Aiwu (Ruth) He, PhD

Mark Yarchoan, MD

James Harding, MD

Namrata Vijayvergia, MD

GI Oncology Now

Aiwu (Ruth) He, PhD, MedStar Georgetown University Hospital, is joined by Mark Yarchoan, MD, Johns Hopkins Medicine; James Harding, MD, Memorial Sloan Kettering Cancer Center; and Namrata Vijayvergia, MD, Fox Chase Cancer Center, for a roundtable discussion on the current and future treatment considerations for advanced hepatocellular carcinoma (HCC).
In the fourth segment, the panel discusses treatment options following frontline therapy for advanced HCC, highlighting the lack of definitive data and the rationale behind using TKIs or immune checkpoint inhibitors in the second-line setting. They also explore the role of multidisciplinary collaboration in managing treatment-related toxicities and share insights into emerging drug development, including triplet regimens, GPC3-targeted therapies, and bispecific antibodies.
View the next segment on <a href="https://www.gioncologynow.com/post/the-biomarker-black-hole-in-hcc-where-are-we-now" target="_blank" rel="noopener">The Biomarker Black Hole in HCC: Where Are We Now?</a>
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Dr. He: Now let us shift to the next topic. After first-line therapy, what do you consider in selecting a second-line treatment? There are limited data after frontline ICI-based regimens, so what are your guiding principles?
Dr. Harding: That is a great question. We are all struggling with it, right? After ICI-based therapy, there is no randomized phase 3 trial guiding what comes next. We have tried to address this at our institution by focusing on class-switching. That means if a patient receives immunotherapy in the frontline, we often use a VEGF TKI in the second-line. If they had a TKI in the first-line, then we might introduce an immune checkpoint inhibitor in the second-line.
One complexity is that a number of phase 3 trials that led to second-line approvals were based on progression after sorafenib. So, for example, regorafenib and cabozantinib were studied only after sorafenib. We extrapolate that data when we are now using these drugs after other front-line regimens, but of course, there is no direct evidence for that sequence.
In short, it is challenging. We are trying to individualize based on what the patient previously received, their liver function, their tolerability, and also what toxicities they may have experienced. It requires nuance and judgment.
Dr. He: That makes sense. Would you say that multidisciplinary collaboration is even more important in these settings?
Dr. Harding: Absolutely. These decisions are not made in isolation. If a patient is experiencing immune-related adverse events, I always consult with our hepatology colleagues. Their input is essential, especially when managing patients with borderline liver function. I also think having pharmacists, nursing staff, and even interventional radiology involved can be critical for optimizing outcomes.
Dr. Yarchoan: I agree with everything that has been said. It is worth emphasizing that a significant percentage of patients unfortunately never make it to second-line therapy. So getting the frontline therapy right is extremely important.
But if patients do make it to second-line, I usually switch classes, as Dr. Harding mentioned. The clinical trials in the second-line were done after sorafenib, and it is not always clear how to apply that to someone who received, for example, atezolizumab and bevacizumab up front. Still, I think those same second-line options are reasonable.
We are also seeing promising data now with cabozantinib in combination with checkpoint inhibitors. For example, cabozantinib and atezolizumab is being studied in the COSMIC trial. So I think we will get more data soon that may help guide us more definitively.
Dr. Vijayvergia: Yes, and while we wait for more data, we rely on our understanding of the mechanisms and patient characteristics. I also think it is important to assess what the patient wants at that point. Some patients may not wish to pursue another systemic therapy after progression, depending on how their quality of life has been.
When they are eligible and interested, I usually opt for TKIs in the second-line if they started with an ICI-based regimen. There are still limited data for what is optimal, but switching classes feels like a sound approach for now.
Dr. He: Looking ahead, what are some directions in drug development that excite you?
Dr. Yarchoan: There is a lot happening. One of the most exciting areas is bispecific antibodies. These agents can target both the tumor and immune cells simultaneously, which may increase efficacy without necessarily increasing toxicity.
I am also excited about triplet regimens. For example, combining a TKI, an anti-VEGF agent, and a checkpoint inhibitor. The data are early, but some studies suggest this approach might achieve deeper responses.
Dr. Harding: I would add GPC3-targeted therapies to that list. GPC3 is expressed on many HCC tumors but not on normal tissue, making it a promising target. There are antibody-drug conjugates, CAR T cells, and other modalities being explored in this space.
I think the goal in all of these is to find therapies that can both shrink tumors and be tolerable in patients who often have limited liver reserve.
Dr. Vijayvergia: Absolutely. I think we will also see more personalization of treatment. Right now, we mostly treat all advanced HCC the same way, regardless of underlying etiology or molecular profile. But I think in the future, we will better identify which patients are most likely to benefit from specific therapies, perhaps through biomarkers or genetic profiling.
That would be a real step forward for the field.

Aiwu (Ruth) He, PhD, MedStar Georgetown University Hospital, is joined by Mark Yarchoan, MD, Johns Hopkins Medicine; James Harding, MD, Memorial Sloan Kettering Cancer Center; and Namrata Vijayvergia, MD, Fox Chase Cancer Center, for a roundtable discussion on the current and future treatment considerations for advanced hepatocellular carcinoma (HCC).In the fourth segment, the panel discusses treatment options following frontline therapy for advanced HCC, highlighting the lack of definitive data and the rationale behind using TKIs or immune checkpoint inhibitors in the second-line setting. They also explore the role of multidisciplinary collaboration in managing treatment-related toxicities and share insights into emerging drug development, including triplet regimens, GPC3-targeted therapies, and bispecific antibodies.View the next segment on <a href="https://www.gioncologynow.com/post/the-biomarker-black-hole-in-hcc-where-are-we-now" target="_blank" rel="noopener">The Biomarker Black Hole in HCC: Where Are We Now?</a>—Dr. He: Now let us shift to the next topic. After first-line therapy, what do you consider in selecting a second-line treatment? There are limited data after frontline ICI-based regimens, so what are your guiding principles?Dr. Harding: That is a great question. We are all struggling with it, right? After ICI-based therapy, there is no randomized phase 3 trial guiding what comes next. We have tried to address this at our institution by focusing on class-switching. That means if a patient receives immunotherapy in the frontline, we often use a VEGF TKI in the second-line. If they had a TKI in the first-line, then we might introduce an immune checkpoint inhibitor in the second-line.One complexity is that a number of phase 3 trials that led to second-line approvals were based on progression after sorafenib. So, for example, regorafenib and cabozantinib were studied only after sorafenib. We extrapolate that data when we are now using these drugs after other front-line regimens, but of course, there is no direct evidence for that sequence.In short, it is challenging. We are trying to individualize based on what the patient previously received, their liver function, their tolerability, and also what toxicities they may have experienced. It requires nuance and judgment.Dr. He: That makes sense. Would you say that multidisciplinary collaboration is even more important in these settings?Dr. Harding: Absolutely. These decisions are not made in isolation. If a patient is experiencing immune-related adverse events, I always consult with our hepatology colleagues. Their input is essential, especially when managing patients with borderline liver function. I also think having pharmacists, nursing staff, and even interventional radiology involved can be critical for optimizing outcomes.Dr. Yarchoan: I agree with everything that has been said. It is worth emphasizing that a significant percentage of patients unfortunately never make it to second-line therapy. So getting the frontline therapy right is extremely important.But if patients do make it to second-line, I usually switch classes, as Dr. Harding mentioned. The clinical trials in the second-line were done after sorafenib, and it is not always clear how to apply that to someone who received, for example, atezolizumab and bevacizumab up front. Still, I think those same second-line options are reasonable.We are also seeing promising data now with cabozantinib in combination with checkpoint inhibitors. For example, cabozantinib and atezolizumab is being studied in the COSMIC trial. So I think we will get more data soon that may help guide us more definitively.Dr. Vijayvergia: Yes, and while we wait for more data, we rely on our understanding of the mechanisms and patient characteristics. I also think it is important to assess what the patient wants at that point. Some patients may not wish to pursue another systemic therapy after progression, depending on how their quality of life has been.When they are eligible and interested, I usually opt for TKIs in the second-line if they started with an ICI-based regimen. There are still limited data for what is optimal, but switching classes feels like a sound approach for now.Dr. He: Looking ahead, what are some directions in drug development that excite you?Dr. Yarchoan: There is a lot happening. One of the most exciting areas is bispecific antibodies. These agents can target both the tumor and immune cells simultaneously, which may increase efficacy without necessarily increasing toxicity.I am also excited about triplet regimens. For example, combining a TKI, an anti-VEGF agent, and a checkpoint inhibitor. The data are early, but some studies suggest this approach might achieve deeper responses.Dr. Harding: I would add GPC3-targeted therapies to that list. GPC3 is expressed on many HCC tumors but not on normal tissue, making it a promising target. There are antibody-drug conjugates, CAR T cells, and other modalities being explored in this space.I think the goal in all of these is to find therapies that can both shrink tumors and be tolerable in patients who often have limited liver reserve.Dr. Vijayvergia: Absolutely. I think we will also see more personalization of treatment. Right now, we mostly treat all advanced HCC the same way, regardless of underlying etiology or molecular profile. But I think in the future, we will better identify which patients are most likely to benefit from specific therapies, perhaps through biomarkers or genetic profiling.That would be a real step forward for the field.

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The panel highlights the lack of definitive data and the rationale behind using second-line TKIs or ICIs.