Reduction in the frequency of Bacillus Calmette-Guérin (BCG) vaccine instillations during induction and maintenance treatment for non-muscle-invasive bladder cancer (NMIBC) results in earlier disease recurrence relative to a standard instillation schedule.
Prof. Marc-Oliver Grimm (University Hospital Jena, Germany) presented an analysis of the recurrence risk in patients with high-grade NMIBC in the randomized phase-3 NIMBUS trial . Prof. Grimm explained that, given the BCG shortage and the currently known BCG-associated toxicities, NIMBUS set out to investigate whether a reduced frequency of BCG instillations during induction and maintenance would result in non-inferior clinical efficacy, with potentially fewer adverse events, as well as reduced inconvenience and cost. The primary endpoint was time to the first recurrence. Key secondary outcomes were the number and grade of recurrent tumors, the rate of progression to muscle-invasive disease, and safety.
At data cut-off, 345 BCG-naïve high-grade NMIBC patients were randomized. Patients could have primary or recurrent disease, solitary or multiple tumors with or without concurrent carcinoma in situ (CIS), and with the absence of high-grade papillary disease following repeat transurethral resection of bladder tumor (TURBT). The “standard frequency arm” followed EAU Guidelines recommendation which states that intermediate or high-risk NMIBC patients, and those with CIS, receive 15 adjuvant BCG instillations (n=170; week 1-6 induction doses, followed by maintenance doses weeks 1-3 during the postoperative months 3, 6, and 12). Baseline characteristics were well balanced between the arms. The reduced-frequency arm had a total of 9 BCG instillations (n=175; induction doses at weeks 1, 2, and 6, then maintenance doses at weeks 1 and 3 in months 3, 6, 12). Safety data was based on 165 patients in each arm.
In the entire NIMBUS cohort, 67 patients (19.4%) had a recurrence and 7 (2%) had progression to muscle-invasive disease. Recurrences were more frequent in patients with reduced-frequency BCG instillations (27% vs 12%), yet progression was numerically lower in patients treated with reduced frequency (0.6% vs 3.4%). The primary endpoint, time to recurrence, was significantly different between the arms. There was lower recurrence-free survival among patients who received the reduced frequency of BCG (34% vs 15%; HR 0.403; 95% CI 0.241-0.676). Meanwhile, time to recurrence in the patients who had been observed for at least 6 months since randomization in the study, provided similar results (33% vs 14%; HR 0.391; 95% CI 0.231-0.662).
In conclusion, reducing the frequency of BCG instillations during induction and maintenance is inferior to the standard BCG schedule regarding time to the first recurrence. Moreover, the fact that early recurrences happened in the reduced-frequency arm, points to the value of every-week instillation in the induction phase. As anticipated, reduced frequency did result in fewer patients with adverse advents, with consequent lower symptom burden. Discussant Prof. Peter Black (University of British Columbia, Canada) pointed out that BCG is effective, and instead of replacing it in the future, the next steps should focus on expanding its efficacy, perhaps by immune priming (e.g. SWOG 1602 trial), using genetically modified BCG (e.g. VPM1002), or through rational-combination therapies (e.g. STING agonist).
1. Grimm MO, et al. Recurrent risk in patients with high grade non-muscle invasive bladder carcinoma in the randomized phase III clinical trial ‘NIMBUS’ stratified for EORTC and CUETO risk categories. A contemporary trend to less recurrences? EAU20 Virtual Congress, 17-26 July 2020, Game-Changing Session.