(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023 was host to a bladder preservation strategies oral session. Following a case presentation by the session moderator, Dr. Andrea Necchi, Dr. Joost Boormans discussed organ preservation strategies for refractory non-muscle invasive bladder cancer (NMIBC) from a surgeon’s perspective.
Dr. Boormans began by highlighting the current challenges for BCG-unresponsive NMIBC. >50% of patients will recur, however <20% will progress to muscle-invasive disease. However, patients with progressive disease have poor outcomes, and, as such, novel treatment strategies are needed in this space.
The current issues with emerging novel therapies for BCG-unresponsive NMIBC remain numerous:
- Different primary endpoints chosen for different trials, limiting comparisons
- Not all trials mandate biopsies to assess disease response
- Use of single arm phase II trial design with no comparator group
- Numerous visits required during the 1st year, ranging between 4 and 18
- Different toxicity profiles with intravesical versus intravenous agents
BCG-unresponsive disease is defined as being at least one of the following:
- Persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy
- Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy
- T1 high-grade disease at the first evaluation following an induction BCG course
In this context, adequate BCG therapy is defined as at least one of the following:
- At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy
- At least five of six doses of an initial induction course plus at least two of six doses of a second induction course
The importance of this definition becomes clearer when we consider studies of less frequently dosed BCG, compared to standard dosing frequency BCG. The NIMBUS study published in 2020 compared the clinical outcomes of 340 patients treated with reduced frequency BCG (induction: 1, 2, and 6 weeks followed by 2 weeks of maintenance at 3, 6, and 12 months) versus standard BCG. Patients in the reduced frequency dosing had a clearly higher recurrence rate (46/170 versus 21/70).1
Next, Dr. Boormans went on to discuss currently available intravesical and intravenous drugs for patients with BCG unresponsive NMIBC.
He first highlighted the eligibility criteria for these drug trials. These trials classically included patients with both CIS (+/- papillary disease), with the Nadofarogene Firadenovec trial,2 KEYNOTE-057 Cohort B,3 QUILT,4 and the retrospective gemcitabine/docetaxel series5 including patients with pure papillary disease. Another important issue is the variability in mandated biopsies between these studies. Biopsies were mandated for the Nadofarogene Firadenovec trial (12 months), QUILT (3 months), and S1605 (6 months) only. Dr. Boormans argued that biopsies should be mandated in this setting to ‘faithfully’ evaluate the response rate, although he argued that 3 months as in the QUILT trial may be too soon.
From an efficacy standpoint, the complete response rate at 3 months appears to range between 41% and 71% (highest in QUILT), although we do note a steep drop off by 12 months with response rates almost halving to 20 – 40%. The longest follow-up for these studies remains the longest for pembrolizumab (KEYNOTE-057), with a median reported follow-up of 45.4 months.
From a surgeon’s perspective, agents that are administered intravesically may be more appealing from a practical standpoint. Dr. Boormans further questioned whether exposing agents to intravesical immunotherapeutics with their systemic effects is appropriate for patients with localized disease. The rate of grade 3 or worse toxicity remains comparatively higher for atezolizumab (38%), compared to the other intravesical agents available in this space (4 – 20%). We also need to factor in the number of treatment visits required in the 1st year. While Nadofarogene Firadenovec only requires 4 visits in the first year, BCG + IL-15 in the QUILT trial required 18 visits, with the other treatments ranging between 14 and 16 visits in the first year. To date, only Nadofarogene Firadenovec and pembrolizumab have been approved by the FDA approved in this space, with gemcitabine + docetaxel commonly used off-label in clinical practice.
While Dr. Boormans is a surgeon by training, what is clear is that most patients (~90%) do not prefer radical cystectomy in the BCG-unresponsive setting. As such, it is incumbent upon us to continue to discover/test novel agents and combinations in this setting. In his opinion, an intravesical component for therapy remains key, with systemic therapy having a significant risk of toxicity. Radical surgery must remain a last resort for ‘ultimate’ refractory NMIBC with bladder preservation being the key patient preference.
Presented by: Joost Boormans, MD, PhD, Urologist, Professor of Urology, Head of Department, Erasmus Medical Center, Utrecht University, The Randstad, Netherlands
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 Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
References:
4. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer. NEJM Evid 2022; 2(1)
5. 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(5):902-909.