Enfortumab Vedotin/Pembrolizumab Outperforms Chemotherapy in mUC

Thomas Powles, MD, MBBS, MRCP

Previously untreated patients with locally advanced or metastatic urothelial carcinoma (mUC) demonstrated a statistically significant improvement in overall survival (OS) vs chemotherapy when administered the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda; EVP), according to findings from the phase 3 EV-302 trial (NCT04223856).¹

The EV-302 study randomly assigned patients in a 1:1 fashion to receive standard-of-care chemotherapy consisting of gemcitabine/cisplatin or gemcitabine/carboplatin for a maximum of 6 cycles (n = 444) or enfortumab vedotin given at a dose of 1.25 mg/kg via intravenous (IV) infusion on days 1 and 8 and pembrolizumab 200 mg IV on day 1 of 3-week cycles (n = 442).

Among those enrolled in the study, the median number of cycles received was 12 (range, 1-46) in the EVP arm and 6 (range, 1-6) in the chemotherapy arm. Between arms, 67% and 45.7% remained on the study at the time of the analysis, and 34.6% and 16.4% of patients discontinued treatment due to progressive disease on the EVP arm vs the chemotherapy arm. In the EVP and chemotherapy arms, 21.9% and 14.0% of patients discontinued treatment due to adverse events. Further, 59% of patients received subsequent immunotherapy with a PD-1/ L1 inhibitor in the chemotherapy arm compared with 30% who received maintenance avelumab (Bavencio) in the EVP arm.

According to Thomas Powles, MD, MBBS, MRCP, the combination led to a reduced risk of death by 53% compared with chemotherapy at a median follow-up of 17.2 months, and the median OS was 31.5 months (95% CI, 25.4-not reached) among patients in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P <.00001). This OS benefit was seen regardless of PD-L1 status or the presence of visceral metastases, and findings were consistent regardless of whether the patient was treated with cisplatin or carboplatin.

The median PFS in the EVP arm was 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) in the chemotherapy arm, resulting in a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P <.00001). This PFS benefit was sustained across all prespecified subgroups, such as those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.

In the EVP vs chemotherapy arms, the confirmed objective response rates were 67.7% and 44.4% and consisted of a complete response rate of 29.1% a partial response rate of 38.7%, stable disease rate of 18.8%, and progressive disease rate of 8.7% in the EVP arm vs 12.5%, 32%, 33.8%, and 13.6% in the chemotherapy arm.

“We have shown an unusual and impressive result of a 50% reduction in the risk of death, a 50% reduction in the risk of progression, much higher response rates, complete responses, and a good tolerability profile in line with expectations. Overall, it is reasonable to say this will supersede other treatments, explained Powles, professor of genitourinary oncology, Queen Mary University of London and director, Barts Cancer Center, in an interview with Targeted Oncology^TM. “I can see doctors wanting to give this new combination to their patients, and we are excited about it.”

In the interview, Powles discussed the impressive performance of enfortumab vedotin plus pembrolizumab for the treatment of locally advanced or mUC, as seen in the EV-302 trial.

Targeted Oncology: What is important to know regarding enfortumab vedotin?

Powles: Enfortumab vedotin is an antibody-drug conjugate. It is an exciting drug in the urothelial cancer field. Antibody-drug conjugates essentially have 3 components. They have the targeted antibody, a link molecule, and a payload attached to that. The antibody acts as a homing device to attach, essentially, to the cancer. In the case of enfortumab vedotin, that antibody is Nectin-4. It binds to Nectin-4, and about 98% of urothelial cancers overexpress Nectin-4. It's also important to recognize that other organs overexpress Nectin-4, like the skin, and that is why there's some skin toxicity with the drug.

The linker molecule attaches the payload, and [vedotin] is the payload. That is essentially a microtubule disrupting agent, which is a type of chemotherapy. The drug therefore is an antibody-drug conjugate; it was tested in phase 1, phase 2, and phase 3 as a monotherapy. The key to that data is that it was tolerable as a monotherapy and associated with a 30% reduction in the risk of death in patients with heavily treated urothelial cancer in a randomized phase 3 trial vs chemotherapy. It became the standard-of-care in patients whose cancers have progressed after chemotherapy and immunotherapy.

The drug as a single agent is associated with adverse event profiles. The adverse events of special interest are skin toxicity, peripheral neuropathy, and hyperglycemia. There are other components, some nausea and fatigue, and there's not really too much interstitial pneumonitis like what people talk about with antibody-drug conjugates. It is actually not that common with enfortumab vedotin. The toxicity is manageable, and the drug as a monotherapy was given on day 1, day 8, and day 15 in a 4-week cycle. The drug is associated with a 40% response rate, which is much higher than other agents that we've seen in this disease. Normally, immunotherapy is about 20%, chemotherapy about 10%-15%. We knew it was a great drug, and we feel as a monotherapy, in my opinion, it is probably the best drug that we have.

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Can you discuss the background of the EV-302 study?

The EV-302 study is a randomized, phase 3 study which explores enfortumab vedotin in previously untreated metastatic urothelial cancer. It is a large, randomized, phase 3 study, but the important thing about it is we are not exploring monotherapy with enfortumab vedotin. We are looking at enfortumab vedotin with pembrolizumab. The reason we are doing that is we know pembrolizumab has monotherapy activity with response rates of about 20% in the frontline setting. We know that those responses are long-term and durable. We also know the combination of enfortumab vedotin plus pembrolizumab, within phase 2 data, shows response rates of about 68%, progression-free survival of about 12 months, and overall survival of about 2 years. When you pull that package together and compare that with historical data like chemotherapy, the chemotherapy response rate is much lower than that. It is probably about 45%, progression-free survival of about 6 months, and overall survival of 12-18 months.

We looked at that phase 2 data and said, that looks really good. We know the monotherapy data; we did a randomized phase 2 trial of enfortumab vedotin and pembrolizumab, the combination vs monotherapy vs enfortumab vedotin alone, and we showed that the combination had higher and more durable responses, which actually underpins the importance of the combination. With this great data and the fact that we previously showed the combination is better than monotherapy and the historical control chemotherapy data, we thought, let's do a frontline, randomized, phase 3 trial to see if the combination is indeed better than standard chemotherapy.

No one has ever beaten standard chemotherapy before. I have tried many times in my career and never done it successfully. For standard chemotherapy, gemcitabine and cisplatin or gemcitabine and carboplatin, the choice is based around performance status and renal function. Those patients with poor performance statuses and poor renal function tend to get gemcitabine and carboplatin rather than gemcitabine and cisplatin. The progression-free survival and overall survival of gemcitabine/carboplatin is a little inferior to gemcitabine/cisplatin, but it is not massively different from each other. That is the control arm of the trial.

There is 1 caveat to that as during the conduct of the trial, maintenance durvalumab became a standard-of-care. About 30% of patients on the standard control arm also got maintenance durvalumab. Although the control arm changed during the conduct of the trial, many patients got maintenance durvalumab; 's gemcitabine/cisplatin, gemcitabine/carboplatin plus or minus durvalumab vs enfortumab vedotin and pembrolizumab.

The primary end points of the study are progression-free survival and overall survival. It is a large study of over 800 patients. It is a classic, randomized, phase 3 trial. It's an open-label study, but there is a blinded central radiological review, which gives us confidence about progression-free survival as the end point. We've had follow-up. The minimum follow-up is not long, but the trial took a long time to recruit. The median follow-up is reasonable as it currently stands.

Can you discuss the patient characteristics observed in the study?

It is classic urothelial cancer. A high proportion of patients were getting gemcitabine/cisplatin and gemcitabine/carboplatin in the control arm with upper tract urothelial cancer as well as bladder urothelial cancer. PD-L1 positivity is in line with expectations. The patient characteristics of the 2 groups are nicely balanced.

What top-line data and findings have already been observed?

The findings of the trial are exceptionally positive. The overall survival shows a 50% reduction in the risk of death. We've never really seen anything like that in bladder cancer before. Progression-free survival was also a 50% reduction in the risk of progression. We've reproduced those phase 1 and phase 2 data for [enfortumab vedotin and pembrolizumab]. In fact, the data looks—because we've included cisplatin-eligible patients here, which I think have slightly better performance data in my opinion—at least as good as what we saw in the phase 1 and phase 2 trials.

The subset analysis didn't show any particular subgroup where chemotherapy was better. It was really consistently better across the board, irrespective of platinum use, irrespective of upper tract or lower tract disease, irrespective of PD-L1 status, and that was progression-free and for overall survival. The response rate was high, in the region of 70%, complete response rate of 30%, and we've not seen that before. Now we'll have to look to see what happens to those patients, but I also have to tell you that those responses were durable and more durable than with chemotherapy. It's possible that we're putting a group of patients into long-term durable remission. We have not really seen that before either, which is really exciting.

The tolerability profile needs to be looked at, of course, and the adverse event profile overall was not that much worse than chemotherapy about. It was about the same as chemotherapy, which I think is reassuring. But remember, [enfortumab vedotin and pembrolizumab] continues until progression, where chemotherapy is only given for 6 cycles. So if you weigh the adverse events for duration of therapy, the frequency of the adverse events on enfortumab vedotin and pembrolizumab is actually lower than what we saw in chemotherapy.We then did some quality-of-life [research] and showed time to pain deterioration was similar in both groups overall.

In summary, it's fair to say it was a well conducted, randomized, phase 3 study, a large study, a global study that was recruited around the world. It showed, as you would expect, that the 2 groups were balanced. We have shown an unusual and impressive result of a 50% reduction in the risk of death, a 50% reduction in the risk of progression, much higher response rates, complete responses, and a good tolerability profile in line with expectations. Overall, it is reasonable to say this will supersede other treatments. I can see doctors wanting to give this new combination to their patients, and we are excited about it.

Are there any next steps for this research?

We are confident that the community is going to look at these data positively. There are other bits that we'd like to look at, [including] subset analysis in the future, maybe looking at liver and bone metastasis. In a forest plot, we showed that those patients did much better with enfortumab vedotin and pembrolizumab, but we do not know those median values. We may look at biomarkers in more detail like PD-L1. People always talk about Nectin-4 as well. I think that has a relevant role to play, although the vast majority of patients' tumors are overexpressing Nectin-4, so I am not sure how useful that is going to be. We've looked at Nectin-4 previously in other trials, and we have not had consistent results, so that is relevant. Then of course, we ought to look at the quality-of-life in more detail. Then, we will have a look at biomarkers doing whole exome sequencing, also looking at RNA sequencing.

It is also important to say that enfortumab vedotin/pembrolizumab has a future in early disease. It is being explored in muscle-invasive bladder cancer and is being explored in other randomized phase 3 trials, and this includes the neoadjuvant setting. There are 2 randomized phase 3 trials in the neoadjuvant setting. With the knowledge that we are beating chemotherapy with a 50% reduction in the risk of death, one would assume that we might be able to do that again in that perioperative setting. I would expect this combination to be used both in the advanced setting, which we are going to do now, but also in the perioperative setting in the not too distant future.

Then there is another generation of antibody-drug conjugates, disitamabvedotin [RC48], which is targeting HER2, sacituzumab govitecan-hziy [Trodelvy], which is a TROP2 ADC with SN38 as the payload. I think this is opening a new chapter in urothelial cancer. I also think it has implications beyond that. It is important to remember that chemotherapy and immunotherapy was not hugely successful in urothelial cancer but pembrolizumab has been. It might be that this combination may turn out to be better than the chemotherapy/[immuno-oncology (IO)] combination. In those other cancers where we are currently using immunotherapy and chemotherapy together, I think we will see ADC/IO trials to see if we can beat that.

What should a community oncologist know about enfortumab vedotin and pembrolizumab moving forward?

Enfortumab vedotin with pembrolizumab has clearly outperformed standard chemotherapy in frontline metastatic urothelial cancer. I think that gemcitabine and cisplatin and gemcitabine and carboplatin, which we have been used to using with maintenance durvalumab for some period of time, has now been completely superseded. I think it works in unselected patients. I also think it's a tolerable regime. I think there is important education and training around the adverse event profile, which is distinct from chemotherapy, but actually not more toxic than chemotherapy, just different. There is no neutropenic sepsis, there's not as much nausea and vomiting, there's not as much renal impairment. We are seeing skin toxicity, which is manageable, [and] peripheral neuropathy which accumulates with time. We need to think about when we stop the drug [and]how we reduce the dose, so there is education and training associated with that, but this is a new chapter for the treatment of metastatic urothelial cancer.

REFERENCE:
1. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/keynote-A39: Open-label, Randomized Phase III study of enfortumab vedotin in combination with Pembrolizumab (EV+P) vs Chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (LA/MUC). Annals of Oncology. 2023;34. doi:10.1016/j.annonc.2023.10.106