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Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial

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A Publisher Correction to this article was published on 02 July 2024

An Author Correction to this article was published on 18 June 2024

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Abstract

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette–Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder map** biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7–73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4–95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9–68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlap** or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461.

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Fig. 1: CONSORT patient flow diagram.
Fig. 2: High-grade recurrence-free survival in CORE-001.
Fig. 3: Cystectomy-free survival, PFS and OS in CORE-001.

Data availability

Clinical data from this study used to support this publication will be made available upon request from a qualified medical or scientific professional for the specific purpose laid out in that request and may include de-identified individual participant data. Requests for secondary use of this data will require a data use agreement created with CG Oncology and submitting a data access request to K.A.K. at pat.keegan@cgoncology.com. Response to external data requests will be provided within an estimated 4–6-week time frame as much as possible. Source data are provided with this paper.

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Acknowledgements

This study was funded by CG Oncology in collaboration with Merck. The funders contributed to the study design, data analysis and data interpretation in collaboration with the authors; the primary investigator (R.L.) had full access to the data. The funder had no role in data collection. Investigators and site personnel collected data, which were housed on CG Oncology’s database. In addition, we thank N. Hnat, J.-H. Kim, C. Lai and V. Kasturi, who provided coordinating and operational support. E. and Y. Zhang PhD led the statistical analyses. Additional support for investigators include BCAN CDA (R.L.), 5R01 CA235032-02 (R.L.), W81XWH-22-1-0395 (CA210846) (R.L.) and RS24-IM-LOA (R.L.).

Author information

Authors and Affiliations

  1. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Roger Li

  2. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Roger Li

  3. Department of Urology, Mayo Clinic, Rochester, MN, USA

    Paras H. Shah

  4. Department of Medicine, UC San Diego, La Jolla, CA, USA

    Tyler F. Stewart

  5. Pusan National University, Yangsan Hospital, Yangsan, South Korea

    Jong Kil Nam

  6. Department of Urology, University of Pennsylvania, Philadelphia, PA, USA

    Trinity J. Bivalacqua

  7. BCG Oncology, Phoenix, AZ, USA

    Donald L. Lamm

  8. Department of Urology, UC Irvine, Irvine, CA, USA

    Edward M. Uchio

  9. Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

    Daniel M. Geynisman

  10. Department of Urology, SUNY Medical Center, Upstate, Syracuse, NY, USA

    Joseph M. Jacob

  11. Department of Urology, Northwestern University Medical Center, Chicago, IL, USA

    Joshua J. Meeks

  12. Chesapeake Urology, Hanover, MD, USA

    Rian Dickstein

  13. Spokane Urology, Spokane, WA, USA

    Shane M. Pearce

  14. Korea University, Anam Hospital, Seoul, South Korea

    Seok Ho Kang

  15. Chonnam National University, Hwasun Hospital, Bundang, South Korea

    Seung Il Jung

  16. Department of Urology, UT MD Anderson Cancer Center, Houston, TX, USA

    Ashish M. Kamat

  17. Billings Clinic, Billings, MT, USA

    James M. Burke

  18. CG Oncology, Irvine, CA, USA

    Kirk A. Keegan

  19. Department of Urology, Vanderbilt University, Nashville, TN, USA

    Kirk A. Keegan

  20. Department of Urology, Rush University Medical Center, Chicago, IL, USA

    Gary D. Steinberg

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  1. Roger Li
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Contributions

R.L.: conceptualization, formal analysis, supervision, investigation, original writing, writing review and editing. P.H.S.: investigation, writing review and editing. T.F.S.: investigation, writing review and editing. J.K.N.: investigation, writing review and editing. T.J.B.: investigation, writing review and editing. D.L.L.: investigation, writing review and editing. E.M.U.: investigation, writing review and editing. D.M.G.: investigation, writing review and editing. J.M.J.: investigation, writing review and editing. J.J.M.: investigation, writing review and editing. R.D.: investigation, writing review and editing. S.M.P.: investigation, writing review and editing. S.H.K.: investigation, writing review and editing. S.I.J.: investigation, writing review and editing. A.M.K.: conceptualization, writing review and editing. J.M.B.: conceptualization, formal analysis, supervision, investigation, writing review and editing. K.A.K.: original writing, writing review and editing. G.D.S.: conceptualization, supervision, original writing, writing review and editing.

Corresponding author

Correspondence to Roger Li.

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Competing interests

R.L.: research support: Predicine; Veracyte; CG Oncology; Valar labs; scientific advisor/consultant: BMS, Merck, CG Oncology, Iconovir; speaker bureau: Predicine; travel: Predicine, CG Oncology. T.S.: research support: GRAIL; scientific advisor/consultant: Astellas, AstraZeneca, Pfizer, Seagen. E.M.U.: clinical trials: CG Oncology, Pfizer, Janssen, Merck, enGene; consultant: Pfizer, Janssen, Merck. D.M.G.: research support to institution: Genentech, Merck, Arvinas, Astellas, Harpoon Therapeutics; scientific advisor/consultant: Pfizer, Exelixis, AstraZeneca, Seattle Genetics/Astellas, Merck, BMS. J.M.J.: consulting: Pfizer, Janssen. J.J.M.: consultant: Merck, AstraZeneca, Incyte, Janssen, BMS, UroGen, Prokarium, Imvax, Pfizer, Seagen/Astellas, Ferring; research funding: VHA, NIH, DoD; compensation for talks/educational courses: AUA, OncLive, Olympus, UroToday; Clinical Trials: SWOG, Genentech, Merck, AstraZeneca; two patents: T1 and TCGA classifier. R.D.: consulting: CG Oncology, CIVCO, Ferring, ImmunityBio, Johnson & Johnson, Olympus; speaker: BMS, Uorgen. A.M.K.: grants: FKD Therapies (Ferring), PCORI, Photocure, Seagen, EnGene, Arquer Diagnostics, SWOG; consulting: Astellas Pharma, Biological Dynamics, BMS, CG Oncology, Cystotech, Eisai, EnGene, Ferring, Imagin Medical, Imvax, Incyte, Janssen, Medac, Merck, Nonagen Bioscience, Pfizer, Protara Therapeutics, Roche, Seagen, Sessen Bio, Theralase, Urogen Pharma, US Biotest, Vivet Therapeutics; patent: CyPRIT. J.M.B.: CG Oncology consultant, former CMO, stock/options; Kalivir CMO, stock options; Affyimmune consultant. K.A.K.: employee of CG Oncology, stock/options. G.D.S.: clinical trial committee: Merck, BMS, Janssen, CG Oncology, Pfizer, Fidia, Seagen, Protara, EnGene Bio; consulting: CG Oncology, PhotoCure, Merck, Taris Biomedical (Now Janssen), Fidia Farmaceuticals, Urogen, Ferring, BMS, AstraZeneca, Pfizer, Janssen, Epivax Therapeutics, EnGene Bio, Astellas, SeaGen, Verity Pharmaceuticals, Protara, xCures, Nonagen, Nanology, Imvax, Asieris, UroViu, Aura Biosciences, Nucleix, Vesica Health; stock/options: Epivax Therapeutics, CG Oncology, EnGene Bio, Vesica. All other authors declare no competing interests.

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Nature Medicine thanks Sangeeta Goswami and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Table 1 Investigator-determined treatment related adverse event attributed to cretostimogene
Full size table
Extended Data Table 2 Investigator-determined treatment related adverse events attributed to pembrolizumab
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Supplementary information

Supplementary information

Supplementary Tables 1 and 2 and clinical study protocol.

Reporting Summary

Source data

Source Data Extended Data Fig./Table 1

Source data for clinical trial endpoints.

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Li, R., Shah, P.H., Stewart, T.F. et al. Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03025-3

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