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Christopher Wallis: Hello. Thank you for joining us for this UroToday Journal Club. Today we are discussing a recent publication titled Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt. And with me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent publication in the New England Journal of Medicine.

For patients with muscle-invasive urothelial carcinoma, radical surgery is the standard of care. And for patients who are receiving a cystectomy for muscle-invasive bladder cancer, neoadjuvant chemotherapy prior to radical cystectomy is recommended. In spite of this, lethal metastatic recurrence is relatively common affecting nearly half of all patients. Adjuvant chemotherapy has been proven to prolong disease-free survival in upper tract disease on the basis of the POUT trial, but there is a lack of consensus on its use. And there is no standard of care for patients who have received neoadjuvant chemotherapy, either for upper tract disease or for muscle-invasive bladder cancer.

Nivolumab is an IgG4 monoclonal antibody against PD-1. And in the post-chemotherapy space, it has been approved for the treatment of metastatic bladder cancer based on the data from CheckMate 275. Thus, the hypothesis for this study was to assess the role of adjuvant nivolumab in muscle-invasive urothelial carcinoma after radical surgery for patients who have had or who have not had prior neoadjuvant chemotherapy.

So this was an open-label, multi-center double-blind, phase three, randomized controlled trial. We will walk through all the details of the inclusion criteria, randomization, and treatment in the coming slides. But this just gives you an overview of the treatments and study schema.

So patients were included if they had radical surgery within 120 days of randomization, and had negative surgical margins. They could have had neoadjuvant chemotherapy, but this was not required. There had to be pathologic evidence of urothelial carcinoma in the bladder, renal pelvis, or ureter. And they further had to have a high recurrence risk. And this was defined among patients who did not have neoadjuvant chemo as either pT3 or pT4 disease or node positivity, as well as an unwillingness or inability to receive adjuvant chemotherapy. For patients who did have neoadjuvant chemotherapy, ypT2 to ypT4a or yp node-positive disease was required. In the study, while upper tract disease was allowed, and this was capped at a maximum of 20% of the study cohort, patients had to have no evidence of disease on the basis of a physical examination and imaging within four weeks of randomization as well and they had to have adequate tumor for biomarker analysis and ECOG performance status of zero or one.

Patients were then randomized in a one-to-one fashion with stratification according to PD-L1 status, pathological nodal status, and the use of neoadjuvant cisplatin-based chemotherapy. Patients were then administered either nivolumab 240 milligrams IV every two weeks for one year or until recurrence, whichever was first, or placebo. And treatment delay and discontinuation were allowed to manage adverse events associated with nivolumab.

The primary endpoints were disease-free survival in the ITT population and disease-free survival in those with PD-L1 positivity defined as greater than 1%. Disease-free survival was defined as the time from randomization to the first of local recurrence, distant recurrence, or death. Secondary endpoints included survival free from recurrence outside the GU tract, so overall survival and disease-specific survival. There were further exploratory endpoints, including metastasis-free survival, safety, toxicity, and health-related quality of life.

Biomarker assessment was performed using PD-L1 expression assessed by using this assay and the percentage of positive tumor cell membrane staining was assessed and scored as a percentage from zero to 100. In terms of safety analysis, all patients who received at least one dose were included, and this was again stratified by PD-L1 expression. And these AEs were graded according to the CTCAE version 4.0.

In terms of statistical analysis, the authors planned to recruit 700 patients. A total of 410 DFS events in the ITT population would allow an 87% power to detect hazard ratio of 0.72 with an alpha of 0.025, which the authors operationalized as a one-sided alpha. 162 DFS events in the PD-L1 positive population would allow an 80% power to detect hazard ratio of 0.61 again, with an alpha of 0.025, which was one-sided. Interim analysis was planned at 85% of the event rate, which would be 348 events in the ITT population, and 137 events in the PD-L1 positive population. And the authors used alpha spending with the allocation as you can see here.

DFS was compared for patients who received adjuvant nivolumab versus placebo using the log-rank test and stratified Cox Proportional Hazards models. And the authors then performed a hierarchical analysis of OS based on ongoing longer follow-up. And for measures of health-related quality of life, they used mixed-effects linear regression.

At this point in time. I am now going to hand it over to Zach to walk us through the results of this important trial.

Zachary Klaassen: Thanks, Chris. So this table is the baseline characteristics table for this trial and it's a large table. So I've split it into two parts: the first part on the left and the second part on the right. And you can see, when we look at nivolumab versus placebo, the mean age was mid-sixties for both of these groups. About three-quarters of these patients were male, about three-quarters of these patients in each arm of the trial were white, and looking at ECOG performance status, the majority of these patients were ECOG zero and one in both of these arms. In terms of the tumor origin and initial diagnosis, about 80% of these patients had bladder cancer and about 12% to 15% had renal pelvis cancer. In terms of time from the initial diagnosis to randomization, the majority of these patients were less than one year at 92% in the nivolumab arm and 91% in the placebo arm. In terms of previous neoadjuvant cisplatin chemotherapy, there were about 43% of patients in each of these arms.

Moving to the right side of the slide for the remaining baseline characteristics. The majority of these patients in both arms at 44% had pT3 or 4, node-negative disease. In terms of the nodal status at the time of resection, N0 or Nx with less than 10 nodes removed, 26.6% in the nivolumab group and 27.8% in the placebo group.

So we'll go through a series of Kaplan-Meier curves for the next couple of slides. This is the disease-free survival in the intention-to-treat population. And you can see a nice, early, and wide splitting of the curves between nivolumab in green and placebo in blue. And looking at the disease-free survival at six months at 74.9% for nivolumab and 60.3% for placebo. At 12 months, 62.8% for nivolumab and 46.6% for placebo with a hazard ratio for disease recurrence or death favoring nivolumab of 0.70 and a 98.22% confidence interval of 0.55 to 0.90. Looking at DFS in patients with a PD-L1 expression level of greater than, or equal to 1%, again, an early and wide splitting of the curves favoring nivolumab. In terms of DFS at six months for nivolumab, was 74.5%, and for placebo was 55.7%. And at 12 months for nivolumab, 67.2% and for placebo 45.9%, again, with a hazard ratio favoring nivolumab of 0.55 and a 98.72% confidence interval of 0.35 to 0.85.

This is a subgroup analysis looking at disease-free survival with the intention-to-treat population. And just sort of generally looking at this figure, favoring nivolumab is to the left, and favoring placebo is to the right. So the majority of these subgroups did favor nivolumab. Certainly, with smaller populations, there was less of a benefit for renal pelvis and ureteral tumors, but generally, we see a benefit across all these subgroups for the nivolumab arm.

This is survival-free from recurrence outside of the urothelial tract in the intention-to-treat population. Again, favoring the nivolumab arm with survival outside the GU tract at six months for nivolumab of 77% and for the placebo of 62.7%. And at 12 months favoring nivolumab at 65.1%, and for placebo at 50.4% with a hazard ratio of 0.72 and a 95% confidence interval of 0.59 to 0.89.

This again looks at the freedom from recurrence outside the urothelial tract and those with a PD-L1 expression greater than 1%. Once again, favoring nivolumab at six months, 75.3% compared to placebo at 56.7%. And at 12 months, 68.4% for nivolumab and 46.7% percent for placebo with a hazard ratio of 0.55, and a 95% confidence interval of 0.39 to 0.79. In terms of the adverse event rate, we have the nivolumab versus the placebo arm stratified by any grade and grade greater than and equal to three, which we will focus on for this discussion. In terms of any adverse event of any cause greater than or equal to three, for the nivolumab arm, 42.7% compared to 36.8% for the placebo arm. Any adverse events related to nivolumab or placebo, 17.9% for the nivolumab arm and 7.2% for the placebo arm. In terms of specific adverse events of interest, 5.1% increased lipase level for the nivolumab arm compared to 2.6% for the placebo arm and 3.7% increased amylase level in the nivolumab arm compared to 1.4% in the placebo arm.

So several discussion points from the CheckMate 274 trial. In the intention to treat population, the median disease-free survival with nivolumab was nearly double that with placebo at 20.8 months versus 10.8 months. And CheckMate 274 adjuvant nivolumab improved outcomes among high-risk urothelial carcinoma patients undergoing surgery, which is in contrast to the IMvigor010 trial, looking at adjuvant atezolizumab, that did not show a significant difference in disease-free survival. A subgroup analysis of disease-free survival showed a larger effect size in patients with bladder urothelial carcinoma than in those with the renal pelvis and ureteral tumors. And also a larger effect size in patients previously treated with neoadjuvant chemo than in those without neoadjuvant chemotherapy.

So, in conclusion, disease-free survival was significantly longer with adjuvant nivolumab than with placebo among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery with curative intent. Further follow-up is planned to assess overall survival in this population. And nivolumab monotherapy was associated with the expected level of toxicity, and no deterioration in the quality of life was observed relative to placebo. The CheckMate 274 trial showed a significantly and clinically meaningful benefit of adjuvant systemic immunotherapy as compared to placebo, both in the intention to treat population and in patients with PD-L1 expression greater than or equal to 1%.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussion of the CheckMate 274 trial recently published in the New England Journal of Medicine.