Dissecting the Potential of Neoadjuvant Chemotherapy as a Standard of Care for UTUC

In the second part of our interview with Drs. Michael Whalen and Vincent Xu, potential alternative treatments for patients who are ineligible for chemotherapy are discussed, including options other than radical nephroureterectomy. They also explain the barriers to neoadjuvant chemotherapy becoming a standard of care, and the next steps for their research.

Watch the first part of this interview: Neoadjuvant Chemotherapy Versus Radical Nephroureterectomy in Upper Tract Urothelial Carcinoma

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For patients who are not eligible for chemotherapy, are there any other alternative treatment options other than RNU?

Dr. Whalen:
Immunotherapy is being studied for both bladder urothelial cancer and upper tract urothelial cancer. Checkpoint inhibitors, drugs like pembrolizumab, nivolumab, which can be used in the locally advanced or metastatic setting, meaning the cancer has already spread and either is inoperable or patients are not good candidates for surgical extirpation.

And there’s even a growing role for targeted therapies, something called enfortumab vedotin, which is an antibody drug conjugate that delivers basically almost like a localized chemotherapy. It’s an antibody that binds to a particular compound called nectin-4, which is found in urothelial cancer cells, and then is complexed to a microtubule interfering agent, basically, so it’s like delivering chemotherapy locally to the cell, rather than having to have it circulate throughout the entire body, and that’s where a lot of the side effects from chemo comes from: hair loss, mucositis, inflammation or sores in the mouth, susceptibility to infections, low blood cell counts, white cells, red cells, platelets, things like that.

It’s an exciting area, and that’s been approved for first line, even cisplatin-eligible patients with bladder or upper tract urothelial carcinoma, that’s locally advanced or metastatic. It was an exciting development, something called the EV-302 trial.

In chemotherapy in the localized setting, so that’s for metastatic disease, when patients don’t have any other options, or not likely to get surgery.

But in the other thing that’s notable about that, those treatments that are very exciting is that, one, they’re targeted for urothelial cancer cells specifically with that nectin-4 binding and delivering that local chemotherapy, usually given in combination with immune checkpoint inhibitor blockade, pembrolizumab, is that in the past, metastatic urothelial cancer used to be a uniformly fatal diagnosis, with average survival being like a year and a half or certainly less than two years.

Nowadays, with that combination of EV and PEMBRO, the overall response rate, meaning either having a complete response or partial response, was about 70%, and about 30% of patients had complete response, which was basically cure of the disease. That was after only a couple years of follow-up. It wasn’t long term follow-up, but it was very, very exciting for a disease space that used to be uniformly lethal, where we’re actually finding combinations of drugs that help to cure patients.

And the studies that have been done in the localized setting when it’s still high-grade disease but has not spread, in the upper track setting, the evidence is a little more sparse. There’s a phase two trial of neoadjuvant chemo, which showed good partial and complete response rates.

So that likely is practice-changing in terms of understanding who we should prioritize for getting neoadjuvant chemo, one, for the rationale of treating the micrometastatic disease that might exist even if you can’t see it on a scan because they have aggressive cancer found in blood system, the kidney or the ureter; and two, as I said before, that once you remove their kidney, they’re not the best candidates to get cisplatin therapy.

Are there any other barriers to NAC becoming a standard of care other than patient access?

Dr. Whalen:
Urothelial carcinoma of the upper tract is more rare than bladder cancer, so there’s fewer patients to recruit into trials, and so it definitely relies on multi-institutional cooperative group trials to be able to derive meaningful conclusions and high-level evidence, so I would say that the rarity of the disease.

And I suppose dissemination of the utility of the information. Like I said, there was a phase two trial that looked at the benefit in terms of some patients having a complete response. But what remains to be seen is the magnitude of that benefit. Not every patient that gets neoadjuvant chemotherapy is going to have the survival advantage from that, and it’s exposing them to the toxicities of that therapy when they may not have derived a benefit.

So better understanding the criteria for who we give neoadjuvant chemo for the upper tract setting: is it just patients with very bulky tumors? Patients who have locally advanced disease? Those who have nodal involvement on a scan? Or should we be giving it to every patient that’s high-grade? And that remains to be seen.

The other thing is looking at other biomarkers, either genetic biomarkers like in the tumor that might predict or forecast a favorable response to neoadjuvant chemotherapy that remains to be seen. If we can develop sort of a molecular or genetic profile that might predict who’s going to have a good response and achieve a complete response where the tumor basically shrinks down and shrinks down to nothing.

And in the same vein, can we run a genetic profile, either of the tumor or of the patient, to understand who may be more prone to having side effects, such as hearing issues, kidney function issues, peripheral neuropathy, that kind of thing? That’s been studied in bladder cancer and it’s not conclusive right now. We couldn’t necessarily predict who was going to respond to MVAC or gemcitabine or cisplatin or neoadjuvant chemo.

But that remains to be seen, and I suppose could be a potential barrier to physician and oncologist buy-in in terms of the utility of the neoadjuvant chemo. You’re exposing people to chemo who may not derive a benefit. We don’t have exact understanding of who’s going to benefit.

Even with bladder cancer, we say there’s about a 5-10% overall survival advantage. So that means for every 10 people you treat, only about nine or so will have… I’m sorry, excuse me, one out of 10 will derive a benefit, and nine patients would’ve been exposed to chemotherapy who may not have derived a benefit in terms of survival. So developing more refined understanding of who benefits the most is important to justify the side effects of these therapies.

As immunotherapy comes on the scene like with the checkpoint inhibitors and the more favorable side effect profile, potentially neoadjuvant therapy will be more embraced.

What are the next steps for this study?

Dr. Xu:
I think, as more data accrues in the NCDB, at least given that it was the most, in the 2023 guideline updates, that I think started recommending neoadjuvant chemo for upper tract urothelial cancer. It’ll be interesting to see as more data accrues then more recent years in the NCDB, our data poll was really only from 2004 to 2019, to see how those practice guideline changes influence adoption and utilization of neoadjuvant chemo.

Additionally, with more studies weighing in on the benefit of immunotherapy for UTUC, especially potentially in the neoadjuvant setting, as well, it’ll be interesting to see how those practice changes evolve over time, as well. But it’ll just take some more years, I suspect, for those to become available in the NCDB.