SUO 2024: Setting the Stage: Our Current Options for BCG Unresponsive NMIBC

(UroToday.com) The 2024 SUO annual meeting included a session on BCG unresponsive non muscle invasive bladder cancer (NMIBC), featuring a presentation by Dr. Eugene Pietzak III discussing our current options for BCG unresponsive NMIBC. The BCG unresponsive definition based on expert opinion is as follows:

• Patients with HGT1 at the first evaluation following induction BCG (at least 5 of 6 doses)
• Persistent/recurrent high grade Ta/T1 within 6 months of “adequate” BCG
• Persistent/recurrent CIS within 12 months of “adequate” BCG
  • “Adequate” BCG is defined as at least 5 of 6 induction + 2 of 3 maintenance or 2 of 6 for another induction course

The current state of BCG unresponsive NMIBC includes already FDA approved agents, those that will likely be FDA approved in the near future, and off-label chemotherapy, as highlighted below:
Dr. Pietzak notes that there are numerous issues with evaluating treatment efficacy in single-arm, non-randomized NMIBC trials:

• Pre-treatment TURBT quality, treatment center effects, referral patterns/where was the initial treatment, and consistency of “enhanced” cystoscopy
• Inter-pathologist variability
• Varying patient populations and tumor risk, prior BCG naïve/exposed treatment history, and the national history of “contemporary” CIS
• Trial design and methodology variations, treatment failure definitions, and whether re-treatment is allowed 

The current tools we have in our toolbox are as follows:

• Clinical trials
• Radical cystectomy
• FDA approved agents: pembrolizumab, nadofaragene firadenovec, NAI + BCG
• Intravesical chemotherapies: gemcitabine + docetaxel, gemcitabine, mitomycin

Dr. Pietzak notes that pembrolizumab has a 12 month complete response rate of < 20%, but there are no pre-treatment biomarkers, and pembrolizumab can be associated with significant toxicity (and somewhat similar to radical cystectomy complications):^1,2

For nadofaragene firadenovec, 103 patients with CIS were enrolled in a phase 3 trial, with a 3 month complete response rate of 53%, and a 12 month complete response rate of 24 months after a mandatory trial biopsy. Treatment related grade 3-5 adverse events were 4%, with no treatment related deaths. Notably, Dr. Pietzak highlighted that only 5 patients (5%) enrolled were cT1 + CIS, of which 3 patients (60%) had disease progression, thus he states that we should be cautious with HGT1 + CIS patients. However, this is not unique to the nadofaragene trial, as all of the single arm BCG unresponsive NMIBC trials are under-represented for HGT1 + CIS patients:
FDA approvals are for BCG unresponsive CIS +/- Ta and for CIS +/- T1, yet there are very few T1 tumors in the clinical trials. Thus, we need more stage specific clinical trials, perhaps looking at immune checkpoint blockade combinations for HGT1 + CIS and intravesical only approaches for HGTa/Tis. Currently, we do not know who which patients with NMIBC are most appropriate for immune checkpoint blockade, as 80-90% of patients with immune checkpoint blockade based BCG unresponsive trials are at low risk for disease progression:

Next, Dr. Pietzak discussed NAI + BCG, which is the third FDA approved agent. Of note, NAI alone has poor single agent activity, and cohort C of NAI alone was closed due to futility, as only 2 of 10 (20%) patients had complete response at 3 months. So, what is the relative contribution of BCG versus NAI? “BCG unresponsive” criteria are based only on expert opinion, and we know that BCG alone provides clinical benefit to a subset of “BCG unresponsive” NMIBC, especially in patients with BCG relapsing disease (~50% of NAI + BCG trial). Conversely, how much of a treatment effect is from NAI versus BCG? The ongoing BCG naïve RCT of BCG +/- NAI will be important to see if the addition of NAI is worth the extra cost:
Of note, and for comparison, gemcitabine + BCG is $6,055/year. Dr. Pietzak emphasized that gemcitabine + docetaxel is the elephant in the room. In the wake of the BCG shortage over the last several years, intravesical gemcitabine + docetaxel has emerged as a combination therapy for patients with NMIBC. In 2020, Steinberg et al.⁴ investigated intravesical gemcitabine/docetaxel as rescue therapy for NMIBC. Among 276 patients over a median follow-up of 22.9 months, 39% of patients were CIS alone, 26% were Ta high grade, 21% were T1 high grade, and 13% were Ta low grade. Overall, 53% had one BCG induction course, and 46% had 2+ BCG induction courses, and 38% were “BCG unresponsive.” Of note, some responders went on to maintenance therapy (monthly versus the SWOG schedule) for 24 months. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection, and 43 patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion.

Finally, Dr. Pietzak discussed two emerging therapies, TAR-200 and cretostimogene. TAR-200 is a gemcitabine intravesical system that has shown early efficacy. However, Dr. Pietzak notes that there have been no head to head comparisons with standard intravesical gemcitabine +/- docetaxel. How does this option fit with gemcitabine + docetaxel? Does cross resistance occur? Furthermore, TAR-200 requires every 3 week cystoscopies to remove and exchange, which may be logistically difficult and have increased cost. Secondly, cretostimogene reported updated results at SUO 2024 for the pivotal BOND-003 trial for BCG unresponsive CIS. The complete response rate at any time was 74.5%:
However, Dr. Pietzak notes that he has some concerns, given that the previous phase 2 trial (n = 57) showed an any time complete response rate of 65%, a 12 month complete response rate of 30%, and 18 month complete response rate of 23%.

Dr. Pietzak concluded his presentation discussing our current options for BCG unresponsive NMIBC by highlighting two ongoing problems:

• Problem #1: Which current treatment is best?
  • There is an urgent need for RCTs to evaluate approved treatments (and gemcitabine + docetaxel)
    • Using a broader BCG failure definition than “unresponsive” may improve accrual and generalizability of the data
    • There is an opportunity for biomarker integration
  • How to conduct these RCTs is the bigger question
    • What is the income incentive for pharmaceutical companies?
    • Do the cooperative groups have the agility and nimbleness for such trials?
• Problem #2: We need better treatments
  • Single arm, non randomized trials should go back to being “signal finding” studies
    • It may be okay to stick with the “unresponsive” criteria
    • But there are endless numbers of new treatments and potential combinations that need to be tested
    • Can biomarkers (ie. urinary tumor DNA) serve as a surrogate endpoint for quicker read outs?
    • More stage specific trials are needed: HGT1 + CIS is not the same as HGTa/Tis

Presented by: Eugene Pietzak, MD, Urologic Surgeon, Clinical Investigator, Department of Surgery, Memorial Sloan Kettering Cancer Center, Urology Service Assistant Professor, Weill Cornell Medicine, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Society of Urologic Oncology (SUO) Annual Meeting, Dallas, TX, Tues, Dec 3 – Fri, Dec 6, 2024.

References:

1. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicenter, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930.
2. Necchi A, Roumiguié M, Kamat AM, et al. Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2024 Jun;25(6):720-730.
3. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan;22(1):107-117.
4. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol. 2020;203:902-909.