Latest on Neoadjuvant Immunotherapy in Muscle-Invasive Bladder Cancer

In this exclusive roundtable video by MedPage todaythree expert leaders in the field of bladder cancer Discuss the latest data presented on the American Society of Clinical Oncology (ASCO GU) Urogenital Cancer Symposium.

moderation Matthew Galsky, MD, of the Icahn School of Medicine at Mount Sinai in New York City, is supported by Guru Sonpavde, MD, of the AdventHealth Cancer Institute in Orlandoand John P. Sfakianos, MD, from the Icahn School of Medicine at Mount Sinai, in this second of four Episodes in which they discuss the different combinations available in the neoadjuvant setting.

A transcript of their comments follows:

Galsky: Hello, my name is Matt Galsky from the Icahn School of Medicine. Welcome to this 2023 ASCO GU Bladder Cancer News Roundtable. Guru Sonpavde of Advent Health Orlando and Dr. John Sfakianos of the Icahn School of Medicine at Mount Sinai with me.

So we talked about adjuvant therapy for bladder cancer. So let’s talk neoadjuvant therapy. Neoadjuvant therapy, arguably the standard of care. Cisplatin-based chemotherapy has shown a survival benefit in two randomized trials. Part of all practice guidelines. But there is definitely room for improvement. And so there have been a number of studies trying to move immune checkpoint blockade into the neoadjuvant setting, either alone or with cisplatin-based chemotherapy.

Guru, can you tell us a little bit about the data so far and what we know and don’t know with concomitant chemotherapy plus immune checkpoint blockade?

Sonpavde: Correct, in the neoadjuvant setting, inhibition of immune checkpoints looked promising. Therefore, single-agent PD-1 and PD-L1 inhibitors showing the CR pathway have been studied [pathologically complete response] Rates of around 30%, 35%, sometimes 40%. And similarly cisplatin-based chemotherapy, cis/gem [cisplatin plus gemcitabine]and indeed once re-dosed it is MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), and cisplatin] in combination with the various PD-1/L1 inhibitors looked promising. But it’s not clear that it’s clearly better than combination chemotherapy alone. The way CR rates with the chemo IO [immunotherapy] were in the range of 45%. The rate of less than pT2 was approximately in the 60% range.

But I think we have to wait for phase III studies, which of course are still ongoing. In a cisplatin-based setting, cis/gem plus/minus various PD-1/L1 inhibitors, nivolumab [Opdivo]pembrolizumab [Keytruda]durval ab [Imfinzi] is looked at.

And for cisplatin-ineligible patients, there are immune checkpoint inhibitor-based treatments. And interestingly also EV/pembro [enfortumab vedotin (Padcev) and pembrolizumab] Approach that I think would have great promise in this area in both cis-unsuitable and cis-suitable environments.

Galsky: And guru, you are running a study in this area with carboplatin based chemotherapy, is that correct?

Sonpavde: That’s right, Matt, so we have a randomized phase II trial going at SWOG and Intergroup. This applies to patients who are not suitable for cisplatin. The study was planned a long time ago, so this is not standard neoadjuvant therapy for either invasive upper urinary tract disease or bladder muscle invasive disease. So a preliminary operation in the standard arm compared to Carbo/Gem [carboplatin and gemcitabine] plus avelumab [Bavencio] in the experimental arm.

The difference is that there is no pre-stratification for PD-L1. So it’s a user/patient friendly approach, rapid neoadjuvant therapy or surgery, and then the adjuvant component is not prescribed, so the doctor can decide to use adjuvant nivolumab or just follow carbo/gem/avelumab.

Galsky: John, you’ve operated on patients, you’ve had neoadjuvant single-drug immune checkpoint blockade, combinations of antibody-drug conjugates, chemotherapy plus immune checkpoint blockade. Any concerns from an operational perspective about getting these drugs in the neoadjuvant setting?

Sfakianos: Yes, thanks Matt I mean, thanks to the partnership with you, we’ve had a lot of different clinical trials. So, like you said, we operated on all these different combinations of patients who got these different combinations. And to be honest, I really don’t see any difference. There were no, at least significant, delays that I can imagine for the combination chemotherapy plus checkpoint. And we don’t see any difference in outcomes – morbidity or mortality – after we perform these procedures on patients. So I think bringing patients to surgery after these neoadjuvant combinations I really don’t see any concern from a surgical perspective.

So very promising data, really exciting time ahead. But just to reiterate Guru’s point, I’m not sure how well these will compare to standard chemotherapy in these large randomized trials. So we’ll wait and see.

Galsky: Yeah, I think these studies are going to be really interesting because I think we’re betting on these pathway CR endpoints being good for these combinations. And I think that’s a consideration. I think the other consideration is that the adjuvant component, which is obviously not reflected in the pathway CR, will drive the time to event results. And that could certainly make a difference. Even if you don’t see any benefit in the CR endpoints of the pathway, you may see these long-term benefits, and some of these could be driven by what is given in the adjuvant setting.

Sfakianos: I have to agree 100% with that. I think it’s more about what is given in the adjuvant/maintenance setting, which I think will really add to the survival benefit, even without the CR pathway in the neoadjuvant setting. There are some exciting maintenance or adjuvant trials currently going on with combinations that I think I’m most excited to see what the results are rather than the pathway CRs for the neoadjuvant setting.

Galsky: And there seems to be this emerging theme. You can see this in the switch maintenance treatment in the metastatic setting in the subgroup analysis. In CheckMate-274, you see a larger effect size in patients receiving neoadjuvant chemotherapy. Perhaps this sequential approach of chemotherapy followed by immunotherapy will do something special.

Watch Episode 1: Updated Results on Adjuvant Immunotherapy in Muscle Invasive Bladder Cancer