Exposure-Response Analysis of Enfortumab Vedotin Plus Pembrolizumab as First-Line Therapy for Locally Advanced or Metastatic Urothelial Cancer.

Authors

Vaishali L Chudasama, Helen Kastrissios, Hossam Kadry, Daping Zhang, Salaheldin Hamed, Srinivasu Poondru, Souvik Bhattacharya, Russ Wada, Amit Garg, Yen Lin Chia

Published in

Clinical pharmacology and therapeutics. Sep 09, 2026. Epub Sep 09, 2026.

Abstract

Enfortumab vedotin is a nectin-4-directed antibody-drug conjugate currently approved in combination with pembrolizumab for the first-line treatment of locally advanced or metastatic urothelial cancer. Here we describe the exposure-response relationship between enfortumab vedotin exposures and efficacy/safety endpoints in patients who received ≥1 dose of enfortumab vedotin 1.25 mg/kg (on days 1 and 8 of a 21-day dosing cycle) plus pembrolizumab (recommended dosage) and had evaluable pharmacokinetics in the EV-103 (N = 121) and EV-302 (N = 432) studies. Overall, most patients were older (median age of 69 years), White (74%), and male (77%), with median body weight in EV-103 (79 kg) trending higher than that in EV-302 (75 kg). Higher exposures of enfortumab vedotin were associated with consistently higher objective response rates across all exposure quartiles in both studies, and longer survival than chemotherapy in EV-302. Increased and faster incidence of treatment-related adverse events (Grade ≥ 3 hyperglycemia, Grade ≥ 3 skin reactions, and Grade ≥ 2 peripheral neuropathy) was also observed with increased exposures. However, dose modifications were effective in managing most adverse events, with most patients having at least partial resolution (hyperglycemia, >75%; skin reactions, >85%; and peripheral neuropathy, >50%). Responses attained with higher early cycle exposure were not impacted by subsequent dose modifications. Overall, exposure-response analysis supports the use of enfortumab vedotin at a starting dose of 1.25 mg/kg and in combination with pembrolizumab for first-line treatment of locally advanced or metastatic urothelial cancer.

PMID:
42717277
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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