GU Oncology Now spoke with Peter C. Black, MD, of the University of British Columbia, Department of Urologic Sciences, regarding the current treatment and therapy landscape for patients with high-risk non-muscle invasive bladder cancer (NMIBC) who are unresponsive to bacillus Calmette-Guérin (BCG), the basis for testing atezolizumab in this setting, and the design, results, and implications of the SWOG S1605 trial.
Could you please highlight the bladder-sparing treatment and therapy options currently used for patients with BCG-refractory, high-risk NMIBC?
Dr. Black: The most common treatment worldwide is single-agent intravesical chemotherapy, which, though relatively ineffective, is accessible and easy to administer. In Canada and the United States, the combination of gemcitabine and docetaxel has gained popularity, despite relying on retrospective data rather than clinical trials. Pembrolizumab gained US Food and Drug Administration (FDA) approval in the United States based on results of the KEYNOTE-057 trial, but its use is limited due to reimbursement issues in other jurisdictions; it is approved in Canada but not often given because provincial payers do not reimburse it.
The latest addition is nadofaragene firadenovec, an adenovirus gene therapy, that has promising clinical trial results. It is approved in the United States, and Ferring, the drug’s manufacturer, will expand nadofaragene firadenovec to other markets once production ramps up.
What led to the decision to test atezolizumab in this context? Was there prior research supporting its safety and efficacy in bladder cancer?
Dr. Black: When we initiated the atezolizumab SWOG S1605 trial, there was no existing evidence of immune checkpoint therapy for non-muscle invasive disease. However, there were established data indicating the effectiveness of these drugs in advanced metastatic disease, which led to their approval and use. The earliest trial results for atezolizumab in advanced bladder cancer were reported in 2014.
For atezolizumab, SWOG S1605 began in 2016, marking the early stages of systemic immunotherapy use. We had some indirect evidence, like increased PD-L1 expression post-BCG therapy, suggesting a role for immunotherapy in BCG-unresponsive disease.
How was atezolizumab administered and evaluated in your phase 2 SWOG study? What were the criteria for patient selection?
Dr. Black: The SWOG S1605 trial strictly followed FDA guidelines for defining BCG-unresponsive patients. The primary focus was on patients with carcinoma in situ (CIS), with or without papillary disease (Ta or T1). At 6 months, we conducted mandatory biopsies and cytology to assess the primary end point of complete response, effectively eliminating CIS. Notably, we chose a 6-month end point, unlike some other trials that used 3 or 6 months.
The trial’s second cohort involved patients with papillary-only disease (Ta or T1 without CIS), and the end point was event-free survival at 18 months after treatment initiation. Treatment for both groups consisted of intravenous atezolizumab every 3 weeks for 12 months (unlike Keynote-057, in which pembrolizumab was administered for 24 months).
The analysis described the safety and efficacy results as “modest.” Is there enough evidence to consider atezolizumab a viable second-line treatment, or do the adverse events outweigh the potential benefits?
Dr. Black: The key issue here is the sample size of our trial, which was smaller than most other trials in this disease state. We included only 74 patients compared with the 96 patients enrolled in KEYNOTE-057. While our results at different time points were similar to KEYNOTE-057, the FDA discouraged the final submission of atezolizumab due to the small sample size, which led to wider confidence intervals and less certainty about the true benefit. It will not seek FDA approval and will not be used in this setting.
Additionally, we conducted a futility analysis that did not meet criteria for continuing the trial. However, at the time of this analysis, we had already accrued the intended sample size to the CIS arm of the trial, so we ended up with complete results for these patients.
Three patients died out of 166 who received the drug. Grade 3 or greater adverse events occurred in 13.5% of patients, which was the same as pembrolizumab. These risks have to be matched to the modest efficacy: 20% of patients with CIS were disease-free at 1 year and 14% at 18 months.
Considering the toxicity, death rate, and risk of progression to muscle-invasive bladder cancer, it is challenging to justify the use of immune checkpoint inhibitors in BCG-unresponsive non-muscle invasive bladder cancer. They should be considered a last resort when no other options are available, or if the patient cannot undergo cystectomy.
Is this the end for atezolizumab in this space since it will not pursue FDA approval? What direction should research take for this specific patient population?
Dr. Black: While I cannot speak specifically for atezolizumab, I believe the future of immunotherapy lies in combination therapy rather than single-agent monotherapy. Trials testing combinations like the oncolytic adenovirus CG0070 with pembrolizumab in BCG-unresponsive disease have shown promising results. Nadofaragene firadenovec combined with immunotherapy also seems like a good combination to test, as does N-803—the interleukin-15 super agonist—combined with checkpoint inhibition.
Combinations could substantially raise the bar and reduce the need for cystectomy, and I am excited about these possibilities. The future of immunotherapy likely involves combining different agents for greater effectiveness, which would then likely justify the associated risk of adverse events.