Petros Grivas, MD, PhD, discusses phase Ib trial results of neoadjuvant nivolumab or lirilumab for cisplatin-ineligible patients with MIBC.

Transcript

Hello, I am Dr Petros Grivas. I am a medical oncologist at the Seattle Cancer Care Alliance and associate professor at University of Washington and Fred Hutchinson Cancer Research Center.

We are very excited about the very productive and, I would say, despite the virtual nature, interactive ASCO 2021 virtual meeting, with a plethora of important and impressive data across the field of oncology, including genitourinary cancers.

Specifically, we are very excited about the data from the plenary session, as well as the data we presented as a group at the ASCO virtual meeting. I would like to update you today about a couple of those abstracts which I hope you find useful.

The first one was, I would say, a long effort, which includes a phase Ib feasibility trial in the neoadjuvant setting of patients with localized muscle-invasive bladder cancer, evaluating nivolumab anti-PD-1 alone or with lirilumab, which is an anti-KIR antibody which activates the natural killer cells - NK cells - in patients who are not fit for cisplatin and have localized, resectable, muscle-invasive bladder cancer, and they go for radical cystectomy lymph node dissection.

This is the so-called PrE0807 Trial. As I mentioned, it took us a few years to get this trial designed, launched, and completed, and we are very excited to show the results. This particular neoadjuvant trial, again, is focusing on patients who were not eligible, not fit for cisplatin, and they were undergoing radical cystectomy lymph node dissection.

The first cohort of patients, cohort one, received nivolumab alone, single-agent, at the dose of 480 milligrams. As I mentioned, single-agent, for a total of two doses, four weeks apart. They got the first dose, and then a month later, the second dose, and then underwent radical surgery.

The second cohort started after the first cohort was completed and included the combination of nivolumab at the same dose, 480 milligrams, for two doses, four weeks apart - so one month apart, a total of two doses - plus lirilumab, an anti-KR antibody, activating natural killer cells.

Lirilumab was given at the dose of 240 milligrams, two doses, four weeks apart. Both antibodies were given one month apart, so a total of two doses in cohort two. Overall, the primary endpoint of this study was safety and feasibility.

We wanted to make sure that the immunotherapy is safe and feasible to be given in the neoadjuvant setting. Also, we looked at the efficacy as well as the pathological complete response rates and pathologic downstaging at the time of the cystectomy.

Just to make the point, that this new drug called lirilumab, the way it works is inhibits, as I mentioned, the KIR 2DL, which is an important molecule modulating the tumor microenvironment. When you inhibit that receptor, then you activate natural killer cells.

You engage the innate immune system, in conjunction, in combination, with the anti-PD-1 nivolumab that engages the adaptive immune system. The goal was, if you engage both innate and adaptive immune system, can you achieve higher pathological good response rates?

Overall, we had 43 patients who enrolled in the study. Again, this was a phase Ib study in the neoadjuvant setting. All patients except one completed neoadjuvant immunotherapy. One patient just withdrew consent before starting.

From those 42 patients, all but one, so a total of 41 patients underwent radical cystectomy lymph node dissection. The most common cause of not-fitness for cisplatin, cisplatin ineligibility, was kidney impairment. Most patients had T2 clinical states.

Overall, the treatment was very well-tolerated in both cohorts, either single-agent nivolumab or the combination of nivolumab and lirilumab. There were no grade three or higher treatment-related adverse events with nivo alone, and there were only four grade three treatment-related adverse events with a combination, specifically arthralgias, gout, and heat pain with a combination of nivolumab and lirilumab.

Despite this very good safety profile and overall a very good feasibility, all patients got radical surgery within six weeks on the last dose of immunotherapy. The combination is feasible. Despite that, the efficacy was not as high as expected in cohort one with nivolumab alone.

We saw a pathologic complete response defined as pT0N0. Only 8 percent with nivo alone and 18 percent with the combination. If you look at pathologic downstaging, you see 17 percent with nivo alone and 29 percent with the combination.

Overall, this study showed that the immunotherapy in the neoadjuvant setting is safe, and the approach is feasible. There was no problem at all with getting people to radical surgery. We know that from a plethora of other phase II studies.

There are now multiple phase III trials. I can count at least six neoadjuvant immunotherapy phase III trials. These trials are going to define further that all of the immune checkpoint inhibitors in the neoadjuvant setting.

As I mentioned, in the neoadjuvant setting, clearly, the role of immune checkpoint inhibitors remains investigational, while we are also out waiting on the regulatory agencies, the FDA and EMA, to review the data with a purely adjuvant CheckMate 274 Trial that evaluated nivolumab versus placebo in the adjuvant setting.

We will see how the landscape will change in the future, but our trial is going to do further work looking at biomarkers, trying to shed some light in the tumor microenvironment and different correlative endpoints, translational research endpoints in this neoadjuvant trial.

More to come in terms of our manuscript and the translational biomarker work, but overall, we saw that immunotherapy is safe and feasible in the neoadjuvant setting, despite the lower-than-expected complete response rates.