Jonathan Rosenberg, MD, Memorial Sloan Kettering Cancer Center, shares his insight on results from Cohort K of the EV-103 study, evaluating enfortumab vedotin monotherapy or enfortumab vedotin in combination with pembrolizumab for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. The cohort study showed enfortumab vedotin plus pembrolizumab yielded a confirmed objective response rate of 64.5%, demonstrating that this is a highly active combination.

These results were first presented at the 2022 European Society for Medical Oncology (ESMO) Congress.

Transcript:

Hi. I'm Jonathan Rosenberg, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center in New York. At the 2022 ESMO Congress in Paris, France, I had the pleasure of presenting the results of Cohort K in the EV-103 trial. This was a randomized, non-comparative, phase 2 study comparing enfortumab vedotin monotherapy with enfortumab vedotin and pembrolizumab combination therapy in cisplatin-ineligible patients who had not previously received chemotherapy for metastatic urothelial cancer.

This study is a multi-cohort study and recently the results of the dose-escalation in cohort A cohorts were reported in JCO. Here, we're presenting the data from the roughly 75-patient-per-arm, randomized cohorts of monotherapy and combination therapy. It was a non-comparative study that was evaluating the contribution of components to try to understand how enfortumab vedotin fares in the first-line setting in untreated patients, and further explore and confirm the activity of enfortumab and pembrolizumab in the first-line setting.

The study had a typical urothelial cancer, cisplatin-ineligible population, primarily consisting of patients who had renal insufficiency, with about 10% to 15% of patients who had poor performance status or hearing loss, or some combination of the above. The patients were randomized 1-to-1 to enfortumab vedotin and pembrolizumab, or enfortumab monotherapy. This was stratified by the presence of liver metastases and ECOG performance status. The study, again, was designed to understand the 95% confidence intervals around the objective response rate for each regimen individually, and so it was not a comparative trial. Of course, the temptation is to always compare arms, but I would be careful and do that with a very large grain of salt.

The results show that the response rate for enfortumab vedotin plus pembrolizumab is 64.5%, which appears dramatically higher than we might expect with historical therapies like gemcitabine and carboplatin, which typically are in the 30% to 40% range. The response rate for enfortumab monotherapy was 45%, which is similar to the anti-tumor activity seen throughout the clinical trials of enfortumab in second- and third-line setting, suggesting very predictable activity for enfortumab monotherapy. About 10% of patients in the combination arm had complete responses and about 4% of patients in the single-agent arm had complete responses.

The data for overall survival duration of response and progression-free survival are immature, but do suggest that the data that we're going to see from this study are similar to what we observed in cohort A, which showed an overall survival approaching over 2 years in this study. The immature data for overall survival shows a 22-month survival. The median duration of response has not been reached for the combination therapy and the median progression-free survival has not been reached for combination therapy. This data will continue to mature and evolve, and I expect to see the overall survival number change substantially because the median follow-up is only 14.5 months. There is tremendous amount of censoring in the Kaplan-Meier analyses, and so that data will evolve over time and probably will lengthen but might shorten. We never know.

The toxicity of the combination appeared similar to what we previously reported in the prior cohorts of this trial of the combination. There was an increase in skin toxicity in the patients receiving the combination therapy, as opposed to the monotherapy arm, which looked very similar to enfortumab monotherapy. This is not surprising, given that's an overlapping toxicity for both enfortumab and pembrolizumab. There were not new, unusual treatment-related adverse events from the combination therapy. The adverse events represented toxicities related to pembrolizumab and toxicities related to enfortumab. Peripheral sensory neuropathy was the most common reason for discontinuation and patients were treated for an average of 11 cycles within enfortumab and pembrolizumab and eight cycles with enfortumab monotherapy.

In summary, this is a highly active combination and enfortumab vedotin plus pembrolizumab has a high objective response rate, substantially higher than historical data with conventional chemotherapy. Enfortumab vedotin monotherapy looks like enfortumab monotherapy in the second- and third-line setting, which is actually a very respectable drug, even as a monotherapy. The toxicity profiles are consistent with each drug and while not minimizing the toxicities, they generally have been manageable for most patients with dose interruptions and dose reductions, and when necessary, topical or oral corticosteroids.

I look forward to seeing the potential that this regimen might receive accelerated approval in the United States by the United States Food and Drug Administration, based on cohort case results. There are multiple phase 3 trials going on, looking at enfortumab vedotin and pembrolizumab, both for metastatic disease as well as neoadjuvant therapy.

Source:

Rosenberg JE, Milowsky M, Ramathurthy C, et al. LBA73 - Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Presented at: ESMO Congress; September 9-13, 2022. Paris, France and virtual. Abstract LBA73.