Sasanlimab Plus BCG Improves EFS in High-Risk NMIBC

Sasanlimab in NMIBC |
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Treatment with the anti–PD-1 monoclonal antibody sasanlimab in combination with BCG induction and maintenance therapy resulted in significant improvements in event-free survival (EFS) compared with BCG induction and maintenance therapy alone in patients with BCG-naive, high-risk, non–muscle-invasive bladder cancer (NMIBC), according to results from the phase 3 CREST study (NCT04165317) presented at the 2025 AUA Annual Meeting.

Findings showed that the addition of sasanlimab to BGC reduced the risk of experiencing an EFS event by 32% compared with BCG induction and maintenance therapy alone (stratified HR, 0.68; 95% CI, 0.49-0.94; 1-sided P = .0095). At 24 months, EFS rates were 84.7% with sasanlimab plus BCG induction and maintenance therapy (n = 352) vs 79.9% with BCG induction and maintenance therapy alone (n = 351); at 36 months, rates were 82.1% and 74.8%, respectively.

“This is the first [study] to show and report…a statistically significant prolongation of EFS with sasanlimab in combination with BCG. In patients with carcinoma in situ [CIS], the probability of continued complete response [CR] was greater for the combination at 36 months, and the safety profile was as expected,” lead study author Neal Shore, MD, FACS, explained in a presentation of the data. Shore is the medical director for the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

CREST Study Design

The randomized, open-label, multicenter trial enrolled 1055 patients with high-risk, NMIBC across multiple centers and evaluated the efficacy and safety of subcutaneously administered sasanlimab in combination with BCG compared with BCG monotherapy. Eligible patients included those who were BCG-naïve with stage T1, high-grade Ta, or CIS disease and had no prior exposure to immune checkpoint inhibitors or other immunomodulatory agents. Stratification at randomization was based on CIS status (yes vs no) and geographic region.

Patients were randomly assigned 1:1:1 to receive either sasanlimab plus BCG induction and maintenance (Arm A), sasanlimab plus BCG induction alone (Arm B), or BCG induction and maintenance alone (Arm C). BCG induction consisted of 6 doses, with maintenance administered for up to 2 years in applicable arms. Sasanlimab was administered subcutaneously every 4 weeks for up to 25 cycles.

The primary end point was EFS, defined as recurrence of high-grade disease, progression, persistence of CIS, or death from any cause, for Arm A vs Arm C. Key secondary end points included EFS for Arm B vs Arm C, and OS. Additional secondary end points included complete response (CR) rate among patients with CIS, duration of CR, safety, and quality of life (QOL) outcomes.

Baseline Patient Characteristics

The median age was 67 years in both the sasanlimab plus BCG arm (range, 31-85) and the BCG monotherapy arm (range, 31-91). Male patients accounted for 79.5% and 80.9% of the sasanlimab plus BCG and BCG monotherapy arms, respectively.

Regarding race, 63.9% of patients in the sasanlimab combination arm and 59.8% in the BCG monotherapy arm were White; 32.7% and 35.9%, respectively, were Asian. The majority of patients had an ECOG performance status of 0 (84.7% vs 82.9%), and the remainder had a performance status of 1.

Smoking history was similar between arms, with 36.1% and 35.9% of patients identified as never smokers, and 20.2% and 15.4% as current smokers in the sasanlimab and control arms, respectively.

Most patients had urothelial carcinoma histology (96.3% vs 94.6% for the experimental vs control arms, respectively). In terms of disease stage at diagnosis, 58.0% and 55.3% of patients had T1 disease, 27.3% and 30.5% had Ta disease, and 14.8% and 14.2% had pure CIS across both arms. High-grade tumors were predominant, reported in 90.6% of patients treated with sasanlimab and 90.0% of those receiving BCG monotherapy. A majority of patients had a single tumor at baseline (56.5% vs 51.9%), and the size of the largest tumor was less than 3 cm in 54.8% and 54.1% of patients in the respective arms.

Safety and QOL Analysis

The rate of recurrence of high-grade disease was 7.4% with sasanlimab plus BCG therapy with 15.1% for BCG alone. Progressive disease occurred in 5.1% vs 6.3% of patients, and deaths were reported in 4.5% vs 3.7%, respectively. Subgroup analyses showed that the EFS benefit with sasanlimab was consistent across key populations, including age groups, geographic regions, disease stage, and presence of CIS.

Notably, no significant EFS difference was observed between Arm B (sasanlimab plus BCG induction without maintenance) and Arm C (BCG induction and maintenance therapy; stratified HR, 1.16; 95% CI, 0.87-1.55; P = .8439).

Interim OS findings similarly suggested no meaningful difference between Arm A and Arm C (stratified HR, 1.13; 95% CI, 0.68-1.87; P = .6791) after a median follow-up of 40.9 months.

Among patients with CIS, the probability of continued CR at 36 months was 92% with sasanlimab plus BCG compared with 84.7% with BCG alone. The CR rate at any time was comparable between treatment groups (89.8% vs 85.2%; difference, 4.4%; 1-sided P = .1878).

The safety profile of sasanlimab in combination with BCG therapy was consistent with the known profiles of each individual agent.

The most frequently observed treatment-related adverse effects (TRAEs) with sasanlimab plus BCG included dysuria (29.4%), pollakiuria (22.9%), hematuria (16.9%), and urinary tract infection (17.1%). Any-grade laboratory abnormalities such as elevated lipase levels (11.4%), amylase levels (9.4%), alanine aminotransferase levels (8.6%), and aspartate aminotransferase (8.6%) were reported.

Serious TRAEs were observed in 17.7% of patients receiving sasanlimab plus BCG. Immune-mediated AEs occurred in 26.9% of patients; the most common included thyroid disorders (17.1%) and rash (10.3%). Grade 3/4 immune-mediated AEs occurred in 15.7% of patients; no immune-mediated AEs led to death.

“It's important to recognize the unique subcutaneous administration of this therapy is very important, and that we will need continued collaborative, multidisciplinary efforts to [ensure optimized] shared decision-making for patients who are at risk,” Shore explained.

Reference

Shore ND, Powles T, Bedke J, et al. Sasanlimab in combination with Bacillus Calmette-Guérin improves event-free survival versus Bacillus Calmette-Guérin as standard of care in high-risk non–muscle-invasive bladder cancer: Phase 3 CREST study results. Presented at: 2025 AUA Annual Meeting; April 26-29, 2025; Las Vegas, NV.