Enfortumab Vedotin With Pembrolizumab May Usher in New Standard for Treatment of Urothelial Carcinoma

Terence Friedlander, MD

Frontline enfortumab vedotin-ejfv (Padcev) combined with pembrolizumab (Keytruda) generated beneficial objective response rates (ORR) with durable responses in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy, according to Terence Friedlander, MD.

The promising responses with the combination were garnered from cohort A and cohort K of the phase 1/2 EV-103/KEYNOTE-869 study (NCT03288545), which led to the FDA accelerated approval of the combination within this patient population.¹

Within the combined dose-escalation/cohort A and cohort K (n = 121), enfortumab vedotin combined with pembrolizumab elicited an ORR of 68% (95% CI, 59%-76%), with a 12% complete response rate and a 55% partial response rate. Additionally, the median duration of response (DOR) in the dose-escalation cohort plus cohort A was 22.1 months (range, 1.0+ to 46.3+); it was not reached (range, 1.2 to 24.1+) in cohort K.

“We have not had a new drug approved in the frontline setting [for urothelial cancer] with the exception of immunotherapy in many years,” Friedlander explained in an interview with OncLive^®. “The data that came out of the EV-103 study pushes the bar in terms of efficacy, and in terms of getting benefit to patients who are platinum ineligible with metastatic urothelial cancer.”

In the interview Friedlander discussed the significance of the FDA approval of enfortumab vedotin combined with pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma and expanded on the data from EV-103/KEYNOTE-869 that supported the approval. Friedlander is the chief of Hematology-Oncology, an associate director of Cancer Research at the Zuckerberg San Francisco General, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, and is an associate clinical professor in the Division of Hematology/Oncology at UCSF.

OncLive^®: What is the significance of the FDA approval of enfortumab vedotin combined with pembrolizumab?

Friedlander: Looking back to 10 years ago, we had carboplatin-based regimens with a 35% to 36% response rate, which was decent, but most patients didn’t respond to chemotherapy in the frontline setting. However, in [EV-103/KEYNOTE-869], we’ve seen both in cohort A and cohort K, that the response rates were impressive. Moreover, we’re seeing a consistent signal with enfortumab vedotin and pembrolizumab in the frontline, which is pretty exciting. This means that more than the majority of patients will respond. Traditionally this was a poor prognosis group who had very limited options; [this approval is] a step forward for the field.

What are the mechanisms of action of these agents? What was the rationale for combining them in this population?

Both enfortumab vedotin and pembrolizumab have been independently tested in large, randomized trials in later-line settings and in bladder cancer. Enfortumab vedotin is an antibody-drug conjugate [ADC] which targets Nectin-4 which is expressed on the surface of urothelial cancer, as well as some targets in the healthy tissues such as skin, for example. The payload for the ADC is MMAE, a known chemotherapy drug, which is by itself toxic, making it hard to give as a monotherapy. It stabilizes microtubules similar to how taxane chemotherapy works. Many of the adverse effects [AEs] mimic taxane chemotherapy in terms of neuropathy; [however,] some are different because this isn’t a targeted drug that goes after cells that express Nectin-4.

When the antibody binds to the cell, the whole linker molecule is dissolved in the cell in the cytoplasm of the cell, which releases the active drug, and the active drug is goes to paralyze these microtubules. This results in cell death and apoptosis. There’s some evidence that when enfortumab vedotin activates the immune system and draws immune cells into the tumor microenvironment. That led to the connection to giving this drug with immune therapy, such as pembrolizumab.

Pembrolizumab is an antibody that targets PD-1, [which] is a cell surface protein on immune cells and cancer cells, most providers are very familiar with it. It helps to stimulate the immune system to attack cancer. Because enfortumab vedotin may induce some immunogenic activity, the thought was that combining these 2 active drugs together would provide some synergy and we would see more benefits than you’d expect when giving them one followed by the other.

The question of synergy is still not completely solved. We have data from just a few 100 [individuals] who were treated with this combination. However, that’s a major area of research and focus going forward.

What were some of the key efficacy data from the cohorts A and K from this trial?

We first had data from cohort A, which was a dose-escalation and expansion cohort in 45 patients. All patients had cisplatin-ineligible metastatic urothelial cancer. We saw a 73% response rate from cohort A and were impressed by this. As I mentioned earlier, carboplatin-based regimens, which is standard of care, only have a 36% response rate. That was good to see in the initial data set.

We looked at the DOR once patients began to respond, which was 22 months, and the median DOR was over 1 year. Once a patient’s tumor shrunk, it tended to stay small, and it didn’t start growing for at least 1 year in half of patients. In terms of the [progression-free survival] PFS and [overall survival] OS, that data was what you’d expect. We saw a 12.3-month long PFS. The OS in cohort A was 26.1 months with over 2 years of survival. However, in the studies from 10 years ago, looking at carboplatin-based regimens, the OS was only 9 months. This was promising that giving these 2 drugs together is engendering to a long-term control of the cancer.

Cohort K followed cohort A and was a larger cohort that looked at the combination in 76 patients, and enfortumab vedotin alone in 73 patients. What we saw were similar results in terms of the response rate. The response rate for the combination was 64.5% which was good. In the monotherapy arm, the response rate was 45% and that mimics what we’ve seen in other studies of enfortumab vedotin monotherapy in the second line, and then third line, including in the phase 3 EV-301 trial [NCT03474107], which was in the 40% range.

There’s data from cohort K in terms of long-term outcomes, as of now, but we’re expecting more to be released at upcoming meetings.. My sense is that given that we’ve seen a very similar response rate for enfortumab vedotin and pembrolizumab in cohort K as we’re seeing in cohort A, that the longer-term outcomes will be similar, but we need to wait for the data.

What does the safety profile look like for this combination?

Although everyone is excited about enfortumab vedotin and pembrolizumab, there is real toxicity [with the treatment]. When looking cohort A, the most common AEs were sensory neuropathy, which occurred in over 50% of patients. Fortunately, most of the events were grade 1 and 2, which were mild to moderate. There are very few serious grade 3 and higher sensory neuropathy events. Fatigue was common with this combination, as you might expect. Alopecia was seen in a fair number of patients, as almost half of patients have alopecia, which is consistent with the mechanism of action.

The AE that concerned me the most, in addition to the neuropathy is the skin toxicity. We saw different types of rashes and pruritis that occurred. In cohort A for example, 35% of patients had maculopapular rashes, and another 33% had pruritis or itching; dry skin was fairly common, too.

There are a number of other less common AEs, but fortunately, most of those were grade 1 and grade 2.

Overall, the toxicity we saw in cohort A was consistent with what we’ve seen and when you add the drugs together, there may be increased risk for toxicity. That is not unexpected. Cohort K in the big picture mirrored cohort A when we looked at the combination. Fatigue was reported in over 50% of patients, as well as sensory neuropathy. Most of those were grade 1 and grade 2, and the rashes in cohort K led to grade 3 toxicity in patients.

When I talk to providers who haven’t used this combination, I try to emphasize that close attention to skin is important, because many patients will experience this toxicity and knowing how to diagnose it and how to treat it is really important.

How did AEs factor into treatment discontinuation rates in this study?

Fortunately, it wasn’t that common to see treatment discontinuation for AEs. In the dose-escalation cohort, very few patients withdrew due to AEs at just 24% of the patients. Dose reductions [occurred] in 31% of the patients in cohort A. The numbers were similar in cohort K.

Overall, most patients can tolerate this, and a minority of patients will have toxicity that does mandate dose reduction. I try and emphasize that with community providers, as well. Some patients will have to stop because of AEs, [such as] increasing neuropathy or skin AEs. Those are probably the 2 most common [reasons for discontinuation or dose limitations].

How does this combination fulfill some unmet needs in patients with metastatic urothelial cancer who are not eligible for cisplatin containing chemotherapy?

This regimen is very active for patients who have frontline metastatic urothelial cancer who aren’t eligible for cisplatin. The standard of care for those patients has historically been to give carboplatin- and gemcitabine-based regimens, with response rates in the 30% range and poor OS. However, between cohort A and cohort K, there has been a near doubling of the historical rate.

I have a hard time seeing why a patient who is eligible for the enfortumab vedotin and pembrolizumab regimen or a carboplatin-based regimen wouldn’t [be treated with] the enfortumab vedotin and pembrolizumab regimen when [it is known] that there is a good chance of having a response.

It also allows patients to get a PD-1 therapy. We talked a lot about [the combination of] enfortumab vedotin and pembrolizumab, but we haven’t talked much about [anti–]PD-1 therapy. It allows patients to get the PD-1 therapy early in the treatment course, and we know from other major trials of PD-1 therapy that [approximately] 20% of patients who get PD-1 inhibitors with advanced urothelial cancer will have long term durable responses; I’ve seen that personally. I’ve seen patients responding to PD-1 therapy for many years and it’s incredibly satisfying to treat a patient and see that happen.

Rather than the current paradigm where patients get upfront chemotherapy, we stop the chemotherapy and then consider giving maintenance [anti–]PD-1 therapy such as avelumab [Bavencio], or wait for progression and then give them a PD-1 therapy in the second line, we’re now moving the PD-1 therapy up. That means we're catching patients earlier and getting the therapy to them earlier and that's good.

We know in urothelial cancer, based on some large registry, that of all patients who are diagnosed with advanced disease, almost one-quarter never get treated for urothelial cancer because they’re too sick or they don’t have access to care. Once you look at patients who get frontline therapy, almost 50% of them never get to the second line as the disease progresses rapidly. There’s a logic to giving enfortumab vedotin and pembrolizumab early on, trying to put your best foot forward really and give active agents up front. We’ll see how that bears out in larger phase 3 trials in the setting. However, it intuitively makes sense to be aggressive with patients up front with a regimen that’s tolerable with some known toxicity.

Looking to the future, what is the rationale for the phase 3 EV-302 trial (NCT04223856)?

EV-302is a randomized, phase 3 trial looking at the combination of enfortumab vedotin and pembrolizumab, comparing it to cisplatin-based chemotherapy or carboplatin-based chemotherapy.

All the data that we have for enfortumab vedotin and pembrolizumab to date has been in phase 1/2 studies. There’s always concerns that there may be some bias in smaller studies [such as] this, as we may select healthier patients, for example. However, this new study will test in a very large set of patients to understand how well this combination performs.

There are 2 opportunities here. One is to show that enfortumab vedotin and pembrolizumab is better than carboplatin-based regimens, and the other opportunity is to show that it’s better than cisplatin-based regimens. That could have potential not just for the cisplatin ineligible patients, but for all patients with metastatic disease. [That data] can tell us whether enfortumab vedotin and pembrolizumab will be the go-to frontline regimen for all patients, or whether it only be for certain patients.

What is a main takeaway message based on our conversation?

This is an exciting time in urothelial cancer. We haven’t had a major phase 3 study in the frontline setting be positive in a long time. We’re waiting for EV-302 trialas the phase 3 study, but the data that I think is important is that the response data has been remarkably consistent across different lines of therapy. That gives me some more confidence when using this combination in the front line, even though it’s based on phase 2 data.

It gives me a lot of confidence that what we’re seeing is very likely true that there is a lot of activity from this treatment, and a lot more comfort in using that regimen in patients who have frontline metastatic disease vs platinum-ineligible [disease].

Reference

FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed April 6, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications