Intravesical Recombinant BCG Plus Chemoimmunotherapy Yields High pCR in MIBC

Adding intravesical recombinant BCG (rBCG; VPM1002BC) to perioperative chemo-immunotherapy achieved a pathological complete response (pCR) rate of 68%, which was more than double the 32% rate observed in a propensity score–weighted comparison with a prior chemoimmunotherapy regimen and far exceeding the prespecified efficacy threshold in patients with muscle-invasive bladder cancer (MIBC), according to the primary analysis of SAKK 06/19, presented at the 2026 ASCO Annual Meeting.¹

The pathological response (PaR) rate was 83%, the 12-month event-free survival (EFS) rate was 90%, and the 12-month overall survival (OS) rate was 96%, establishing a compelling early efficacy signal for this novel perioperative strategy.

“Intravesical rBCG in combination with cisplatin/gemcitabine/atezolizumab achieves promising efficacy with high pCR and PaR. The combination of rBCG plus chemoimmunotherapy is feasible and tolerable,” said lead author Richard Cathomas, MD, Division of Oncology, Cantonal Hospital Graubunden, Chur, Switzerland.

Background and Rationale

Despite the integration of immunotherapy into perioperative MIBC treatment improving EFS and OS compared with chemotherapy alone, pCR rates remain below 40% with current regimens. Intravesical BCG, long used for NMIBC, induces local inflammation activating innate and adaptive immune responses. A novel rBCG (VPM1002BC) was engineered with enhanced immunogenicity—through listeriolysin-mediated antigen and dsDNA egresss—and improved safety via more rapid autophagy-mediated elimination. Prior evaluation in BCG-exposed NMIBC (SAKK 06/14) demonstrated safety and promising efficacy. The investigators hypothesized that intravesical rBCG induction would improve the efficacy of systemic perioperative chemo-immunotherapy in operable MIBC.

Study Design

SAKK 06/19 is a prospective, single-arm, open-label, multicenter phase 2 trial. Eligible patients had clinical stage cT2-T4a cN0/N1 urothelial carcinoma (UC; subtypes allowed except pure squamous or glandular histology), WHO performance status 0-1, and were cisplatin-fit (GFR >50 mL/min). Patients with prior intravesical BCG or a small cell component were excluded. The neoadjuvant regimen consisted of 3 intravesical rBCG instillations (days 1, 8, and 15), atezolizumab starting day 1 every 3 weeks for 4 cycles, and cisplatin/gemcitabine starting day 22 every 3 weeks for 4 cycles, followed by radical cystectomy with lymph node dissection 4 to 8 weeks after completion of chemotherapy. Adjuvant atezolizumab every 3 weeks for 13 cycles was administered only to patients with pathological stage of ypT2 or greater or ypN+; patients with ypT1 ypN0 or lower were transferred to follow-up. The primary endpoint was pCR (ypT0 ypN0) at cystectomy by central review. The trial used a Simon's minimax two-stage design with a null hypothesis of pCR ≤ 35% and alternative hypothesis of pCR ≥ 55%, requiring 39 resected patients, with a total sample size of 46 accounting for 15% dropout.

Patient Enrollment and Treatment Delivery

Between April 2022 and April 2025, 50 patients were screened and 47 were enrolled. Accrual was suspended between October 2022 and August 2023 due to an out-of-specification batch of rBCG requiring remanufacturing. Of 47 enrolled patients, all completed neoadjuvant therapy. Treatment delivery was high: 79% received all 3 planned rBCG doses, 92% received 4 doses of atezolizumab, 92% received 4 doses of platinum (81% all cisplatin, 19% switched to carboplatin), and 87% received 7 or more of 8 gemcitabine doses. Seven patients did not undergo cystectomy, 6 due to patient refusal (including 1 withdrawal) and 1 deemed unfit for surgery by physician decision. Of the remaining 40 patients who underwent cystectomy, 31 did not receive adjuvant atezolizumab (30 per protocol due to achieving ≤ ypT1ypN0, 1 by physician decision); 9 started adjuvant atezolizumab, of whom 7 have terminated and 2 remain ongoing.

The full analysis set had a median age of 67 years (range, 24-78), 81% were male, and 79% had WHO performance status 0. Clinical T stage at presentation was cT2 in 60%, cT3 in 32%, and cT4a in 8%. Most patients (89%) were cN0. Macroscopically incomplete TURBT resection was present in 64%, and 23% had UC with a histological subtype.

Primary End Point: Pathological Complete Response

Among the 40 patients in the cystectomy set, 27 achieved pCR (ypT0 ypN0), corresponding to a pCR rate of 68% (one-sided 95% CI, 53%-100%), rejecting the null hypothesis (p < .0001). The PaR rate (≤ ypT1 ypN0) was 83% (n = 33). Among non-pCR patients within the PaR category, pathological findings included ypTa in 3%, ypTis in 8%, and ypT1 in 5%. Non-PaR (≥ ypT2 and/or ypN+) occurred in 18% (n = 7), including ≥ ypT2 ypN0 in 5%, ≥ ypT2 ypN+ in 10%, and ypT0 ypN+ in 3%.

A Sankey plot analysis of 25 patients with pre-surgical restaging data demonstrated that clinical CR (cCR)—defined by CT thorax/abdomen/pelvis, MRI bladder, cystoscopy, and urine cytology—had a positive predictive value of 92% and a negative predictive value of 69% for pCR, suggesting that cCR is a strong predictor of pathological eradication in this setting.

Secondary End Points: EFS and OS

At a median follow-up of 16.7 months, the 12-month EFS rate was 90% (95% CI, 76%-96%) and the 12-month OS rate was 96% (95% CI, 84%-99%), reflecting encouraging early survival outcomes in this perioperative setting, though longer follow-up will be required to draw definitive conclusions.

Safety

Treatment-Related Adverse Events (TRAEs) were predominantly driven by chemotherapy. The most frequent any-grade TRAEs overall included decreased neutrophil count (55%), nausea (47%), fatigue (45%), renal impairment (44%), and decreased platelet count (33%). Grade 3/4 events were most commonly attributable to chemotherapy and included neutropenia, thrombocytopenia, urinary tract infections, anemia, thromboembolic events, and renal impairment.

Across treatment components, rBCG-related TRAEs were notably mild: grade 1 in 18%, grade 2 in 16%, grade 3 in 9%, and no grade 4 events (N = 45). No systemic BCG infection occurred. Atezolizumab-related TRAEs were grade 1 in 19%, grade 2 in 19%, grade 3 in 15%, and grade 4 in 2% (N = 47). Chemotherapy-related TRAEs were grade 1 in 15%, grade 2 in 26%, grade 3 in 38%, and grade 4 in 17% (N = 47), consistent with the known toxicity profile of cisplatin/gemcitabine-based regimens.

Comparison With SAKK 06/17

A pre-planned propensity score–weighted comparison was conducted between SAKK 06/19 and SAKK 06/17, the predecessor trial which evaluated cisplatin/gemcitabine/durvalumab without rBCG.² In the propensity score–weighted multivariate analysis, the odds ratio for pCR with SAKK 06/19 vs SAKK 06/17 was 5.13 (95% CI, 2.63-10.02; p < .001), with pCR rates of 67% in SAKK 06/19 vs 32% in SAKK 06/17. The non-PaR rate was also markedly lower in SAKK 06/19 (17% vs 42%), suggesting a meaningful shift toward deeper pathological responses with the addition of rBCG. The investigators acknowledged several important limitations of this comparison, including the non-randomized design, small sample sizes, short follow-up, potential selection bias due to the complex interdisciplinary regimen and 15% non-surgery rate, use of different checkpoint inhibitors (atezolizumab vs durvalumab) across the two trials, and the possibility of unmeasured confounders.

“Further investigation of intravesical rBCG in combination with next-generation systemic regimens in randomized trials is warranted,” Cathomas said in his concluding remarks.

REFERENCES

1. Cathomas R, Petrausch U, Hayoz S, et al. Intravesical recombinant BCG (rBCG) combined with chemo-immunotherapy as perioperative therapy for patients with muscle-invasive bladder cancer (MIBC): primary analysis of SAKK 06/19. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 4503.

2. Cathomas R, Hayoz S, Gächter P, et al. Perioperative chemoimmunotherapy with durvalumab for muscle-invasive urothelial carcinoma: primary endpoint analysis of the single-arm phase II trial SAKK 06/17. J Clin Oncol. 2024;42(10):1140-1148.