GU Cancers 2021 | INTACT: safety results of CRT with and without atezolizumab in MIBC

So, thank you so much for giving me an opportunity to talk about INTACT study. This is a Phase III trial of concurrent chemoradiation with or without atezolizumab for localized muscle invasive bladder cancer. We presented the safety update on first 73 patients. I am the overall study PI with my collaborators, Jason Efstathiou and Seth Lerner. This is a NCTN sponsored trial being designed and run through the collaboration of all cooperative groups here in the US, including NRG, SWOG, Alliance, ECOG, and it’s in part being funded by Genentech.

This is in fact, one of the key studies which may move the needle in the space of localized muscle invasive bladder cancer forward. As we know that bladder preservation is now becoming more and more important as more and more patients are asking for it and it’s a life changing event for patients losing their bladder and they have to get used to a new way of living. And now bladder preservation is category one recommendation by NCCN for patients who are declining, radical cystectomy, or are not surgical candidates. And so, there was always a need to improve upon the results of chemoradiation, and it became logical to combine immunotherapy with concurrent chemoradiation as the data of combination started, started emerging in other tumor types. And so, this trial was designed.

It’s a large Phase III registration trial looking at enrolling around 432 patients. These patients with stage T2 to T4. These are lymph node negative medicines, metastasis negative. So T2 T4 M0 M0 patients. These patients will be stratified based on the chemotherapy regimen after physician choice, radiation field after physician choice, performance status of the patient and clinical stage. These patients will be randomized in one-to-one fashion. It’s an unblinded study, so half the patients will receive trimodality therapy and the other half would receive trimodality therapy in combination with atezolizumab for nine infusions which will start at the start of the trimodality therapy and will continue up to the six months.

The endpoints on this study are very novel for a registration trial. The end point is not overall survival. After conversations among the investigators and FDA, it was decided that this trial, because it, the question is novel in the sense that we want to see if we can, if a patient can preserve their bladder. So, we have to have a component as part of the endpoint. If the patient is, patient’s bladder is intact because patients may lose their bladder for toxicity. And so, and event-free survival was designed as a primary outcome for this study. So the events which are part of the BI-EFS include muscle invasive bladder cancer recurrence, regional pelvic soft tissue nodal recurrences, distant metastases, patients getting a radical cystectomy for recurrent cancer or for toxicity, and any cause of death during or after the treatment.

And so this composite endpoint of the BI-EFS is now the primary endpoint and the secondary endpoint obviously include overall survival, clinical response, disease-specific survival, metastasis-free survival, non-muscle invasive bladder cancer recurrences, cystectomy rates, and global quality of life questionnaires.

There’s an extensive translational medicine component going in. In this study, we are going to look at different markers like MRE11, DNA damage repair mutations, immune markers, whole genome sequencing. We are also looking at TruCulture for assessing immune response in these patients.

So this trial, which started April 19th of 2019 is now up into one another, a year and a half, and we have now enrolled 130 patients, which is remarkable for US because the biggest previous trial took seven years to enroll over 100 patients in the US. So, it is remarkable and it shows the interest of the patients who go onto this trial.

This abstract which we presented in the ASCO GU was mandated by NCI because this trial was not preceded by a Phase I or Phase II study. And so we had to build in a safety check at first 80 patients. And so, once the first 80 patients were enrolled, we had data on 73 patients who had received their protocol-specific treatment at the time of submission of the abstract. So, this abstract include data on those 73 patients, of which 36 patients had received chemoradiation which is trimodality therapy alone, and 37 patients had received trimodality therapy with atezolizumab.

We were happy to report that there were no grade three or higher colitis reported on the atezolizumab. If you look back into the data from other contemporary trials in bladder preservation, if you look at BC2001, or we look at RTOG-0712, these trials have reported close to 10% patients having grade three or higher GI toxicity. A recent trial, which was just published from Canada, looking at combining immunotherapy and radiation, and in bladder cancer reported high GI toxicity.

But in our first 80 patients, we actually didn’t report any patient having grade three or higher colitis. So that’s very encouraging. We reported seven patients having grade three UTI on the atezolizumab arm versus no patients on the standard therapy getting UTI. One of the patients developed radiation cystitis, which was diagnosed after finishing immunotherapy and no steroids were given. So, the treating investigator labeled it as a non-immune related side effect, more likely a radiation-induced cystitis.

And if we look at the other trials in the previous trials in this space, the GU toxicity is close to 25, 30%. And so, we were not surprised by these events. However, we did see a lot more hemotoxicity. 23 patients experienced grade three hemotoxicity in the atezo arm versus 11 patients in the non atezo arm. Obviously, this update was not built in with statistics. So, we cannot analyze statistically how significant that difference is, but something we’ll be watching as we enroll more patients. None of the patients were given steroids so it was not immune-related, but clearly it could be explained by radiation of the pelvis in this all men who or women who are getting radiation for their bladder cancer.

So based on this data, the DSMC gave us a green light to move forward to continue with the enrollment on this trial which is now enrolling, I would say pretty well, despite challenges faced by COVID pandemic with the support of over 30, 34 institutions, which are all over US who have opened this trial. And we are very appreciative of their contribution in patients families and patients to participate in this trial.