Supplements and Featured Publications
ASCO 2023 Meeting Reporter: Updates in GU Cancers
Volume 1
Issue 1

Enfortumab Vedotin Plus Pembrolizumab Produces Durable Responses, Safety in Metastatic Urothelial Carcinoma

The combination of enfortumab vedotin-ejfv and pembrolizumab generated rapid and durable responses and demonstrated a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin.

Shilpa Gupta, MD

Shilpa Gupta, MD

The combination of enfortumab vedotin-ejfv (Padcev; EV) and pembrolizumab (Keytruda) generated responses and demonstrated a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin, according to long-term data from cohort A of the phase 1/2 EV-103 trial (NCT03288545) presented at the 2023 ASCO Annual Meeting.

“As a background, despite [gemcitabine/carboplatin] as the frontline treatment for cisplatin-ineligible patients with locally advanced and metastatic urothelial cancer, there is a significant need to further improve outcomes. Avelumab [Bavencio] maintenance is only indicated in patients who do not progress after gem/carbo, and PD-1 or PD-L1 monotherapy is only indicated in a very select group of patients,” explained first author Shilpa Gupta, MD, director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic, Cleveland, Ohio.

The FDA approved the combination of EV and pembrolizumab in the treatment of cisplatin-ineligible locally advanced or metastatic urothelial carcinoma based on findings from EV-103 dose-escalation cohort, cohort A, and cohort K, which showed that the combination has rapid and durable responses as well as a manageable safety profile in patients with previously untreated urothelial cancer. For the present study, Gupta presented an update on the results of dose escalation/cohort A after a median follow-up of 47 months.

“Enfortumab vedotin has a multifaceted mechanism of action due to the intracellular release of MMAE, which leads to direct cytotoxicity of the nectin-4-containing cancer cells, as well as induces the hallmark of immunogenic cell death…When combined with a checkpoint inhibitor there’s believed to be a complementary activity for further immune engagement and hence pembrolizumab is a rational partner for this combination,” Gupta said.

The analysis included a total of 45 patients, who received EV, 1.25 mg/kg intravenously (IV) on days 1 and 8, and pembrolizumab, 200 mg IV on day 1 of every 3-week cycle. Primary end points included adverse events (AEs) and lab abnormalities, and key secondary end points included confirmed objective response rate (ORR), duration of response (DOR), profession-free survival, and overall survival (OS).

Most of the patients were male (36, 80.0%), and median age was 69.0 years. Nearly all the patients were Caucasian (42, 93.3%), with ECOG performance status of 0, 1, or 2 in 15 (33.3%), 22 (48.9%), and 8 (17.8%) patients, respectively. Fourteen patients (31.1%) had liver metastases, and 38 patients (84.4%) had visceral disease.

After nearly 4 years of follow-up 40% of patients remained on study. All had discontinued treatment. Median treatment duration was 7 months, and median number of treatment cycles was 9. Reason for treatment discontinuation included progressive disease in 19 patients (42.2%), AEs in 15 patients (33.3%), patient decision in 9 patients (20.0%), and physician decision or other in 1 patient each (2.2%). Death was most common reason for study discontinuation, occurring in 22 patients (48.9%).

ORR was 73.3% (95% CI, 59.1-85.4), and disease control rate was 84.4% (95% CI, 70.5-93.5). Median DOR was 22.1 months, and median OS was 26.1 months.

Any-grade AEs occurred in 43 patients (95.6%) and included peripheral sensory neuropathy (25 patients, 55.6%), fatigue (23 patients, 51.1%), alopecia (22 patients, 48.9%), diarrhea (21 patients, 46.7%), decreased appetite (18 patients, 40.0%), maculo-papular rash (16 patients, 35.6%), pruritus (15 patients, 33.3%), and dysgeusia (15 patients, 33.3%). AEs of grade 3 or higher occurred in 29 patients (64.4%) and included increased lipase (8 patients, 17.8%); maculo-papular rash in 5 patients (11.1%); fatigue in 5 patients (11.1%); neutropenia, anemia, hyperglycemia, and increased amylase in 4 patients each (8.9%); and increased transaminases in 3 patients (6.7%).

Treatment-related AEs of special interested for EV included skin reactions of any grade in 30 patients (66.7%) and grade 3 or higher in 9 patients (20.0%), as well as peripheral neuropathy in 28 patients (62.2%). The investigators noted that treatment-related AEs for EV were consistent with previously reported results.

The most common treatment-emergent AEs of special interest for pembrolizumab included severe skin reaction of any grade in 11 patients (24.4%) and grade 3 or higher in 10 patients (22.2%).

Of patients receiving subsequent cancer-related therapy(ies), the most common was systemic therapy in 22 patients (48.9%).

“In EV-103 dose escalation/cohort A, the safety profile of the combination was manageable, with no new safety concerns observed at nearly 4 years of follow-up. EV and pembrolizumab demonstrated clinically meaningful efficacy, with a high confirmed high confirmed overall response rates, durable responses and a median survival exceeding two years in this patient population,” Gupta said in her concluding remarks.


Gupta S, Rosenberg JE, McKay RR, et al. Study EV-103 dose escalation/cohort A: Long-term outcome of enfortumab vedotin + pembrolizumab in first-line (1L) cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow-up. J Clin Oncol. 2023;41(suppl):4505. doi:10.1200/JCO.2023.41.16_suppl.4505

Related Videos
Aaron Gerds, MD
Manali Kamdar, MD
Ibrahim Aldoss, MD
Laurence Albigès, MD, PhD
Suneel Kamath, MD
Joaquim Bellmunt, MD, PhD
Suneel Kamath, MD
Timothy Hughes, MD, MBBS, FRACP, FRCPA
 Bernard H. Bochner, MD, FACS
Ana Christina Garrido-Castro, MD