In an interview with Targeted Oncology, Jonathan Rosenberg, MD, further discussed the background and results of the EV-103 study in patients with locally advanced metastatic urothelial cancer.
Enfortumab vedotin (Padcev) in addition to pembrolizumab (Keytruda) showed high objective response rates (ORR) and median duration of response (DOR) not reached in patients with cisplatin-ineligible, locally advanced or metastatic urothelial cancer treated in the first line.
The safety profile of the combination was tolerable and consistent with the known profile for enfortumab vedotin plus pembrolizumab. Enfortumab vedotin monotherapy was also consistent with prior experience.
Data come from cohort K of the multi-cohort, open-label, multicenter EV-103 study (NCT03288545) presented at ESMO (European Society for Medical Oncology) Congress 2022 by Jonathan E. Rosenberg, MD. These data support ongoing investigations of enfortumab vedotin plus pembrolizumab in the first line for patients with locally advanced metastatic urothelial cancer.
In the trial, 149 patients were randomly assigned 1:1 to receive either enfortumab vedotin at 1.25 mg/kg as monotherapy (n = 76) on days 1 and 8 or in combination with pembrolizumab 200 mg on day 1 of 3-week cycles (n = 73).
The primary end point of the trial was confirmed ORR, with secondary end points consisting of DOR and safety, including treatment-related adverse events (TRAEs).
Findings revealed that the confirmed ORR was 64.5% (95% CI, 52.7-75.1) and the median DOR was not reached for patients given the combination compared with a confirmed ORR of 45.2% (95% CI, 33.5-57.3) and median DOR of 13.2 months (95% CI, 6.1-16.0) for those given enfortumab vedotin alone.
Regarding safety, TRAEs of special interest consisted of skin reactions (67.1% for the combination arm vs 45.2% for the monotherapy arm), peripheral neuropathy (60.5% vs 54.8%), ocular disorders (26.3% vs 28.8%), and hyperglycemia (14.5% vs 11.0%).
In an interview with Targeted OncologyTM, Rosenberg, chief of Genitourinary Oncology Service, Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, further discussed the background and results of the EV-103 study in patients with locally advanced or metastatic urothelial cancer.
Targeted Oncology: What does the frontline treatment landscape for metastatic urothelial cancer currently look like?
Rosenberg: Today, there are several treatment options for patients with metastatic urothelial cancer who have not yet received prior therapy. For patients who are cisplatin candidates, cisplatin-based combination chemotherapy is the standard. Either gemcitabine and cisplatin or dose-dense MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin] are the 2 options.
For patients who are cisplatin ineligible, gemcitabine and carboplatin followed by maintenance nivolumab [Opdivo], if they respond, is the most common option for PD-L1–positive patients in the United States. Atezolizumab [Tecentriq] is an option as well.
For those patients who are not eligible for any platinum chemotherapy or people who have multiple comorbidities, checkpoint inhibitor monotherapy with either atezolizumab or pembrolizumab are both possible treatment choices for those patients
What has been previously shown with enfortumab vedotin in this patient population?
There was a dose escalation and dose expansion cohort A of EV-103, which enrolled about 45 patients total. It showed that the ORR was 73% in that patient population of patients with cisplatin ineligible metastatic urothelial cancer. The [median] overall survival in that cohort was an impressive 26.2 months, which is roughly at least double of what you might expect with gemcitabine and carboplatin based on historical data. I suspect it is better than the current treatment paradigm of chemotherapy followed by maintenance of nivolumab, although there have not been any randomized trials. That first cohort has led to the development of subsequent trials, which are testing enfortumab vedotin and pembrolizumab further.
Can you provide some background on the EV-103 study?
EV-103 is a multi-cohort study of enfortumab vedotin in combination with multiple agents in different substudies. EV-103 dose escalation in cohort A was the initial exploratory cohort for enfortumab vedotin and pembrolizumab. There have been several other cohorts in combination with chemotherapy and neoadjuvant therapy. Some of those data have been reported already [in] other meetings, particularly that enfortumab vedotin monotherapy as neoadjuvant therapy.
EV-103 cohort K was a randomized trial, focusing on enfortumab vedotin and pembrolizumab or enfortumab vedotin monotherapy to try and understand the contribution of pembrolizumab with enfortumab compared with enfortumab alone in patients with metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy, or otherwise would have been ineligible to receive gemcitabine or carboplatin.
Can you explain the efficacy and safety results that were presented at ESMO Congress 2022?
Enfortumab vedotin and pembrolizumab led to an ORR of 64.5% and that was by blinded independent central review. Enfortumab vedotin monotherapy had a response rate of 45%. Enfortumab vedotin and pembrolizumab had 10% of patients having complete responses; enfortumab vedotin monotherapy had 4% of patients with complete responses. The median DOR and progression-free survival has not yet been reached with enfortumab vedotin and pembrolizumab. The median overall survival that was observed in the study, which is quite premature, because the median follow-up is 14.8 months, was 22.6 months. I expect that number will evolve substantially over time and might lengthen. It's possible it could shorten, but it looks relatively similar to what we saw on EV-103 cohort A. Similarly, the median overall survival for enfortumab vedotin is very immature, at around 21 months, but I suspect that may change as well.
The data for safety show that there is some additional toxicity of the combination in terms of overlapping skin toxicities from enfortumab vedotin and pembrolizumab. While there was no dramatic increase—it was higher than enfortumab vedotin monotherapy and higher than what you might expect with pembrolizumab monotherapy. The skin toxicities were generally manageable with dose interruptions, dose reductions, or even discontinuation of treatments. Patients often received topical steroids; some patients received corticosteroids.
There were no serious skin events that occurred in this study, which I think is a credit to the study team that worked with the investigators to manage the toxicity and prevent serious skin reactions. There were no treatment-emergent, unusual toxicities that we saw with the combination. It was otherwise the toxicities of pembrolizumab and enfortumab vedotin. We did see expected rates of immune-related adverse events from pembrolizumab. Pneumonitis was present as grade 3 in about 5% of patients on the enfortumab vedotin and pembrolizumab arm and is something to bear in mind when using the drugs together as well.
How do you manage the skin toxicity issues associated with this combination?
Management of skin toxicity is an important topic for patients receiving enfortumab vedotin. In my practice, I try to see patients within the first several cycles at each visit to monitor the skin toxicity or events closely. It's important for oncologists using enfortumab vedotin to develop a relationship with a dermatologist who they can refer patients to for assistance with more significant skin toxicities.
We tell all of our patients that they should notify us, even in between visits, if they're noticing new skin reactions, and to let us know so that we can intervene early. It has been my experience that early intervention with skin toxicity leads to improved clinical outcomes because you're more able to maintain therapy and give patients access to treatments.
What are the implications of these findings?
These data suggest that enfortumab vedotin and pembrolizumab is a viable treatment option for cisplatin-ineligible patients, based on this activity of the doublet regimen. The safety is manageable, and physicians need to be aware of skin toxicity as a concern. Early recognition and management of this for patients will be important. It is very possible that this will receive an FDA approval as an accelerated approval in the United States in advance of the phase 3 data given the totality of the evidence and the similarity of the outcomes between the 2 clinical trials in EV-103 cohort A and cohort K. I'm optimistic that this will be a treatment option for patients in the future, but we need to see what the regulator's think of this.
What other research is being examined in this space?
In the meantime, if you EV-302 (NCT04223856) is accruing. This is a randomized phase 3 trial of enfortumab vedotin and pembrolizumab compared with gemcitabine and platinum as first-line therapy or cisplatin or carboplatin. That will answer definitively whether or not patients will be receiving enfortumab vedotin and pembrolizumab in the long term regardless of platinum eligibility.