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Key Takeaway 3: Role of Frontline I/O Still Pending

Insights From: Richard Finn, MD, Geffen School of Medicine at UCLA
Published: Thursday, Aug 15, 2019



Transcript:

Richard Finn, MD: With regard to frontline studies, the long-awaited CheckMate-459 study recently had a press release. CheckMate-459 is the definitive study to establish nivolumab’s activity in advanced liver cancer. Nivolumab is an anti–PD-1 [programmed cell death protein 1] antibody. It’s really changed the management of many tumors. A large phase I/II study established that the drug does have activity in liver cancer, as well. Response rates were around 14% to 15% in a population of patients who had progressed on prior sorafenib. If a patient responded, the median duration of response was quite long at over 16 months.

We’re moving from sorafenib, which had no significant response, to lenvatinib, where we see mRECIST [modified response evaluation criteria in solid tumors] response rates of around 20%. Now, we have the checkpoint inhibitors like nivolumab and pembrolizumab, which have response rates in the 15% range, but the duration of responses is very long. That was a very impressive dataset. The drug didn’t have any new toxicities in this liver population, as compared to other malignancies, and it got accelerated approval in the second-line setting, as did pembrolizumab. The CheckMate-459 study was launched to try to show that nivolumab is superior to sorafenib in the frontline setting.

It’s always been felt that sorafenib isn’t an easy hurdle to beat, especially now, with a drug that had such provocative data in the second line, and these long, durable responses. The press release that came out just a few weeks ago suggested the study did not meet its statistical endpoint. It was powered for superiority. Unlike the lenvatinib study, which was a noninferiority study, this one was powered for superiority. We’re waiting to see those results presented. I suspect we’ll see those at a meeting in the near future. Is this the end for nivolumab in liver cancer? I don’t think so.

We’ll have to see that data in detail, because what we’re seeing in both frontline and second-line studies is that our assumptions of how long patients will live in the control arm—for example, with sorafenib—are getting longer. They’re getting longer because we have other agents to use in liver cancer after progression on sorafenib. When the CheckMate-459 study was designed, sorafenib was the only drug approved in liver cancer, and now we have 5 drugs available in the United States for liver cancer. That’s probably changing the natural history of advanced liver cancer. These data will be scrutinized and looked at very carefully. The press release does suggest it has some activity. I believe the hazard ratio in the intent-to-treat population was published at 0.87, and we’ll have to see those results in detail.

Transcript Edited for Clarity
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Transcript:

Richard Finn, MD: With regard to frontline studies, the long-awaited CheckMate-459 study recently had a press release. CheckMate-459 is the definitive study to establish nivolumab’s activity in advanced liver cancer. Nivolumab is an anti–PD-1 [programmed cell death protein 1] antibody. It’s really changed the management of many tumors. A large phase I/II study established that the drug does have activity in liver cancer, as well. Response rates were around 14% to 15% in a population of patients who had progressed on prior sorafenib. If a patient responded, the median duration of response was quite long at over 16 months.

We’re moving from sorafenib, which had no significant response, to lenvatinib, where we see mRECIST [modified response evaluation criteria in solid tumors] response rates of around 20%. Now, we have the checkpoint inhibitors like nivolumab and pembrolizumab, which have response rates in the 15% range, but the duration of responses is very long. That was a very impressive dataset. The drug didn’t have any new toxicities in this liver population, as compared to other malignancies, and it got accelerated approval in the second-line setting, as did pembrolizumab. The CheckMate-459 study was launched to try to show that nivolumab is superior to sorafenib in the frontline setting.

It’s always been felt that sorafenib isn’t an easy hurdle to beat, especially now, with a drug that had such provocative data in the second line, and these long, durable responses. The press release that came out just a few weeks ago suggested the study did not meet its statistical endpoint. It was powered for superiority. Unlike the lenvatinib study, which was a noninferiority study, this one was powered for superiority. We’re waiting to see those results presented. I suspect we’ll see those at a meeting in the near future. Is this the end for nivolumab in liver cancer? I don’t think so.

We’ll have to see that data in detail, because what we’re seeing in both frontline and second-line studies is that our assumptions of how long patients will live in the control arm—for example, with sorafenib—are getting longer. They’re getting longer because we have other agents to use in liver cancer after progression on sorafenib. When the CheckMate-459 study was designed, sorafenib was the only drug approved in liver cancer, and now we have 5 drugs available in the United States for liver cancer. That’s probably changing the natural history of advanced liver cancer. These data will be scrutinized and looked at very carefully. The press release does suggest it has some activity. I believe the hazard ratio in the intent-to-treat population was published at 0.87, and we’ll have to see those results in detail.

Transcript Edited for Clarity
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