EV-103 Study Highlights Promise of Enfortumab Vedotin and Pembro in mUC

Shilpa Gupta, MD

Promising trends in survival and rapid, durable responses have been maintained with the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) in first-line cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (mUC), according to findings from the phase 1b/2 EV-103 study (NCT03288545).¹

In the dose-escalation cohort A of this ongoing study, patients were treated with 3-week cycles of enfortumab vedotin at a dose of 1.25 mg/kg on days 1 and 8 in combination with pembrolizumab on day 1. The primary end point was safety/tolerability and secondary end points were objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

A total of 45 patients with a median age of 69 years (range, 51-90) received treatment, and at a median follow-up of 47 months, the confirmed ORR by BICR after a median of 9 cycles was 73.3% (95% CI, 58.1-85.4). The DCR seen with the combination was 84.4% (95% CI, 70.5-93.5) and the complete response rate was 15.6%. The median DOR was 22.1 months, median PFS was 12.7 months, and median OS was 26.1 months.

Regarding safety, the treatment-related adverse events that were most frequently observed included skin reactions (66.7%), peripheral neuropathy (62.2%), and ocular disorders (40.0%) with enfortumab vedotin. The most common treatment-emergent adverse events with pembrolizumab were severe skin reactions (24.4%), pneumonitis (8.9%), colitis (6.7%), and hypothyroidism (6.7%).

“I think these findings really show the durability of this combination and how effective it is. The ongoing phase 3 EV-302 study [NCT04223856] has now completed accrual and is looking at this combination against gemcitabine/cisplatin or gemcitabine/carboplatin. This will further lead to our understanding of whether it can surpass chemotherapy,” Shilpa Gupta, MD, told Targeted Oncology^TM, in an interview.

In the interview, Gupta, genitourinary medical oncologist, and the lead for the GU program at the Cleveland Clinic, Ohio, discussed findings from cohort A of Study EV-103 in patients with cisplatin-ineligible locally advanced or mUC.

Targeted Oncology: Can you explain the purpose of cohort A of study EV-103?

Gupta: This is the dose-escalation and cohort A of the EV-103 phase 1b study where the enfortumab vedotin and pembrolizumab combination was studied in cisplatin-ineligible patients with locally advanced in metastatic urothelial cancer who were unfit to receive cisplatin. This was for treatment-naive patients. Patients received enfortumab vedotin on day 1 and day 8 and pembrolizumab every 21 days. The primary end point was safety, and secondary end points were overall response rates, overall survival, progression-free survival, and PKs.

What was the rationale behind the study?

The rationale of the combination is that enfortumab vedotin has a multifaceted mechanism of action with the active molecule of MMAE, which is used intracellularly, and kills the nectin-4-expressing cancer cells directly, and also has a bystander effect on neighboring tumor cells, and causes immunogenic cell death. This is felt to be complemented with the addition of a checkpoint inhibitor like pembrolizumab.

What were the main findings from this study?

After a 4-year follow-up, previous results have already led to the approval in the accelerated approval program by the FDA based on cohort A and cohort K, which was enfortumab vedotin and pembrolizumab vs enfortumab vedotin alone. In this report with 4-year follow-up from the cohort, we saw that the objective response rates were around 73.3% by BICR, which is highly concurrent with the investigator assessed responses which were reported earlier. The median overall survival is exceeding 2 years at 26.1 months, and the tail of the curve is still holding strong. The median progression-free survival is 12.7 months, complete responses were 16%. We did not see any new safety signals of the combination.

I think these findings really show the durability of this combination and how effective it is. The ongoing phase 3 EV-302 study [NCT04223856] has now completed accrual and is looking at this combination against gemcitabine/cisplatin or gemcitabine/carboplatin. This will further lead to our understanding of whether it can surpass chemotherapy.

Are there any next steps planned for this research?

This has already had FDA accelerated approval in the United States. Now, depending on the phase 3 readout of the EV-302, it remains to be seen if this will become the new standard-of-care for all platinum eligible patients or not.

How do you anticipate this changing the field moving forward?

I think it is a big advancement in our treatment paradigm with such durable and effective results. I think the key here is that the use of the enfortumab vedotin and pembrolizumab combination, especially with enfortumab vedotin, there can be a toxicities like peripheral neuropathy which can become disabling and it takes a long time to resolve if dose modifications and dose discontinuations can’t control that, but I think the understanding of this new regimen and the toxicities are very important because the rash and the peripheral neuropathy can be challenging. It is important to talk to the patients and understand any toxicities because it's well managed if it's caught early. I think moving forward, if this were to become the standard, there's a lot of learning that needs to happen in terms of management of adverse effects.

REFERENCE:

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