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 mapping 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. Immune-related adverse effects were exclusively associated with pembrolizumab. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects, all related to pembrolizumab. There was no evidence of overlapping 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 .
Nature medicine. 2024 Jun 06 [Epub ahead of print]
Roger Li, Paras H Shah, Tyler F Stewart, Jong Kil Nam, Trinity J Bivalacqua, Donald L Lamm, Edward M Uchio, Daniel M Geynisman, Joseph M Jacob, Joshua J Meeks, Rian Dickstein, Shane M Pearce, Seok Ho Kang, Seung Il Jung, Ashish M Kamat, James M Burke, Kirk A Keegan, Gary D Steinberg
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. ., Department of Urology, Mayo Clinic, Rochester, MN, USA., Department of Medicine, UC San Diego, La Jolla, CA, USA., Pusan National University, Yangsan Hospital, Yangsan, South Korea., Department of Urology, University of Pennsylvania, Philadelphia, PA, USA., BCG Oncology, Phoenix, AZ, USA., Department of Urology, UC Irvine, Irvine, CA, USA., Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Urology, SUNY Medical Center, Upstate, Syracuse, NY, USA., Department of Urology, Northwestern University Medical Center, Chicago, IL, USA., Chesapeake Urology, Hanover, MD, USA., Spokane Urology, Spokane, WA, USA., Korea University, Anam Hospital, Seoul, South Korea., Chonnam National University, Hwasun Hospital, Bundang, South Korea., Department of Urology, UT MD Anderson Cancer Center, Houston, TX, USA., Billings Clinic, Billings, MT, USA., CG Oncology, Irvine, CA, USA., Department of Urology, Rush University Medical Center, Chicago, IL, USA.