The key questions in NMIBC remain:
- How do we define high-risk NMIBC?
- Does Bacillus Calmette-Guérin (BCG) still play a role?
- What are the trials in the BCG-naïve space
- How do we define BCG unresponsiveness and what are alternatives to radical cystectomy?
- What is the role of multi-disciplinary care for patients with NMIBC?
Currently, the International Bladder Cancer Group (IBCG) risk stratifies NMIBC as follows:
In a recently published study in The Journal of Urology, Dr. Kamat and colleagues demonstrated that all HG-Ta tumors should be classified as high-risk. As demonstrated in the Kaplan-Meier curves below, irrespective of the subclassification of HG Ta tumors into “intermediate” or “high” risk, all HG Ta tumors in patients treated with BCG had similarly inferior time to progression on BCG and time to progression to MIBC/distant metastatic disease, when compared to patients with “intermediate” risk LG Ta tumors as a reference.1
Does BCG still play a role in these patients? The answer appears to be yes. In another study by Dr. Kamat and colleagues, the authors retrospectively evaluated patients receiving “adequate” BCG at MDACC between 2004 and 2018. Of the 542 patients who received adequate BCG, 518 (90%) had EAU high-risk disease, with carcinoma in situ present in 175 patients (32%). With a median follow-up of 47.8 months, progression-free survival was 97%, 93% and 92%, and was significantly worse in patients with EAU high risk disease, when compared to those with intermediate risk disease.2
The corresponding high-grade disease recurrence-free and cancer specific survivals also remain excellent, particularly in the EAU intermediate risk group as summarized in the table below. These reinforce the importance of BCG for these patients in this setting.
It is important to note that the EAU risk calculator overestimates the risk of disease progression, and, importantly, does not account for the effect of BCG therapy. A recent study by Kamat and colleagues evaluated the validity of the updated EAU prognostic factor risk groups in patients with NMIBC treated with BCG.3 This validation study included 529 patients receiving at least induction BCG, with a median follow-up of 47.3 months. Of these patients, 494 received adequate BCG. The investigators found:
- Lower progression rates at 1 year in the very-high-risk group patients receiving at least induction (6.9%) and adequate BCG (4.0%), versus 16.0% for the EAU predicted rates.
- Progression rates were also lower at 5 years in the high-risk group: 7.4% for at least induction and 5.3% for adequate BCG versus 9.6% for EAU predicted rates
- The progression rates in the very-high-risk group were as follows: 16.7% for at least induction and 14.9% for adequate BCG versus 40.0% for EAU predicted rates.
Dr. Kamat next highlighted the various BCG strains available, with significant geographic variations in the strain product available:
What about the emerging role of intravesical gemcitabine/docetaxel in the NMIBC space? A recent retrospective analysis by McElree et al. published in 2022 in The Journal of Urology retrospectively reviewed 107 patients with BCG naïve, high risk NMIBC who received gem/doce (6 weeks induction course followed by maintenance monthly). Impressively, at a median follow-up of 15 months, the high-grade disease recurrence-free survival at 24 months was 84%.4
Published in JAMA Network Open in 2023, McIlree and colleagues compared the outcomes of 312 patients with high-risk NMIBC treated with gemcitabine and docetaxel versus BCG in the first line setting. As demonstrated below, the high-grade recurrence-free survival was superior in the gem/doce group. These findings persisted on multivariable Cox regression analyses controlled for age, sex, treatment year, and presence of carcinoma in situ with superior high-grade RFS in the gem/doce group (hazard ratio, 0.57; 95% CI: 0.33 - 0.97; P = .04).5
BCG-IO combinations are currently being evaluated in trials of BCG naïve patients as demonstrated in the study design of POTOMAC, which is a 3-arm trial evaluating BCG induction/maintenance, BCG induction/maintenance + durvalumb, and BCG induction + durvalumab, with a primary endpoint of disease-free survival. Similar trials in this setting include:
- ALBAN: Atezolizumab
- CREST: Sasanlimab
- KEYNOTE-676: Pembrolizumab
The SunRISe-3 trial is evaluating the combination of TAR-200 (gemcitabine 225 mg) + cetrelimab (anti-PD-1) in BCG-naïve, high-risk NMIBC patients with primary endpoints of EFS in the overall cohort and CR in CIS patients:
Similarly, the non-inferiority BRIDGE trial is prospectively comparing the combination of intravesical gem/doce to BC in patients with BCG naïve, HG NMIBC.
Over the last decade, significant efforts have been put into defining BCG unresponsiveness. While not as clinically relevant, this definition has had important implications for trial design. Based on this definition, and in collaboration with the FDA, numerous treatment options for BCG unresponsive NMIBC have emerged, with only pembrolizumab (KEYNOTE-057) and Nadofaragene Firadenovec currently FDA approved for this indication:
Among the FDA approved agents, the complete response rates are 40% for pembrolizumab (best response of complete response of 40%) and 60% for patients receiving Nadofaragene Firadenovec (60% CR at 3 months, down to 46% freedom from HG recurrence at 12 months). Using these figures as benchmarks, we see promising results with emerging agents in this BCG unresponsive setting. Among patients receiving gem/doce in the BCG unresponsive setting, patients with papillary only and CIS tumors had HG-RFS of 58% and 50%, respectively.
The IL-15 superagonist, N-803, has demonstrated a 71% CR rate at any time:
Impressively, the combination of CG0070 + pembrolizumab for BCG-unresponsive NMIBC has demonstrated an overall CR rate of 88% in 32 patients within the singe-arm CORE1 study.
Finally, as more systemic therapy options are emerging in this disease space, Dr. Kamat highlighted the importance of a multi-D approach to the management of these patients, which will only increase in the upcoming years.
Presented by: Ashish M. Kamat, MD, MBBS, Endowed Professor of Urologic Oncology (Surgery) and Cancer Research, Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Association of Urology (EAU) 38th annual congress held in Milan, Italy between March 10-13, 2023
References:
- Bree KK, et al. Repeat Transurethral Resection of Muscle-invasive Bladder Cancer Prior to Radical Cystectomy is Prognostic but Not Therapeutic. J Urol, 2022. doi.org/10.1097/JU.0000000000003015.
- Matulay JT, et al. Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design. J Urol, 2021. 205(6):1612-1621.
- Lobo N, et al. Updated European Association of Urology (EAU) Prognostic Factor Risk Groups Overestimate the Risk of Progression in Patients with Non-muscle-invasive Bladder Cancer Treated with Bacillus Calmette-Guérin. Eur Urol Oncol, 2021. 5(1):84-91.
- McElree I, Steinberg R, Martin A, et al. Sequential Intravesical Gemcitabine and Docetaxel for bacillus Calmette-Guérin-Naïve High-Risk Nonmuscle-Invasive Bladder Cancer. J Urol. 2022;208(3):589-599.
- McElree I, Steinberg R, Mott S, et al. Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer. JAMA Network Open. 2023;6(2):e230849