ADCs and Immunotherapy Broaden the Bladder Cancer Treatment Paradigm

Jonathan E. Rosenberg, MD

The combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda), which is becoming more widely used for patients with locally advanced or metastatic urothelial carcinoma, should be used as a foundation for the further investigation of targeted agents in this patient population, according to Jonathan E. Rosenberg, MD.

“[These are] still not curative agents, so we need to consider what [else we can] do, but it’s gratifying to see that change,” Rosenberg said in an interview with OncLive^®.

In December 2023, the FDA granted full approval to enfortumab vedotin plus pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial cancer. This regulatory decision was supported by findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the combination elicited statistically significant improvements in overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy in the frontline setting.¹

Subsequently, in March 2024, the FDA approved frontline nivolumab (Opdivo) plus cisplatin and gemcitabine for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer.² In the pivotal phase 3 CheckMate 901 trial (NCT03036098), the combination generated statistically significant OS and PFS benefits vs cisplatin and gemcitabine alone.

In the interview, Rosenberg discussed how these approvals have revolutionized the standard of care for patients with locally advanced or metastatic bladder cancer, potential future directions with enfortumab vedotin for patients with this disease, and the growing role of Nectin-4–directed antibody-drug conjugates (ADCs) in this armamentarium.

Rosenberg is chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology and the Enno W. Ercklentz, Jr. Chair at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York.

OncLive: What has been the significance of the full FDA approval of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma?

Rosenberg: Data from EV-302 blew away the distinctions around the types of treatments patients should receive for first-line metastatic disease. We had spent decades debating cisplatin eligibility, who’s ineligible and who’s eligible. In 1 broad stroke, EV-302 eliminated that whole debate.

The results are dramatically better for patients who receive enfortumab vedotin plus pembrolizumab, regardless of the type of chemotherapy they get and regardless of platinum eligibility. The results aren’t subtle. [We saw] a doubling of PFS, a doubling of OS, and hazard ratios of approximately 0.5 or less [with the combination compared with platinum-based chemotherapy], which transformed the field quickly. 

In the United States [(US), this combination] has full approval; around the world, access is spotty. Eventually [this combination may] become the global first-line standard until maybe something better comes along. It’s been exciting to see that change.

The primary progression rate with this combination seems quite low, at approximately 10%. Although [primary progression] does happen, most patients experience a response. The confirmed overall response rate was 67.7%, and 29.1% of patients had complete responses [CRs]. We haven’t seen the data on duration of CR from the phase 3 trial, but my guess is it’s long. I’m hopeful we might be giving durable, long-term remissions to some of these patients. 

The long-term follow-up data from the [phase 1/2] EV-103 trial [NCT03288545] indicate that approximately 40% of cisplatin-ineligible patients from the first cohort [are surviving for years]. That’s astounding considering [the historical OS rate in this patient population was approximately] 15% at 5 years. Hopefully we will see updated data over the next several years, both from the phase 2 and phase 3 trials with the combination. [This is an] extraordinary leap forward.

What advice do you have for community oncologists who may not be as familiar with using an agent such as enfortumab vedotin?

The combination [of enfortumab vedotin and pembrolizumab] is administered on a 3-week schedule, not a 4-week schedule like [we do for] enfortumab vedotin monotherapy, [which is] a practical point. [We need to monitor] patients [more] frequently earlier on in the course of treatment.The severe skin toxicity we hear about with enfortumab vedotin tends to occur within the first 1 to 2 months. Perhaps you don’t need to see patients at every day 8 visit going forward after the first few cycles, but in the beginning, make sure they’re seen frequently, because that’s when life-threatening toxicity might emerge. 

Over time, peripheral neuropathy becomes the more prominent problem [because] patients who are responding are on treatment for quite a while. The sensory and motor neuropathy can be bothersome, and sometimes, if not managed, can be incapacitating. Dose reductions [can make treatment more manageable] for those patients.

The skin toxicities are frequent early in the course of disease but [you can often] get them under control. I have a friend who is a dermatologist to help manage some of [these toxicities]. By seeing patients early during treatment and recognizing the onset of some of these skin toxicities, you can ameliorate them or abort them by holding the dose, reducing the dose, and having an intervention [ready] such as topical steroids and maybe [other forms of] steroids, depending on the severity [of the toxicities] and what you think the cause is. My general experience is that many of these patients do well even with the skin toxicity. As long as it’s not the severe blistering type of skin toxicity, it can be managed, and treatment can be continued, although sometimes with a break.

In what other treatment settings might enfortumab vedotin be used to improve outcomes for patients with bladder cancer?

The perioperative setting is the next frontier for enfortumab vedotin plus pembrolizumab. Two phase 3 trials are evaluating that [combination], 1 for cisplatin-eligible patients, [where the combination is being] compared with cisplatin-based chemotherapy, and 1 for cisplatin-ineligible patients [where the combination is being] compared with surgery alone. Those are probably the next big data to come through and might move enfortumab vedotin plus pembrolizumab up to the perioperative setting. That would then give us a whole new set of challenges about what to do in the metastatic setting after patients relapse, if they relapse.

My gut feeling is that at least 1 if not both of those trials will be positive, based on the data in EV-302. We may be faced with the question of how to integrate this [regimen] most effectively into the care of patients with muscle-invasive bladder cancer. The magnitude of benefit will determine whether platinum-based chemotherapy as a standard goes away as a primary therapy for these patients. All of that remains to be seen, but it is the next big thing.

What has been the significance of the March 2024 FDA approval of nivolumab plus chemotherapy for patients with unresectable or metastatic bladder cancer, and how might this combination fit into the treatment paradigm alongside enfortumab vedotin plus pembrolizumab?

The approval of gemcitabine plus cisplatin and nivolumab was good to see. It is hard for me to imagine that there are patients in the US for whom that regimen is preferred over enfortumab vedotin plus pembrolizumab. One of the interesting findings from the [CheckMate 901] trial was the duration of CR in patients who had CRs [with the nivolumab combination]. If there’s a way to pick [those patients] in advance and have a robust predictive biomarker, then perhaps that is a way forward for that combination. The perioperative trial with that combination has not been reported yet, but that may be a place where that triplet will live as well, depending on the results of the trials with enfortumab vedotin plus pembrolizumab in that setting.

Perhaps in a patient with poorly controlled diabetes, you might consider gemcitabine plus cisplatin and nivolumab, although many of those patients don’t tolerate cisplatin well. Patients with bad neuropathy probably shouldn’t get cisplatin or enfortumab vedotin, so the role [of the nivolumab combination] in the US may be relatively limited. There are areas around the world though where we won’t see access to enfortumab vedotin plus pembrolizumab for some time, but where there is access to nivolumab in combination with chemotherapy. In that context outside the US, perhaps we’ll see more uptake [of the nivolumab combination].

This raises the question of sequencing immune checkpoint blockade with chemotherapy in urothelial cancer. Maintenance avelumab [Bavencio] is better than not giving immunotherapy after chemotherapy response or stable disease, whereas at least in combination with cisplatin, starting earlier seems to be better. However, a lot of the benefit seems to be from the maintenance phase when you look at the shape of the survival curves.

I also worry that we are missing a whole swath of the population who never get to maintenance therapy because they have progression, or they stop and [undergo observation]. Some of those patients never get a checkpoint inhibitor at all. My bias is that for cisplatin-eligible patients who are getting gemcitabine plus cisplatin as their metastatic first-line therapy, gemcitabine plus cisplatin and nivolumab is appropriate. If enfortumab vedotin plus pembrolizumab moves up to the perioperative setting, and a patient relapses maybe a year or more after, gemcitabine plus cisplatin and nivolumab might be the preferred treatment option. However, there are several “ifs” in that statement, so we need to see what the data show.

What unmet needs remain to be addressed in patients with bladder cancer, and what kind of future research might be aimed at addressing these needs, particularly in the metastatic setting?

There’s a lot of opportunity to improve our current treatments for metastatic disease. Many patients will relapse and progress after enfortumab vedotin plus pembrolizumab. One of the big questions is whether Nectin-4 is still a viable target in those patients. Many trials are now launching with novel Nectin-4–directed ADCs with novel antibodies, different linkers, and different payloads to try to see whether we can build perhaps a more tolerable agent that has activity and will work well in refractory patients and maybe even in untreated patients. I don’t know whether [these agents] will displace enfortumab vedotin plus pembrolizumab. I suspect we’re going to see some drugs that still hit the pathway, even after progression on enfortumab vedotin plus pembrolizumab.

We now have a HER2-targeted ADC that we can prescribe for patients who have HER2 3+ overexpression. Fully fleshing out the role of HER2-targeted therapy in urothelial cancer is a major focus. We have an investigational agent, tisotumab vedotin-tftv [Tivdak] which is another ADC that also has monomethyl auristatin E, is highly active, and seems to synergize with immune checkpoint blockade based on data from China. It’s being investigated now in the US, and there’s a global phase 3 trial.

We also need better FGFR inhibitors. Erdafitinib [Balversa] is now fully FDA approved for patients [with FGFR3-positive locally advanced or metastatic urothelial cancer] who’ve had a prior checkpoint inhibitor and, presumably, enfortumab vedotin and/or chemotherapy in the past. The toxicity profile is not what we’d love it to be, with a lot of [toxicities that affect] quality of life but are not necessarily life-threatening. For the next generation of drugs, FGFR3-selective agents are being investigated. Those are exciting. I’m hopeful we’ll see some of those hit the market in the next several years. They’re all in clinical trials now and may be the [most effective way of managing] FGFR3-positive metastatic urothelial cancer.

What other urothelial cancer clinical trials are you interested in seeing results from?

We’re about to open 2 phase 1/2 trials of 2 Nectin-4–directed ADCs [in patients with urothelial cancer] at MSK and other sites around the US and the world. These are both [investigating] novel Nectin-4–directed antibodies [with] novel linkers and topoisomerase payloads, [which are] different payloads than SN38 and deruxtecan. We’re excited about the possibility of testing these agents sequentially after enfortumab vedotin to determine definitively on a clinical level whether these agents have activity.

The preclinical data with these agents are intriguing and promising, showing activity in enfortumab vedotin–refractory animal models. If the same holds up in people, perhaps we’ll be able to plan for Nectin-4–directed therapy following progression on Nectin-4–directed therapy. [This would be] similar to the breast cancer story in the past with ado-trastuzumab emtansine [T-DM1; Kadcyla] followed by fam-trastuzumab deruxtecan [T-DXd; Enhertu] which [later] replaced T-DM1. [There is] more to come on all that. More than a few [ADCs are] in development at the moment.

Since May is bladder cancer awareness month, what would you like colleagues to know about the progress being made in this field?

For patients who are diagnosed with advanced disease, the future is much brighter than it used to be. We haven’t yet cracked the case completely, unfortunately, and there’s still a lot of work to be done. We’d like to prevent patients from getting metastatic disease, so moving some of these highly active agents up to earlier lines of therapy is a huge priority, and understanding how well they work in the perioperative setting is terrific.

Ultimately, prevention [strategies are] probably the best way to prevent bladder cancer from ever happening. [Advocating for] smoking cessation and investigating other causes of bladder cancer beyond tobacco are going to be important down the road. Right now, for patients with aggressive, advanced disease, we’re finally seeing the types of advances we have been hoping to see for the past 20 years.

References

1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
2. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed May 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial