Hello, I’m Petros Grivas, I’m a medical oncologist at the Seattle Cancer Care Alliance and associate professor at the University of Washington Fred Hutchinson Cancer Research Center. We were very excited at the ASCO 2021 meeting to present data from our PrECOG 0807 trial that was a feasibility trial, phase Ib, a trial of neoadjuvant nivolumab with or without lirilumab in cisplatin-ineligible, cisplatin unfit, patients with localised muscle-invasive bladder cancer. This particular study was conceived and designed by me and colleagues a few years ago and now we are very, very excited to present the data.

For context, this trial, again, is in the neoadjuvant setting before radical cystectomy. Cohort 1 included patients who received nivolumab anti-PD-1 as single agent and those were two doses given four weeks apart followed by radical cystectomy and pelvic lymph node dissection. Cohort 2 in sequence was after cohort 1 was concluded and evaluated patients with a combination of nivolumab plus lirilumab. Lirilumab is an interesting molecule, it inhibits the KIR2DL which are receptors that inhibit natural killer cells. So the idea here was to combine the anti-PD-1 with an NK cell activator so we can engage both the adaptive and the immune components of the immune system. The goal was to see if we could get more CD80 cells, CD40 cells and NK, natural killer, cells in the tumour microenvironment and hopefully translate into a higher pathological complete response rate. I’m happy to answer questions about the results and the data.

The primary endpoint was safety and feasibility and we saw that the neoadjuvant nivolumab alone or the combination was safe and feasible. All patients were able to get radical surgery without delays and there were no grade 3 or higher treatment related adverse events with nivolumab. There were only four treatment related adverse events with nivolumab plus lirilumab and all of those four events were grade 3 and there were no grade 4 or 5 adverse events. So overall the combination was very feasible and safe, again, did not compromise cystectomy in those patients. We had 43 patients enrolled in the study, all but one, 42 patients, completed neoadjuvant immunotherapy and 41 patients, so everybody except one who got neoadjuvant chemotherapy, got radical surgery.

We had also a look at the pathologic complete response rate and we saw that the pT0N0 was only 8% with nivolumab alone and was 18% with the combination of nivolumab lirilumab. If you look at pathologic downstaging this was a pathology less than T2N0, it was 17% with nivolumab and 29% with the combination. So, overall the combination and nivolumab alone were safe and feasible, however, the pathologic response rates were lower than expected. However, we are doing further work looking at biomarkers and translational research on tumour tissue, blood and urine. We are also working on the manuscript to be released in the near future.

Overall there are now phase III trials that are evaluating nivolumab as neoadjuvant and adjuvant therapy in this setting. One of them is looking at the combination of nivolumab plus NKTR-214, a PEGylated form of IL2, in arm A versus nivolumab alone, in arm B versus no perioperative therapy. That phase III trial is ongoing, again three arms, this for cisplatin and for cisplatin ineligible patients. There is also a separate trial that is called ENERGIZE that is looking at gemcitabine cisplatin plus nivolumab in the neoadjuvant setting and those phase III trials will further define the role of nivolumab in the neoadjuvant setting.  We also wait to see what happens by the FDA review of the CheckMate274 trial that evaluated nivolumab versus placebo in the adjuvant setting and saw significant disease free survival with nivolumab. We have to see whether this will result or not in the approval of nivolumab in the purely adjuvant setting. So more to come with immunotherapy in the neoadjuvant and adjuvant setting.