Arlene Siefker-Radtke: So, I'd like to thank you all for the opportunity to meet with you today, and it's so wonderful to see everyone in person again as we've survived all the variants from the recent COVID pandemic. So, as we know about the perioperative management of urothelial cancer, it's always been focused on a combination of toxicity and efficacy where we're hoping to get this efficacy that cures patients and find a strategy that is less toxic, something that's very tolerable in our patient population.

But unfortunately, these current standards of care, arguably cisplatin based chemotherapy, has toxicity that some have been concerned compete with the efficacy of this therapy. But despite that for over 20 years now, we have the SWOG intergroup trial, which has remained the standard of care of traditional MVAC over cystectomy alone. But the truth is neoadjuvant chemotherapy is associated with morbidity and is not tolerable in almost 50% of patients diagnosed with urothelial cancer.

And the side effects from this can be long-term with neuropathy and hearing loss that can be permanent in these elderly, frail patients. We also know some patients are downstage from a TUR alone and don't experience benefit from systemic therapy. And as the SWOG intergroup trial showed us, regardless of whether you were downstage from a TUR or chemotherapy outcomes appeared similar.

It also appears that the greatest impact of treatment has been on improving outcomes for those bulkier disease states, those T3b or N+ disease, with a more substantial increase in benefit in that patient population. But as we move on to some of the more modern questions, we still have that age-old question of Dose-Dense MVAC versus GemCis. Since GemCis never truly beat MVAC and was only designated a standard on the basis of a failed clinical trial in metastatic disease.

We saw some recent data coming out from the VESPER trial, which compared patients with Dose-Dense MVAC versus gemcitabine cisplatin, and saw an improvement in progression-free survival with the use of Dose-Dense MVAC. Again, raising that debate whether Dose-Dense MVAC may still be better than GemCis, although GemCis is used significantly often in the community setting. But when we start thinking about efficacy, do we start losing it or have worse outcomes when giving chemotherapy in the adjuvant setting? We all know we should do it in the neoadjuvant, but there's a lot of reasons why patients are unable to tolerate chemotherapy and why they may be taken for initial surgery.

And this was a trial Reed MD Anderson, where we gave MVAC chemotherapy in either the neoadjuvant setting or we gave it in patients who had initial surgery and we utilized high-risk features, which in the cohort taken to initial surgery had over 80% likelihood of being upstage to T3b or node positive disease in the OR. And yet we didn't see significant differences in outcomes comparing this neoadjuvant versus adjuvant paradigm. So, we do also see evidence that adjuvant treatment may be beneficial despite multiple adjuvant trials being unable to prove that significant benefit due to the inclusion of stage two patients. Although there have definitely been a benefits observed in that stage three or greater disease. And this is just a nice summary of all of these adjuvant trials, again, showing that higher stage patient may be the ones who benefit the most.

But more recently as we've started using immune checkpoint inhibitors in the metastatic setting, we've raised the question, can adjuvant nivolumab contribute to the cure of patients in the perioperative space? And I would argue the goal is cure. The bar is high in treating these patients. We want to be curing patients. When we look at the data with adjuvant nivolumab, unfortunately we don't yet have survival data. And what we see with the disease-free survival, we see an improvement or delay in recurrence of tumors. Although some concern that these curves may be meeting up. When I look at the PDL-1 high group of tumors, we start seeing some plateau in the curves making me hopeful that there is a cohort in this trial where there will be a definitive cure through their treatment.

Although, we've all seen early curves on trials meet and suggest a delay rather than a definitive curative strategy. And I think that's perhaps why on the NCCN guidelines, there is a suggestion if no cisplatin neoadjuvant treatment is given and a patient has that higher stage disease. Adjuvant cisplatin-based chemotherapy is the preferred strategy over adjuvant nivolumab. And whereas adjuvant nivolumab doesn't have a level one indication due to the lack of survival data that's been produced so far.

But moving on, we're also seeing other novel agents now approved in earlier stage disease, including pembrolizumab in non-muscle invasive bladder cancer. On the basis of this Keynote trial showing a three-month complete response rate in a group of patients who had carcinoma in situ present, 40% of them had a complete response in their CIS and pembrolizumab is given for up to two years. Yet I don't think we're seeing this used as commonly as we initially thought it might be used. And there's some concerns whether this may have only delay recurrences in patients may eventually need treatment.

So in conclusion, as we start considering where the standards are now, neoadjuvant, cisplatin-based chemotherapy remains the standard for that muscle invasive bladder cancer patient. Dose-Dense MVAC may be favored give adjuvant chemo if they're upstaged at surgery to T3b or node positive disease rather than adjuvant nivolumab, if they did not receive prior cisplatin. And a current concern whether nivolumab is curative or whether it delays recurrence.

And I'm very hopeful that we'll see some overall survival data at least some point soon to help us determine is this indeed a curative strategy. But in the meantime, we also have pembrolizumab is an option for BCG unresponsive muscle invasive bladder cancer. And as Dr. Denny indicated, lots of novel clinical trials trying to incorporate immune checkpoint inhibitors and novel agents earlier in the treatment paradigm. And I'd like to thank you all for your time and again, a pleasure seeing everyone in person despite the recent pandemic.