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ASCO GI 2019 Update: REFLECT Study

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, University of California Los Angeles; R. Kate Kelley, MD, University of California San Francisco; Andrew X. Zhu, MD, PhD, Harvard Medical School; Tony Saab, MD, Mayo Clinic
Published: Monday, Mar 04, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD: With this said, let’s start, and I’ll take it in this sequence. I like the sequence that you brought up and it probably will make sense. Andrew, let’s talk a little bit about, short of the sorafenib, which we all know about, tell us a little bit about lenvatinib. What’s the story there?

Andrew X. Zhu, MD, PhD: So lenvatinib is, I think you can view this as another TKI [tyrosine kinase inhibitor]. But, on the other hand, this is actually a more potent inhibitor against VEGFR2. I think there’s no argument this is a very potent VEGFR2 inhibitor, among many other potential inhibitory targets. So, in a very well conducted landmark study, REFLECT, the drug was comparing directly against sorafenib. Interestingly, if you look at the overall survival [OS], the drug actually meets the positive endpoint of noninferiority, meaning that the drug is actually behaving not inferior to sorafenib in terms of the overall survival.

However, if you look at the important secondary endpoints, including response rate, PFS [progression-free survival], TTP [time to progression], I think the drug is definitely more in favor than sorafenib with all the secondary endpoints being analyzed. So I think for that reason, this is definitely a legitimate option in the first-line setting for patients with newly diagnosed advanced stage HCC [hepatocellular carcinoma]. And also we all know this drug is different from sorafenib in terms of the safety profile. I think we’re very used to the sorafenib related [adverse] effects, including the hand and foot skin reaction, the diarrhea, the fatigue. But lenvatinib also has its unique pattern of safety profile. We see more hypertension as predicted. We see patients are perhaps having worsening ascites occasionally. So the safety profile is definitely different, but overall, I think with both drugs, we have learned how to deal with the safety profile. I think if it’s a well-trained oncologist who is very vigilant, we can get our patients through the treatment with very close monitoring. So I’m glad that this is becoming another option for our patients.

Ghassan K. Abou-Alfa, MD: Absolutely, I agree. If anything, at this GI ASCO [Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology] 2019, there was a nice abstract that was reported by Dr [Masatoshi]  Kudo [MD, PhD,] from Japan that looked at the analyses of the response and survival on the REFLECT study, exactly what Andrew referred to. And, if anything, it was a nice exercise because even the overall survival for the responders to the lenvatinib was 22.4 months. And for the nonresponders it was 11.4 months. And the conclusion was response is an independent predictor of overall survival, which is exactly what we like. And I totally agree that this is quite intriguing. Katie, along that line, lenvatinib, have you had that experience? The fact that this drug is approved. So please tell us a little bit about your experience per se.

R. Kate Kelley, MD: We started using it this fall, really since its approval. I have to say as Andrew described, the main toxicities that we’ve encountered have been hypertension and some edema. Haven’t had any hand-foot syndrome, which is as expected, much lower rates of palmar plantar erythrodysesthesia than with sorafenib. And so I think it’s in the family of TKIs that we’ve become familiar with in terms of the monitoring requirements. One of the key points is having, for all of these TKI family of drugs with antiangiogenic activity, is to have really strong blood pressure control prior to starting the drug. I like to have my patients with a blood pressure reproducibly less than 140/90 [mm Hg] at tops before starting a TKI, particularly lenvatinib but also for sorafenib, and regorafenib, and cabozantinib. All of this family of drugs can cause hypertension that’s problematic on treatment and requires dose interruptions if not well controlled going into it and not monitored closely. So I think that’s the main key for me with lenvatinib is tight blood pressure control going in and close monitoring, especially the first few weeks on treatment at the 12-mg dose for people who are more than 60 kg or 8 if they’re less than 60.

Ghassan K. Abou-Alfa, MD: Fair. And last point on the lenvatinib. Rich, you’ve been involved quite a bit and you’re really one of the experts who understand lenvatinib quite well. No doubt that the study was designed as a noninferiority study. I would love very much if we can hear, for our colleagues who are watching us, what exactly is noninferiority? And number 2 is tell us a little bit more about the real results of REFLECT in regard to response, PFS, etcetera. Because there was quite a big wealth of information there.

Richard S. Finn, MD: Sure. And I commented before, for the last decade we haven’t had a drug that has beat sorafenib, and we still don’t. Because this study was designed to show that by being noninferiority, that there’s a very tight window statistically, that the results of this drug compared to sorafenib are the same. That survival, and ultimately in the study survival was 13.6 months with lenvatinib, about 12.3 months with sorafenib. And that this was the first study of an active control for a new drug, lenvatinib versus sorafenib that met its primary endpoint of noninferiority. Meaning that lenvatinib has similar activity as sorafenib as far as the primary endpoint of OS. Because it met the noninferior endpoint, they were going to look at superiority and it did not meet that endpoint.

But Andy alluded to this before about the secondary endpoints. And because it met a primary endpoint of noninferiority, we can look at the secondary endpoints. And we saw that on all of these, there was a benefit to lenvatinib, a better control of tumor progression radiographically as measured by TTP, significant increase in PFS, and a significant increase in response rate. And this is the first time we have a drug that has a fairly good response rate. And, in this study, they used the modified RECIST [response evaluation criteria in solid tumors] criteria, which is looking at the changes in enhancement of tumors. But, whether by modified RECIST or the traditional RECIST, which is just looking at the size of tumors, lenvatinib essentially doubled that of sorafenib.

And so the question for us is how important is response in advanced liver cancer. Because, again, for the past decade, we said response is not important because it doesn’t affect OS. And now we have a drug that does induce a response and in the overall population, survival is the same, noninferior. But, at this ASCO GI 2019, you alluded to the work by Dr Kudo that shows that if you have a response to either sorafenib or lenvatinib, either drug, your survival is better than if not. And this is a very intriguing idea, especially if we’re trying to differentiate these two drugs. If we have a patient who has a big tumor burden and we think getting that disease under control is more important than just stability, then maybe that’s a patient we lean more towards lenvatinib. At the same time, the REFLECT study excluded patients who had more than 50% of their liver involved or they had main portal vein invasion; maybe those are patients we might feel more comfortable with sorafenib.

If you look at some of the other subgroups that were looked at, historically, patients with hepatitis C have done better with sorafenib than the hepatitis B cohort. With lenvatinib it seems somewhat similar. The high AFP [alpha-fetoprotein] patients seem to get a little more benefit from lenvatinib versus others and this higher tumor burden. So some things to think about. At the end of the day, the primary endpoint, noninferiority, survival, which we’d all I think agree is the most important endpoint, is the same. But in reality, with a patient sitting in front of us, we have a choice. I think we’ll discuss how we choose.

Transcript Edited for Clarity

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Transcript: 

Ghassan K. Abou-Alfa, MD: With this said, let’s start, and I’ll take it in this sequence. I like the sequence that you brought up and it probably will make sense. Andrew, let’s talk a little bit about, short of the sorafenib, which we all know about, tell us a little bit about lenvatinib. What’s the story there?

Andrew X. Zhu, MD, PhD: So lenvatinib is, I think you can view this as another TKI [tyrosine kinase inhibitor]. But, on the other hand, this is actually a more potent inhibitor against VEGFR2. I think there’s no argument this is a very potent VEGFR2 inhibitor, among many other potential inhibitory targets. So, in a very well conducted landmark study, REFLECT, the drug was comparing directly against sorafenib. Interestingly, if you look at the overall survival [OS], the drug actually meets the positive endpoint of noninferiority, meaning that the drug is actually behaving not inferior to sorafenib in terms of the overall survival.

However, if you look at the important secondary endpoints, including response rate, PFS [progression-free survival], TTP [time to progression], I think the drug is definitely more in favor than sorafenib with all the secondary endpoints being analyzed. So I think for that reason, this is definitely a legitimate option in the first-line setting for patients with newly diagnosed advanced stage HCC [hepatocellular carcinoma]. And also we all know this drug is different from sorafenib in terms of the safety profile. I think we’re very used to the sorafenib related [adverse] effects, including the hand and foot skin reaction, the diarrhea, the fatigue. But lenvatinib also has its unique pattern of safety profile. We see more hypertension as predicted. We see patients are perhaps having worsening ascites occasionally. So the safety profile is definitely different, but overall, I think with both drugs, we have learned how to deal with the safety profile. I think if it’s a well-trained oncologist who is very vigilant, we can get our patients through the treatment with very close monitoring. So I’m glad that this is becoming another option for our patients.

Ghassan K. Abou-Alfa, MD: Absolutely, I agree. If anything, at this GI ASCO [Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology] 2019, there was a nice abstract that was reported by Dr [Masatoshi]  Kudo [MD, PhD,] from Japan that looked at the analyses of the response and survival on the REFLECT study, exactly what Andrew referred to. And, if anything, it was a nice exercise because even the overall survival for the responders to the lenvatinib was 22.4 months. And for the nonresponders it was 11.4 months. And the conclusion was response is an independent predictor of overall survival, which is exactly what we like. And I totally agree that this is quite intriguing. Katie, along that line, lenvatinib, have you had that experience? The fact that this drug is approved. So please tell us a little bit about your experience per se.

R. Kate Kelley, MD: We started using it this fall, really since its approval. I have to say as Andrew described, the main toxicities that we’ve encountered have been hypertension and some edema. Haven’t had any hand-foot syndrome, which is as expected, much lower rates of palmar plantar erythrodysesthesia than with sorafenib. And so I think it’s in the family of TKIs that we’ve become familiar with in terms of the monitoring requirements. One of the key points is having, for all of these TKI family of drugs with antiangiogenic activity, is to have really strong blood pressure control prior to starting the drug. I like to have my patients with a blood pressure reproducibly less than 140/90 [mm Hg] at tops before starting a TKI, particularly lenvatinib but also for sorafenib, and regorafenib, and cabozantinib. All of this family of drugs can cause hypertension that’s problematic on treatment and requires dose interruptions if not well controlled going into it and not monitored closely. So I think that’s the main key for me with lenvatinib is tight blood pressure control going in and close monitoring, especially the first few weeks on treatment at the 12-mg dose for people who are more than 60 kg or 8 if they’re less than 60.

Ghassan K. Abou-Alfa, MD: Fair. And last point on the lenvatinib. Rich, you’ve been involved quite a bit and you’re really one of the experts who understand lenvatinib quite well. No doubt that the study was designed as a noninferiority study. I would love very much if we can hear, for our colleagues who are watching us, what exactly is noninferiority? And number 2 is tell us a little bit more about the real results of REFLECT in regard to response, PFS, etcetera. Because there was quite a big wealth of information there.

Richard S. Finn, MD: Sure. And I commented before, for the last decade we haven’t had a drug that has beat sorafenib, and we still don’t. Because this study was designed to show that by being noninferiority, that there’s a very tight window statistically, that the results of this drug compared to sorafenib are the same. That survival, and ultimately in the study survival was 13.6 months with lenvatinib, about 12.3 months with sorafenib. And that this was the first study of an active control for a new drug, lenvatinib versus sorafenib that met its primary endpoint of noninferiority. Meaning that lenvatinib has similar activity as sorafenib as far as the primary endpoint of OS. Because it met the noninferior endpoint, they were going to look at superiority and it did not meet that endpoint.

But Andy alluded to this before about the secondary endpoints. And because it met a primary endpoint of noninferiority, we can look at the secondary endpoints. And we saw that on all of these, there was a benefit to lenvatinib, a better control of tumor progression radiographically as measured by TTP, significant increase in PFS, and a significant increase in response rate. And this is the first time we have a drug that has a fairly good response rate. And, in this study, they used the modified RECIST [response evaluation criteria in solid tumors] criteria, which is looking at the changes in enhancement of tumors. But, whether by modified RECIST or the traditional RECIST, which is just looking at the size of tumors, lenvatinib essentially doubled that of sorafenib.

And so the question for us is how important is response in advanced liver cancer. Because, again, for the past decade, we said response is not important because it doesn’t affect OS. And now we have a drug that does induce a response and in the overall population, survival is the same, noninferior. But, at this ASCO GI 2019, you alluded to the work by Dr Kudo that shows that if you have a response to either sorafenib or lenvatinib, either drug, your survival is better than if not. And this is a very intriguing idea, especially if we’re trying to differentiate these two drugs. If we have a patient who has a big tumor burden and we think getting that disease under control is more important than just stability, then maybe that’s a patient we lean more towards lenvatinib. At the same time, the REFLECT study excluded patients who had more than 50% of their liver involved or they had main portal vein invasion; maybe those are patients we might feel more comfortable with sorafenib.

If you look at some of the other subgroups that were looked at, historically, patients with hepatitis C have done better with sorafenib than the hepatitis B cohort. With lenvatinib it seems somewhat similar. The high AFP [alpha-fetoprotein] patients seem to get a little more benefit from lenvatinib versus others and this higher tumor burden. So some things to think about. At the end of the day, the primary endpoint, noninferiority, survival, which we’d all I think agree is the most important endpoint, is the same. But in reality, with a patient sitting in front of us, we have a choice. I think we’ll discuss how we choose.

Transcript Edited for Clarity
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