Neoadjuvant Enfortumab Vedotin May Be an Option for Cisplatin-Ineligible MIBC

Daniel Petrylak, MD, of Yale Cancer Center

Neoadjuvant administration of the antibody drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) represents a potential future treatment option for patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy, according to Daniel Petrylak, MD.

Results from cohort H of the phase 1b/2 EV-103 trial (NCT03288545), which Petrylak presented at the 2022 ASCO Genitourinary Cancer Symposium, demonstrated enfortumab vedotin elicited pathologic complete responses (pCRs) in 36.4% (95% CI, 17.2%-59.3%) of patients with MIBC (n = 22). This pCR rate mirrored the response rates seen in patients with MIBC who are eligible for cisplatin-based chemotherapy, Petrylak noted.

“Hopefully we will have a new standard of care” after the completion of more clinical trials, Petrylak said. “Particularly for those patients who have to go directly to cystectomy without having treatment, the platinum-ineligible patients.”

In an interview with OncLive^® during the 2022 ASCO Genitourinary Cancer Symposium, Petrylak, a professor of medicine and urology, coleader of Cancer Signaling Networks at the Yale Cancer Center, discussed safety and efficacy findings from EV-103 trial.

OncLive^®: Can you provide some background about what is known about enfortumab vedotin? How does it differ from other agents within this space?

Petrylak: Enfortumab vedotin is an ADC which recognizes a protein called nectin-4, which is on the cell surface of practically all urothelial carcinoma cells. It delivers an anti-tubilin agent called monomethyl auristatin E [MMAE] to the cells, and that is how it effects its cytotoxic activity.

In preliminary studies in patients who are ineligible to receive cisplatin, there was an approximately 40% response rate with enfortumab as a single agent, and this led to its approval in this particular disease state.

What this trial was focusing on were those patients who were not eligible to receive cisplatin neoadjuvant chemotherapy. Cisplatin chemotherapy is the standard of care for those patients, and of those who receive it, about one-third will have a pCR. It has been demonstrated to improve survival compared with cystectomy alone in those patients with locally advanced, muscle-invasive disease.

The objective of this trial was to [assess] patients who were not eligible to receive cisplatin, and these were predominantly patients with poor renal function. They received enfortumab vedotin for 3 cycles [in] a slightly attenuated version of day 1 and day 8, rather than day 1, 8, and 15 regimen, which is approved for metastatic patients.

What we found was that about one-third of patients had a CR. This clearly is comparable to what was seen with cisplatin-based chemotherapy. Although it is not a randomized trial, it does show that there is significant activity in the neoadjuvant state for those patients who are not eligible to receive cisplatin.

In the past, these patients should have gone directly to cystectomy. We may have a new option to investigate in the future for these patients.

Specifically with cohort H, what should be known about this specific patient population?

These were patients who were not eligible to receive cisplatin, based upon their renal function, grade 2 or greater hearing loss, [ECOG] performance status, cardiovascular disease, or peripheral neuropathy. These are the standard criteria for deeming somebody to be ineligible to receive cisplatin.

Can you expand on the efficacy findings from this study?

There were 22 patients in the trial and 36% of these patients had a pCR, meaning that there was no viable tumor present in the specimen at cystectomy. Half of patients had pathological downstaging, which means that they down staged either to ypT0, ypTis, ypTa, or T1, and had no nodal disease. This does seem to have significant effectiveness in this group of patients.

It is also important to talk about toxicity in terms of these patients. There were 4 patients, or 18%, who had grade 3 or higher enfortumab vedotin treatment-related adverse [effects]. These included asthenia, dehydration, erythema multiforme, hyperglycemia, postprocedural urinary leak, rash, as well as a small intestinal obstruction.

It is important to note that although patients did develop sensory neuropathy, it was mild. And this occurred in only 27% of patients.

Did those safety findings mirror what was already known about this agent?

They fall in line with what is known and what has been previously reported. There were 3 deaths on study, but these were deemed not to be related in to enfortumab vedotin. These included an acute kidney injury, cardiac arrest, and pulmonary embolism, all in the post-operative state.

What are next steps for research with this agent?

There is another cohort that is accruing patients, both adjuvantly and neoadjuvantly. It is 3 cycles of neoadjuvant therapy followed by 3 cycles of adjuvant therapy. [Moreover], there are trials that are in evaluating enfortumab vedotin combined with checkpoint inhibitors. As we know, there is very exciting data with enfortumab vedotin combined with pembrolizumab [Keytruda].

All of these are moving forward, and hopefully we will have a new standard of care, particularly for those patients who have to go directly to cystectomy without having treatment, the platinum-ineligible patients.

Based on the data read out from this trial, what is the key takeaway from this cohort?

Enfortumab vedotin has significant activity when used as neoadjuvant therapy in those who are not eligible to receive cisplatin. Approximately 36% of patients will have a pCR, which is comparable to what we see in patients who are treated with platinum [chemotherapy]. This may turn out to be in the future, if proven through randomized trials, a new option for patients.

Reference

1. Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible. J Clin Oncol. 2022;40(suppl 6):435. doi: 10.1200/JCO.2022.40.6_suppl.435