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Spotlight

This roundtable series looks at combination treatments in the unresectable or metastatic bladder cancer population, as discussed by key opinion leaders at virtual live events and interviews.

Patients With Advanced Bladder Cancer Given Combination Therapies

Rana McKay discusses CheckMate 274, AMBASSADOR, and NIAGARA

Differing Trial Designs for Immunotherapy in MIBC Yield Favorable Outcomes

Rana R. McKay, MD, professor of medicine and urology at UC San Diego School of Medicine, discusses the significance of clinical trial data for immunotherapy in muscle-invasive bladder cancer (MIBC) treatment she presented at a Case-Based Roundtable event.

At the event, she discussed data such as an update from the CheckMate 274 trial (NCT02632409) of nivolumab (Opdivo) vs placebo as adjuvant therapy for MIBC. The overall survival (OS) data favored nivolumab in the intent-to-treat population and even more strongly in the population of PD-L1 expression 1% or higher. Investigators in the AMBASSADOR/A031501trial (NCT03244384) reported disease-free survival (DFS) benefit with pembrolizumab (Keytruda) vs observation in the neoadjuvant setting but OS data were immature. This trial was notable for allowing patients with positive margins after resection to enroll.



McKay also brought up the NIAGARA trial (NCT03732677) of durvalumab (Imfinzi) plus neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone. She said this study allowed patients with a creatinine clearance of greater than 40 mL/min per 1.73 m

, a lower threshold than some other studies. The durvalumab arm had superior event-free survival, but she said questions remained since these patients received durvalumab before and after resection. It did not investigate whether patients could avoid adjuvant immunotherapy following a pathologic complete response (pCR). Additionally, the comparator arm did not receive any adjuvant immunotherapy although other studies have now shown this to be beneficial.

 There was a lot of discussion around the role of adjuvant immunotherapy for people with high-risk localized MIBC at the time of cystectomy, evolving data from CheckMate 274, now we see longer-term follow-up data. We've seen OS data that certainly appear to be suggesting that patients may derive an OS benefit with this regimen, particularly those individuals [who] are PD-L1 positive. With the AMBASSADOR study, definitely positive trial with regards to DFS. This was a study that looked at adjuvant pembrolizumab—some slight differences with the enrollment criteria in that this trial did allow patients with positive surgical margins to enroll. The DFS was positive for pembrolizumab. The OS data are still immature.

We also chatted about the NIAGARA data of perioperative durvalumab/cisplatin-based chemotherapy in the perioperative setting. The uniqueness of this study was it actually allowed enrollment of patients with a GFR [glomerular filtration rate] of greater than 40 [mL/min per 1.73 m2] so it had a slightly lower GFR threshold than historically utilized, and patients received cisplatin, gemcitabine, durvalumab, pre- and post- surgery and the post-surgery treatment was not dependent on pathologic responses at the time of surgery, and the control arm patients did not receive adjuvant immunotherapy. So there are some questions that are left unanswered with the NIAGARA study, particularly around [whether] patients with a pCR need outback treatment, and then what's the performance of the control arm in the context of adjuvant immunotherapies now demonstrating improvements in outcomes?

Rana R. McKay, MD, discusses the significance of clinical trial data for immunotherapy in muscle-invasive bladder cancer (MIBC) treatment she presented at a Case-Based Roundtable event.

Matthew R. Zibelman, MD, discusses differing opinions in muscle-invasive bladder cancer treatment he heard when moderating a Case-Based Roundtable event.

Opinions on Treatment Split for Prominent Questions in Bladder Cancer

Matthew R. Zibelman, MD, associate professor in the Department of Hematology/Oncology, director of Genitourinary Clinical Research, and director of Clinical and Translational Research, GU Service Line at Fox Chase Cancer Center, discusses differing opinions in muscle-invasive bladder cancer treatment he heard when moderating a Case-Based Roundtable event.

He said that participating oncologists debated the use of immunotherapy compared with platinum-based chemotherapy in adjuvant high-risk bladder cancer. The standard of care in this space used to be chemotherapy, but now nivolumab (Opdivo) is also considered based on data from the phase 3 CheckMate 274 trial (NCT02632409). According to Zibelman, some participants now consider nivolumab as standard for the majority of these patients.

Another topic of event discussion was in reference to the phase 3 NIAGARA trial (NCT03732677). This randomized trial showed efficacy with perioperative durvalumab (Imfinzi) plus neoadjuvant chemotherapy in muscle-invasive bladder cancer. Participants took sides on whether they would use this regimen to treat patients with have achieved a complete response (CR) after surgery or avoid additional therapy.

 It's very interesting to see clinicians’ perspectives of the adjuvant setting, in particular with using the new immunotherapy options such as nivolumab vs when to still consider platinum-based chemotherapy, which had been an option [that was] standard for a long time. There did seem to be a little bit of a split amongst the participants about who would still be comfortable and prioritize using platinum-based therapies in that setting vs who feels that immunotherapy really has become the standard of care for the majority of patients. I think that part of the discussion was interesting.

 Then I think with the new NIAGARA data, whether to still give treatment after surgery in patients who've had a CR is something that is an interesting question in the field. I think it was a good topic of discussion. [It] somewhat surprised me about people who—whether they're willing to just keep giving a therapy, even in patients who've had a CR, vs others who do see that in some of those patients, maybe continuing treatment is not necessary.

 Matthew Galsky, MD, discusses why some physicians were surprised at the positive outcomes of nivolumab trials in bladder cancer compared with trials of similar agents.

Surprising Findings With Nivolumab in Bladder Cancer Trials

Matthew Galsky, MD, professor of medicine (hematology and medical oncology), director of genitourinary medical oncology, codirector of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute at Mount Sinai in New York, discusses why some physicians were surprised at the positive outcomes of nivolumab (Opdivo) trials in bladder cancer compared with trials of similar agents.

In the phase 3 CheckMate 274 (NCT02632409) and CheckMate 901 trials (NCT03036098), patients with bladder cancer received adjuvant nivolumab in combination with ipilimumab (Yervoy) and chemotherapy vs chemotherapy alone and nivolumab alone vs placebo, respectively. Past trials of checkpoint inhibitors including atezolizumab (Tecentriq) and pembrolizumab (Keytruda) did not meet their primary end points. This led the community to believe nivolumab trials would turn out the same way, according to Galsky. However, this was not the case since both nivolumab trials reached their primary end point. For CheckMate 901, this may be due to the choice of chemotherapy.

 In the CheckMate 274 and the CheckMate 901 studies, the results were encouraging, certainly in the adjuvant setting based on the fact that the first readout of an adjuvant trial with immune checkpoint blockade as a single agent was IMvigor010 (NCT02450331) and that didn't meet its primary end point. So it was encouraging to see that CheckMate 274 met its coprimary end points when that study read out, because we had heard not too long before that a similarly designed trial didn't meet its primary end points and there are some reasons why we think there might be a difference between the 2 trials.

 In the CheckMate 901 study, I would say that there were things that were both surprising and not surprising. I think the surprising things, similarly, were that the experience combining immune checkpoint blockade with platinum-based chemotherapy based on 2 randomized clinical trials reported before CheckMate 901 didn't meet their primary end points, and so there was a lot of pessimism about combining immune checkpoint blockade with platinum-based chemotherapy, based on those 2 studies: IMvigor130 (NCT02807636) and KEYNOTE-361 (NCT02853305).

 However, if one digs a little bit deeper and you look at the subset analyses from both of those prior phase 3 studies, one sees that there does seem to be a difference when immune checkpoint blockade is added to cisplatin-based chemotherapy vs carboplatin-based chemotherapy. Those prior trials included patients who received either cisplatin or carboplatin. CheckMate 901 was restricted to patients receiving cisplatin-based chemotherapy, and so if there was a difference in adding immune checkpoint blockade based on the specific platinum-based chemotherapy, one would have expected to have that confirmed in CheckMate 901, and that's indeed what happened. So when one added PD-1 blockade just to patients receiving cisplatin-based chemotherapy, then you did see an improvement in overall survival. So a little bit surprising, only because there was a lot of pessimism for the approach after IMvigor130 and KEYNOTE-361, but maybe in retrospect, not entirely surprising, because if one digs deeper into those prior datasets, then there is a hypothesis that was then tested and validated in CheckMate 901.

Matthew Galsky, MD, discusses why some physicians were surprised at the positive outcomes of nivolumab trials in bladder cancer compared with trials of similar agents.

Matthew Galsky, MD, discusses the disease-free survival of nivolumab vs placebo in patients with high-risk muscle-invasive bladder cancer.

Nivolumab Shows Improved DFS in ITT and PD-L1–High Bladder Cancer

Matthew Galsky, MD, professor of medicine (hematology and medical oncology), director of genitourinary medical oncology, codirector of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute at Mount Sinai in New York, discusses the efficacy of adjuvant nivolumab (Opdivo) in the phase 3 CheckMate 274 trial (NCT02632409).

Results from the randomized, double-blind, multicenter CheckMate 274 study were initially published in 

 looking at disease-free survival (DFS) in all patients and patients with PD-L1 expression of 1% or higher as the primary end points. Investigators demonstrated that patients with high-risk muscle-invasive bladder cancer experienced longer DFS with adjuvant nivolumab compared with placebo after radical surgery. This was seen in the intention-to-treat (ITT) population and those with positive PD-L1 expression, according to Galsky.

Nivolumab continued to show benefit over placebo for patients’ DFS, non–urothelial tract recurrence-free survival, and distant metastasis-free survival in the extended follow-up of these data. Results for CheckMate 274 were updated at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium.

 In the initial report of CheckMate 274 where the coprimary end points were reported, the median follow-up was about 5.9 months and DFS in the all-comer population was significantly improved with adjuvant nivolumab vs placebo, with an HR of 0.7. In the patients with tumors with high levels of PD-L1 expression, the effect size was a bit larger, and the HR for DFS was 0.55.

 This study has now been analyzed with longer-term follow-up, so now there's a median follow-up of about 3 years, and the effect size in both the ITT population and in patients with tumors with high PD-L1 expression is virtually identical to what it was with the initial report of the data. 