Treatment of recurrent non-muscle invasive bladder cancer (NMIBC) after intravesical BCG remains challenging. Although the standard-of-care is radical cystectomy, many patients are unsuitable for surgery due to their advanced age and/or frailty, or simply refuse to undergo the procedure. The development of bladder sparing agents in this disease space has been hampered by the heterogeneity in the patient population, poor definition of disease states, a lack of appropriate control arms and consensus on trial end points.
Thanks to combined efforts from the US FDA and the academic urology community, consensus definition for BCG Unresponsive NMIBC have been formulated and adopted for trial design. To qualify for bladder sparing therapy trials, patients must have undergone adequate BCG and then recur with high grade papillary disease within 6 months or CIS within 12 months of their last BCG infusion. Adequate BCG, in turn, is defined as having at least 5/6 courses of induction + 2 installations as either maintenance or re-induction.
With such a consensus definition in place, the urologic and medical oncology communities joined hands and have completed accrual and follow up on two key clinical trials using IV pembrolizumab (an immune checkpoint blocker) and intravesical Ad-Stiladrin (gene therapy using IFNα). Twelve-month complete response rates (CRR) in the CIS-containing BCG Unresponsive population were 17% and 24.3%, respectively. Based on these results, the FDA recently approved pembrolizumab for the treatment of BCG Unresponsive disease, with deliberation on Ad-Stiladrin following closely on its heels.
Despite the early enthusiasm, the approval of pembrolizumab based on a 17% 12mo CRR has led to mixed responses, particularly in the face of its potential toxicity. While we await the comprehensive reporting of these results, one thing is certain – a vast majority of patients were not cured. These results are in line with not only results following ICB treatment in metastatic bladder cancer patients, but also when it’s used for other cancer sites. Much effort has been dedicated to elucidating the reasons behind non-response.
One plausible explanation pertains to the tumor microenvironment at the time of therapy administration. Several groups have shown ICB only works in tumor microenvironments featuring a pre-existing robust immune response. The exhausted T cells already present in the microenvironment are re-activated by ICB, and lead to tumor lysis. In contrast, tumor microenvironments that lack a robust immune response will not respond well to ICB treatment.
Following this line of reasoning, perhaps an agent can be used to induce local immunogenic response, which can then be potentiated with the subsequent addition of ICB. CG0070 is an oncolytic virus that induces direct tumor cell killing, leading to release of tumor specific antigens that in turn elicit a robust immune response. As monotherapy, intravesical CG0070 achieved a 12mo CRR of 30% in a cohort of BCG refractory patients.
“We are poised to launch a clinical trial at Moffitt to test the efficacy of combining CG0070 and pembrolizumab in the BCG Unresponsive setting. We are excited about the possibility. This trial offers to patients who are either unqualified or unwilling for cystectomy and the scientific insights to be gained for cancer immunotherapy” said Dr. Li.
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