An oncolytic virus therapy of cretostimogene grenadenorepvec (CG0070) combined with pembrolizumab (Keytruda) produced complete responses in 85% of patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), according to a small phase II trial presented at the American Urological Association annual meeting.
In this exclusive MedPage Today video, Roger Li, MD, of Moffitt Cancer Center in Tampa, Florida, describes the efficacy and safety data from the CORE1 study.
Following is a transcript of his remarks:
Cretostimogene grenadenorepvec, or CG0070, is a cancer selective oncolytic virus that is genetically engineered with a human E2F promoter so that it only attacks cancer cells that are defective in the Rb pathway and also has a GM-CSF [granulocyte-macrophage colony-stimulating factor] transgene. So it expresses GM-CSF to attract antigen-presenting cells to the tumor microenvironment to enhance the anti-tumor attack.
And so this oncolytic virus has been previously used in phase I as well as phase II studies in patients who were refractory to BCG with high-risk NMIBC or non-muscle invasive bladder cancer. And the efficacy rates from a phase II study were found to be about 65% overall with durable response at 12 months, found to be just under 30%.
So we hypothesized that the mechanism of action of the oncolytic virus perhaps has synergism with immune checkpoint blockade through the attraction of the antitumor lymphocytes into the microenvironment by the oncolytic virus that can be reinvigorated with the implementation of the immune checkpoint blockade, and we can deliver a one-two punch to the tumor, thus eradicating it.
And so with that hypothesis, we launched the phase II single-arm open-labeled study combining cretostimogene with pembrolizumab in patients with BCG-unresponsive CIS [carcinoma in situ] containing NMIBC in the CORE1 study.
So bladder cancer typically occurs in an elderly and frail population, and typically the standard of care for BCG-unresponsive CIS is by radical cystectomy to remove the bladder along with pelvic lymph nodes and reconstructing the urinary tract. So, as you can imagine, this is a very morbid procedure that is fraught with a high complication rate, high hospital readmission rate, in this elderly population. And so for many years there has been a critical unmet clinical need to develop efficacious bladder-sparing therapies for this population.
And so with the combination of CG0070 or cretostimogene and pembrolizumab, we're really trying to increase the efficacy level of the combination to one that's much higher than using any of the approved agents in this disease space so far, so as to help patients preserve their bladders and also safely going forward without having to undergo surgery or remove their bladders.
In the CORE1 trial, we accrued a total of 35 patients of whom 34 were evaluable. And this cohort represented a very typical BCG-unresponsive cohort of patients, the vast majority of whom were greater than 65 years old. And it was very well balanced in terms of BCG-unresponsive refractory disease versus relapsing disease. And of course, all patients have carcinoma in situ components within their initial diagnosis.
And in terms of efficacy, we saw overall an 85% complete response at 3 months with a combination, and with a durable response of just under 70%, 68% in 25 patients at 12 months. So in comparison to pembrolizumab monotherapy, which demonstrated in the Keynote-57 trial to have an overall complete response of 40% and a durable response of just under 20% at 12 months, these demonstrated much higher efficacy rates, suggesting a mechanistic synergism between cretostimogene and pembrolizumab.
In terms of the toxicity, we didn't really see any synergistic toxicity at all. The toxicity profile that we saw from the combination trial reflected very much those toxicities that were seen on the monotherapy trials using either cretostimogene or pembrolizumab alone. Although there were a few immune-related severe adverse events that were seen on our trial, which prompted four patients to terminate using pembrolizumab, these patients continued on to receive intravesical cretostimogene, and the immune-related side effects were self-limiting after the pembrolizumab was taken off.
And so we think that overall the combination is fairly well tolerated and has a very high efficacy rate. And we are hoping to launch a phase III trial, a randomized controlled trial, comparing the combination versus pembrolizumab alone, monotherapy, to demonstrate that with the combination we can achieve a much higher complete response rate in this disease space.