(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured an oral abstract session on urothelial carcinoma, and a presentation by Dr. Daniel Petrylak discussing the impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer. Enfortumab vedotin is approved in combination with pembrolizumab (EV-3021) and as a monotherapy for locally advanced or metastatic urothelial cancer based on the pivotal EV-2012 and EV-3013 trials. Enfortumab vedotin, alone and in combination with pembrolizumab, has demonstrated an overall survival benefit and a generally manageable safety profile in patients with previously treated or untreated locally advanced or metastatic urothelial cancer:
Enfortumab vedotin monotherapy was administered at 1.25 mg/kg 3Q4W IV in the pivotal trials and modified per investigator judgment using prespecified guidelines to manage treatment emergent adverse events. Indeed, in practice, dose modifications, including reductions and interruptions, are recommended to manage enfortumab vedotin-related adverse events. This analysis evaluates the association between enfortumab vedotin plasma exposure, which is impacted by dose modifications, and safety and efficacy outcomes using data from the enfortumab vedotin monotherapy trials.
The characterization of dose- and exposure-response for efficacy and exposure-response for safety outcomes included patients in EV-101 (enfortumab vedotin monotherapy 0.75, 1.0, and 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle [3Q4W]), EV-201, and EV-301 (enfortumab vedotin monotherapy 1.25 mg/kg 3Q4W). Time-averaged exposure up to an event of interest, Cavg, was computed using a population pharmacokinetic model. Pharmacokinetic assessment included multiple samples in first 2 cycles and pre-dose samples in subsequent cycles. The characteristics of these three trials are highlighted below:
Baseline characteristics were similar across enfortumab vedotin monotherapy trials and consistent with a previously treated locally advanced or metastatic urothelial carcinoma population:
In the phase 1 EV-101 study, EV 1.25 mg/kg 3Q4W achieved a high response rate and was supported by exposure-response analysis:
Furthermore, higher early enfortumab vedotin dose intensity was generally associated with a greater probability of response in pivotal trials:
Dose modifications were common, including dose reductions to 1.0 mg/kg (EV-201 42.1%; EV-301 35.1%) and 0.75 mg/kg (EV-201 13.6%; EV-301 11.1%). The majority of patients in EV-301 maintained EV 1.25 mg/kg through cycle 7, though dose reductions were more frequent in later cycles:
Importantly, responding patients resumed treatment and continued to have benefits following dose interruptions or dose reductions:
Lower enfortumab vedotin exposure was associated with lower risk of enfortumab vedotin-related grade ≥ 3 rash or skin reactions, grade ≥ 2 peripheral neuropathy, and grade ≥ 3 hyperglycemia (p < 0.0001 for all):
Early time to onset of skin reactions and hyperglycemia (median onset during cycle 1) confounds the interpretation of exposure-safety analysis. Unconjugated MMAE Cavg was not strongly correlated with incidence of these adverse events. Importantly, durable responses were maintained with enfortumab vedotin despite dose modifications in EV-301:
Finally, enfortumab vedotin monotherapy showed a benefit versus chemotherapy across exposure quartiles in EV-301:
Dr. Petrylak concluded his presentation by discussing the impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer with the following take home messages:
- Enfortumab vedotin monotherapy at the 1.25 mg/kg 3Q4W dose has shown a consistent benefit and manageable safety profile across multiple trials of patients with locally advanced or metastatic urothelial carcinoma in the second and third line setting
- Higher enfortumab vedotin dose intensity was generally associated with a greater probability of response
- Dose modifications, including dose reductions, were common across trials, particularly in later cycles. However, the safety and efficacy outcomes with enfortumab vedotin monotherapy were achieved with the use of dose modifications
- Recommended enfortumab vedotin dose modifications assist in managing adverse events and may allow patients to remain on treatment
- Patients continue to benefit from enfortumab vedotin monotherapy in the setting of dose modifications to manage adverse events
- Enfortumab vedotin monotherapy provided a progression free survival and overall survival benefit versus chemotherapy across exposure quartiles
Presented by: Daniel P. Petrylak, MD, Yale School of Medicine, New Haven, CT
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
References:
- Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10)875-888.
- Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of Enfortumab Vedotin in Urothelial Carcinoma after Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29):2592-2600.
- Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-1135.