Enfortumab Vedotin Plus Pembrolizumab Sustains Long-Term Benefit in Metastatic Urothelial Carcinoma

Long-term efficacy and safety data from the phase 1/2 EV-103 trial (NCT03288545) evaluating enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) added to the evidence supporting the combination as a potential chemotherapy-free option in the first-line setting for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin, according Shilpa Gupta, MD.

Updated data from the dose-escalation cohort and cohort A from EV-103 presented at the 2023 ASCO Annual Meeting showed that at a median follow-up of 47 months, patients (n = 45) experienced an objective response rate (ORR) of 73.3% (95% CI, 59.1%-85.4%) and a disease control rate (DCR) of 84.4% (95% CI, 70.5%-93.5%). Moreover, 15.6% of patients achieved a complete response, and 57.8% had a partial response.¹ The median duration of response was 22.1 months (95% CI, 8.38–not estimable [NE]).

Additionally, the median overall survival (OS) was 26.1 months (95% CI, 15.51-NE), and the 24-month OS rate was 56.4% (95% CI, 40.03%-69.91%). The median progression-free survival (PFS) was 12.7 months (95% CI, 6.11-NE), and the 24-month PFS rate was 41.1% (95% CI, 25.96%-55.88%).

Previous findings from the dose-escalation cohort, cohort A, and cohort K of EV-103 supported the FDA’s accelerated approval for enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.²

“The tail of the [PFS] curve still holds strong, and these data are very reassuring for the long-term follow-up efficacy,” Gupta said.

In the interview with OncLive^®, Gupta, expanded on the updated results from EV-103 in patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin, and detailed the next steps for investigating the combination of enfortumab vedotin plus pembrolizumab in the ongoing phase 3 EV-302 trial (NCT04223856).

Gupta is the director of Genitourinary Medical Oncology at the Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at the Cleveland Clinic in Ohio.

OncLive: Could you briefly summarize previous findings from EV-103, particularly in cohort A?

Gupta: Cohort A and the dose-escalation cohort consisted of 45 patients with locally advanced and metastatic urothelial cancer who were ineligible to receive cisplatin. Previously, the data showed that the ORR in these patients who received the enfortumab vedotin and pembrolizumab combination was [73.3%].3 [These data], in addition to [findings from] cohort K, which looked at enfortumab vedotin plus pembrolizumab compared with enfortumab vedotin monotherapy, led to the accelerated approval of this combination in the United States in the frontline setting for cisplatin-ineligible patients [with locally advanced or metastatic urothelial carcinoma].

What long-term efficacy findings from EV-103 were presented at the 2023 ASCO Annual Meeting?

We presented the nearly 4-year follow-up from the dose-escalation cohort and cohort A at the 2023 ASCO Annual Meeting. We found that the ORR by blinded independent central review [BICR] was 73.3%, and the concordance rate [between BICR- and investigator-assessed best overall response] was 95.3%. At a median follow up of 47 months, the median OS exceeded 2 years at 26.1 months, and the median PFS was 12.7 months.

What did updated data show regarding safety?

We did not see any new safety signals other than what had been already reported from the combination. The most common toxicities seen with the combination were peripheral neuropathy, rash, and fatigue. Fortunately, these toxicities, such as rash and neuropathy, were reversible and resolved eventually if appropriate attention was paid early on, and the treatment was either dose reduced or withheld.

Rash appears early on within the first couple of cycles and resolves very quickly if we hold treatment, decrease the dose, discontinue, or give a treatment break. Peripheral neuropathy occurs a bit later in the course and takes about 7 months to resolve, and it can be quite disabling. Therefore, it is important to take a good history from patients at each cycle [to determine] if they are developing any new symptoms.

Hyperglycemia is another adverse effect that tends to occur early on, and with adequate supportive measures, treatment, and dose reductions, it can be well managed.

What are some of the next steps for investigating this combination?

The phase 3 EV-302 trial is comparing the enfortumab vedotin and pembrolizumab combination vs standard-of-care platinum-based chemotherapy for all comers. [Patients in the control arm will receive] gemcitabine plus cisplatin if they're cisplatin eligible or gemcitabine plus carboplatin if they are cisplatin ineligible. [This trial] has completed enrollment, and we hope to see some initial results in the coming year.

References

1. 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
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed August 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
3. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol. 2023;41(1):22-31. doi:10.1200/JCO.22.01643