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Frontline Atezolizumab for Advanced Bladder Cancer

Robert Dreicer, MD, MS, MACP, FASCO, University of Virginia Cancer Center
Published: Friday, May 05, 2017



Transcript:

Robert Dreicer, MD:
There are questions about how to use these new drugs, the checkpoint inhibitors. We know that nivolumab and atezolizumab both have FDA indications in the second-line setting. Within the last few days, atezolizumab actually was also approved. The label was expanded for frontline therapy in patients who are not cisplatin candidates. So, the unfit patient for cisplatin. That approval will significantly alter the management paradigm, at least to half of the patients. About 50% of folks who are treated with chemotherapy have nonoptimal clinical features for cisplatin, which means we’re going to be thinking about using these checkpoint inhibitors—again, atezolizumab being the first. I anticipate others to be approved as frontline therapy. The whole management paradigm is going to evolve. There are going to be a lot of questions. We’re not going to have all the answers. I think it’s an important development.

The approval, or the indication, that was broadened by the FDA for atezolizumab was based partly on what was called IMvigor 210, which was a large phase II study. The larger component, cohort 2, was patients who had already received platinum-based chemotherapy. Cohort 1 was about 111 patients who were unfit for cisplatin. That’s defined by creatinine clearance greater than 60 or less than 60 mL/min, pre-existing hearing loss, more than grade 2 neuropathy, or an ECOG performance status of 2 or 3. That led that cohort to show data that were compelling enough in terms of objective response rate and some very interesting progression-free survival data. That led the agency to broaden the label from the previous approval in postchemotherapy—postplatinum progression—to up front.

Now that atezolizumab has been approved in the frontline setting, the treatment paradigm for patients who are unfit to receive cisplatin will alter. I suspect there will be significant uptake of atezolizumab and then subsequent checkpoint inhibitors in that population, given the fact that traditional regimens like carboplatin and gemcitabine are, frankly, toxic and don’t really offer much in the way of impact on outcome.

We know that about three-quarters of patients who get these agents won’t respond. So, you could suggest that, in a patient who gets a checkpoint inhibitor and doesn’t respond, they’re likely to get the same therapy they would have up front a little later. But for a patient who has a response—especially a patient who has a durable response—the hope would be, perhaps, that patients would have durable responses to upfront therapy, which, again, has never really been seen before in this disease. It’s going to be an interesting challenge in terms of how to optimally sequence. There are other studies that are ongoing and yet to be reported that will provide guidance. But for now, we’re going to have to use the best data that we have, which are really quite limited.

Transcript Edited for Clarity
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Transcript:

Robert Dreicer, MD:
There are questions about how to use these new drugs, the checkpoint inhibitors. We know that nivolumab and atezolizumab both have FDA indications in the second-line setting. Within the last few days, atezolizumab actually was also approved. The label was expanded for frontline therapy in patients who are not cisplatin candidates. So, the unfit patient for cisplatin. That approval will significantly alter the management paradigm, at least to half of the patients. About 50% of folks who are treated with chemotherapy have nonoptimal clinical features for cisplatin, which means we’re going to be thinking about using these checkpoint inhibitors—again, atezolizumab being the first. I anticipate others to be approved as frontline therapy. The whole management paradigm is going to evolve. There are going to be a lot of questions. We’re not going to have all the answers. I think it’s an important development.

The approval, or the indication, that was broadened by the FDA for atezolizumab was based partly on what was called IMvigor 210, which was a large phase II study. The larger component, cohort 2, was patients who had already received platinum-based chemotherapy. Cohort 1 was about 111 patients who were unfit for cisplatin. That’s defined by creatinine clearance greater than 60 or less than 60 mL/min, pre-existing hearing loss, more than grade 2 neuropathy, or an ECOG performance status of 2 or 3. That led that cohort to show data that were compelling enough in terms of objective response rate and some very interesting progression-free survival data. That led the agency to broaden the label from the previous approval in postchemotherapy—postplatinum progression—to up front.

Now that atezolizumab has been approved in the frontline setting, the treatment paradigm for patients who are unfit to receive cisplatin will alter. I suspect there will be significant uptake of atezolizumab and then subsequent checkpoint inhibitors in that population, given the fact that traditional regimens like carboplatin and gemcitabine are, frankly, toxic and don’t really offer much in the way of impact on outcome.

We know that about three-quarters of patients who get these agents won’t respond. So, you could suggest that, in a patient who gets a checkpoint inhibitor and doesn’t respond, they’re likely to get the same therapy they would have up front a little later. But for a patient who has a response—especially a patient who has a durable response—the hope would be, perhaps, that patients would have durable responses to upfront therapy, which, again, has never really been seen before in this disease. It’s going to be an interesting challenge in terms of how to optimally sequence. There are other studies that are ongoing and yet to be reported that will provide guidance. But for now, we’re going to have to use the best data that we have, which are really quite limited.

Transcript Edited for Clarity
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