SUO 2022: Looking Towards the Future: Non-Muscle Invasive Bladder Cancer Trials Reading Out in 24 Months

(UroToday.com) The 2022 Society of Urologic Oncology annual meeting featured a bladder cancer session, including a presentation by Dr. Roger Li discussing looking towards the future, focusing specifically on trials reading out in 24 months. Dr. Li started his presentation by highlighting that BCG is very effective. In a recent assessment of contemporary outcomes at a single institution of patients with non muscle-Invasive bladder cancer treated with BCG, the 1-year high-grade recurrence free survival rate was 81%, 1-year progression free survival rate was 97%, 1-year cancer-free survival rate was 95%, and 1-year overall survival rate was 99% over a median follow-up of 47.8 months.1 Notably, this contemporary cohort had better outcomes for BCG than seen in historical studies. The full 1-, 3-, and 5-year survival analysis outcomes are as follows:

BCG.jpg 

Dr. Li notes that these data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.

However, other options for BCG-naïve patients are needed, given the continual BCG shortages, patients with BCG intolerance, etc. Dr. Li subsequently discussed several upcoming trials in the BCG-naïve disease space that will be reading out in the next ~24 months. The first trial is the SWOG 1602 trial, which is randomizing patients with high-grade BCG-naïve non-muscle invasive bladder cancer (CIS, Ta, T1) 1:1:1 to:

  • Arm 1: Intravesical BCG, induction and maintenance, using TICE BCG
  • Arm 2: Intravesical BCG, induction and maintenance, using the Tokyo-172 strain
  • Arm 3: Priming with intradermal BCG Tokyo-172 vaccination, followed by intravesical BCG, induction and maintenance, using the Tokyo-172 strain

BCG1.jpg

The second trial Dr. Li discussed was the EA8212 BRIDGE study, with the objective of assessing whether event-free survival is non-inferior for gemcitabine + docetaxel versus standard BCG for patients with BCG-naïve high-grade non-muscle invasive bladder cancer. This study will randomize 870 patients 1:1 (stratified by pure CIS, pure papillary, and mixed) to gemcitabine + docetaxel 6 weekly cycles with monthly maintenance versus BCG 6 weekly cycles with SWOG protocol maintenance. The primary outcome for this study is event free survival, defined as the time from randomization to high-grade recurrence in the bladder (CIS, high-grade Ta, high-grade T1 or T2 disease), progression of disease, or death:

BCG-2.jpg

Dr. Li notes that BCG induces PD-L1 expression, with higher PD-L1 expression found in BCG non-responders, thus providing the rationale for combining BCG with other immunotherapy agents. The POTOMAC trial is randomizing 1,018 BCG-naïve patients to (i) BCG induction + maintenance for 24 months versus (ii) BCG induction + maintenance + durvalumab versus (iii) BCG induction only + durvalumab, with a primary endpoint of disease free survival:

BCG-3.jpg

In a similar fashion, the CREST trial is assessing utilization of sasanlimab, and the ALBAN trial is assessing utilization of atezolizumab.

Finally, the KEYNOTE-676 trial is randomizing 550 patients with high-risk non-muscle invasive bladder cancer who have received adequate BCG induction therapy to pembrolizumab + BCG versus BCG monotherapy, with a primary endpoint of complete response rate in the CIS patients. The trial schema for KEYNOTE-676 is as follows: 

SUO BCG-4.jpg

Dr. Li highlighted that there has been a remarkable increase in trials for early stage urothelial carcinoma (intermediate risk disease, high-risk BCG-naïve disease, BCG-persistent/relapsing disease, and BCG-unresponsive disease), particularly from 2014 through to the current trial landscape in 2022:

BCG-5.jpg

Dr. Li concluded his presentation by discussing looking towards the future, focusing specifically on trials reading out in 24 months with the following important questions that remain to be answered:

  • Will combination strategies demonstrate higher efficacy than BCG alone?
  • Will urologists feel comfortable administering IV drugs as part of combination strategies?
  • Is a one-size fits all approach in the BCG-naïve setting the correct approach?
  • Is the adjuvant setting following resection the best time to administer therapy?
  • How will the administration of the anti-PD-(L)1 agents in the earlier disease setting affect treatment options for higher staged disease?

Presented by: Roger Li, MD, Moffitt Cancer Center, Tampa, FL

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 23rd Annual Meeting of the Society of Urologic Oncology (SUO), Nov 30 – Dec 2, 2022. San Diego, CA 

References:

  1. Matulay JT, Li R, Hensley PJ, et al. Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guerin: Implications for Clinical Trial Design. J Urol. 2021 Jun;205(6):1612-1621.
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