Novel Neoadjuvant Approaches in Advanced Urothelial Carcinoma

Petros Grivas, MD, PhD: This is very helpful for the audience. To summarize what you said, in patients who have localized muscle-invasive bladder cancer, when the cancer is amenable to curative intent therapy, we tend to offer these patients neoadjuvant, preoperative, presurgical cisplatin-based chemotherapy. We use dose-dense MVAC [methotrexate, vinblastine, doxorubicin, cisplatin] or gemcitabine and cisplatin for usually 4 cycles if there are no positive nodes on imaging. These patients can undergo a radical cystectomy and a pelvic lymph node dissection with urinary diversion afterward.

About 20% of patients may be ideal candidates for bladder preservation with trimodality therapy, for example maximal or optimal TURBT [transurethral resection of bladder tumor], followed by concurrent chemotherapy and radiation, or chemoradiation. For that chemoradiation, we may use 1 of 3 chemotherapy options: cisplatin once a week; 5-FU [fluorouracil] and mitomycin C, based on the data by [Nicholas] James, [MB, BS, PhD,] and colleagues in the BC2001 trial in the United Kingdom; or gemcitabine given once or twice a week under some phase 2 trial data.

Now there are some interesting phase 3 trials looking at bladder preservation with concurrent chemoradiation plus or minus a checkpoint inhibitor, for example, atezolizumab in the SWOG 1806 trial, or pembrolizumab in the KEYNOTE-992 trial. It’s interesting to see how the field is evolving and whether checkpoint inhibitors may have a role in chemoradiation down the road. The majority of patients in the United States, as you pointed out, get cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy.

The problem is that many patients with localized disease who plan to go for radical surgery are not fit enough and don’t have the ability to get cisplatin because of medical comorbidities, kidney impairment, hearing impairment, cardiac dysfunction, or severe neuropathy. Those patients who we think are not fit for cisplatin can either go for bladder preservation if that’s a good option for them, or straight to radical cystectomy and lymph node dissection, or to clinical trials. Right now, there are many clinical trials in the neoadjuvant setting testing immunotherapy. Immune checkpoint inhibitors remain experimental in the neoadjuvant setting, as you mentioned. Neeraj, are you excited about the phase 3 trials evaluating checkpoint inhibitors in the neoadjuvant setting? The phase 2 trials look promising, but they’re awaiting phase 3.

Neeraj Agarwal, MD: Yes. One of the reasons cisplatin-based neoadjuvant chemotherapy hasn’t become a mainstream therapy in the United States is likely because of the perceived and real toxicities of cisplatin in our patients with bladder cancer, most of whom are frail to begin with. That’s where the biggest unmet need is: how to bring in more well-tolerated neoadjuvant or even adjuvant therapies that can be applicable to a vast majority of our patients. That makes the ongoing trials with checkpoint inhibitors so attractive to me. I won’t go through all the trials, but a simple trial is the combination of ipilimumab and nivolumab in this setting. What do you think about that trial?

Petros Grivas, MD, PhD: It’s very interesting you mention that. To your point, there’s a plethora of phase 2 trials evaluating immunotherapy. You mentioned ipilimumab and nivolumab being tested, and in the neoadjuvant setting there have been a few trials looking at this. In the Netherlands, there was the NABUCCO trial by [Michiel] Van der Heijden, [MD, PhD,] and others looking at ipilimumab and nivolumab as neoadjuvant immunotherapy. The pathologic complete response rate in the neoadjuvant setting in cisplatin-unfit patients was very promising. The pathologic complete response rate was about 46%, which is very encouraging.

I agree that we need to further evaluate the checkpoint inhibitor therapy in phase 3 trials, and the stage has been set nicely by phase 2 studies, which support phase 3. But so far, I haven’t used a checkpoint inhibitor neoadjuvantly or presurgically, and won’t until we get confirmation of the signal in phase 3. But I agree with you, ipilimumab, nivolumab was very promising in the neoadjuvant setting.

Now there are studies in metastatic disease with immunotherapy, which we’re going to talk about. There are also combinations with chemotherapy with checkpoint inhibitors in the neoadjuvant setting for cisplatin-fit patients. We have to see in the ongoing phase 3 trials whether the pathologic complete response rate and event-free survival, which are the end points in the phase 3 trials, will show benefit with a checkpoint inhibitor in the neoadjuvant setting, either in combination with chemotherapy for cisplatin-fit patients, or in combinations with immunotherapy, or as checkpoint inhibitor single-agent therapy in cisplatin-unfit patients.

Transcript edited for clarity.