Triplet Immunotherapy Regimen Yields Durable Responses in pMMR CRPC

A triplet regimen of BN-Brachyury vaccine, bintrafusp alfa, and the IL-15 receptor superagonist nogapendekin alfa inbakicept-pmln (Anktiva) produced prostate-specific antigen (PSA) responses in 7 of 24 evaluable patients (29%) with castration-resistant prostate cancer (CRPC), according to findings from the phase 1/2 QuEST1 trial (NCT03493945) published in the Journal for ImmunoTherapy of Cancer.¹

Six of the 7 responders had proficient mismatch repair (pMMR) disease, yielding a composite response rate of 26% among unselected patients with pMMR CRPC (n = 6 of 23). Two patients in the triplet cohort achieved partial responses (PRs) by RECIST 1.1 criteria, with a median duration of response of 13.8 months (95% CI, 2.5-not estimable). The median progression-free survival (PFS) was 4.24 months (95% CI, 2.7-10.9) and the 12-month overall survival (OS) rate was 91.2% (95% CI, 70.0%-97.8%).

What for QuEST1?

Immune checkpoint blockade monotherapy has failed to produce reproducible clinical benefit or PSA declines in unselected CRPC, with the exception of patients with microsatellite instability–high or mismatch repair–deficient tumors, who represent approximately 5% of metastatic CRPC. Investigators designed QuEST1 to combine 3 mechanistically distinct agents: the poxviral BN-Brachyury vaccine to initiate an immune response against the transcription factor brachyury, nogapendekin alfa inbakicept to activate and expand natural killer (NK) and CD8-positive T cells, and bintrafusp alfa, a bifunctional inhibitor of PD-L1 and TGF-β, to eliminate immunosuppressive entities in the tumor microenvironment. Epacadostat, an indoleamine 2,3-dioxygenase inhibitor, was added in a fourth arm to further reduce immune suppression.

How was the trial designed?

Using an adaptive 3+3 design, 58 patients enrolled at the National Institutes of Health Clinical Center between April 2018 and February 2024.^1,2 Patients with CRPC sequentially enrolled to a doublet arm (BN-Brachyury vaccine plus bintrafusp alfa; Arm 2.1A; n = 13), a triplet arm (vaccine plus bintrafusp alfa plus nogapendekin alfa inbakicept; Arm 2.2A; n = 13), and a quadruplet arm (vaccine plus bintrafusp alfa plus nogapendekin alfa inbakicept plus epacadostat; Arm 2.3A; n = 6); an expansion cohort of the triplet regimen (Arm 2.2B; n = 12) opened after Arm 2.2A met the prespecified threshold of at least 2 clinical responses among 13 patients.

Bintrafusp alfa was dosed at 1200 mg intravenously on days 1 and 15 of each 28-day cycle, and nogapendekin alfa inbakicept was administered at 15 μg/kg subcutaneously on the same schedule, representing the recommended phase 2 dose established in a dose-finding arm of patients with solid tumors.¹ Response was defined as PR or complete response by RECIST 1.1 criteria or a PSA decrease of at least 30% from baseline sustained for more than 21 days.

The primary objective was to determine the clinical benefit for each of the regimens given in a respective arm. PFS was assessed as a secondary end point.

What immune correlates were associated with clinical response?

Patients receiving the nogapendekin alfa inbakicept–containing triplet regimen showed significantly greater increases in absolute lymphocyte count and total NK cells at 2 weeks compared with the doublet arm (P < .0001 for both), along with greater increases in mature NK cells and NK cells expressing the activating receptors NKp46, CD226, and NKp30. Ratios of effector to suppressor immune cell subsets, including CD8 to regulatory T cell (Treg) and NK to myeloid-derived suppressor cell (MDSC) ratios, were also significantly higher with the triplet regimen.

Among patients treated with the triplet regimen, responders had significantly higher baseline frequencies of CD4-positive and CD8-positive T cells expressing the costimulatory molecule 4-1BB (P = .0106 and P = .0054, respectively) and lower baseline frequencies of MDSCs (P = .0337) compared with nonresponders, along with a significantly greater increase in interferon-gamma at 10 weeks relative to baseline (P = .0030). Investigators noted that the development of antigen-specific T-cell responses to brachyury and the cascade antigen mucin-1 did not differ between treatment arms and was not associated with clinical response, suggesting that NK-cell activation and effector-to-suppressor cell shifts, rather than vaccine-induced T-cell responses alone, may drive antitumor activity.

What safety signals were reported?

Treatment-related adverse effects were generally consistent with the known safety profiles of each individual agent, with the exception of isolated adrenocorticotropic hormone deficiency, which occurred in 5 patients across the doublet, triplet, and quadruplet arms and was medically managed with oral hydrocortisone. The quadruplet arm was closed early after 3 of 6 patients developed grade 3 skin toxicity, and no grade 5 treatment-related adverse events were reported in any arm.

The authors noted that further clinical development of bintrafusp alfa and the BN-Brachyury vaccine has been discontinued, limiting the ability to conduct a planned follow-up study deconvoluting the contribution of individual agents, and that the trial's small sample size and heterogeneous population spanning non-metastatic to metastatic CRPC were additional limitations. The authors concluded that this is the first in-human evidence that adding an IL-15 receptor superagonist to vaccine and checkpoint blockade can produce meaningful clinical activity in pMMR CRPC, and proposed that other TGF-β– and PD-1/L1-targeting agents in active development could be paired with NAI in future triplet regimens.

References

1. Redman JM, Madan RA, Donahue RN, et al. Durable responses to triplet immunotherapy targeting TGF-β, PD-L1, and tumor antigen, with an IL-15 receptor superagonist in mismatch repair proficient castration-resistant prostate cancer. J Immunother Cancer. 2026;14:e015336. doi:10.1136/jitc-2026-015336
2. Phase I/​II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, N-803 and Epacadostat (QuEST1). ClinicalTrials.gov. Updated September 30, 2025. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT03493945