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CHICAGO -- An oncolytic virus therapy combined with pembrolizumab (Keytruda) produced complete responses (CRs) in 85% of patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), a small phase II trial showed.

The results showed CRs in 29 of 34 patients with detectable carcinoma in situ (CIS) treated with cretostimogene grenadenorepvec (CG0070) and the PD-1 inhibitor. Two-thirds of the CRs were ongoing at 12 months. The combination was well tolerated, as adverse events (AEs) consisted primarily of grade 1/2 local genitourinary AEs. Four patients developed grade 3 AEs, and no grade 4/5 AEs occurred during the study.

Combined with previous studies of CG0070, the results support continued investigation in ongoing phase III trials of the oncolytic virus as monotherapy and in combination with pembrolizumab in BCG-unresponsive NMIBC, reported Roger Li, MD, of Moffitt Cancer Center in Tampa, Florida, at the American Urological Association (AUA) annual meeting.

"I would like to remind the audience that this [CR rate] is compared to a 40% complete response rate with pembrolizumab alone at 3 months and just under 20% at 12 months," said Li. "So this is very much in support of our hypothesis that there is mechanistic synergism. Moreover, we're seeing a toxicity profile that is very much in line with previously reported [CG0070] monotherapy trials, with most of the AEs being bladder-related symptoms due to the intravesical treatment."

The data got an enthusiastic reception from the AUA audience, who used terms such as "excellent," "fantastic," and "terrific" to describe the preliminary results. However, one British urologist expressed reservations about the urology community's willingness to venture into immunotherapy.

"I have tried to launch some immunotherapy trials for non-muscle-invasive bladder cancer in the U.K., and the anxiety among urologists is such that they think pembrolizumab is not for them, but for oncologists to deliver," said the unidentified speaker.

Acknowledging that immunotherapy is uncharted territory for many urologists, Li said collaboration between urologists and oncologists is essential, regardless of who administers the immunotherapy.

"Most of the centers that participated [in the trial] were tertiary referral centers with a very close collaboration between the urologists and the medical oncologists," said Li. "The close relationship was required not only to administer the drugs but also to monitor the patients. We had patients with immune-related pneumonitis, and that was the first time I had seen it. I got a lot of help from my medical oncology colleagues."

"The key is to recognize the [immune-related] symptoms early on, and that's very, very much outside of our toolbox, but I think it's a skill that can be acquired," he added.

Another questioner asked Li to speculate about the mechanistic underpinnings of the combination's activity. "Do you think it's chemo-resection of residual disease, or do you think you're actually treating the field change?"

Li said the understanding of CIS is incomplete. His center recently acquired blue light cystoscopy with enhanced video, which has led to a new appreciation of "how much residual disease is actually missed without blue light."

"All of our patients had CIS in their tumors, and I think there is tumor antigenic burden that can be unleashed through the use of the crudest imaging and, in turn, elicits an immunogenic response that can be picked up by the pembrolizumab afterwards," said Li.

CG0070 consists of a promoter and a granulocyte macrophage colony-stimulating factor (GM-CSF) transgene inserted into a wild-type adenovirus. The promoter induces selective viral replication in tumor cells but not normal cells, said Li. GM-CSF activates and induces maturation of antigen-presenting cells.

The infects tumor cells and increases viral load, neoantigen release, and tumor major histocompatibility expression, leading to tumor targeting of activated cytotoxic T lymphocytes. In a phase I trial of high-risk BCG-unresponsive NMIBC, led to a CR rate of 46% at 3 months. In a of high-risk, BCG-unresponsive NMIBC, CG0070 monotherapy led to a 65% CR rate at any time during follow-up.

Li reported initial findings from a evaluating CG0070 plus pembrolizumab in high-risk, BCG-unresponsive NMIBC with detectable CIS. Eligible patients had complete resection of Ta/T1 disease with residual CIS. They received concurrent CG0070 and pembrolizumab for two induction cycles, followed by maintenance therapy for 12 to 24 months.

The primary endpoint was CR at any time during follow-up. Data analysis included 35 patients, all but one of whom was evaluable for CR. The results showed an overall CR rate of 85% at any time, with CRs declining slightly over time:

• 6 months: 82%
• 9 months: 81%
• 12 months: 68%

The therapy was well tolerated. Four patients had a total of five grade 3 AEs: one case each of autoimmune hepatitis, reduced ejection fraction, decreased neutrophil count, increased alkaline phosphatase, and adrenal insufficiency. Investigators observed no evidence of additive or synergistic toxicity.

A phase III evaluation of single-agent CG0070 in BCG-unresponsive NMIBC has already begun, and a phase III trial of CG0070 plus pembrolizumab has been planned, said Li.

Correction: This article has been updated to state that residual disease is often missed without use of blue light.

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