Trial to evaluate ivonescimab plus enfortumab vedotin in urothelial carcinoma

Summit Therapeutics has initiated the global phase 2/3 HARMONi-GU1 trial to evaluate the investigational bispecific antibody ivonescimab (SMT112) in combination with enfortumab vedotin-ejfv (EV; Padcev) as first-line treatment for patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).¹

The study will compare the investigational regimen with the combination of pembrolizumab (Keytruda) plus EV, which has become a standard frontline regimen following FDA approval in December 2023. Enrollment in the trial is expected to begin following global site activations planned for later in 2026.

The initiation of HARMONi-GU1 represents the first global registrational study of ivonescimab in a genitourinary malignancy. The agent is currently in late-stage development for non–small cell lung cancer and colorectal cancer.

"The initiation of HARMONi-GU1 reflects our ambition to realize the full potential of ivonescimab across a broad range of solid tumors," said Robert W. Duggan, chairman and co-CEO of Summit Therapeutics, in a news release.¹ "What began as a single development program has evolved into one of the most expansive and advanced global oncology development efforts for a novel bispecific antibody. We believe the breadth of evidence generated to date, together with the scale of the ongoing clinical program, positions ivonescimab as a potentially important future treatment option for patients worldwide. Our commitment is to move rapidly, generate high-quality clinical evidence globally, and evaluate ivonescimab's potential wherever we believe it can make the greatest difference for patients."

Trial overview

HARMONi-GU1 is a randomized, global, multi-regional phase 2/3 study that is expected to enroll approximately 800 patients through the phase 3 portion. Patients with previously untreated la/mUC will be randomly assigned to receive ivonescimab plus EV or pembrolizumab plus EV.

The phase 2 portion of the trial will establish the recommended dose of ivonescimab in combination with EV before proceeding into the registrational phase 3 component. The primary end points for phase 3 are progression-free survival (PFS) and overall survival (OS).

Clinical context

The combination of enfortumab vedotin and pembrolizumab received FDA approval in December 2023 based on data from the phase 3 EV-302/KN-A39 trial (NCT04223856). The study enrolled 886 patients with la/mUC, showing that the combination of enfortumab vedotin and pembrolizumab significantly improved PFS (HR, 0.45; 95% CI, 0.38 to 0.54; P < .0001) and OS (HR, 0.47; 95% CI, 0.38 to 0.58; P < .0001) compared with platinum-based chemotherapy.

These results represented the first time that a regimen demonstrated superiority over platinum chemotherapy in this setting.

Ivonescimab is an investigational tetravalent bispecific antibody designed to simultaneously target PD-1 and VEGF. By combining immune checkpoint inhibition with antiangiogenic activity into a single molecule, the agent is intended to modulate both immune evasion and tumor angiogenesis.

"The initiation of HARMONi-GU1 marks another important step in the continued expansion of our global ivonescimab development program into additional tumor types where significant unmet need remains," said Dr. Maky Zanganeh, President and Co-CEO of Summit Therapeutics, in a news release from the company.¹ "Because both angiogenesis and immune evasion are important features of urothelial carcinoma biology, we believe ivonescimab's tetravalent, intentionally-engineered PD-1 / VEGF bispecific mechanism offers a compelling scientific rationale for evaluation in bladder cancer. Despite recent progress in the treatment of locally advanced or metastatic urothelial carcinoma, many patients still face disease progression and poor long-term outcomes. We believe there remains an important opportunity to advance the standard of care with new treatment approaches that have the potential to deliver deeper, more durable responses and meaningfully extend survival."

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