CREST: phase III study of sasanlimab and Bacillus Calmette-Guérin for patients with Bacillus Calmette-Guérin-naïve high-risk non-muscle-invasive bladder cancer

Abstract

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants.

Plain language summary

Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. Most people have surgery to remove the cancer cells while leaving the rest of the bladder intact. This is called transurethral resection of a bladder tumor (TURBT). For people with high-risk NMIBC, a medicine called Bacillus Calmette-Guérin (BCG) is placed directly inside the bladder after TURBT. A ’high risk’ classification means that the cancer is more likely to spread or come back after treatment. Some people’s cancer does not respond to BCG or returns after BCG treatment. Researchers are currently looking at whether BCG combined with other immunotherapies may prevent cancer growth more than BCG on its own. Immunotherapy helps the immune system recognize and kill cancer cells. Sasanlimab is an immunotherapy medicine that is not yet approved to treat people with NMIBC. It is given as an injection under the skin. In this CREST study, researchers are looking at how safe and effective sasanlimab plus BCG is for people with high-risk NMIBC. Around 1000 people are taking part in CREST. They must have had TURBT 12 weeks or less before joining the study. Researchers want to know how long people live without certain events occurring, such as bladder cancer cells returning. A plain language summary of this article can be found as Supplementary Material.

Clinical Trial Registration: NCT04165317; 2019-003375-19 (EudraCT) (ClinicalTrials.gov)

Tweetable abstract

CREST is a phase III study evaluating the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG versus current standard-of-care BCG monotherapy for patients with high-risk non-muscle-invasive bladder cancer (NMIBC).

Keywords: :

• Bacillus Calmette-Guérin
• BCG
• bladder cancer
• immune checkpoint inhibitor
• immunotherapy
• NMIBC
• non-muscle-invasive bladder cancer
• PD-1
• PD-L1
• sasanlimab

Supplementary data

A plain language summary of publication and video accompanies this paper. To view or download this in your browser please click here: www.tandfonline.com/doi/suppl/10.2217/fon-2023-0271

Author contributions

GD Steinberg, ND Shore, J Palou Redorta, M Galsky, J Bedke, JJ Vermette, JC Tarazi, AE Randall, KJ Pierce, and TB Powles contributed to conceptualization. GD Steinberg, ND Shore, J Palou Redorta, M Galsky, J Bedke, JH Ku, M Kretkowski, H Hu, K Penkov, D Saltzstein, and TB Powles are contributing to the acquisition of data for the work. JJ Vermette, JC Tarazi, AE Randall, and KJ Pierce are contributing to analysis and interpretation of data for the work. All authors reviewed and revised the manuscript. All authors approved the final manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors thank the patients and their families/caregivers who are participating in this study. The authors also thank the investigators, research nurses, study coordinators, and operations staff who are contributing to this study.

Financial disclosure

CREST is sponsored by Pfizer. GD Steinberg reports advisory/consultancy roles for Heat Biologics, CG Oncology, PhotoCure, Merck, Roche/Genentech, Ciclomed, Taris Biomedical (now Janssen), MDxHealth, Fidia Farmaceutici, UroGen, Ferring, Aduro, Boston Scientific, Bristol Myers Squibb, AstraZeneca, Pfizer, Janssen, Epivax Therapeutics, Natera, FKD, EnGene Bio, Sesen Bio, BioCanCell (now Archiano), Nucleix, Ipsen, Combat Medical, Astellas, FerGene, Dendreon, AbbVie, Seagen, Verity Pharmaceuticals, Regeneron, STIMIT, Vyriad, Protara, xCures, Nonagen, Nanology, and Imvax; clinical trial protocol committee membership for Bristol Myers Squibb, CG Oncology, Fidia, Janssen, Merck, Pfizer, PhotoCure, Protara, and Seagen; stock/shares in CG Oncology, EnGene Bio, EpiVax Therapeutics, and UroGen. ND Shore reports consultancy and speaker’s bureau for Bayer, Janssen, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Myovant Sciences, Astellas Pharma, AbbVie, Merck, BMS, Sanofi, Boston Scientific, Clovis Oncology, Exact Imaging, FerGene, Foundation Medicine, CG Oncology, InVitae, MDxHealth, Myriad Genetics, Nymox, Propella Therapeutics, Genzyme, Sanofi, and Sesen Bio; grant or research support from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Boston Scientific, Clovis Oncology, Dendreon, Exact Imaging, Ferring, Foundation Medicine, InVitae, Janssen, MDxHealth, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pfizer, Sanofi, Sesen Bio, and Tolmar; and employment by GenesisCare. JP Redorta reports advisory/consultancy roles for Arquer Diagnostics, Biotech, BTA Pharmaceuticals, Combat, Genomic Expression, and Olympus; steering committee membership for AstraZeneca, Bristol Myers Squibb, Janssen, and Pfizer; and grant or research support from Arquer Diagnostics, Biotech, BTA Pharmaceuticals, Cepheid, TARIS Biomedical, and Nucleix. M Galsky reports research funding from AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech, Merck, and Novartis; advisory/consultancy roles for Alligator, AstraZeneca, Basilea, Bristol Myers Squibb, Curis, Dragonfly, EMD Serono, Fujifilm, Genentech, GlaxoSmithKline, Janssen, Merck, Numab, Pfizer, Rappta Therapeutics, Seagen, Silverback, and UroGen. J Bedke reports institutional research funding from AstraZeneca, Astellas, Bristol Myers Squibb, Eisai, Ipsen, Merck Sharp & Dohme, Novartis, Nektar, Pfizer, Roche, and Seattle Genetics; honoraria for speaker, consultancy, or advisory role from: AstraZeneca, Astellas, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, and Roche on a personal basis. JH Ku, M Kretkowski, and H Hu have nothing to disclose. K Penkov reports honoraria from AstraZeneca, Merck Sharp & Dohme, Nektar, Pfizer, Regeneron Pharmaceuticals, and Roche; consultancy or advisory role for Nektar. JJ Vermette, JC Tarazi, AE Randall, and KJ Pierce report employment by Pfizer and stock/shares in Pfizer. D Saltzstein reports consultancy for UroGen. TB Powles reports consultancy for Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

Medical writing support was provided by S Stones and H Javaid of Engage Scientific Solutions and was funded by Pfizer.

Ethical disclosure

The study is approved by institutional review boards and independent ethics committees at each center and is being conducted in accordance with local legal and regulatory requirements, as well as the general principles set forth in the Council for International Organizations of Medical Sciences International Ethical Guidelines, International Council for Harmonisation Good Clinical Practice Guidelines, and Declaration of Helsinki. All participants provide written informed consent.

Open access

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

Notes

^†A second TURBT is required if indicated according to the current locally applicable guidelines.

BCG: Bacillus Calmette-Guérin; CIS: Carcinoma in situ; T1: Stage of bladder cancer defined as a submucosal invasive tumor; Ta: Stage of bladder cancer defined as a noninvasive papillary carcinoma; TCC: Transitional cell carcinoma; TURBT: Transurethral resection of bladder tumor.

^†As assessed by the investigator.

^‡Severity graded according to NCI CTCAE version 5.0.

^§Measured by EORTC QLQ-C30, EORTC QLQ-NMIBC24, and PTAB.

^¶When in combination with BCG (induction and maintenance period) and BCG (induction only) in Arms A and B, respectively.

ADA: Anti-drug antibody; AE: Adverse event; BCG: Bacillus Calmette-Guérin; CIS: Carcinoma in situ; CR: Complete response; Ctrough: Trough plasma concentration; EORTC: European Organisation for Research and Treatment of Cancer; HRQoL: Health-related quality of life; NAb: Neutralizing antibody; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; PD-L1: Programmed cell death-ligand 1; PTAB: Patient treatment administration burden; QLQ-C30: Core quality-of-life questionnaire; QLQ-NMIBC24: Quality-of-life questionnaire for patients with non-muscle-invasive bladder cancer.