GEN1042 with radiotherapy: a CD40x4-1BB bispecific and no abscopal responses

What was tried

Genmab, with BioNTech, ran a Phase 1/2 study of GEN1042 (DuoBody-CD40x4-1BB, also called BNT312) combined with stereotactic body radiotherapy, with or without pembrolizumab, in metastatic non-CNS solid tumors (NCT05491317). GEN1042 is a bispecific antibody that engages CD40 on antigen-presenting cells and 4-1BB (CD137) on T cells, designed to couple dendritic-cell activation with T-cell costimulation at sites conditioned by radiation (Muik 2022). The trial used a sequential design with a Phase 1 dose-finding part and a planned randomized Phase 2. It enrolled 13 participants across two cohorts, 27 Gy radiotherapy plus GEN1042 and the same plus pembrolizumab, from March 2023 to a primary completion date of August 2025. Genmab then stopped it. The registry reason: "After reviewing all available data from Part 1 of the trial, the Sponsor has decided not to proceed to Part 2 (randomized Phase 2) of the trial due to lack of efficacy" (NCT05491317).

The biological hypothesis

The immunoradiotherapy concept combined three levers. Radiation was meant to release tumor antigen and create an in-situ vaccine. CD40 agonism would license dendritic cells to present that antigen. 4-1BB costimulation would expand and sustain the resulting T cells, and pembrolizumab would release PD-1 braking. The bispecific format was designed to focus 4-1BB agonism where CD40 is engaged, which preclinically raised dendritic-cell maturation and T-cell activation while aiming to limit the liver toxicity that has dogged both CD40 and 4-1BB monospecific agonists (Muik 2022, Vonderheide 2020, Etxeberria 2021). The central readout for the radiation-plus-immunotherapy thesis was the abscopal response, tumor shrinkage in lesions outside the radiation field. CD40 is not a genetically anchored tumor driver. Its Open Targets overall association score with neoplasm is 0.1307, weighted toward literature and clinical annotation rather than causal genetics.

What actually happened

The combination did not deliver. Objective response rate was 0 percent in the radiotherapy-plus-GEN1042 cohort and 14.3 percent, one of seven, in the cohort that added pembrolizumab, a rate indistinguishable from pembrolizumab alone (NCT05491317 posted results). The mechanistic endpoint failed outright: zero abscopal responses in non-irradiated lesions across all 13 participants, a 95 percent Wilson interval of 0 to 22.8 percent. Disease control rates of 66.7 percent and 42.9 percent reflected stable disease and irradiated-lesion control rather than systemic activity, and progression-free survival was 2.8 and 2.6 months. Drug exposure was not the issue. End-of-infusion GEN1042 concentrations reached roughly 29,000 ng/mL, and anti-drug antibodies were infrequent. No dose-limiting toxicities were reported. The biology that would have justified Part 2, systemic and abscopal immune activity, did not appear.

Failure mechanism, best guess

The most likely reading is that dual myeloid and T-cell costimulation, even focused by a bispecific and paired with radiation, was not sufficient to prime a productive systemic antitumor response in this population. The zero abscopal count is the crisp signal. Radiation plus checkpoint blockade has repeatedly failed to produce reliable abscopal responses, and adding CD40 and 4-1BB agonism did not change that here. The clean pharmacokinetics and absence of dose-limiting toxicity argue against an exposure or tolerability ceiling. This is an efficacy failure. The costimulatory hypothesis was mechanistically reasonable but did not translate into the systemic responses the design required, in a small and heterogeneous set of solid tumors.

How to prevent this next time

Two quantitative tools would have set expectations and a stopping point. First, a Bayesian analysis of the mechanistic endpoint. With 0 of 13 abscopal responses and a Beta(1,1) prior, the posterior probability that the true abscopal rate exceeds 20 percent is roughly 0.05, and for objective response the one-of-thirteen result gives a posterior probability near 0.20 of exceeding that same threshold. The posterior form is

PP(success)=∫θ​P(final success∣θ,interim data)⋅π(θ∣interim data)dθ

Second, a biomarker enrichment strategy tied to the mechanism. Requiring baseline evidence of an inflamed, antigen-rich tumor, for example a T-cell-inflamed gene expression signature, would have concentrated the small sample on tumors capable of an abscopal response, and a number-needed-to-screen calculation would have shown how many patients had to be profiled to find one plausible responder. An unenriched 13-patient basket across mixed histologies had little power to detect a real but modest effect.

The single highest leverage change would have been a biomarker-enriched enrollment gate, admitting only T-cell-inflamed tumors, so the abscopal endpoint was tested where the mechanism could plausibly work rather than in an all-comer basket.

What this means for similar programs

Costimulatory agonism remains biologically attractive and clinically stubborn. Bispecific formats reduce the toxicity that sank monospecific CD40 and 4-1BB agonists, but reducing toxicity is not the same as producing efficacy (Vonderheide 2020, Etxeberria 2021). Immunoradiotherapy programs that stake their value on abscopal responses should treat that endpoint as the primary risk and power for it explicitly, ideally in enriched populations. A clean safety profile and strong target engagement, both present here, do not substitute for a systemic response.

Open questions

Would an enriched, single-histology cohort with high baseline T-cell infiltration have separated GEN1042 plus radiotherapy from checkpoint blockade alone. Does the sequence and timing of radiation relative to costimulatory dosing matter enough to rescue the abscopal endpoint. The posted results give response and pharmacokinetic data but not the tumor immune profiling that would explain why systemic activity was absent.

Sources

1. • ClinicalTrials.gov NCT05491317, protocol and posted results: 13 enrolled, ORR 0 percent and 14.3 percent, 0 abscopal responses, GEN1042 concentrations, why-stopped text. - Muik A et al. DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation. J Immunother Cancer 2022.- Vonderheide RH. CD40 Agonist Antibodies in Cancer Immunotherapy. Annu Rev Med 2020.- Etxeberria I et al. Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic. Proc Natl Acad Sci USA 2021.- Open Targets Platform: CD40 and neoplasm overall association 0.1307. - Wilson score intervals and Beta(1,1) posteriors computed from posted-result counts. Available from: https://clinicaltrials.gov/study/NCT05491317.