The FDA Approval of Atezolizumab in Bladder Cancer

Transcript:Mark A. Socinski, MD: So, tell us about the atezolizumab bladder cancer approval.

Dean F. Bajorin, MD: Everybody else at this panel has had new drugs over the past few years. We’ve been waiting 30 years and, then some, for a new drug. The last one that was actually approved in the United States for metastatic disease, believe it or not, was cisplatin. So, that shows you how long we’ve been waiting. We know that bladder cancer is actually the first immunologic tumor. We were using BCG (Bacillus Calmette-Guerin) for years and we had studied and saw that in muscle invasive disease if you had lymphocytic infiltration, CD8-positive cells, patients did better stage for stage. So, we’ve known this for a while.

The atezolizumab study IMvigor 210 is basically what put it on the map. We know about atezolizumab. It is a straightforward, extended phase II trial of 300 patients. And all patients were entered, but their PD-L1 status came back as a planned post hoc analysis. The endpoint was response and survival. If you take a look at overall response, it’s around 15%. That seems low, but in this patient population of previously treated patients, typically we see about a 10% response rate with systemic chemotherapy. The taxanes are one of those highly toxic therapies. And, so, if you take a look at atezolizumab, it’s 15% for all-comers. For the patients who were PD-L1, 2 or 3 plus (tumor-infiltrating immune cell (IC) status1/2/3), it was 28%. And in the patients who were 0/1’s (IC0/1), it was still 8% to 10%. If you look at those swimmer’s plots, you can see that some of those patients were still continuing to respond at a year. And then those are the data with regard to response, and that response in early survival was enough to approve the drug by the FDA. At these meetings, Rob Dreicer is giving an update with regard to survival. The survival of the patients who are 2-3 (IC2/3) positive is 12 months—never seen before in a trial—and 8 months for the patients who are 0-1’s. That rivals the best of chemotherapy, even in the patients who have low expression.

And then, there are also studies with companion diagnostics that are being done. And the same thing holds with regard to mutational load. We’re seeing it, no surprise, like every other disease. It’s been analyzed by looking at gene profiles and the total number of mutations in the foundation medicine gene profile. This very much parallels what we see in mutational load, lymphocytic infiltration. If you look at the responders, they have a higher mutational load than those that did not respond. So, the companion diagnostic studies are really similar to all the others.

There’s a separate 100-patient cohort in that IMvigor 210 trial that we are awaiting final data for this weekend at ASCO, as first-line therapy in patients who are ineligible for cisplatin-based therapy. Now, cisplatin is for metastatic disease, cisplatin is the standard of care. But this is a disease of older patients, smokers, those with a lot of comorbidities. It is very difficult to get cisplatin in these patients frequently. A minority actually tolerate it. So, the cisplatin-ineligible population, their median survival is 8.5 to 9 months. The IMvigor 210 trial had a cohort of 100 patients who are getting first-line therapy. It’s the first talk of the day so I think it’ll be exciting results.

Mark A. Socinski, MD: Any plans to look at atezolizumab in the earlier stages of bladder cancer?

Dean F. Bajorin, MD: There are. Actually, so when we think of bladder cancer, we think across an entire spectrum, and we have disease states and we have metastatic disease both first- and second-line therapy. But then we also have muscle invasive disease, which is managed differently. And then we have non-muscle invasive disease. We typically call it superficial disease, and it seems like it’s a non-threatening disease. In point of fact, it’s treated with resection, TR, or transurethral resection, and then BCG. But, if you take a look at the patient population whose disease recurs, superficial disease recurs within 12 months. And what we now call the BCG unresponsive population, they’re actually a very high-risk population for developing muscle invasive disease, going on to have nodal disease or metastatic disease. Actually, the signature so-called superficial disease belies the aggressiveness. There’s actually no therapy that’s effective in that space. It’s truly an unmet need. The standard of care is a cystectomy and node dissection.

A couple of years ago, the FDA held an open session as to how can we best study that space. And it turns out that it’s very hard to randomize patients, and they accepted what would be a non-comparator trial approval process. Now all these drugs are getting into that space. Atezolizumab is in that space now looking at patients who have BCG unresponsive disease to see if there could be activity. We know that once patients get BCG, there’s a pretty substantial upregulation of PD-L1 positivity. That’s been seen already. So, we know that it’s certainly a good candidate for this therapy.

Mark A. Socinski, MD: And what about in renal cell, any data yet for the atezolizumab?

Dean F. Bajorin, MD: With atezolizumab, there is a trial. It turns out there was a very small trial looking at atezolizumab plus bevacizumab. And it’s actually a very elegant study, a small number of patients who actually had biopsies. They start off with bevacizumab, then get atezolizumab, and then had subsequent biopsies to examine the tumors with regard to CDA (cytidine deaminase) positivity and cytokine release, etc. And it was very interesting how much upregulation there was with regard to lymphocytic infiltration. Bevacizumab does upregulate PD-L1 in renal cell carcinomas. So, that’s been taken further. That’s now a randomized trial looking at atezolizumab plus bevacizumab versus standard first-line therapy. Standard first-line therapy is sunitinib in patients with metastatic renal cell carcinoma, and that trial is ongoing at the present time.

Transcript Edited for Clarity