(UroToday.com) The 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, TX between December 3rd – 6th, 2024 was host to a bladder cancer session. Dr. Gal Wald presented the late-breaking abstract results of a multicenter phase II trial of intravesical gemcitabine plus BCG for patients with BCG-exposed non-muscle invasive bladder cancer (NMIBC).
BCG exposed NMIBC with disease recurrence remains a large population with an unmet need. Recurrences following BCG are common, and the current standard of care for BCG-exposed NMIBC is a BCG re-challenge, although only 50% of patients will experience a clinical benefit. As such, combination strategies that can enhance the effectiveness of BCG to prevent the occurrence of BCG unresponsive disease are sorely needed.
What is the current landscape of BCG-based combinations? BCG has been combined with immune checkpoint inhibitors; however, this combination has been shown to be associated with unacceptable toxicity for majority of NMIBC patients and is expensive ($240,000/year). The combination of BCG + nogapendekin (IL-15) has also been shown to be very expensive (~$525,000/year), and there is no single agent activity for IL-15 superagonist.
What about intravesical chemo-immunotherapy? The combination of BCG + chemotherapy has been shown to be more effective than BCG alone, but at the cost of increased urinary side effects.
If we are to evaluate the combination of BCG + chemotherapy, should we use mitomycin or gemcitabine in this setting? Compared to mitomycin, gemcitabine has been shown to be more effective, better tolerated, and more cost-effective.2 As such, the choice of which agent to use in this setting is clear.
What about BCG compared to gemcitabine? In the BCG-naïve setting, BCG has been shown to be more effective than gemcitabine. In the BCG refractory setting, the reverse is seen with superior efficacy observed for gemcitabine. However, in the BCG exposed setting, gemcitabine + docetaxel has been shown to be equivalent to BCG + IFN.3-5
How does gemcitabine work? Gemcitabine exerts direct cytotoxicity in bladder cancer by inhibiting DNA replication, the formation of deoxyribonucleotides, and the nucleotide excision repair pathway. It may also lead to immunogenic cell death that releases tumor neoantigens, supporting the use of gemcitabine in combination with other agents. Additionally, gemcitabine may prevent cancer cells from repairing BCG-induced oxidative DNA damage, further supporting the use of these agents in tandem.
The combination of BCG + gemcitabine has been recently evaluated in a phase I trial of 25 patients with recurrent high-grade NMIBC. This combination was shown to be safe, with no subjects experiencing grade ≥3 adverse events, thus supporting its evaluating in a phase II setting.
In this phase II trial of intravesical chemo-immunotherapy with gemcitabine + BCG, Dr. Wald and colleagues hypothesized that this combination would lead to improved response rates, compared to historic outcomes with BCG re-treatment. The primary endpoint is complete response at 6 months, with complete response defined as the proportion of patients who are free of disease within the bladder by cystoscopy (+/- biopsy) and urinary cytology.
The study inclusion criteria were as follows:
- Pathologic HG Ta, HG T1, and/or Tis
- BCG exposure within the prior 24 months
- Absence of urothelial carcinoma involving the upper urinary tract within 12 months from the start of treatment
- Adults ≥18 years
- Karnofsky performance status ≥60%
Exclusion criteria were as follows:
- BCG-unresponsive NMIBC
- Current evidence of concurrent extravesical (urethra, ureter, or renal pelvis) urothelial carcinoma
- Contraindication to BCG
The therapy timeline is illustrated below. Patients received gemcitabine 200 mg twice weekly on weeks 1, 4, 7, and 10 and BCG 50 mg TICE strain weekly on weeks 2, 3, 5, 6, 8, and 9. Patients without high-grade recurrences were continued on SWOG maintenance BCG.
A total of 43 patients were enrolled. The median patient age was 70 years, and 70% were male. 74% of patients had CIS +/- papillary disease at study entry. The median number of prior BCG instillations was 6, and 12% had received ≥2 induction courses of BCG. The median duration since the last BCG dose was 6 months. Two patients each (5%) had received either prior induction gemcitabine or gemcitabine plus docetaxel. 
The initial efficacy results are summarized below:
- 3 months: 98% (39/40)
- 6 months: 94% (34/36)
- 12 months: 81% (21/26)
In the CIS +/- papillary cohort, the 3-, 6-, and 12-month complete response rates were 100%, 97%, and 80%, respectively.
The high-grade recurrence-free survival rates at 6, 12, and 18 months were 97%, 85%, and 76%, respectively. The 12-month cystectomy-free survival rate was 100%.
From a safety standpoint, only two patients (5%) experienced a grade 3 treatment-related adverse event (1 urinary tract infection requiring a single dose of intravenous antibiotics and 1 BCG-related pneumonitis that resolved). There were no grade 4-5 adverse events.
Dr. Wald concluded as follows:
- Gemcitabine + BCG in BCG-exposed NMIBC demonstrates excellent early oncological efficacy with low treatment-related adverse events
- The phase II trial is fully accrued with maturing data
- Correlative studies are ongoing
- Based on these data, a phase III randomized trial is opening in May 2025: the GAIN trial
Presented by: Gal Wald, MD, PGY-4 Urology Resident Physician, Weill Cornell Medicine, MSKCC Research Fellow, New York. NY
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, between the 3rd and 6th of December, 2024.
References:
- Chu C, Pietzak E. Immune mechanisms and molecular therapeutic strategies to enhance immunotherapy in non-muscle invasive bladder cancer: Invited review for special issue "Seminar: Treatment Advances and Molecular Biology Insights in Urothelial Carcinoma". Urol Oncol. 2023; 41(10):398-409.
- Asddeo R, Caraglia M, Bellini S, et al. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010; 28(4):543-8.
- Porena M, Del Zingaro M, Lazzeri M, et al. Bacillus Calmette-Guérin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: a randomised prospective study. Urol Int. 2010; 84(1):23-7.
- Steinberg RL, Packiam VT, Thomas LJ, et al. Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG. Urol Oncol. 2022; 40(1):9.e1-7.
- Di Lorenzo G, Perdona S, Damiano R, et al. Gemcitabine versus bacille Calmette-Guérin after initial bacille Calmette-Guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer. 2010; 116(8):1893-900.