Phase 1 Trial Enrollment Expanded

The National Cancer Institute (NCI) is conducting a Phase 1 trial (NCT04235777) evaluating bintrafusp alfa (M7824), PDS01ADC, and stereotactic body radiation therapy (SBRT) in patients with metastatic urologic cancers, excluding prostate cancer. As of the June 2026 registry update, the trial is actively recruiting patients, with a target enrollment of 100 participants and an anticipated completion date of December 1, 2027. This open-label, non-randomized, sequential assignment Phase 1 trial primarily assesses the maximum tolerated dose (MTD) and safety, while also exploring objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A key aspect of the study is its focus on establishing the feasibility of the triple combination rather than confirming early efficacy.

Two Immune Checkpoint Inhibitors and a Tumor-Targeted IL-12

The clinical candidate, bintrafusp alfa, is a dual-functional fusion protein developed by Merck KGaA (ETR:MRK), combining a PD-L1 antibody and a TGF-β receptor II trap. PDS01ADC, from PDS Biotechnology (PDSB), is a tumor-targeted interleukin-12 (IL-12) immunocytokine, also known as M9241 or NHS-IL12. It delivers IL-12 to the tumor microenvironment via an antibody that binds to DNA in necrotic tumor cells. Unlike traditional cytotoxic payload antibody-drug conjugates (ADCs), it carries an immune-activating cytokine, designed to enhance T-cell infiltration, proliferation, and sustained function. Bintrafusp alfa is administered intravenously every two weeks at a dose of 1,200mg, while PDS01ADC is administered subcutaneously every four weeks, starting at 16.8mcg/kg.

SBRT Connects Local Damage to Systemic Immune Response

The study compares a group receiving only the two drugs with two groups receiving SBRT in either sequential or concurrent combination. Radiation is delivered in three fractions of 8Gy each. The rationale is that SBRT induces tumor cell death and antigen release, while PDS01ADC's IL-12 signaling and bintrafusp alfa's PD-L1 and TGF-β blockade simultaneously reduce immune evasion. However, it is a single-institution, early-stage study without a confirmatory control arm, so inter-group efficacy differences should be interpreted as hypothesis-generating data. The expansion of the enrollment target from a previous maximum of 66 to 100 participants indicates a strengthening of the clinical trial design to allow for more detailed analysis of safety and disease-specific signals.

Strengthened Standard of Care Sets the Commercial Benchmark

In metastatic urothelial carcinoma, the combination of Padcev (enfortumab vedotin-ejfv, a Nectin-4 targeted ADC) and Keytruda (pembrolizumab, a PD-1 inhibitor) received FDA full approval on December 15, 2023, raising the bar for first-line treatment and did not require an FDA Advisory Committee (AdComm) review. In renal cell carcinoma, Keytruda and axitinib, Opdivo (nivolumab) and Cabometyx (cabozantinib), and Opdivo and Yervoy (ipilimumab) are established competitive therapies. The market size is reflected in Keytruda's global revenue of $31.68 billion in 2025 and Keytruda Qlex, as well as Astellas Pharma's (TSE:4503) reported FY2024 global in-market revenue of 164.1 billion yen for Padcev. However, bintrafusp alfa is a Phase 1 clinical candidate that has not yet reached the FDA, EMA, or PMDA approval stages, and the previous collaboration between Merck KGaA and GSK, which involved a lung cancer clinical trial, ended on September 30, 2021, after the trial failed.