Reduced BCG frequency, faster NMIBC recurrence

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 a post-hoc analysis of the recurrence risk in patients with high-grade NMIBC in the randomised phase 3 NIMBUS trial, which was run by the EAU Research Foundation [1]. Prof. Grimm explained that, given the BCG shortage and the 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 first recurrence. Key secondary outcomes were the number and grade of recurrent tumours, the rate of progression to muscle-invasive disease, and safety.

At data cut-off, 345 BCG-naïve patients with high-grade NMIBC were randomised. Participants could have primary or recurrent disease, solitary or multiple tumours, with or without concurrent carcinoma in situ (CIS), and with the absence of high-grade papillary disease following repeat transurethral resection of bladder tumour (TURBT). The standard-frequency arm (n=175) followed EAU Guidelines recommendation that intermediate- or high-risk NMIBC patients and those with CIS receive 15 adjuvant BCG instillations (induction doses through weeks 1-6, followed by maintenance doses weeks 1-3 during the post-operative months 3, 6, and 12). The reduced-frequency arm (n=170) had a total of 9 BCG instillations (induction doses at weeks 1, 2, and 6, followed by maintenance doses at weeks 1 and 3 in months 3, 6, and 12). Safety data was based on 165 patients in each arm. Baseline characteristics were well balanced between the arms.

In the entire NIMBUS cohort, 67 patients (19.4%) had recurrence and 7 (2.0%) had progression to muscle-invasive disease. Recurrences were more frequent in patients with reduced-frequency BCG instillations (27%) compared with the standard-frequency arm (12%). Yet, progression was numerically lower in patients treated with reduced frequency (0.6%) versus the standard-frequency arm (3.4%). The primary endpoint, time to recurrence, was significantly different between the arms: a lower recurrence-free survival was observed among patients who received the reduced frequency of BCG compared with those receiving the standard frequency (34% vs 15%; HR 0.403; 95% CI 0.241-0.676; see Figure). Time to recurrence in the patients who had been observed for at least 6 months since randomisation in the study provided similar results (33% vs 14%; HR 0.391; 95% CI 0.231-0.662).

Figure: Cumulative recurrence-free survival for all patients in the intention-to-treat cohort of NIMBUS [2]



Adapted from Grimm et al. 2020.

In conclusion, reducing the frequency of BCG instillations during induction and maintenance is inferior to the standard BCG schedule regarding time to first recurrence. Moreover, the fact that early recurrences occurred 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 building on 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. 
   
   1. Grimm MO, et al. EAU20 Virtual Congress, 17-26 July 2020, Game-Changing Session.
   2. Grimm MO, et al. Eur Urol 2020, May 20, in press.

 



Posted on 20 August 20205 August 2021