Clinical deep dive 

Bladder cancer is a common type of cancer that starts in the cells of the bladder, most often in the urothelial cells that line the inside of the bladder. The cells develop mutations in their deoxyribonucleic acid (DNA) that cause the cells to grow out of control. Types of bladder cancer include urothelial (most common), squamous cell, adenocarcinoma and small cell carcinoma. Bladder cancer can be described as non-muscle invasive (most common in 75% of cases) and muscle invasive. Bladder cancer is also classified based on appearance under microscope, low-grade (grows more slowly and less likely to invade the muscle wall) and high-grade (grows more aggressively and more likely to spread to the muscle wall). It can also be described based on stages of disease or the extent of cancer, such as tumor size or how far it has spread. Smoking is a major risk factor for developing bladder cancer. 

In 2022, it was estimated that there were 744,039 people living with bladder cancer in the US. About 84,870 new cases of bladder cancer are expected to be diagnosed in 2025. Bladder cancer is highest among older adults, with the average age of diagnosis around 73 years of age. Bladder cancer is more common in men. It is estimated that half of bladder cancer cases are carcinoma in situ (only in originating layer of cells) at diagnosis which have a 5-year relative survival of 97.9%. About 34% of bladder cancer cases are localized and confined to the primary site at diagnosis and have a 5-year relative survival of 72.6%.  

The National Comprehensive Cancer Network (NCCN) guidelines version 3.2025 for bladder cancer recommends intravesical therapy following TURBT for treatment for bladder cancer to reduce the risk of recurrence or delay disease from progressing to a higher grade or stage. Intravesical chemotherapy with gemcitabine (preferred) and mitomycin are both category 1 and are recommended for immediate use after TURBT, ideally within 6 hours of the procedure but a single instillation should be administered within 24 hours of the surgery.  

In BCG-naïve, high-risk NMIBC with very-high risk features, cystectomy is preferred or BCG (induction and maintenance), initiated 3 to 4 weeks post TURBT, both category 2A recommendations. For patients with no very-high risk features, BCG is preferred (category 1) or cystectomy (category 2A). Although BCG induction and maintenance is standard of care in BCG naïve, high-risk NMIBC, disease recurrence or disease progression occurs in about 40% of patients at 2 years and has unfavorable prognosis. The induction regimen consists of weekly instillations of BCG for 6 weeks followed by maintenance therapy. While there is no standard maintenance regimen, most follow the Southwest Oncology Group (SWOG) protocol which recommends 3 weekly doses of BCG at 3, 6, 12, 18, 24, 30 and 36 months. Treatment length varies based on patient response and is recommended for up to 3 years in BCG naïve, high-risk NMIBC. 

Drug and clinical trial overview 

Sasanlimab was studied in CREST, a global randomized (1:1:1), open-label, Phase 3 study (n=1,055) in BCG-naïve, high-risk NMIBC, with two cohorts. Cohort A has three arms, Arm A; sasanlimab plus BCG (induction and maintenance); Arm B: sasanlimab plus BCG (induction only); Arm C: BCG alone (induction and maintenance). Patients received sasanlimab 300 mg every 4 weeks for up to 25 cycles via SC administration in combination with intravesical BCG (induction and maintenance). The primary endpoint was Event-Free Survival (EFS) (defined as time from randomization to recurrence of high-grade disease, progression of disease, persistence of CIS (if present at randomization) or death due to any cause, for Arm A compared to Arm C, as assessed by the investigator. Results demonstrated that Arm A significantly improved EFS compared to Arm C, with a hazard ratio (HR) of 0.68 showing a 32% reduction in risk of disease related events, including high-grade disease recurrence or progression. Median EFS was not reached in either arm; however, 36-month EFS probability was 82.1% with Arm A compared to 74.8% with Arm C. The results demonstrated EFS benefit for Arm A compared with Arm C in prespecified subgroups, including CIS and T1 group. In higher risk disease, HR was 0.63 for T1 disease and 0.53 for CIS. Complete response achieved, at any time was 89.8% with Arm A compared to 85.2% with Arm C. In CIS responders, the probability of remaining in complete response at 36 months was 91.7% in Arm A compared with 67.7% with Arm C. 

Key secondary endpoints were EFS and overall survival (OS) in Arm B compared with Arm C which was not significantly different. The median OS had not been reached at the time of final analysis, there was no difference between arms, and the median follow-up was 40.9 months for OS. Cohort B (two arms): Arm B1, BCG unresponsive CIS or Arm B2, BCG unresponsive papillary only disease, was discontinued and not for safety reasons. 

No new safety signals were observed with sasanlimab in combination with BCG. Adverse events were manageable and found to be comparable with PD-1/PD-L1 inhibitors and BCG. Most adverse events were Grade 1 or 2, and treatment related adverse events Grade ≥3 in arm A occurred in 29.1% compared with 21.8% in Arm B and 6.3% in Arm C. While no treatment-related deaths occurred in Arms A or C, two occurred in Arm B (bacterial pneumonia and myocarditis, one each). The most common adverse events were dysuria, pollakiuria, hematuria, urinary tract infection, hypothyroidism and increases in lipase and amylase levels.