Treating R/R Advanced Bladder Cancer With Novel Sequencing Strategies

Vadim S. Koshkin, MD: A lot of doctors who treat bladder cancer also still very much believe in the use of platinum-based therapy, and we don’t have a good comparison with enfortumab in that setting. In that situation, there are multiple right answers, but you end up going with one therapy over another.

It’s especially crucial to make sure that we manage adverse effects with that said therapy pretty well. With enfortumab, standard adverse effects, like neuropathy, often develop in patients—usually a few months into treatment—and then it becomes a question of how to treat them appropriately with dose reductions, dose holds and by altering the schedule. I rarely previously altered the schedule, which is 3 weeks on, 1 week off. A lot of other physicians do. That’s something that we should look into. We should also gather data from retrospective studies on how this drug is being used in the real world, where many physicians end up altering the schedule, and about whether patients benefit as a result in terms of their adverse effect profile. One larger retrospective study that I’m a part of is UNITE. We’re going to publish some initial efficacy findings of the real-world use of enfortumab in the near future. Eventually, we’ll look into tolerability of alternate regimens as well.

Many providers end up doing dose holds and dose reductions. There are pretty good data from prospective trials of enfortumab of the steps to take in that situation. Where we have fewer data is specifically with altering the schedule, so instead of 3 weeks on and 1 week off, doing every other week, or 2 weeks on and 1 week off. In other clinical trials of enfortumab in combination with pembrolizumab, including EV-103, that was exactly the schedule, where enfortumab was given on day 1 and day 8 of a 21-day cycle and then patients would get a week break.

The question is whether it’s better tolerated in that setting. At this point, we don’t fully know. The numbers from the trials are small. But we do have more of this anecdotal evidence that for many patients, the FDA-approved dose level and regimen may be too much, and that you need to find an individual dose level for each patient. That may mean not administering the drug as frequently, maybe doing it every other week.

Some of these strategies we were just discussing would come up. On the one hand, you can start them at the lower dose. To start lower than the typical 1.25 mg/kg of enfortumab, we could start at 1 mg/kg. Many physicians do that in clinical practice. On the other hand, you could give them longer breaks. You can give them treatment every other week, or 2 weeks on and 1 week off. For patients who are more frail, those may be viable strategies that physicians are already using. But we need to aggregate the data and really describe it. That would be instructive for others.

In terms of other comorbidities, such as baseline neuropathy, diabetes, impaired renal function, or significantly enough impaired renal function that they wouldn’t have been included in clinical trials of enfortumab, that’s a cutoff of a GFR [glomerular filtration rate] of 30 mL/min. In terms of experience with those patients, we’re already aggregating those data. That’s the UNITE study I was referring to earlier. The preliminary findings are that these patients benefit from enfortumab just as well as those who don’t have those significant comorbidities. We see that even with patients with comorbidities, frail patients, and patients with poor performance status, the response rates to enfortumab are consistent across the board with more fit patients. Those data from the UNITE study will be published soon. It’s a very potent drug, and we’re able to treat more patients who previously had no options or whom I’d be hesitant to give something like carboplatin to.

This reflects the dynamic space in bladder cancer, suddenly having this wealth of options for patients that we didn’t have even a few years ago. Because even just a few years back, prior to May of 2016, only chemotherapy was approved for patients with metastatic urothelial bladder cancer. Starting in 2016 through 2017, a number of checkpoint inhibitors were approved for platinum-refractory patients, then eventually for frontline patients as well. Then in 2019, erdafitinib was approved, followed by enfortumab at the end of the year. Earlier this year, sacituzumab govitecan was approved. Then we got the promising data from the JAVELIN Bladder 100 trial suggesting the benefit of a maintenance checkpoint inhibitor following benefit from platinum-based therapy.

We’re getting into this space where many patients with bladder cancer will have chemotherapy, then a checkpoint inhibitor, either upon progression on chemotherapy or as maintenance, and then a decision has to be made of what they’ll get next. That’s a situation where there are probably multiple right answers, particularly for patients who are eligible for erdafitinib. For the 15% to 20% of patients with metastatic urothelial who have FGFR3 mutations or fusions, the question is whether erdafitinib or enfortumab is the right next drug. On the one hand, with a patient with an FGFR3 alteration, there’s an impulse almost to target that alteration and give the targeted drug rather than enfortumab. But on the other hand, although enfortumab is also a targeted drug, its target is universally expressed across urothelial cancers.

There was a discussion on whether one is more tolerable than the other, when it comes to enfortumab vs erdafitinib. If you look across the board at clinical trials of both drugs, the incidence of treatment-related adverse events is comparable. You wouldn’t say just by looking at those data that one is better tolerated than the other. In clinical practice, my experience has been that enfortumab is oftentimes easier to use, but not for all patients. But it often ends up being more tolerable. It seemed that a few others agreed with me there. It’s not for everyone. There are other considerations as well. Enfortumab is an infusion drug, and erdafitinib is an oral drug. For some patients who don’t want to come in for regular infusions, the oral drug may be better.

Other questions that come up are with insurance coverage and co-pays, which are different for oral agents and infusion drugs. It’s becoming a pretty complex decision that there’s no right answer to. You individualize each case. Taking a step back, what stands out to me and still astounds me is that this is a very new problem. This is an issue that even a couple of years ago wasn’t even a question because we didn’t have these options. That’s great for patients and the doctors who treat them.

The key message is what we were just discussing, that you individualize each treatment based on the patient. When there were few options—just chemotherapy and then second-line chemotherapy, or just chemotherapy and then maybe checkpoint inhibitors—there wasn’t that opportunity. There was a cookie-cutter approach. But as we’re learning more about the biology and different molecular subsets of the disease, and we have different agents available, even some that address specific molecular subsets, we’re individualizing treatment more.

A few years ago, this was more of a theoretical discussion that we’d be individualizing treatments more. This is our goal and the goal of precision oncology, but now we’re increasingly seeing this come to fruition. It’s great that we actually have to think hard and deeply about how we treat each individual patient. Of course, it also makes it more challenging, because in a situation where there are potentially multiple right answers, you want to select the one that’s most right. At the same time, the stakes here are still quite high because this is still urothelial cancer. This is very aggressive disease, where attrition rates for each line of therapy are quite high. Not all patients who get frontline therapy will get second-line therapy, although the rates are higher than they were even a few years ago. The attrition goes down even further as you get into the third line, and now we have fourth-line therapies.

At each decision point, the stakes are still high. You want to really try to give the patient therapy that will benefit them, because if you’re wrong, there may not be another opportunity. We’re focused more on getting better biomarkers for each of these treatments. We’re also getting better at using these treatments, optimizing the tolerability and minimizing the adverse effects, what we were discussing earlier in this conversation.

All of that goes into better treatment of patients with bladder cancer, and hopefully eventually much better outcomes. We’re already seeing that to some extent. We’re seeing more patients who are making it into multiple lines of therapy, but much work remains to be done. The more progress we make, the more it still stands out that we’re not curing most of these patients. Our focus should be on how to produce longer and more durable responses. That includes using more effective treatments and making the treatments we have more tolerable for patients, which brings to the forefront the skill of the oncologist treating the patient.

Transcript edited for clarity.