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Evolution of Systemic Therapy in HCC

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: Tuesday, Feb 26, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD: In 2017, there was a lot of hype with regard to radioembolization. And there was some kind of intrigue with regard to how it could replace systemic therapy. And these trials were negative. But tell us a little bit more about radioembolization. What is it exactly?

R. Kate Kelley, MD: So radioembolization is another type of arterial therapy following upon the successes of TACE, or transarterial chemoembolization, which has been around since the early 2000s for liver cancer. Radioembolization is a technique wherein beads or little glass or resin particles are employed through the artery into the tumor vasculature with the intent to deliver payload-baring radiation instead of chemotherapy, instead of the traditional chemotherapy or embolic material we used to deliver with embolization alone. And so radioembolization, usually with Y-90 as the isotope at hand, has shown the ability to have prolonged responses and has certainly been an important relatively new addition, I should say, in the intermediate or BCLC stage B liver-dominant or liver-localized tumor burden setting, when surgery or curative therapies like surgery, ablation, or transplant are not feasible.

And so, the trials you were alluding to include the SIRveNIB trial, which was conducted in Asia, comparing SIRveNIB with sorafenib in a BCLC stage B or early C—sort of a quasi-advanced, early advanced setting—and the SARAH trial in a European population, with a similar degree of disease. Both of those studies highlight some of the challenges of comparing a device therapy with a systemic therapy. And I think 1 of the take-home points of the data is that neither of them showed superiority of the radioembolization over sorafenib as the control arm.

And so with sorafenib, they were both negative studies. And the challenge of interpreting these is that both of them suffered from a high proportion of dropout, meaning patients with poor prognoses who progressed before they ever got to device. And that makes it very hard to interpret the data, but the take-home point is in the intention-to-treat population. They were negative studies, but again it’s hard to interpret their true benefit when you lose a lot of patients because of the wait time required to get a device on board.

Ghassan K. Abou-Alfa, MD: By all means. I finally think we have the data—if I recall, the last effort of that nature was presented at ASCO [American Society of Clinical Oncologists Annual Meeting] last year—from the OPTIMA study, and they are trying to understand more about the TACE setting. If anything, if I recall, Dr Markus Peck-Radosavljevic—and forgive me if I forget your name, or I don’t know how to say it. Nonetheless, great work that you did at that time. Interestingly, he kind of concluded that, at the end of the day, we are not really necessarily treating TACE by guidelines. And this really brings in a very important opportunity for discussion with regard to where we really set up the point between local therapy, to whom to apply it, and more importantly, what the value for systemic therapy is, per se. And with this, actually, it would be nice to kind of carry on the discussion with regard to systemic therapy. I’ll start probably with Rich. We’re going to dissect them all, but give us a snapshot. Our job was easy. Sorafenib, period. Out of nothing we have to memorize more names. So tell us more about that.

Richard S. Finn, MD: Well, we’ve had a lot of activity in the past 2 years. We’ve seen that for a decade all we had was sorafenib. Sorafenib has repeatedly shown its activity in liver cancer and its ability to extend survival in patients with Child-Pugh, well-compensated disease, and patients who have advanced disease, Barcelona-C [BCLC stage C]. This includes patients with vascular invasion, or extrahepatic spread, or patients who had intermediate disease that progressed on TACE or are refractory to TACE.

Many drugs had tried to beat that, and we had a gap in the frontline setting, something better than sorafenib or as an option and then something after sorafenib. At a very high level, we now have several drugs that are approved. And going in chronology, in early 2017 we had regorafenib approved. That’s the first drug that showed an improvement in survival after progression on sorafenib. We then had data with lenvatinib, which showed that this drug was noninferior to sorafenib in the frontline setting. We then had the accelerated approval of nivolumab in the second-line setting, based on the single-arm CheckMate 040 study.

And then we had results that you presented at GI ASCO [Gastrointestinal Cancers Symposium] 2018 of cabozantinib in the second-line after progression on sorafenib. And then Andy [Andrew Zhu, MD] presented the results of the REACH-2 study showing that ramucirumab improved survival in a high AFP [alpha-fetoprotein] population after progression on sorafenib. And then in November, again, based on a study Andy led, we saw the single-arm phase II study of pembrolizumab in the second-line setting. And, as we sit here today, we have sorafenib and lenvatinib approved in the frontline, and second-line options approved include regorafenib, nivolumab, pembrolizumab, and cabozantinib.

Ghassan K. Abou-Alfa, MD: Incredible. So as we just heard, we moved from 1 drug to 7. And the joke around is that if we’re writing a review article, by the time we’re finalizing it, maybe they have to go back because maybe some drugs really were already reported in between when we wrote it and were trying to publish it.

Transcript Edited for Clarity 

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Transcript: 

Ghassan K. Abou-Alfa, MD: In 2017, there was a lot of hype with regard to radioembolization. And there was some kind of intrigue with regard to how it could replace systemic therapy. And these trials were negative. But tell us a little bit more about radioembolization. What is it exactly?

R. Kate Kelley, MD: So radioembolization is another type of arterial therapy following upon the successes of TACE, or transarterial chemoembolization, which has been around since the early 2000s for liver cancer. Radioembolization is a technique wherein beads or little glass or resin particles are employed through the artery into the tumor vasculature with the intent to deliver payload-baring radiation instead of chemotherapy, instead of the traditional chemotherapy or embolic material we used to deliver with embolization alone. And so radioembolization, usually with Y-90 as the isotope at hand, has shown the ability to have prolonged responses and has certainly been an important relatively new addition, I should say, in the intermediate or BCLC stage B liver-dominant or liver-localized tumor burden setting, when surgery or curative therapies like surgery, ablation, or transplant are not feasible.

And so, the trials you were alluding to include the SIRveNIB trial, which was conducted in Asia, comparing SIRveNIB with sorafenib in a BCLC stage B or early C—sort of a quasi-advanced, early advanced setting—and the SARAH trial in a European population, with a similar degree of disease. Both of those studies highlight some of the challenges of comparing a device therapy with a systemic therapy. And I think 1 of the take-home points of the data is that neither of them showed superiority of the radioembolization over sorafenib as the control arm.

And so with sorafenib, they were both negative studies. And the challenge of interpreting these is that both of them suffered from a high proportion of dropout, meaning patients with poor prognoses who progressed before they ever got to device. And that makes it very hard to interpret the data, but the take-home point is in the intention-to-treat population. They were negative studies, but again it’s hard to interpret their true benefit when you lose a lot of patients because of the wait time required to get a device on board.

Ghassan K. Abou-Alfa, MD: By all means. I finally think we have the data—if I recall, the last effort of that nature was presented at ASCO [American Society of Clinical Oncologists Annual Meeting] last year—from the OPTIMA study, and they are trying to understand more about the TACE setting. If anything, if I recall, Dr Markus Peck-Radosavljevic—and forgive me if I forget your name, or I don’t know how to say it. Nonetheless, great work that you did at that time. Interestingly, he kind of concluded that, at the end of the day, we are not really necessarily treating TACE by guidelines. And this really brings in a very important opportunity for discussion with regard to where we really set up the point between local therapy, to whom to apply it, and more importantly, what the value for systemic therapy is, per se. And with this, actually, it would be nice to kind of carry on the discussion with regard to systemic therapy. I’ll start probably with Rich. We’re going to dissect them all, but give us a snapshot. Our job was easy. Sorafenib, period. Out of nothing we have to memorize more names. So tell us more about that.

Richard S. Finn, MD: Well, we’ve had a lot of activity in the past 2 years. We’ve seen that for a decade all we had was sorafenib. Sorafenib has repeatedly shown its activity in liver cancer and its ability to extend survival in patients with Child-Pugh, well-compensated disease, and patients who have advanced disease, Barcelona-C [BCLC stage C]. This includes patients with vascular invasion, or extrahepatic spread, or patients who had intermediate disease that progressed on TACE or are refractory to TACE.

Many drugs had tried to beat that, and we had a gap in the frontline setting, something better than sorafenib or as an option and then something after sorafenib. At a very high level, we now have several drugs that are approved. And going in chronology, in early 2017 we had regorafenib approved. That’s the first drug that showed an improvement in survival after progression on sorafenib. We then had data with lenvatinib, which showed that this drug was noninferior to sorafenib in the frontline setting. We then had the accelerated approval of nivolumab in the second-line setting, based on the single-arm CheckMate 040 study.

And then we had results that you presented at GI ASCO [Gastrointestinal Cancers Symposium] 2018 of cabozantinib in the second-line after progression on sorafenib. And then Andy [Andrew Zhu, MD] presented the results of the REACH-2 study showing that ramucirumab improved survival in a high AFP [alpha-fetoprotein] population after progression on sorafenib. And then in November, again, based on a study Andy led, we saw the single-arm phase II study of pembrolizumab in the second-line setting. And, as we sit here today, we have sorafenib and lenvatinib approved in the frontline, and second-line options approved include regorafenib, nivolumab, pembrolizumab, and cabozantinib.

Ghassan K. Abou-Alfa, MD: Incredible. So as we just heard, we moved from 1 drug to 7. And the joke around is that if we’re writing a review article, by the time we’re finalizing it, maybe they have to go back because maybe some drugs really were already reported in between when we wrote it and were trying to publish it.

Transcript Edited for Clarity 
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