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Treatment of Bladder Cancer-Immune Checkpoint Inhibitors

David I. Quinn, MD
Published: Friday, Jun 23, 2017



Transcript:

David I. Quinn, MD:
There has been a lot of practice change in bladder cancer, where we’re seeing the approval of 5 new agents that inhibit either PD-1 or PD-L1 and have significant activity. They have all received accelerated approval from the FDA, and have moved from initial breakthrough status based on high-response rates that have been confirmed in follow-up studies. So, we have atezolizumab, pembrolizumab, durvalumab, nivolumab, and avelumab now approved in the United States for use in patients with urothelial cancer, or bladder cancer, who have previously been treated with platinum-based agents. In addition, 2 of the drugs are approved for treatment of patients who are not eligible for cisplatin in the first-line setting. That would be atezolizumab and also pembrolizumab.

We’ve had some data recently. We’re starting to get our first phase III data with the checkpoint inhibitors that target PD-L1 or PD-1. And so, late last year, we first saw data from KEYNOTE-045, a study where pembrolizumab is compared to chemotherapy with choices of paclitaxel, docetaxel, or vinflunine for patients who have been previously treated with platinum combinations. And these data have been published in the New England Journal of Medicine and led to the full approval of pembrolizumab in this space, because there’s a survival advantage that’s significant at the median of 10.3 months for pembrolizumab versus 7.4 months for the chemotherapies. And so, that represents an advance, the first level 1 evidence that we have, and in addition, the toxicity of the immune agent—in this case a PD-1 inhibitor—is much less than chemotherapy. So, that’s of interest and frames the space in a particular way where I think we have our first comparative evidence of the checkpoint inhibitors versus a standard therapy—in this case, chemotherapy.

What was interesting is in the past 2 weeks, there was the press release on a study, IMvigor 211, that compared atezolizumab to the same chemotherapy agents: paclitaxel, docetaxel and vinflunine. We don’t know much about this and we’re waiting for the data to be fully presented at a meeting, and hopefully be published. But the study did not meet its primary endpoint. Now, this was interesting because when we originally did the early phase studies of atezolizumab in urothelial cancer, it looked like the PD-L1 marker with the antibody they were using—which is different to the antibody that other companies used, including the other PD-L1 drug, durvalumab, that we’ve just seen approved—looked like expression of PD-L1 in the tumor tissue correlated with the response and outcome of the patients.

We’ve since had other data in the first-line cisplatin-ineligible setting with atezolizumab where the marker doesn’t seem to differentiate very much at all. So, in the IMvigor 211 study, the study was set up so the primary endpoint was a difference in the PD-L1-high patient—those that expressed immunohistochemically at levels 2 and 3. And so, from that perspective, we’re not sure whether that endpoint was just narrowly missed, we’re not sure whether there were patients that didn’t quite have the characteristics of the earlier studies, and we’re also not sure whether there was a crossover that occurred after chemotherapy so that the patients who were in the normal checkpoint inhibitor arm actually got checkpoint inhibitor therapy after they progressed on chemotherapy. We’ll see.

One would expect that atezolizumab has still activity across the board. I think it’s a good agent, and that it will be less toxic overall than the chemotherapy. But we’ll be seeing that in the coming months, and I think it’s an interesting point for discussion for the medical oncologist who’s treating a urothelial cancer patient because we’ve had atezolizumab approved now since May of 2016. It was the first to market, clearly an active drug, and so for the oncologist prescribing, they’ll be interested to see this information be dissected from IMvigor 211. At the moment, until I get more details, we’ll still be certainly using atezolizumab as we did before, although we do now have more choice with now 5 agents approved in this space.

Transcript Edited for Clarity
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Transcript:

David I. Quinn, MD:
There has been a lot of practice change in bladder cancer, where we’re seeing the approval of 5 new agents that inhibit either PD-1 or PD-L1 and have significant activity. They have all received accelerated approval from the FDA, and have moved from initial breakthrough status based on high-response rates that have been confirmed in follow-up studies. So, we have atezolizumab, pembrolizumab, durvalumab, nivolumab, and avelumab now approved in the United States for use in patients with urothelial cancer, or bladder cancer, who have previously been treated with platinum-based agents. In addition, 2 of the drugs are approved for treatment of patients who are not eligible for cisplatin in the first-line setting. That would be atezolizumab and also pembrolizumab.

We’ve had some data recently. We’re starting to get our first phase III data with the checkpoint inhibitors that target PD-L1 or PD-1. And so, late last year, we first saw data from KEYNOTE-045, a study where pembrolizumab is compared to chemotherapy with choices of paclitaxel, docetaxel, or vinflunine for patients who have been previously treated with platinum combinations. And these data have been published in the New England Journal of Medicine and led to the full approval of pembrolizumab in this space, because there’s a survival advantage that’s significant at the median of 10.3 months for pembrolizumab versus 7.4 months for the chemotherapies. And so, that represents an advance, the first level 1 evidence that we have, and in addition, the toxicity of the immune agent—in this case a PD-1 inhibitor—is much less than chemotherapy. So, that’s of interest and frames the space in a particular way where I think we have our first comparative evidence of the checkpoint inhibitors versus a standard therapy—in this case, chemotherapy.

What was interesting is in the past 2 weeks, there was the press release on a study, IMvigor 211, that compared atezolizumab to the same chemotherapy agents: paclitaxel, docetaxel and vinflunine. We don’t know much about this and we’re waiting for the data to be fully presented at a meeting, and hopefully be published. But the study did not meet its primary endpoint. Now, this was interesting because when we originally did the early phase studies of atezolizumab in urothelial cancer, it looked like the PD-L1 marker with the antibody they were using—which is different to the antibody that other companies used, including the other PD-L1 drug, durvalumab, that we’ve just seen approved—looked like expression of PD-L1 in the tumor tissue correlated with the response and outcome of the patients.

We’ve since had other data in the first-line cisplatin-ineligible setting with atezolizumab where the marker doesn’t seem to differentiate very much at all. So, in the IMvigor 211 study, the study was set up so the primary endpoint was a difference in the PD-L1-high patient—those that expressed immunohistochemically at levels 2 and 3. And so, from that perspective, we’re not sure whether that endpoint was just narrowly missed, we’re not sure whether there were patients that didn’t quite have the characteristics of the earlier studies, and we’re also not sure whether there was a crossover that occurred after chemotherapy so that the patients who were in the normal checkpoint inhibitor arm actually got checkpoint inhibitor therapy after they progressed on chemotherapy. We’ll see.

One would expect that atezolizumab has still activity across the board. I think it’s a good agent, and that it will be less toxic overall than the chemotherapy. But we’ll be seeing that in the coming months, and I think it’s an interesting point for discussion for the medical oncologist who’s treating a urothelial cancer patient because we’ve had atezolizumab approved now since May of 2016. It was the first to market, clearly an active drug, and so for the oncologist prescribing, they’ll be interested to see this information be dissected from IMvigor 211. At the moment, until I get more details, we’ll still be certainly using atezolizumab as we did before, although we do now have more choice with now 5 agents approved in this space.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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