Intravesical recombinant BCG combined with chemo-immunotherapy (chemo-IO) as perioperative therapy for patients with muscle-invasive bladder cancer (MIBC): Primary analysis of SAKK 06/19.

Abstract

4503 Background: Perioperative chemo-IO is a new standard for MIBC but pathological complete remission (pCR) rates remain modest. Intravesical Bacillus Calmette Guérin (BCG) is very effective in non-muscle invasive bladder cancer, inducing a local immune response and likely activation of adaptive immunity, with evidence of systemic immune modulation that may enhance downstream immune-oncological effects. The use of BCG in MIBC has not yet been explored, primarily due to concerns about systemic complications. The recombinant BCG vaccine VPM1002BC (rBCG) is associated with enhanced immunogenicity and an improved safety profile. We hypothesize that the combination of intravesical rBCG and chemo-IO in MIBC may act synergistically, augmenting systemic immune activation and hereby improve antitumor efficacy without compromising safety. Methods: SAKK 06/19 is an open-label single arm phase II trial for cT2-T4a N0-1 MIBC patients (pts) eligible for cisplatin and radical cystectomy with lymphadenectomy (RC). rBCG was instilled weekly x3 (day 1, 8, 15). Atezolizumab (Atezo) 1200 mg was administered on day 1 and then x4 every 3 weeks (q3w). Cisplatin and gemcitabine started on day 22 and were given for 4 cycles q3w followed by RC. Only in case of ≥ ypT2 or ypN+, Atezo q3w was given after surgery for 13 cycles. pCR defined as ypT0 ypN0 and assessed by central pathological review was the primary endpoint. Based on Simon’s minimax 2-stage design with H0 pCR ≤ 35% and H1 pCR ≥ 55%, accrual of 46 pts was needed (including 15% dropouts). Secondary endpoints included event free survival (EFS), overall survival (OS), pathological response (PaR, ≤ ypT1N0), feasibility and safety. NCT04630730. Results: 47 pts were included between 04/22 and 04/25 at 10 Swiss sites. 7 pts did not undergo RC (6 refused, 1 unfit for surgery). Of the 40 resected pts 53% had cT2, 37% cT3, 10% cT4 and 88% cN0, 12% cN1. rBCG was instilled in 95% of pts, 78% had all 3 doses. 98% received 4 doses of Atezo and 95% had 4 cycles of platinum (20% switched to carboplatin). pCR according to central review was 65% (26/40; one-sided 95% CI lower boundary of 51%) and PaR was 80% (32/40). Overall pCR for all included pts was 55% (26/47). TRAEs overall, G3, G4 were 48%, 9%, 0% to rBCG, 55%, 15%, 2% to Atezo and 98%, 38%, 17% to chemotherapy. No treatment-related deaths occurred. At a median follow-up of 11.8 months 1-year overall EFS was 88% (95% CI 71 - 95) and OS 95% (95% CI 81 - 99). Conclusions: This is the first trial to combine intravesical rBCG with chemo-IO in MIBC. The combination was feasible and safe without unexpected toxicities. The centrally assessed pCR rate of 65% and PaR of 80% are among the highest reported in an unselected MIBC population. Integration of intravesical rBCG into novel MIBC treatment regimens appears highly promising, particularly in the context of bladder-preservation approaches. Clinical trial information: NCT04630730 .