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Novel I/O Combination HCC Therapies

Panelists: Ghassan K Abou-Alfa, MD, Memorial Sloan Kettering Center; Katie Kelley, MD, Hellen Diller Family Comprehensive Cancer Center; Farshid Dayyani, MD, University of California Irvine School of Medicine; Amit Singal, MD, University of Texas Southwestern Medical Center
Published: Friday, Sep 06, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD:
We spoke about checkpoint inhibitors, and we declared that 5 TKIs [tyrosine kinase inhibitors] already are FDA approved solid, and on top of that, 2 checkpoint inhibitors, they are still kind of lingering, waiting for phase III data. Some of it we’re going to hear at ASCO [the American Society of Clinical Oncology] 2019 Annual Meeting for pembrolizumab, and some for nivolumab, still we didn’t hear about. One question is, and of course, we are asked as oncologists this question all the time, why don’t we do something else and what about combining those things together? I’ll start by asking about the combination of a checkpoint inhibitor plus tyrosine kinase inhibitor or anti-VEGF, or what have we. And I’ll start with Farshid. Any idea that comes to mind in that scenario?

Farshid Dayyani, MD: I think of some of the largest trials that we’re waiting for results on is the combination of atezolizumab and bevacizumab versus sorafenib in the first-line setting. We have atezolizumab ongoing with cabozantinib in the first-line setting versus sorafenib. I don’t think a randomized trial with pembrolizumab/lenvatinib is ongoing or completed already. So there are a number of trials that combine VEGF inhibition with checkpoint inhibitors in the first-line setting. We look forward to seeing those results.

Ghassan K. Abou-Alfa, MD: Fair enough. So atezolizumab plus bevacizumab, and remember bevacizumab was studied at length in regard to HCC [hepatocellular carcinoma] and unfortunately did not show positive results. What do you think?

Amit Singal, MD: When this was initially presented, the response rates were extremely high. It was a poster presentation, and my understanding is that it actually got some of the most press coming out of the meeting, actually more than many of the oral presentations.

Ghassan K. Abou-Alfa, MD: I remember, this was here in Chicago last year.

Amit Singal, MD: Last year. And since, we’ve seen updated data. I think the data have come back down to earth a little bit, the response rates are lower than initially presented. But it’s still higher than what we’re used to seeing with single-agent I/O [immunotherapy] or single-agent TKI. So I still think it’s a promising path forward, but we’ll have to wait for the final data. I think it’s still too early to tell in terms of the combination therapies.

Ghassan K. Abou-Alfa, MD: I think this is a very fair assessment of that specific situation. Katie, along the same line, there’s quite a bit of activity in regard to, for example, pembrolizumab plus lenvatinib, atezolizumab plus cabozantinib. Tell us about those.

Katie Kelley, MD: Right. These are also logical combinations to ask about their efficacy in HCC because  both individual drug components we think have potential for benefit. In the case of TKIs, there are some data that there is remodeling of the immune microenvironment that may reduce the immunosuppressive factors, particularly with drugs like lenvatinib or cabozantinib, and promote a greater likelihood of immune response when combined with a checkpoint inhibitor. Right now these are based on data from small phase I and phase II trials across tumor types.

There’s a phase Ib trial I believe of lenvatinib plus pembrolizumab that showed a promising response rate by modified RECIST [response evaluation criteria in solid tumors], over 25%. That led to the trial in development of lenvatinib plus pembrolizumab. It is awaited. And likewise, a combination of cabozantinib plus atezolizumab that has also shown higher than expected response rates for either drug singly or in combination across tumor types, which has prompted a phase III trial of cabozantinib plus atezolizumab.

Ghassan K. Abou-Alfa, MD: That’s incredible. This is really quite fascinating that after this whole kind of fooling around between the TKIs and then adding the checkpoint inhibitors, now we’re looking at the combination of the 2. On top of that, what about a combination of checkpoint inhibitors? I think this is an effort that is critical, which is combining an anti–PD-L1 [programmed death-ligand 1] and an anti–CTLA-4 [cytotoxic T-lymphocyte–associated protein 4]. Katie, because you’re involved quite a bit in that, and full disclosure, you and I are involved in this, tell us a little bit more about the DURVA/TREME [durvalumab/tremelimumab].

Katie Kelley, MD: You’re of course referring to the ongoing phase I/II trial that has grown into a rather large trial of approximately 300 patients looking at a randomized design comparing durvalumab, the PD-L1 inhibitor, as 1 arm; tremelimumab, a CTLA-4 inhibitor, alone, is 1 arm; 2 different combination regimens of both drugs are the third and fourth arms. That trial is ongoing, and we’re looking forward to results sometime in the future. The phase I component that we already presented at ASCO several years back in 2017, I believe, showed acceptable safety, most importantly, for the starting point. It showed that the combination of the CTLA-4 plus durvalumab had no unexpected safety signal and led to the development of the ensuing trial.

Further, there were a number of durable responses seen, and the unconfirmed response rate was about 25% in the phase I small cohort, only about 40 patients. But that prompted not only the phase II expansion, but in parallel, the development of a large phase III trial called HIMALAYA, which looks at durvalumab versus the combination of tremelimumab plus durvalumab versus an active control arm of sorafenib.

Ghassan K. Abou-Alfa, MD: It is interesting. By the way, this whole concept of the checkpoint inhibitors is quite fascinating because, as we know, the T cell trying to attack the tumor is offered by the body because of that self behavior, a nice chair, so it doesn’t attack the tumor cell. And this anti–PD-1 [programmed cell death protein 1] will kick that chair out, or the anti–PD-L1 will also kick that chair out, and the T cell will fall onto the tumor. Interestingly however, this might be well enough as we saw with the nivolumab and the pembrolizumab. But it appears to be that this kind of kicking thing is actually activated from the upper floors at the lymph node level with the CTLA-4. Because what happens is CD28 will talk to CD80 and CD86, and they will activate all that’s necessary to really lead to that preventive effect that we just spoke about at the T-cell level and the tumor.

But interestingly, CTLA-4 will come into play and try to hang out with CD80 and CD86, which are 2 important molecules, and let alone this prevention of this kind of messaging to happen down to the tumor cell. And as such, an anti-CTLA-4 will be a critical component of activating the chain of command that will ultimately lead to further activation of the anti–PD-L1 at the tumor level. And that’s where tremelimumab and the anti–CTLA-4 will come into play, with anti–PD-L1 with durvalumab come under. This is where the HIMALAYA study is ongoing, that we’re again as I said, in full disclosure, Katie and I were heavily involved in regard to first the phase II study as well as the HIMALAYA study. This definitely will bring in quite a bit of further information down the road in regard to combination, not only of checkpoint inhibitors plus TKI, but also checkpoint inhibitors plus checkpoint inhibitor.

Let’s say that you’re going to tweet in a minute about HCC to your friends or to your followers. The tweet with our rules, 1 sentence only. What is your tweet sentence about HCC?

Farshid Dayyani, MD: Combination is very exciting and hopeful.

Ghassan K. Abou-Alfa, MD: I like that. Katie?

Katie Kelley, MD: Now that we have more tools at our disposal, we need to understand the underlying biology to use them best.

Ghassan K. Abou-Alfa, MD: OK, great. I like that, understand better the biology of what we’re doing.

Amit Singal, MD: I’m pretty sure that was over the character limit.

Ghassan K. Abou-Alfa, MD: Oh well, see, it went.

Amit Singal, MD: Early detection is critical. Curative therapies should be done.

Ghassan K. Abou-Alfa, MD: I like that as well. These are 3 very important messages that we hear. Number 1 is we really have to make sure that we continue to monitor for patients and make sure that we do early detection and try to cure patients. This is very critical. On the other hand, we’re very excited about the advent of different therapies, and I like the innovative thoughts brought by Farshid that it’s the combination we have to really invest further in. But also, the very important and strategic decision is to make sure we understand what we’re doing, and Katie as well mentioned. I totally agree on all those 3. I’m not tweeting myself, but I can put them all together in 1 tweet.

I have to say that this really has been extremely informative. And I thank you very much for those discussions. We very much appreciate all the input that Dr Farshid Dayyani has given us, with the recommendation for further evaluating the different combinations of therapy. Dr Katie Kelley, who again recommended for us continue with a better understanding of the combination therapies that we have. Dr Singal, who suggests that we continue an important obligation to make sure we screen patients, we prevent the disease, and we cure the disease wherever we can, very important. So I thank you all for your contributions to this discussion. On behalf of our panel, we thank you very much for joining us, and we hope you find this Peer Exchange discussion to be useful and informative.


Transcript Edited for Clarity 

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Transcript: 

Ghassan K. Abou-Alfa, MD:
We spoke about checkpoint inhibitors, and we declared that 5 TKIs [tyrosine kinase inhibitors] already are FDA approved solid, and on top of that, 2 checkpoint inhibitors, they are still kind of lingering, waiting for phase III data. Some of it we’re going to hear at ASCO [the American Society of Clinical Oncology] 2019 Annual Meeting for pembrolizumab, and some for nivolumab, still we didn’t hear about. One question is, and of course, we are asked as oncologists this question all the time, why don’t we do something else and what about combining those things together? I’ll start by asking about the combination of a checkpoint inhibitor plus tyrosine kinase inhibitor or anti-VEGF, or what have we. And I’ll start with Farshid. Any idea that comes to mind in that scenario?

Farshid Dayyani, MD: I think of some of the largest trials that we’re waiting for results on is the combination of atezolizumab and bevacizumab versus sorafenib in the first-line setting. We have atezolizumab ongoing with cabozantinib in the first-line setting versus sorafenib. I don’t think a randomized trial with pembrolizumab/lenvatinib is ongoing or completed already. So there are a number of trials that combine VEGF inhibition with checkpoint inhibitors in the first-line setting. We look forward to seeing those results.

Ghassan K. Abou-Alfa, MD: Fair enough. So atezolizumab plus bevacizumab, and remember bevacizumab was studied at length in regard to HCC [hepatocellular carcinoma] and unfortunately did not show positive results. What do you think?

Amit Singal, MD: When this was initially presented, the response rates were extremely high. It was a poster presentation, and my understanding is that it actually got some of the most press coming out of the meeting, actually more than many of the oral presentations.

Ghassan K. Abou-Alfa, MD: I remember, this was here in Chicago last year.

Amit Singal, MD: Last year. And since, we’ve seen updated data. I think the data have come back down to earth a little bit, the response rates are lower than initially presented. But it’s still higher than what we’re used to seeing with single-agent I/O [immunotherapy] or single-agent TKI. So I still think it’s a promising path forward, but we’ll have to wait for the final data. I think it’s still too early to tell in terms of the combination therapies.

Ghassan K. Abou-Alfa, MD: I think this is a very fair assessment of that specific situation. Katie, along the same line, there’s quite a bit of activity in regard to, for example, pembrolizumab plus lenvatinib, atezolizumab plus cabozantinib. Tell us about those.

Katie Kelley, MD: Right. These are also logical combinations to ask about their efficacy in HCC because  both individual drug components we think have potential for benefit. In the case of TKIs, there are some data that there is remodeling of the immune microenvironment that may reduce the immunosuppressive factors, particularly with drugs like lenvatinib or cabozantinib, and promote a greater likelihood of immune response when combined with a checkpoint inhibitor. Right now these are based on data from small phase I and phase II trials across tumor types.

There’s a phase Ib trial I believe of lenvatinib plus pembrolizumab that showed a promising response rate by modified RECIST [response evaluation criteria in solid tumors], over 25%. That led to the trial in development of lenvatinib plus pembrolizumab. It is awaited. And likewise, a combination of cabozantinib plus atezolizumab that has also shown higher than expected response rates for either drug singly or in combination across tumor types, which has prompted a phase III trial of cabozantinib plus atezolizumab.

Ghassan K. Abou-Alfa, MD: That’s incredible. This is really quite fascinating that after this whole kind of fooling around between the TKIs and then adding the checkpoint inhibitors, now we’re looking at the combination of the 2. On top of that, what about a combination of checkpoint inhibitors? I think this is an effort that is critical, which is combining an anti–PD-L1 [programmed death-ligand 1] and an anti–CTLA-4 [cytotoxic T-lymphocyte–associated protein 4]. Katie, because you’re involved quite a bit in that, and full disclosure, you and I are involved in this, tell us a little bit more about the DURVA/TREME [durvalumab/tremelimumab].

Katie Kelley, MD: You’re of course referring to the ongoing phase I/II trial that has grown into a rather large trial of approximately 300 patients looking at a randomized design comparing durvalumab, the PD-L1 inhibitor, as 1 arm; tremelimumab, a CTLA-4 inhibitor, alone, is 1 arm; 2 different combination regimens of both drugs are the third and fourth arms. That trial is ongoing, and we’re looking forward to results sometime in the future. The phase I component that we already presented at ASCO several years back in 2017, I believe, showed acceptable safety, most importantly, for the starting point. It showed that the combination of the CTLA-4 plus durvalumab had no unexpected safety signal and led to the development of the ensuing trial.

Further, there were a number of durable responses seen, and the unconfirmed response rate was about 25% in the phase I small cohort, only about 40 patients. But that prompted not only the phase II expansion, but in parallel, the development of a large phase III trial called HIMALAYA, which looks at durvalumab versus the combination of tremelimumab plus durvalumab versus an active control arm of sorafenib.

Ghassan K. Abou-Alfa, MD: It is interesting. By the way, this whole concept of the checkpoint inhibitors is quite fascinating because, as we know, the T cell trying to attack the tumor is offered by the body because of that self behavior, a nice chair, so it doesn’t attack the tumor cell. And this anti–PD-1 [programmed cell death protein 1] will kick that chair out, or the anti–PD-L1 will also kick that chair out, and the T cell will fall onto the tumor. Interestingly however, this might be well enough as we saw with the nivolumab and the pembrolizumab. But it appears to be that this kind of kicking thing is actually activated from the upper floors at the lymph node level with the CTLA-4. Because what happens is CD28 will talk to CD80 and CD86, and they will activate all that’s necessary to really lead to that preventive effect that we just spoke about at the T-cell level and the tumor.

But interestingly, CTLA-4 will come into play and try to hang out with CD80 and CD86, which are 2 important molecules, and let alone this prevention of this kind of messaging to happen down to the tumor cell. And as such, an anti-CTLA-4 will be a critical component of activating the chain of command that will ultimately lead to further activation of the anti–PD-L1 at the tumor level. And that’s where tremelimumab and the anti–CTLA-4 will come into play, with anti–PD-L1 with durvalumab come under. This is where the HIMALAYA study is ongoing, that we’re again as I said, in full disclosure, Katie and I were heavily involved in regard to first the phase II study as well as the HIMALAYA study. This definitely will bring in quite a bit of further information down the road in regard to combination, not only of checkpoint inhibitors plus TKI, but also checkpoint inhibitors plus checkpoint inhibitor.

Let’s say that you’re going to tweet in a minute about HCC to your friends or to your followers. The tweet with our rules, 1 sentence only. What is your tweet sentence about HCC?

Farshid Dayyani, MD: Combination is very exciting and hopeful.

Ghassan K. Abou-Alfa, MD: I like that. Katie?

Katie Kelley, MD: Now that we have more tools at our disposal, we need to understand the underlying biology to use them best.

Ghassan K. Abou-Alfa, MD: OK, great. I like that, understand better the biology of what we’re doing.

Amit Singal, MD: I’m pretty sure that was over the character limit.

Ghassan K. Abou-Alfa, MD: Oh well, see, it went.

Amit Singal, MD: Early detection is critical. Curative therapies should be done.

Ghassan K. Abou-Alfa, MD: I like that as well. These are 3 very important messages that we hear. Number 1 is we really have to make sure that we continue to monitor for patients and make sure that we do early detection and try to cure patients. This is very critical. On the other hand, we’re very excited about the advent of different therapies, and I like the innovative thoughts brought by Farshid that it’s the combination we have to really invest further in. But also, the very important and strategic decision is to make sure we understand what we’re doing, and Katie as well mentioned. I totally agree on all those 3. I’m not tweeting myself, but I can put them all together in 1 tweet.

I have to say that this really has been extremely informative. And I thank you very much for those discussions. We very much appreciate all the input that Dr Farshid Dayyani has given us, with the recommendation for further evaluating the different combinations of therapy. Dr Katie Kelley, who again recommended for us continue with a better understanding of the combination therapies that we have. Dr Singal, who suggests that we continue an important obligation to make sure we screen patients, we prevent the disease, and we cure the disease wherever we can, very important. So I thank you all for your contributions to this discussion. On behalf of our panel, we thank you very much for joining us, and we hope you find this Peer Exchange discussion to be useful and informative.


Transcript Edited for Clarity 
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