An oncolytic therapy delivered within the urinary bladder in combination with pembrolizumab has yielded the “best results seen in the field” in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer, according to data presented during the 2022 Society for Immunotherapy of Cancer (SITC) Annual Meeting.¹

Results of the phase II, single-arm CORE1 trial showed a nearly 90% complete response rate at the initial 3-month timepoint for patients who received the combination of the oncolytic vaccine CG0070 and the PD-1 inhibitor pembrolizumab, and 73% of those who responded maintained a response at the 12-month assessment. The combination was also generally well tolerated, study authors reported, with an adverse event profile consistent with that observed in prior studies of each agent alone.

“There is a critical unmet need for efficacious bladder-sparing therapies for patients with BCG-unresponsive bladder cancer,” said Roger Li, MD, lead study investigator and urologic oncologist at H. Lee Moffitt Cancer Center & Research, Tampa, Florida. “CG0070 has continued to show very promising results, more than doubling complete response rates previously seen with immune checkpoint inhibitors.”

“We’re very excited about the data emerging from the combination trials using CG0070 plus immune checkpoint blockade to take to the next step.”

— Roger Li, MD

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“With a unique dual mechanism of action that first engages an immune response and then amplifies that response with immune checkpoint blockade, this novel combination of CG0070 with pembrolizumab could potentially change the outlook for patients with BCG-unresponsive bladder cancer,” he added.

As Dr. Li explained, BCG-unresponsive disease occurs when tumors become resistant to intravesical BCG therapy. Although the standard of care for these patients is surgical removal of the bladder and reconstruction of the urinary tract, this procedure is “fraught with a high complication rate,” he explained. “Because this disease afflicts patients who tend to be older and frail, this procedure is unfit for many of the patients inflicted with this disease,” he continued.

Study Rationale

CG0070 is a targeted oncolytic adenovirus with a genetically engineered E2F promoter and granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene that replicates inside tumor cells with dysfunctional Rb pathways, causing selective cancer cell lysis and death.

“We hypothesized that upon viral infection and release of GM-CSF, the antigen presenting cells are drawn into the tumor microenvironment, uptake the tumor presenting antigens, and present them to the T lymphocytes that are in the microenvironment, causing an antitumor immunogenic response,” Dr. Li stated. “Over time, this response becomes exhausted, but with the implementation of immune checkpoint blockade, it’s reinvigorated to eradicate the tumor.”

To enhance viral access to the bladder cancer cells, the investigators also applied DDM (4,4-diaminodiphenylmethane), an agent that has been been shown to strip away “the GAG [glycosaminoglycan] layer” within the bladder to increase viral replication. In the clinic, patients underwent a serial bladder wash, starting with normal saline followed by DDM, before CG0070 was infused for a dwell time of 60 minutes.

For this phase II study, Dr. Li and colleagues combined induction CG0070 (six weekly infusions) with pembrolizumab, followed by maintenance CG0070 (three weekly infusions at months 3, 6, 9, 12, and 18). Pembrolizumab was also administered every 6 weeks through year 2. The primary endpoint for the study was complete response rate seen at 12 months.

Nearly 90% of Patients Responded

As of the interim analysis, based on a data cutoff on October 10, 2022, a total of 32 patients were evaluable for efficacy with a minimum of 3-month follow-up. As Dr. Li reported, 88% of patients (n = 28/32) on study achieved a complete response at the initial 3-month timepoint, and 73% (n = 11/15) of patients evaluable for complete responses at additional timepoints were able to maintain that response at the 12-month assessment.

“These results are the best we have seen in the field to date,” said Dr. Li. “In comparison, using pembrolizumab monotherapy, the complete response rate at 3 months was 41%, with a durable response rate of 20% at 1 year.”

The combination therapy was also reported to be well tolerated, with no unanticipated adverse events. The most common treatment-related adverse events reported include transient grade 1 or 2 local genitourinary symptoms.

“Most of the toxicities were bladder-related symptoms that are associated with intravascular treatment,” said Dr. Li. He also noted that the few immune-related toxicities were “mostly transient.”

Ongoing Trials

Studies of CG0070 monotherapy (phase III BOND3, ongoing registration trial) are ongoing in BCG-unresponsive non–muscle-invasive bladder cancer as well as other types of bladder cancer.

“Pembrolizumab has been the only approved agent for this patient population in the past 20 years, so treatment options are still needed,” Dr. Li concluded. “We’re very excited about the data emerging from the combination trials using CG0070 plus immune checkpoint blockade to take to the next step.” 

DISCLOSURE: Dr. Li has reported no conflicts of interest.

REFERENCE

1. Li R. Steinberg GD, Lamm D, et al: CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non muscle invasive bladder cancer unresponsive to bacillus Calmette-Guérin. 2022 SITC Annual Meeting. Abstract 666. Presented November 10, 2022.