of tumor-targeted vaccine + cytokine + ICB in CRPC.Clinical trial identificationNCT03493945.Legal entity responsible for the studyCenter for Cancer Research, National Cancer Institute.FundingThis study was funded by the Intramural Program of the Center for Cancer Research, National Cancer Institute, NIH with this research being part of individual Cooperative Research and Development Agreements (CRADAs) between National Cancer Institute and the following individual entities: EMD Serono (a business of Merck KGaA), ImmunityBio and Bavarian Nordic, Inc.DisclosureP. Soon-Shiong: Financial Interests, Personal, Other, Employee, Board Member, Equity Owner, Patent holder: ImmunityBio. All other authors have declared no conflicts of interest.