Pfizer's investigational anti-PD-1 monoclonal antibody, sasanlimab, in combination with Bacillus Calmette-Guérin (BCG), has demonstrated positive topline results in a pivotal Phase 3 CREST trial. The study evaluated the combination as induction therapy, with or without maintenance, for patients with BCG-naive, high-risk non-muscle invasive bladder cancer (NMIBC). The trial met its primary endpoint of event-free survival (EFS), showing a clinically meaningful and statistically significant improvement compared to BCG alone.
CREST Trial Details
The CREST trial is a Phase 3, multinational, randomized, open-label study involving three parallel arms. Patients with BCG-naive, high-risk NMIBC were randomized to receive:
- Sasanlimab 300 mg subcutaneously every four weeks for up to 25 cycles in combination with BCG induction and maintenance (Arm A)
- Sasanlimab 300 mg subcutaneously every four weeks for up to 25 cycles in combination with BCG induction only (Arm B)
- BCG induction and maintenance alone (Arm C)
The primary endpoint was EFS, defined as the time from randomization to the earliest recurrence of high-grade disease, progression of disease, persistence of carcinoma in situ (CIS), or death, as assessed by the investigator between Arm A and Arm C. Key secondary endpoints included EFS as assessed by the investigator between Arm B and Arm C.
Clinical Significance
Each year, approximately 100,000 people globally are diagnosed with high-risk NMIBC. Induction therapy with BCG followed by maintenance has been the standard of care for decades. However, 40-50% of patients experience recurrent disease, often requiring radical cystectomy, which is associated with significant risks, and bladder-sparing treatment options are limited.
According to Neal Shore, M.D., FACS, Medical Director for the Carolina Urologic Research Center, and lead investigator for the CREST trial, “Patients with BCG-naive high-risk non-muscle invasive bladder cancer have high rates of recurrence and progression. These study results demonstrate the potential for sasanlimab in combination with BCG to redefine the treatment paradigm…providing prolonged event-free survival which may delay or reduce the need for more aggressive treatment options. Administered subcutaneously every four weeks, sasanlimab, if approved, could also help lower the treatment burden on both patients and healthcare systems.”
Sasanlimab Mechanism of Action
Sasanlimab is a humanized immunoglobulin G4 monoclonal antibody (mAb) that binds to human programmed death-1 (PD-1), blocking its interaction with PD-1 and PD-L1/PD-L2. PD-1 is a protein expressed on T cells, dendritic cells, natural killer cells, macrophages, and B cells, functioning as an immune checkpoint that negatively regulates T-cell activation and effector function. Blocking this interaction may play a crucial role in tumor evasion from host immunity.
Safety and Future Plans
The overall safety profile of sasanlimab in combination with BCG was generally consistent with the known profile of BCG and data reported from clinical trials with sasanlimab. Pfizer plans to submit the results for presentation at an upcoming medical congress and discuss the data with global health authorities to support potential regulatory filings. Sasanlimab is also being investigated in combination with Pfizer’s antibody-drug conjugate (ADC) portfolio in advanced solid tumors.
Roger Dansey, M.D., Chief Oncology Officer at Pfizer, stated, “The initial therapy of high-risk, non-muscle invasive bladder cancer with BCG has not advanced in decades. Today’s pivotal Phase 3 CREST results are potentially practice-changing, representing the first advance in therapy for BCG-naive, high-risk, non-muscle invasive cancer in over 30 years.”
