CR Rate of 30% With Agent for High-Risk Bladder Cancer

Nick Mulcahy

May 25, 2018

SAN FRANCISCO — With dozens of clinical trials underway, there's a race to develop, test, and receive approval for the first drug since 1998 for the treatment of high-risk bladder cancer that is unresponsive to bacillus Calmette-Guérin (BCG).

One of the agents in this race, the experimental intravesical agent CG0070, under development by Cold Genesys, was featured in a plenary session here at the American Urological Association (AUA) 2018 Annual Meeting.

The agent yielded an overall 12-month complete response (CR) rate of 30% in a phase 2 single-arm trial in patients with BCG-unresponsive, high-grade Ta, T1, or CIS ± Ta/T1 non-muscle-invasive bladder cancer, reported Vignesh T. Packiam, MD, a urologist at the University of Chicago in Illinois.

CR was defined as the absence of evidence of disease on cystoscopy, cytology, and/or random biopsies.

A 30% CR at 1 year is a good rate, said Richard J. Lee MD, PhD, a medical oncologist at the Massachusetts General Hospital Cancer Center in Boston, who was approached for comment.

"I think a complete response rate of 30% at 6 months and definitely at 12 months would be considered interesting," said Lee in an email to Medscape Medical News.

He explained that the last drug to be approved by the FDA for these patients was valrubicin (Valstar, Endo Pharmaceuticals), in 1998. However, valrubicin is associated with only an 18% CR rate at 6 months. "The response is not very durable, so newer drugs are needed," said Lee.

Intravesical gemcitabine (Gemzar, Lilly) is also an option, he commented. But both Lee and trial investigator Packiam emphasized that new intravesical agents, which are administered directly into the bladder through a catheter, and systemic immunotherapies (anti-PD-1 or anti-PD-L1 antibodies) could represent important new therapies for this disease.

CG0070 is a selective oncolytic adenovirus that leads to selective expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in retinoblastoma pathway–defective cells that are found in many tumors. It stimulates the expression of GM-CSF and has a direct oncolytic effect after local treatment (ie, intravesical administration), and it may also induce systemic, tumor-specific immunity (Clin Cancer Res. 2006;12:305-313).

After Failure of BCG

Currently, BCG is the main intravesical immunotherapy for early-stage bladder cancer.

In the current trial, all patients (n = 67) had experienced disease progression while receiving BCG therapy: they were either unable to achieve a disease-free state at 6 months after adequate BCG therapy (BCG-refractory), or they experienced recurrence after CR with BCG therapy (BCG-relapsed).

All of the patients refused the next treatment option, cystectomy or surgical removal of the bladder, and opted instead to take part in the clinical trial.

Ultimately, 10 of the 61 patients who were included in interim analysis underwent cystectomy. Pathology assessment revealed that six patients had muscle-invasive disease, not the less threatening non-muscle-invasive cancer, as first indicated.

These findings clearly illustrate the need for more treatment options, interjected Lee.

"This non-muscle-invasive disease has a high risk of progression to muscle-invasive disease, and we know that bladder cancer is very commonly understaged. So we have a disease in which clinical staging is often inaccurate, progression rates are high, and available therapies for noncystectomy candidates have low durable complete response rates, all of which point to the need for more therapeutic options," he said.

Lee also noted that non-muscle-invasive disease is typically managed by urologists and that medical oncologists such as himself only become involved after disease progresses to muscle-invasive status.

In his presentation, Packiam highlighted that CG0070 also yielded a CR rate of 27% in patients with carcinoma in situ–containing tumors and in 48% in patients with refractory disease. These are interim results, as the trial is ongoing.

No patients with T1/CIS or Ta/CIS (n = 6) had 12-month CR. Among BCG-relapsed patients, 19% (n = 31) had a 12-month CR.

Treatment-related adverse events at 12 months included influenza-type illness (7%), fatigue (4%), and chills (1%). Five deaths occurred secondary to progressive urothelial carcinoma, esophageal carcinoma, lung carcinoma, and cardiac disease.

The study was funded by Cold Genesys, the maker of CG0070. Dr Packiam and Dr Lee have disclosed no relevant financial relationships.

American Urological Association (AUA) 2018 Annual Meeting. Abstract LBA24, presented May 21, 2018.

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