CG0070 Plus Nivolumab Under Investigation in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

The safety and efficacy of the combination of the oncolytic immunotherapy CG0070 and nivolumab (Opdivo) is under exploration as a potential therapeutic option in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy, as part of the phase 1b CORE-002 trial (NCT04610671).¹

CG0070 is designed to preferentially replicate through a transcriptionally regulated promoter that is upregulated in retinoblastoma (Rb) pathway–defective cells. Additionally, the agent expresses granulocyte macrophage colony-stimulating factor to attract antigen-presenting cells to the tumor microenvironment.

“Oncolytic immunotherapy [involves] tumor-selective infection and replication of the virus, followed by cell killing, inducing local inflammation and trafficking of immune cells to the infected tumor site,” lead study author Roger Li, MD, of Moffitt Cancer Center, and colleagues, wrote in a poster presentation delivered at the 2022 AACR Annual Meeting. “[It also involves] priming and amplification of systemic antitumor immunity, resulting in the induction of tumor antigen–specific T cells that can eliminate uninfected tumor cells, including distant metastases.”

It has been shown that with CG0070, the human E2F-1 promoter drives the expression of essential viral genes and limits replication to Rb pathway–defective tumor cells. The agent selectively kills these cells and spares normal cells. Notably, the Rb pathway is altered in more than 90% of patients with bladder cancer.²

CORE-002 is enrolling patients who are aged 18 years or older and who have histologically confirmed MIBC and who are ineligible for cisplatin-based chemotherapy because of any of the following: having a creatinine clearance of less than 60 mL/min with an ECOG performance status of 0 or 1, have grade 2 or higher impaired hearing by Common Terminology Criteria for Adverse Events (CTCAE) criteria, having heart failure NYHA that is class III or higher, having grade 2 or higher neuropathy by CTCAE criteria, having an ECOG performance status of 2 or higher, or refusing to undergo treatment with cisplatin chemotherapy.³

Patients were also required to have adequate organ function within 4 weeks of trial enrollment, and this was defined by having an absolute neutrophil count of at least 1000/mm³ (stable off growth factor within 4 weeks of first study drug administration), a platelet count of at least 100,000/mm³, hemoglobin levels of at least 8 g/dL, a serum creatinine clearance of at least 20 mL/min using the Cockcroft-Gault formula, alanine and aspartate aminotransferase of no more than 2.5 times the upper limit of normal (ULN), and total Bilirubin of no more than 1.5 times ULN in the absence of previously diagnosed Gilbert's disease.

Patients were excluded if they had autoimmune disease within 2 years of enrollment to the trial, or if they had concurrent invasive upper-tract carcinoma or another active cancer.

The safety lead-in phase will enroll 6 patients, who will be assessed for dose-limiting toxicities (DLTs). If DLTs occur in less than 33% of those patients, the trial will be expanded to 30 patients.

The trial is slated to enroll 30 participants, who will receive intravesical CG0070 at 1 x 10¹² virus particle/mL once weekly for 6 weeks, plus two 480-mg doses of nivolumab given at weeks 2 and 6, followed by cystectomy.

The primary end point of the trial is to examine the safety of CG0070 and nivolumab per CTCAE v5.0 criteria. Secondary objectives include the assessment of changes in the lymphocytic infiltration following combination therapy and the efficacy of the combination.

Exploratory end points include evaluating the predictive value of E2F expression, tumor mutational burden, immune infiltration, and peripheral blood specimens for treatment response.

The combination of CG0070 and pembrolizumab (Keytruda) is also under exploration in patients with Bacille Calmette-Guérin–unresponsive non–muscle invasive bladder cancer (NMIBC) as part of the phase 2 CORE1 trial (NCT04387461. Data presented during the 2022 AACR Annual Meeting showed that the combination induced an overall complete response (CR) rate of 88.9% (n = 16/18); CRs occurred at 12 months in 75% of patients (n = 6/8).⁴ No grade 3 to 5 toxicities were observed with the regimen in this population.

Previously, the agent was examined as a monotherapy in the phase 1 V0046 trial (NCT00109655) and the phase 2 BOND2 trial (NCT02365818). The phase 1 trial examined CG0070 in 35 patients with bladder cancer following BCG failure. Here, the agent produced a CR rate of 46%, with toxicities that were grade 1 or 2 in severity.⁵ The phase 2 trial evaluated the agent in 65 patients with high-grade NMIBC after BCG failure, and data showed that CG0070 elicited a CR rate of 65% in these patients, with responses maintained in 28% of patients at 12 months.⁶

References

1. Li R, Sexton W, Spiess P, et al. A phase 1b study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; Virtual. Abstract 20371.
2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315-22. doi:10.1038/nature12965
3. Study of CG0070 combined with nivolumab in cisplatin ineligible patients with MIBC. ClinicalTrials.gov. Updated February 3, 2022. Accessed May 3, 2022. https://clinicaltrials.gov/ct2/show/NCT04610671
4. Li R, Steinberg G, Shah P, et al. CORE1: phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG). Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; Virtual. Abstract CT036.
5. 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. J Urol. 2012;188(6):2391-2397. doi:10.1016/j.juro.2012.07.097
6. 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. Urol Oncol. 2018;36(10):440-447. doi:10.1016/j.urolonc.2017.07.005