Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial

Background

  • Bladder cancer is the ninth most prevalent cancer worldwide, and ~75% of cases are non–muscle-invasive bladder cancer (NMIBC)1-3
  • High-risk NMIBC is treated with transurethral resection of the bladder tumor (TURBT) followed by intravesical induction and maintenance with Bacillus Calmette-Guérin (BCG-I+M), the current standard of care (SOC)2,3
  • Disease recurrence and/or progression are common and may result in patients requiring subsequent treatment, including radical cystectomy2,3
  • Treatments that allow bladder preservation remain limited; therefore, there is a need for enhanced treatment options that provide durable disease control by delaying disease recurrence and progression while maintaining quality of life3
  • Sasanlimab is a humanized, monoclonal antibody specific for human PD-1 that blocks the interaction between PD-1 and PD-L1/PD-L24
  • Exposure to BCG was associated with increased PD-L1 expression in preclinical models and in tumors from patients with high-risk NMIBC5-7
    • Enhanced PD-L1 expression might contribute to the immune escape mechanism in bladder cancer cells,8 thus justifying the combination of PD-(L)1 inhibition with BCG to improve therapeutic efficacy
  • CREST (NCT04165317) is a global, phase 3, randomized, open-label, 3-arm trial examining the efficacy and safety of sasanlimab administered subcutaneously in combination with BCG compared with BCG for BCG-naive high-risk NMIBC9
  • The primary objective is to demonstrate that sasanlimab in combination with BCG-I+M is superior to BCG-I+M in prolonging event-free survival in patients with high-risk NMIBC

The full publication is available at this link:

https://doi.org/10.1038/s41591-025-03738-z

Methods

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Study Design

Key Inclusion and Exclusion Criteria

Endpoints

Results

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Patient Disposition

Baseline Demographics and Disease Characteristics (All Arms)

Primary Endpoint: Event-Free Survival (Sasanlimab + BCG-I+M Versus BCG-I+M)

Key Secondary Endpoint: Event-Free Survival (Sasanlimab + BCG-I Versus BCG-I+M)

Key Secondary Endpoint: Overall Survival (Sasanlimab + BCG-I+M Versus BCG-I+M)

Key Secondary Endpoint: Overall Survival (Sasanlimab + BCG-I Versus BCG-I+M)

Additional Secondary Endpoints

Complete Response (Sasanlimab + BCG-I+M Versus BCG-I+M)

Plot of Mean Change From Baseline Over Time for EORTC QLQ-C30 Global Health Status by Visit (Sasanlimab + BCG-I+M Versus BCG-I+M)

Treatment-Related Adverse Events by Preferred Term and Maximum CTCAE Grade During the On-treatment Period (All Arms)

Summary of Adverse Events Classified as Immune-Related Adverse Events (All Arms)

Summary

  • The CREST trial showed a statistically significant and clinically meaningful benefit for sasanlimab in combination with BCG-I+M over the SOC (BCG-I+M) in prolonging EFS in patients with BCG-naive high-risk NMIBC
    • The risk of recurrence of high-grade disease, persistence of carcinoma in situ (for patients with CIS at randomization), disease progression, or death due to any cause in the sasanlimab + BCG-I+M arm was 32% lower than the BCG-I+M arm
    • The efficacy benefit was seen across all pre-specified subgroups, including the geographic regions and the diagnosis of CIS or T1 at randomization
  • Sasanlimab + BCG-I was investigated with the intent to reduce the burden of BCG treatment for patients
    • Sasanlimab combined with BCG-I did not result in prolongation of EFS versus BCG-I+M, underscoring the need for BCG maintenance not only as a component of SOC treatment but also in combination with sasanlimab
  • At data cutoff, overall survival follow-up was ongoing, with deaths occurring in 8.6% of patients, most of which were non-bladder cancer and not treatment related as assessed by investigator
    • Overall, the interim survival data suggest no difference between treatment arms
  • In patients with CIS at randomization, the complete response rate in the sasanlimab + BCG-I+M arm was approximately 5% higher than the BCG-I+M arm; additionally, improved durability of the observed complete responses with the combination was reflected by the higher proportion of patients sustaining a meaningful complete response over time compared with the BCG-I+M arm (92% vs 68% at 36 months)
  • Quality of life was maintained with the addition of sasanlimab to BCG-I+M
  • The observed safety profile was consistent with the known safety profile for each individual agent
    • The addition of sasanlimab did not compromise the ability to administer BCG-I+M
    • As expected, higher frequencies of patients with treatment-related adverse events and immune-related adverse events were observed in the sasanlimab + BCG-I+M arm versus BCG-I+M
  • Patient and caregiver education and healthcare provider monitoring of adverse events remain fundamental to optimal patient care
  • Sasanlimab in combination with BCG-I+M has the potential to redefine the current treatment paradigm for patients with BCG-naive high-risk NMIBC

References

  1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63. DOI: 10.3322/caac.21834.
  2. Holzbeierlein JM, Beler BR, Buckley DI, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline: 2024 Amendment. J Urol. 2024;211:533-8. DOI: 10.1097/JU.0000000000003846.
  3. Gontero P, Birtle A, Capoun O, et al. European Association of Urology Guidelines on non–muscle-invasive bladder cancer (TaT1 and carcinoma in situ)–a summary of the 2024 Guidelines Update. Eur Urol. 2024;86:531-49. DOI: 10.1016/j.eururo.2024.07.027.
  4. Youssef S, Abdiche Y, Nguyen H, et al. Abstract 2667: In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1. Cancer Res. 2017;77(13_suppl):2667. DOI: 10.1158/1538-7445.AM2017-2667.
  5. Hashizume A, Umemoto S, Yokose T, et al. Enhanced expression of PD-L1 in non–muscle-invasive bladder cancer after treatment with Bacillus Calmette-Guérin. Oncotarget. 2018;9:34066-78. DOI: 10.18632/oncotarget.26122.
  6. Maas M, Hilseortecker A, Pertoll A, et al. PD-L1 expression in high-risk non–muscle-invasive bladder cancer is influenced by intravesical Bacillus Calmette-Guérin (BCG) therapy. Cancers (Basel). 2024;16:1356. DOI: 10.3390/cancers16071356.
  7. Wang Y, Liu J, Yang X, et al. Bacillus Calmette-Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer. Onco Targets Ther. 2018;11:2891-9. DOI: 10.2147/ott.s165840.
  8. Cui JW, Li Y, Yang Y, et al. Tumor immunotherapy resistance: Revealing the mechanism of PD-1 / PD-L1-mediated tumor immune escape. Biomed Pharmacother. 2024; 171:116203. DOI: 10.1016/j.biopha.2024.116203.
  9. Steinberg G, Shore N, Redorta J, et al. CREST: phase III study of sasanlimab and Bacillus Calmette-Guérin for patients with Bacillus Calmette-Guérin–naive high-risk non–muscle-invasive bladder cancer. Future Oncology. 2024; 20:891-901. DOI: 10.2217/fon-2023-0271

©2025 Pfizer Inc. All rights reserved.

Study Design

aRe-induction permitted for patients with CIS at randomization who had persistent disease or recurrence of high-grade Ta disease at 3 months after initiating study treatment. BCG, Bacillus Calmette-Guérin; CIS, carcinoma in situ; CR, complete response; CTLA-4: cytotoxic T lymphocyte-associated antigen 4; EFS, event-free survival; HR, high-risk; I, induction; M, maintenance; NMIBC, non-muscle invasive bladder cancer; PD-1, Programmed cell death-1; PD-L1/PD-L2, Programmed cell death-ligand 1/2; QOL, quality of life.

Inclusion and Exclusion Criteria
  • Age ≥18 years
  • Histologically confirmed high-risk non-muscle-invasive transitional cell carcinoma of the bladder urothelium (T1 tumor, high-grade Ta tumor, and/or carcinoma in situ)
  • Complete resection of all Ta/T1 papillary disease, with the most recent TURBT ≤12 weeks prior to randomization
  • Evidence of muscle-invasive, locally advanced, or metastatic urothelial cancer or concurrent extravesical, non-muscle-invasive transitional cell carcinoma of the bladder urothelium
  • Intravesical BCG treatment ≤2 years prior to randomization; prior intravesical chemotherapy permitted
Endpoints
  • Investigator-assessed event-free survival for sasanlimab + BCG-I+M versus BCG-I+M. Event-free survival was defined as time from randomization to recurrence of high-grade disease, progression of disease, persistence of carcinoma in situ (for patients with carcinoma in situ at randomization), or death due to any cause, whichever occurred first.
  • Investigator-assessed event-free survival for sasanlimab + BCG-I versus BCG-I+M
  • Overall survival for sasanlimab + BCG-I+M versus BCG-I+M and sasanlimab + BCG-I versus BCG-I+M
  • Investigator-assessed complete response and duration of complete response for patients with carcinoma in situ at randomization and who achieved complete response
  • Health-related quality of life
  • Safety
Patient Disposition

aThe first patient was randomized January 20, 2020, and the last patient was randomized November 16, 2021.

bOne patient was a screen failure but randomized in error.

cTwo patients withdrew from study treatment in the sasanlimab + BCG-I arm due to recurrence of low grade disease.

dLack of efficacy refers to patients who experience an EFS event of recurrence of high-grade disease, persistence of CIS, or progression disease.

BCG, Bacillus Calmette-Guérin; BCG-I, Bacillus Calmette-Guérin induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; det., deterioration.

Baseline Demographics and Disease Characteristics (All Arms)

Characteristic

Sasanlimab + BCG-I+M (N=352)

Sasanlimab + BCG-I (N=352)

BCG-I+M (N=351)

Median age, y (range)
67 (31-85)
67 (34-90)
67 (31-91)
Male, n (%)
280 (79.5)
299 (84.9)
284 (80.9)
Race, n (%)
White
225 (63.9)
211 (59.9)
210 (59.8)
Asian
115 (32.7)
133 (37.8)
126 (35.9)
Black or African American
3 (0.9)
2 (0.6)
5 (1.4)
Unknown
9 (2.6)
6 (1.7)
10 (2.8)
Eastern Cooperative Oncology Group performance status, n (%)
0
298 (84.7)
293 (83.2)
291 (82.9)
1
54 (15.3)
57 (16.2)
59 (16.8)
2
0
2 (0.6)
1 (0.3)
Presence of CIS per CRF at randomization, n (%)
88 (25.0)
93 (26.4)
88 (25.1)
Geographic region, n (%)
US
49 (13.9)
47 (13.4)
47 (13.4)
Western Europe or Canada
85 (24.1)
87 (24.7)
86 (24.5)
Rest of world
218 (61.9)
218 (61.9)
218 (62.1)
Histological classification, n (%)
Urothelial carcinoma
339 (96.3)
346 (98.3)
332 (94.6)
Urothelial carcinoma with squamous differentiation
6 (1.7)
2 (0.6)
8 (2.3)
Urothelial carcinoma with glandular differentiation
2 (0.6)
4 (1.1)
3 (0.9)
Urothelial carcinoma with variant histology
4 (1.1)
0
6 (1.7)
Other
1 (0.3)
0
2 (0.6)
Worst T stage, n (%)
CIS
52 (14.8)
42 (11.9)
50 (14.2)
Ta
96 (27.3)
136 (38.6)
107 (30.5)
T1
204 (58.0)
174 (49.4)
194 (55.3)
Smoking history, n (%)
Never smoker
127 (36.1)
108 (30.7)
126 (35.9)
Current smoker
71 (20.2)
70 (19.9)
54 (15.4)
Former smoker
154 (43.8)
174 (49.4)
171 (48.7)
PD-L1 status, n (%)
Higha
77 (22.6)
68 (20.2)
73 (21.7)
Lowb
252 (74.1)
256 (76.0)
253 (75.1)
Unknown
11 (3.2)
13 (3.9)
11 (3.3)

aPD-L1 status was defined as High if TC ≥25% or (ICP >1% and IC+ ≥25%) or (ICP=1% and IC+=100%).

bPD-L1 status was defined as Low if TC <25% and (ICP >1% and IC+ <25%) or (ICP=1% and IC+ <100%) or ICP=0.

BCG-I, induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; CRF, case report form; IC+, PD-L1-positive immune cells; ICP, immune cells present in the tumor area; TC, tumor cell.

Primary Endpoint

Event-Free Survival (Sasanlimab + BCG-I+M Versus BCG-I+M)

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; EFS, event-free survival.

Event-Free Survival (Sasanlimab + BCG-I+M Versus BCG-I+M)

Sasanlimab + BCG-I+M(N=352)

BCG-I+M (N=351)

Patients with EFS event, n (%)
61 (17.3)
89 (25.4)
Progressive disease
18 (5.1)
22 (6.3)
Progression to metastatic disease (N+, M+), n
3
7
Progression to muscle-invasive disease (≥T2), n
7
7
Stage progression (Ta high-grade, T1), n
7
7
Unknown, n
1
1
Recurrence of high-grade disease
26 (7.4)
53 (15.1)
Persistence of CIS
1 (0.3)
1 (0.3)
Death
16 (4.5)
13 (3.7)
Probability of being event free, % (95% CI)
 
 
12 mo
87.0 (82.8-90.2)
85.3 (81.0-88.7)
24 mo
84.7 (80.2-88.2)
79.9 (75.2-83.9)
36 mo
82.1 (77.4-85.9)
74.8 (69.7-79.2)
EFS stratified hazard ratio (95% CI); 1-sided stratified log-rank test P-value
0.68 (0.49-0.94)
0.0095

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; EFS, event-free survival.

Event-Free Survival in Prespecified Subgroups for Sasanlimab + BCG-I+M Versus BCG-I+M

Data are presented as hazard ratio (center) with 95% confidence intervals (error bars). BCG, Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; CRF, case report form

Event-Free Survival for Patients With CIS: Sasanlimab + BCG-I+M Versus BCG-I+M

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; EFS, event-free survival.

Event-Free Survival for Patients With T1: Sasanlimab + BCG-I+M Versus BCG-I+M

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; EFS, event-free survival.

Key Secondary Endpoints

Event-Free Survival (Sasanlimab + BCG-I Versus BCG-I+M)

BCG-I, induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; EFS, event-free survival.

Event-Free Survival (Sasanlimab + BCG-I Versus BCG-I+M)

Sasanlimab + BCG-I(N=352)

BCG-I+M (N=351)

Patients with EFS event, n (%)
97 (27.6)
89 (25.4)
Progressive disease
14 (4.0)
22 (6.3)
Progression to metastatic disease (N+, M+), n
2
7
Progression to muscle-invasive disease (≥T2), n
3
7
Stage progression (Ta high-grade, T1), n
9
7
Unknown, n
0
1
Recurrence of high-grade disease
61 (17.3)
53 (15.1)
Persistence of CIS
2 (0.6)
1 (0.3)
Death
20 (5.7)
13 (3.7)
Probability of being event free, % (95% CI)
 
 
12 mo
81.2 (76.5-85.0)
85.3 (81.0-88.7)
24 mo
75.5 (70.4-79.9)
79.9 (75.2-83.9)
36 mo
71.5 (66.1-76.2)
74.8 (69.7-79.2)
EFS stratified hazard ratio (95% CI); 1-sided stratified log-rank test P-value
1.16 (0.87-1.55)
0.8439

BCG-I, induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CIS, carcinoma in situ; EFS, event-free survival.

Key Secondary Endpoints

Overall Survival (Sasanlimab + BCG-I+M Versus BCG-I+M)

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; OS, overall survival.

Key Secondary Endpoints

Overall Survival (Sasanlimab + BCG-I Versus BCG-I+M)

BCG-I, Bacillus Calmette-Guérin induction regimen of intravesical Bacillus Calmette-Guérin; OS, overall survival.

Additional Secondary Endpoints

Complete Response (Sasanlimab + BCG-I+M Versus BCG-I+M)

Sasanlimab + BCG-I+M(N=88)

BCG-I+M (N=88)

CR at any time for patients with CIS at randomization, n (%)
79 (89.8)
75 (85.2)
Difference in CR rate (95% CI);
1-sided Mantel-Haenszel (MH) test P-value
4.4 (-5.4-14.2)
0.1878
Duration of response: probability of remaining in CR for patients with CIS at randomization who achieved a CR, % (95% CI)
 
 
12 mo
97.3 (89.7-99.3)
90.3 (80.7-95.2)
24 mo
93.2 (84.3-97.1)
84.7 (74.1-91.2)
36 mo
91.7 (82.5-96.2)
67.7 (52.9-78.7)

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; CI, confidence interval; CIS, carcinoma in situ; CR, complete response; MH, Mantel-Haenszel.

Duration of Complete Response (Sasanlimab + BCG-I+M Versus BCG-I+M)

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; EFS, event-free survival.

Additional Secondary Endpoints

Plot of Mean Change From Baseline Over Time for EORTC QLQ-C30 Global Health Status by Visit (Sasanlimab + BCG-I+M Versus BCG-I+M)

BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin; C, cycle; D, day.

Additional Secondary Endpoints

Treatment-Related Adverse Events by Preferred Term and Maximum CTCAE Grade During the On-treatment Period (All Arms)

Sasanlimab +
BCG-I+M(N=350)
Sasanlimab +
BCG-I(N=348)
BCG-I+M(N=349)
Any grade
Grade ≥3
Any grade
Grade ≥3
Any grade
Grade ≥3
Patients with any event, n (%)
305 (87.1)
102 (29.1)
275 (79.0)
76 (21.8)
245 (70.2)
22 (6.3)
Dysuria
103 (29.4)
0
46 (13.2)
0
112 (32.1)
0
Pollakiuria
80 (22.9)
0
27 (7.8)
0
66 (18.9)
0
Hematuria
73 (20.9)
14 (4.0)
31 (8.9)
5 (1.4)
70 (20.1)
11 (3.2)
Urinary tract infection
67 (19.1)
7 (2.0)
28 (8.0)
2 (0.6)
70 (20.1)
2 (0.6)
Lipase increased
61 (17.4)
21 (6.0)
42 (12.1)
5 (1.4)
0
0
Pyrexia
54 (15.4)
1 (0.3)
35 (10.1)
0
41 (11.7)
0
Hypothyroidism
50 (14.3)
2 (0.6)
44 (12.6)
0
0
0
Amylase increased
41 (11.7)
8 (2.3)
33 (9.5)
3 (0.9)
0
0
Alanine aminotransferase
increased
38 (10.9)
8 (2.3)
24 (6.9)
2 (0.6)
6 (1.7)
1 (0.3)
Cystitis
38 (10.9)
1 (0.3)
10 (2.9)
0
30 (8.6)
0
Aspartate aminotransferase
increased
37 (10.6)
7 (2.0)
21 (6.0)
4 (1.1)
5 (1.4)
0
Micturition urgency
36 (10.3)
0
11 (3.2)
0
37 (10.6)
0
Fatigue
35 (10.0)
1 (0.3)
26 (7.5)
1 (0.3)
11 (3.2)
0
Pruritus
34 (9.7)
0
37 (10.6)
1 (0.3)
1 (0.3)
0
Asthenia
27 (7.7)
1 (0.3)
19 (5.5)
0
9 (2.6)
0
Hyperthyroidism
27 (7.7)
0
26 (7.5)
0
0
0

Included are treatment-related adverse events that occurred in at least 7.5% of the patients in any treatment group and grade ≥3 treatment-related adverse events that occurred in at least 2% of the patients in any treatment group.

BCG-I, induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin.

Additional Secondary Endpoints

Summary of Adverse Events Classified as Immune-Related Adverse Events (All Arms)

Sasanlimab +
BCG-I+M(N=350)
Sasanlimab +
BCG-I(N=348)
BCG-I+M(N=349)
Any grade
Grade 3/4
Any grade
Grade 3/4
Any grade
Grade 3/4
THYROID DISORDERS
62 (17.7)
2 (0.6)
71 (20.4)
1 (0.3)
5 (1.4)
0
RASH
46 (13.1)
10 (2.9)
48 (13.8)
8 (2.3)
0
0
HEPATITIS
15 (4.3)
12 (3.4)
14 (4.0)
11 (3.2)
0
0
PANCREATITIS
14 (4.0)
7 (2.0)
10 (2.9)
6 (1.7)
0
0
ADRENAL INSUFFICIENCY
12 (3.4)
6 (1.7)
12 (3.4)
5 (1.4)
0
0
PNEUMONITIS
61 (17.4)
21 (6.0)
42 (12.1)
5 (1.4)
0
0
COLITIS
9 (2.6)
5 (1.4)
9 (2.6)
3 (0.9)
0
0
HYPOPHYSITIS/
HYPOPITUITARISM
8 (2.3)
4 (1.1)
9 (2.6)
3 (0.9)
0
0
TYPE 1 DIABETES MELLITUS
7 (2.0)
6 (1.7)
4 (1.1)
4 (1.1)
0
0
NEPHRITIS AND RENAL DYSFUNCTION
6 (1.7)
4 (1.1)
9 (2.6)
7 (2.0)
0
0
MYASTHENIC SYNDROME/
MYASTHENIA GRAVIS
2 (0.6)
1 (0.3)
0
0
0
0
MYOCARDITIS
1 (0.3)
1 (0.3)
3 (0.9)a
1 (0.3)
0
0
MYOSITIS
1 (0.3)
1 (0.3)
2 (0.6)
1 (0.3)
0
0
UVEITIS
1 (0.3)
1 (0.3)
0
0
0
0
Other irAEs
8 (2.3)
1 (0.3)
16 (4.6)
4 (1.1)
0
0
Psoriasis
5 (1.4)
0
3 (0.9)
1 (0.3)
0
0
Vitiligo
2 (0.6)
0
3 (0.9)
0
0
0
Rheumatoid arthritis
1 (0.3)
1 (0.3)
1 (0.3)
0
0
0
Polymyalgia rheumatica
1 (0.3)
0
5 (1.4)
2 (0.6)
0
0
Dermatitis soriasiform
1 (0.3)
0
1 (0.3)
0
0
0
Sjogren's syndrome
1 (0.3)
0
1 (0.3)
0
0
0
Immune thrombocytopenia
0
0
1 (0.3)
1 (0.3)
0
0
Pulmonary sarcoidosis
0
0
1 (0.3)
0
0
0

Terms in capital letters include a group of Preferred Terms and may represent similar clinical symptoms or syndromes. an=1 event with fatal outcome.

BCG-I, Bacillus Calmette-Guérin induction regimen of intravesical Bacillus Calmette-Guérin; BCG-I+M, induction and maintenance regimen of intravesical Bacillus Calmette-Guérin.