Gemcitabine-BCG shows early promise in BCG-exposed NMIBC

In BCG-exposed non–muscle invasive bladder cancer (NMIBC), combination gemcitabine-BCG was associated with strong early oncological efficacy and safety, according to a late-breaking abstract presented at the Society of Urologic Oncology (SUO) 25th Annual Meeting in Dallas, Texas.

Gal Wald, MD

The data were presented by Gal Wald, MD, a urology resident at Weill Cornell Medicine and research fellow at Memorial Sloan Kettering Cancer Center in New York City, New York. “BCG exposed patients represent a population with an unmet need. More than half of patients who initially respond to BCG monotherapy relapse within 5 years. These patients are typically given another course of BCG, but they tend to have even lower response rates,” Wald told Urology Times.

“The current standard of care for BCG-exposed NMIBC is re-treatment with BCG alone, but only 50% will have clinical benefit,” the authors wrote. “Combination strategies that can enhance the effectiveness of BCG to prevent BCG unresponsive disease are needed.”

Reviewing the current armamentarium of BCG-based combination treatments, Wald pointed to high costs as well as toxicity in the case of many of the agents. Wald also discussed mitomycin vs intravesical gemcitabine, pointing to 2 studies attesting to greater efficacy and tolerability with the latter.^2,3 Comparing BCG with gemcitabine, Wald cited research that the latter is more effective in the BCG-refractory space.⁴

For the current study, the authors hypothesized that the combination of gemcitabine and BCG “will have improved response rates compared to historic outcomes with re-treatment with BCG alone.”

The primary end point was complete response (CR) at 6 months, defined as “proportion of patients who are disease free within the bladder by cystoscopy (+/- biopsy) and urinary cytology.”

The study had a 2-stage design, with 15 patients accrued for the first stage and 28 additional patients for the second stage. Patients were eligible for inclusion if they had pathologic HGTa, HGT1, and/or Tis disease, were within 24 months of prior BCG exposure, had an absence of urothelial carcinoma involving the upper urinary tract within 12 months from start of treatment, were at least 18 years of age, and had a Karnofsky performance status of at least 60%. Patients with current BCG-unresponsive NMIBC, current evidence of concurrent extravesical (urethra, ureter, or renal pelvis) urothelial cell carcinoma, a history of muscle-invasive (stage ≥T2 or higher) or metastatic urothelial cell carcinoma, or a contraindication to BCG were excluded from the study.

The treatment regimen consisted of gemcitabine 2000 mg twice weekly and BCG TICE strain 50 mg weekly. Patients who did not have high-grade recurrence were continued on SWOG maintenance BCG.

Median patient age was 70 years (interquartile range, 66-76). Most of the patients were male (70%) and White (95%). At trial entry, histology was as follows:

• CIS only: 21 (49%) patients

• Ta plus carcinoma in situ (CIS): 10 (23%) patients

• T1 plus CIS: 1 (2.3%) patient

• Ta only: 8 (19%) patients

• T1 only: 3 (7.0%) patients

In terms of prior treatments, median total number of prior BCG instillations was 6 (range, 5-24), 5 (12%) had received prior maintenance BCG, and 5 (12%) had received at least 2 induction courses. In addition, median time since last BCG was 6 months (interquartile range, 4-15). In terms of other intravesical regimens, 2 (4.7%) patients received induction gemcitabine, 2 (4.7%) patients received gemcitabine plus docetaxel, and 1 (2.3%) patient received BCG plus interferon.

CR rate was 98% (39/40) at 3 months, 94% at 6 months (34/36), and 81% at 12 months (21/26). In the CIS +/- papillary disease cohort, the CR rate was 100% at 3 months (31/31), 97% at 6 months (28/29), and 80% at 12 months (16/20).

High-grade recurrence-free survival was 97% at 6 months, 85% at 12 months, and 76% at 18 months. In addition, 12-month cystectomy-free survival was 100% (26/26).

Treatment-related adverse events (TRAEs), 2 (5%) patients experienced a grade 3 TRAE. One was urinary tract infection, and the other was BCG-related pneumonitis. No grade 4-5 toxicity was observed.

Wald said that based on the findings of the study presented at SUO 2024, a phase 3 randomized trial, GAIN, will be opening in May 2025.

“Our study does demonstrate excellent early oncological efficacy, but it does represent a relatively small cohort of 43 patients,” Wald told Urology Times. “The data are yet to mature, so we don't think the early results of [this] phase 2 [trial] should be practice changing right now. I think we have to wait until our data fully mature and we see the results from a phase 3 trial.”

REFERENCES

1. Wald G, Gaffney C, Alam SM, et al. Initial results of a multicenter phase II trial of intravesical gemcitabine and BCG FOR patients with BCG-exposed non-muscle invasive bladder cancer (NCT04179162). Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Late-breaking abstract

2. Addeo R, Caraglia R, 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):543-548. doi:10.1200/JCO.2008.20.8199

3. Li R, Li Y, Song J, et al. Intravesical gemcitabine versus mitomycin for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized controlled trial. BMC Urol. 2020;20(1):97. doi:10.1186/s12894-020-00610-9

4. Di Lorenzo G, Perdonà 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. doi:10.1002/cncr.24914