IBCN 2022: Clinical Application of CG0070 in Bladder Cancer: Lessons Learned

(UroToday.com) Another oncolytic virus that has been in clinical development for the treatment of bladder cancer is CG0070. Dr. Roger Li presented the preclinical data supporting its use and the history of its clinical development. CG0070 is a selective replicative oncolytic adenovirus that was genetically engineered with a E2F1 promoter region and a GM-CSF transgene. Through its E2F1 promoter, the virus selectively replicates only in Rb pathway deficient tumor cells. It is administered intravesically following the removal of the glycosainoglycan layer by a sugar compound called DDM.

In animal studies, the cytolytic properties of the virus was demonstrated using an orthotopic model of SW780 tumor cells treated with 3 weeks of intravesical CG0070 infusion.   ¹  In the clinic, a dose finding study demonstrated optimal dosing with weekly x 6 at a dose of 1 trillion vp per mL.   ²  Based on this dosing and scheduling regimen, a phase 2 study was carried out in patients with recurrent NMIBC following BCG treatment, and CR at 3mo was found to be 65%, with a 28% durable CR at 12mo.   ³  On the heels of the Phase 1 and 2 studies, there is an ongoing Phase 3 study using the oncolytic virus as a monotherapy in BCG unresponsive CIS containing patients.

Based on the hypothesis of mechanistic synergism with immune checkpoint blockade, another trial – CORE1 – was launched to study the efficacy of the combination in BCG unresponsive CIS. This trial accrued 35 patients, treated with the same dosing and scheduling of CG0070 as on BOND3. In addition, patients were treated concomitantly using pembrolizumab, which has been approved in this disease space. An interim analysis demonstrated CR in 22/24 (92%) of the patients at 3mo, and a durable 12mo CR rate of 75% (6/8 patients). Importantly, toxicity profile of the treatment combination were restricted mainly to bladder related symptoms grade 1-2 in nature. There were very few immune related AEs thus far. 

Along the same lines, the combination of CG0070 + nivolumab is also currently being tested in patients with muscle invasive bladder cancer who are ineligible for cisplatin chemotherapy. In the CORE-2 trial, CG0070 was given as a 6 weekly dose, along with nivolumab given at weeks 2 and 6, purposely staggered to wait until the immunogenic effect has been engendered by the virus. Of the first 13 evaluable patients treated on trial, 6 obtained pathologic CR, while another patient achieved clinical CR and refused radical cystectomy. On correlative analysis, E2F1 expression level at baseline appears to be a promising biomarker for treatment response. In addition, using a bioinformatics pipeline, neopeptides were predicted based on WES and transcriptomic analysis performed on the baseline tumor samples. Using these peptides, ELISPOT analyses were performed using peripheral blood samples collected at weeks 2 and 6, demonstrating a heightened response to the predicted tumor specific neoantigens along with progression of the treatment course. Tertiary lymphoid structures were also observed, primarily in the complete responders, and may represent a histologic biomarker for treatment response.

In closing, Dr. Li presented the trial concept for the first ever randomized control trial in the BCG Unresponsive space, using a 2:1 randomization for patients to be treated with CG0070 + pembrolizumab vs. pembrolizumab alone. The primary endpoint of the study will look at CR rate at any time, while secondary endpoints include CR at 12mo, PFS, cystectomy free survival, OS, and safety.

Presented by: Roger Li, MD, Assistant Member, Department of Genitourinary Oncology, Assistant Professor of Urologic Oncology, Moffit Cancer Center, Tampa FL

1. Ramesh N, Ge Y, Ennist DL, et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor--armed oncolytic adenovirus for the treatment of bladder cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(1):305-313.
2. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. The Journal of urology. 2012;188(6):2391-2397.
3. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urologic oncology. 2018;36(10):440-447.