Adjuvant and Neoadjuvant Therapies Shape Future of MIBC Treatment

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Tracy Rose, MD, discussed the future of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer specifically using cisplatin-based regimens.

Cisplatin-based chemotherapy has been the standard-of-care (SOC) for muscle-invasive bladder cancer (MIBC) before surgery with radical cystectomy for a while. However, researchers are always looking to build upon the combination in order to further treat patients, according to Tracy Rose, MD, MPH.

There are a number of potential SOCs for patients who are cisplatin-ineligible and undergoing radical cystectomy including surgery alone, neoadjuvant immune checkpoint inhibition, neoadjuvant enfortumab vedotin (Padcev), or a combination of these agents. According to Rose, an assistant professor of Medicine in the Division of Oncology at the University of North Carolina at Chapel Hill, investigators in this space are currently working on how to avoid surgery altogether for these patients.

Rose proposes the idea that if one is able to improve pathologic complete response, it may be possible to omit radical cystectomy with bladder-sparing approaches.

This is currently being tested in 2 ongoing trials, RETAIN-2 (NCT02710734) and A031701 (NCT03609216). Though they have not yet learned how to identify these patients and avoid cystectomy, there are a lot of ongoing studies looking to answer the question.

In an interview with Targeted OncologyTM following the American Society of Clinical Oncology Genitourinary Cancer Symposium (ASCO GU), Rose discussed the future of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer specifically using cisplatin-based regimens.

Can you provide a brief overview of what you discussed during your presentation at ASCO GU?

Cisplatin-based chemotherapy has been the standard of care for muscle invasive bladder cancer before surgery with radical cystectomy for a while now. It's a exciting time to see the landscape of where the field is going in this regard, because there's a ton of recently reported and ongoing studies looking at how we can improve on outcomes from just standard cisplatin-based chemotherapy and muscle-invasive bladder cancer. Essentially, the talk was an overview of what's going on, recent studies, currently ongoing randomized studies, and how the field is likely to change in the near future.

How has the landscape changed over the last few years?

We've had a ton trying to build on the current standard of cisplatin-based combination chemotherapy. The first thing that happened was instead of the conventional dose of cisplatin, there's been several studies that have come out now with randomized data of what's called dose-dense cisplatin, or dose density. That's essentially giving chemotherapy more frequently, to try to increase dose density and tumor response.

We've seen some good outcomes that look like these regimens are safe, they're associated with slightly higher pathologic response rates. Last year at ESMO, there was a presentation that one of the dose-dense regimens is associated with a longer progression free survival than Gemcitabine and cisplatin after surgery. They gave different doses of cisplatin between those 2 regimens. The jury's still out whether the same amount of cisplatin really would improve outcomes or not, but it's certainly provocative. Then there's been several combination studies of cisplatin-based combination chemotherapy plus immune checkpoint inhibitors, which have really changed the landscape of metastatic disease.

Those all look safe and relatively consistent across the trials. We're getting pretty good pathologic, downstaging and pathologic, complete responses with those combinations. They now need to be tested in the randomized setting to see if we can improve on just chemotherapy alone.

In the cisplatin ineligible group of patients that can't get chemotherapy, how can we improve their outcomes? There's been a number of studies recently looking at immune checkpoint inhibitors alone, which look like they have activity and are now going to be studied randomized against surgery alone. Enfortumab vedotin is a drug that's being studied extensively now in the new adjuvant setting, including in an exciting abstract that was presented of enfortumab vedotin given before surgery.

With all the new available therapies, what is your advice on how to sequence them?

We still sequence chemotherapy and immunotherapy in the metastatic setting. I think the perioperative setting is interesting to see if combination therapy may find its home. It may be that harnessing this slightly higher response rate is more important in the neoadjuvant setting when you have sort of a limited time to give therapy before surgery. I think it's certainly intriguing to look at the combination studies. I think a lot of questions are still going to be open because there's a recent adjuvant study looking at nivolumab that shows a disease-free survival benefit. Do we really need to combine things before surgery? Can we just give chemotherapy followed by immunotherapy after surgery? Is there a benefit of giving immunotherapy before surgery? These still may be unanswered questions, even when some of the ongoing trials readout.

Are there any other studies that are exciting to you right now?

I think where the real interest and money is in this space is figuring out how to avoid surgery altogether. We have patients that get new adjuvant chemotherapy and if we're making upwards of a third to 50% of patients have no residual cancer, those are not people that we necessarily need to take the bladders out of. We haven't quite learned how to find these patients and identify them and avoid cystectomy, but there's a lot of ongoing studies that are looking at this question. I think that's really the most exciting thing going on in this space.

There's a couple I highlighted in my talk. One called RETAIN-2 that gives combination accelerated AMVAC [accelerated methotrexate/vinblastine/adriamycin/cisplatin] plus nivolumab [Opdivo] immunotherapy, and then tries to select patients with DNA repair defects and a clinical complete response on cystoscopy to avoid surgery. There's a similar study looking at the gemcitabine cisplatin regimen, trying to select patients based on DNA repair defects and clinical response. That paradigm is exciting if we can safely avoid surgery and patients. I think that's a very patient centered outcome, and that would be amazing.

What other exciting things are happening in this field right now?

There's lots of big, randomized studies. All of the current combination studies right now are using gemcitabine and cisplatin backbone as what we're combining immunotherapy with, and I think some of those studies should consider using other backbones, like the dose-dense regimens, to see if perhaps that can give us even greater responses or be better partners for immunotherapy.

Figuring out which patients should get combination therapies, and which shouldn't, figuring out which patients should get immunotherapy and which shouldn't, should get other targeted therapies that have slightly higher response rates [is exciting]. I think that is really where the field is going and sort of personalized care and not a one size fits all for either perioperative therapy or metastatic therapy of sort of what treatment is really best for you.



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