Developers Initiate Phase 2/3 Ivonescimab/EV Trial in Bladder Cancer

Investigators have initiated the global, multiregional phase 2/3 HARMONi-GU1 trial evaluating ivonescimab (SMT112) plus the antibody-drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) against pembrolizumab (Keytruda) plus enfortumab vedotin as first-line therapy for patients with previously untreated locally advanced or metastatic urothelial carcinoma, or bladder cancer, according to a news release from the developer, Summit Therapeutics.¹ The comparator regimen is considered the global standard of care in this setting; the FDA expandedthis indication to include pembrolizumab plus enfortumab vedotin following results from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856).^2,3 Clinical trial site activations are planned to begin by the fourth quarter of 2026.

What is the design of the HARMONi-GU1 trial?

Investigators in the randomized phase 2/3 HARMONi-GU1 study will enroll approximately 800 patients globally. The phase 2 portion will identify the recommended phase 3 dose of ivonescimab in combination with enfortumab vedotin, while the phase 3 portion will compare that combination against pembrolizumab plus enfortumab vedotin. The dual primary end points for the phase 3 portion are progression-free survival (PFS) and overall survival (OS).

How does ivonescimab work in urothelial carcinoma?

Ivonescimab is an investigational, tetravalent bispecific antibody engineered to combine PD-1 blockade with anti-VEGF activity in a single molecule. The drug is designed for cooperative binding, showing multifold higher affinity to PD-1 in the presence of VEGF, with a half-life of 6 to 7 days after the first dose that extends to approximately 10 days at steady state.

“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,” stated Maky Zanganeh, PhD, president and co-chief executive officer of Summit Therapeutics, in the press release.¹

What is the regulatory history of the comparator regimen?

The FDA approved enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma in December 2023, converting an earlier accelerated approval limited to cisplatin-ineligible patients into a full approval for all previously untreated patients.⁴ That decision was based on EV-302/KEYNOTE-A39, an open-label trial of 886 patients who were randomly assigned to enfortumab vedotin plus pembrolizumab or platinum-based chemotherapy.

The median PFS was 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), respectively (HR, 0.45; 95% CI, 0.38-0.54; P <.0001). The application received breakthrough therapy and priority review designations and was reviewed under Project Orbis. Updated results from the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting showed that the combination produced a median OS of 33.6 months (95% CI, 26.6-39.8) vs 15.9 months (95% CI, 13.6-18.3) with chemotherapy (HR, 0.53; 95% CI, 0.45-0.63).³

What is ivonescimab's broader development program in oncology?

With the addition of HARMONi-GU1, ivonescimab is being evaluated in a total of 16 phase 3 trials across multiple tumor types, including 5 Summit-sponsored global studies and additional trials led by Akeso in China. Four phase 3 ivonescimab trials in non–small cell lung cancer have read out to date, all with positive results, including a statistically significant OS benefit in 2 of those studies.

“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,” Robert W. Duggan, chairman and co-chief executive officer of Summit Therapeutics, explained in the press release.¹

Despite recent advances, many patients with locally advanced/metastatic urothelial cancer still experience progression on frontline therapy. Emerging nectin-4–directed and biomarker-selected strategies, including early data suggesting resistance to enfortumab vedotin often reflects payload-specific mechanisms rather than loss of target expression, are being explored for use after progression on frontline enfortumab vedotin plus pembrolizumab.⁴ Ivonescimab is not approved by any regulatory authority in Summit's license territories, including the US, though it was approved for marketing in China in May 2024.

References

1. Summit Therapeutics further expands ivonescimab global development program with phase II/III HARMONi-GU1 study in 1L bladder cancer. News release. Summit Therapeutics Inc. August 5, 2026. Accessed August 6, 2026. https://tinyurl.com/ymvzcfzx
2. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. July 10, 2026. Accessed August 6, 2026. https://tinyurl.com/ywwuhr5k
3. Powles TB, van der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma: 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):4503. doi:10.1200/JCO.2026.44.16_suppl.4503
4. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed August 6, 2026. https://tinyurl.com/y54snes4
5. Iyer G, Gao X, Wei AZ, et al. Initial results from NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma. J Clin Oncol. 2026;44(16 suppl):4508. doi:10.1200/JCO.2026.44.16_suppl.4508