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Novel Combinations for Treating mHCC

Panelists: Ghassan K. Abou-Alfa, MD, MBA, Memorial Sloan Kettering Cancer Center; Anthony B. El-Khoueiry, MD, Southern California Clinical and Translational Science Institute; Catherine T. Frenette, MD, MD Anderson Cancer Center; Pierre Gholam, MD, UH Westlake Health Center; Ahmed Kaseb, MD, MD Anderson Cancer Center
Published: Friday, Mar 20, 2020



Transcript:

Ghassan K. Abou-Alfa, MD, MBA: It’s not really as simple as we thought because, Anthony, there are other combinations that at the moment we are still looking into. Tell us, beside ATEZO-BEV [atezolizumab-bevacizumab], what else is going on?

Anthony B. El-Khoueiry, MD: As far as other combinations, sticking with the concept of combining immuno-oncology agents, like anti–PD-1 [programed cell death protein 1] or anti–PD-L1 [programmed death-ligand 1] agents—what we call anti-VEGF agents. We talked about bevacizumab, which is an anti-VEGF antibody. However, the TKIs [tyrosine kinase inhibitors] all have VEGF inhibition, among other targets.

We have a combination of pembrolizumab with lenvatinib. We’ve seen phase Ib data with that combination. That looks promising. Again, the response rates with these combinations are all sitting around the 30% range roughly, and the median PFS [progression-free survival] is about 7 months or so. There’s a phase III ongoing, the LEAP-002 trial, combining, comparing pembrolizumab-lenvatinib with lenvatinib. We’re awaiting the completion of that trial. There are multiple similar combinations. Cabozantinib with atezolizumab is being evaluated in a phase III study as well.

Ghassan K. Abou-Alfa, MD, MBA: The COSMIC-312, correct?

Anthony B. El-Khoueiry, MD: The COSMIC-312 trial, thank you. There are several phase Ib studies that are being reported—lenvatinib plus nivolumab from Japan, pembrolizumab with regorafenib—all around the same theme. Again, all are showing this response rate in the 30% range. What’s important to wait for is, are the readouts related to survival? Are the readouts related to toxicity?

There’s no question that based on the early data we are seeing, combining an anti–PD-1 or PD-L1 antibody with a TKI can result in some toxicity requiring dose interruptions and dose reductions. And probably a slightly higher rate of grades 3 and 4 toxicities compared with single agent. That’s something to keep in mind.

The last comment I’ll make is that the other combination that’s being evaluated in first line, is I/O-I/O [immuno-oncology], specifically PD-1 or PD-L1 with CTLA4. We’ve seen phase Ib, phase II data from the CheckMate040 with nivolumab plus ipilimumab. And we know that there are early phase data from durvalumab-tremelimumab, which is being evaluated in a phase III trial known as HIMALAYA. This is ongoing, and the nivolumab-ipilimumab combinations are being evaluated in another CheckMate trial. I forget the number of it.

To comment briefly on the I/O-I/O combinations, what we’ve seen from the nivolumab-ipilimumab combination, there were 3 different schedules on doses being evaluated. It makes it a bit complicated. The response rate again is about 31% with that. There was higher toxicity with the higher ipilimumab dosage of 3 mg/kg. But when looking at survival, the higher IPI [ipilimumab] dose resulted in a median OS [overall survival] of 22 months or so compared with 12 to 13 months with the lower IPI [ipilimumab] doses.

The study was not powered to compare survival across these different schedules and doses, so more follow-up is needed there. And with DURVA-TREME [durvalumab-tremelimumab], we saw some early data with response rates around 17%. But again, we await the phase III data for that.

Ghassan K. Abou-Alfa, MD, MBA: Ahmed, of those different combinations that we’re talking about— understandably, we don’t have the data; I totally agree with Anthony that we don’t have the data yet—is any of them more appealing, from your perspective? Do you think one is more interesting scientifically? What are the potential adverse events?    

Ahmed Kaseb, MD: The major advantage that you know we’re watching—the field is evolving so fast—is the fact that we have gone beyond the last feeling of monotherapy, of immunotherapy, given off 15% response rate for month of PCP. Now we’re at a different level where we went up to about 30%. It’s not a home run yet; we still have a way to go. But it’s really providing our patients with an advantage of prolonged survival with drugs we can tolerate. We’re still encountering this major issue of being just in the palliative space.

I think back to our point earlier about moving systemic to earlier stages. It’s very, very critical at this point, even not only in Barcelona Clinic Liver Cancer stage B, but maybe A, for patients who are undergoing surgery. We’re going to see a way if our team and others are doing neoadjuvant, adjuvant. These strategies are really going to transform the role of immunotherapy and targeted therapy from palliative to potentially being cured in the future.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD, MBA: It’s not really as simple as we thought because, Anthony, there are other combinations that at the moment we are still looking into. Tell us, beside ATEZO-BEV [atezolizumab-bevacizumab], what else is going on?

Anthony B. El-Khoueiry, MD: As far as other combinations, sticking with the concept of combining immuno-oncology agents, like anti–PD-1 [programed cell death protein 1] or anti–PD-L1 [programmed death-ligand 1] agents—what we call anti-VEGF agents. We talked about bevacizumab, which is an anti-VEGF antibody. However, the TKIs [tyrosine kinase inhibitors] all have VEGF inhibition, among other targets.

We have a combination of pembrolizumab with lenvatinib. We’ve seen phase Ib data with that combination. That looks promising. Again, the response rates with these combinations are all sitting around the 30% range roughly, and the median PFS [progression-free survival] is about 7 months or so. There’s a phase III ongoing, the LEAP-002 trial, combining, comparing pembrolizumab-lenvatinib with lenvatinib. We’re awaiting the completion of that trial. There are multiple similar combinations. Cabozantinib with atezolizumab is being evaluated in a phase III study as well.

Ghassan K. Abou-Alfa, MD, MBA: The COSMIC-312, correct?

Anthony B. El-Khoueiry, MD: The COSMIC-312 trial, thank you. There are several phase Ib studies that are being reported—lenvatinib plus nivolumab from Japan, pembrolizumab with regorafenib—all around the same theme. Again, all are showing this response rate in the 30% range. What’s important to wait for is, are the readouts related to survival? Are the readouts related to toxicity?

There’s no question that based on the early data we are seeing, combining an anti–PD-1 or PD-L1 antibody with a TKI can result in some toxicity requiring dose interruptions and dose reductions. And probably a slightly higher rate of grades 3 and 4 toxicities compared with single agent. That’s something to keep in mind.

The last comment I’ll make is that the other combination that’s being evaluated in first line, is I/O-I/O [immuno-oncology], specifically PD-1 or PD-L1 with CTLA4. We’ve seen phase Ib, phase II data from the CheckMate040 with nivolumab plus ipilimumab. And we know that there are early phase data from durvalumab-tremelimumab, which is being evaluated in a phase III trial known as HIMALAYA. This is ongoing, and the nivolumab-ipilimumab combinations are being evaluated in another CheckMate trial. I forget the number of it.

To comment briefly on the I/O-I/O combinations, what we’ve seen from the nivolumab-ipilimumab combination, there were 3 different schedules on doses being evaluated. It makes it a bit complicated. The response rate again is about 31% with that. There was higher toxicity with the higher ipilimumab dosage of 3 mg/kg. But when looking at survival, the higher IPI [ipilimumab] dose resulted in a median OS [overall survival] of 22 months or so compared with 12 to 13 months with the lower IPI [ipilimumab] doses.

The study was not powered to compare survival across these different schedules and doses, so more follow-up is needed there. And with DURVA-TREME [durvalumab-tremelimumab], we saw some early data with response rates around 17%. But again, we await the phase III data for that.

Ghassan K. Abou-Alfa, MD, MBA: Ahmed, of those different combinations that we’re talking about— understandably, we don’t have the data; I totally agree with Anthony that we don’t have the data yet—is any of them more appealing, from your perspective? Do you think one is more interesting scientifically? What are the potential adverse events?    

Ahmed Kaseb, MD: The major advantage that you know we’re watching—the field is evolving so fast—is the fact that we have gone beyond the last feeling of monotherapy, of immunotherapy, given off 15% response rate for month of PCP. Now we’re at a different level where we went up to about 30%. It’s not a home run yet; we still have a way to go. But it’s really providing our patients with an advantage of prolonged survival with drugs we can tolerate. We’re still encountering this major issue of being just in the palliative space.

I think back to our point earlier about moving systemic to earlier stages. It’s very, very critical at this point, even not only in Barcelona Clinic Liver Cancer stage B, but maybe A, for patients who are undergoing surgery. We’re going to see a way if our team and others are doing neoadjuvant, adjuvant. These strategies are really going to transform the role of immunotherapy and targeted therapy from palliative to potentially being cured in the future.

Transcript Edited for Clarity
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