Zelenectide Pevedotin Plus Pembrolizumab Shows Promise in First-Line Urothelial Carcinoma

The combination of the novel Nectin-4–targeted Bicycle drug conjugate zelenectide pevedotin (BT8009) and pembrolizumab (Keytruda) has demonstrated encouraging clinical activity and an improved safety profile as a first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC), according to an interim analysis from the phase 2/3 Duravelo-2 trial (NCT06225596).¹ The data identify the 6 mg/m² dose of zelenectide pevedotin administered on days 1 and 8 of a 21-day cycle as the optimized regimen, offering substantial reductions in severe toxicities typically associated with standard-of-care antibody-drug conjugates (ADCs).

“Despite major progress…in the first line, there is still need for more tolerable first-line treatment options for these patients,” said Yohann Loriot, MD, PhD, medical oncologist at Gustave Roussy Cancer Institute, who presented the data at the 2026 ASCO Annual Meeting. “In this interim analysis…the response rate with the zelenectide pevedotin and pembrolizumab [was] promising, supporting its benefit-risk profile and supporting…the optimized dosing.”

Duravelo-2 Study Rationale

First-line therapeutic options for la/mUC are frequently limited by treatment-limiting toxicity. Conventional Nectin-4–targeted ADCs often result in high rates of grade 3 or higher skin reactions and lead to treatment discontinuation in approximately 30% of patients due to adverse events (AEs). Zelenectide pevedotin is a low-molecular-weight, 4.2 kDa synthetic bicyclic peptide linked via a peptidic cleavable linker to a monomethyl auristatin E (MMAE) cytotoxic payload. This unique structure is engineered to enable rapid tumor penetration while facilitating rapid systemic clearance, theoretically minimizing exposure to normal tissues and reducing off-target toxicities. Preliminary data from the expansion cohort of the phase 1/2 Duravelo-1 study (NCT04561362) previously demonstrated a 50% confirmed objective response rate (ORR), establishing a foundation for the current trial.²

Study Design

The ongoing global, open-label, randomized Duravelo-2 study utilizes an adaptive design to optimize front-line dosing. Eligible patients are adults with previously untreated, measurable la/mUC of the renal pelvis, ureter, bladder, or urethra, an estimated glomerular filtration rate (eGFR) of 30 mL/min or higher, and an ECOG performance status of 2 or lower. Within cohort 1, patients were stratified by cisplatin eligibility, presence of liver metastases, and ECOG performance status (0 vs 1/2), and randomized 1:1:1 to receive either zelenectide pevedotin 5 mg/m² on days 1, 8, and 15 plus pembrolizumab 200 mg on day 1; zelenectide pevedotin 6 mg/m² on days 1 and 8 plus pembrolizumab 200 mg on day 1; or standard platinum-based chemotherapy.

As of the July 23, 2025 data cutoff, 30 patients were evaluable in each investigational arm, with a median follow-up of 7.0 months. Baseline demographics were balanced between the 5 mg/m² and 6 mg/m² cohorts. In the 6 mg/m² group, the median age was 68 years (range, 29-87), 66.7% were male, 63.3% had an ECOG status of 0, 83.3% had metastatic disease (23.3% with liver metastases), and 66.7% were deemed cisplatin-ineligible.

Efficacy and Safety

Efficacy findings revealed strong antitumor activity in the optimized 6 mg/m² cohort (n = 26 evaluable), which achieved a confirmed ORR of 57.7% (95% CI, 36.9%-76.6%), including a 30.8% complete response (CR) rate and a 26.9% partial response (PR) rate. Stable disease was observed in 19.2% of patients, while 15.4% experienced progressive disease. By comparison, the 5 mg/m² cohort (n = 29 evaluable) achieved an ORR of 55.2% (95% CI, 35.7%-73.6%), with a 24.1% CR rate and a 31.0% PR rate. The median duration of zelenectide pevedotin treatment at the 6 mg/m² dosage was 6.3 months (range, 0.7-10.6).

The optimized 6 mg/m² regimen demonstrated superior tolerability and dose delivery, maintaining a median relative dose intensity of 97.0%. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 60.0% of patients in the 6 mg/m² arm vs 66.7% in the 5 mg/m² arm. Crucially, the treatment discontinuation rate due to drug-related AEs was 3.3% (n = 1) in the 6 mg/m² group, compared with 16.7% (n = 5) in the 5 mg/m² group. Related serious adverse events occurred in 16.7% of the 6 mg/m² cohort.

Adverse events of clinical interest remained predominantly low grade in the 6 mg/m² arm. Peripheral neuropathy occurred in 36.7% of patients (3.3% grade 3), skin reactions in 16.7% (0% grade 3), and eye disorders in 10.0% (0% grade 3). No cases of hyperglycemia or severe cutaneous toxicities, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, were reported. Analysts noted that across a broader safety database of 595 patients treated with the conjugate as of June 2025, skin toxicities have remained consistently low grade and clinically manageable.

These interim results suggest that the combination of the Nectin-4–targeted Bicycle drug conjugate and pembrolizumab at the 6 mg/m² D1/8 dosage provides an optimized benefit-risk profile, improved convenience, and a safety profile that distinctively differentiates it from existing ADCs. The regimen represents a promising, highly tolerable front-line option for advanced urothelial carcinoma, addressing a critical therapeutic gap for patients intolerant to conventional standard-of-care regimens.

DISCLOSURES: Loriot disclosed conslulting or advisory roles with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Janssen, Loxo/Lilly, Merck, MSD Oncology, Pfizer/EMD Serono, Roche, and Seagen, and travel expenses from Astellas Pharma, AstraZeneca, Janssen Oncology, MSD Oncology, Roche, and Seagen.

REFERENCES

1. Loriot Y et al. Interim analysis results from Duravelo-2: Zelenectide pevedotin (zele; BT8009) + pembrolizumab in patients (pts) with previously untreated locally advanced/metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 44, 2026 (suppl 16; abstr 4516). doi: 10.1200/JCO.2026.44.16_suppl.4516

2. Giannatempo P et al. Phase 1/2 Duravelo-1 study: Preliminary results of nectin-4–targeting zelenectide pevedotin (BT8009) plus pembrolizumab in previously untreated, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J Clin Oncol. 43, 45674567(2025). doi: 10.1200/JCO.2025.43.16_suppl.4567