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Durable Activity in Synergistic Combination for 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: Wednesday, Mar 27, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD: Andrew, tell us a little bit about your interpretation of the atezo [atezolizumab] plus bevacizumab data that you have seen.

Andrew X. Zhu, MD, PhD: So the trial that you’re referring to is the combinations of a PD-L1 [programmed death-ligand 1] antibody.

Ghassan K. Abou-Alfa, MD: Correct.

Andrew X. Zhu, MD, PhD: Atezo in combination with a VEGF antibody, bevacizumab.

Ghassan K. Abou-Alfa, MD: Correct.

Andrew X. Zhu, MD, PhD: And in a very, very interestingly executed clinical trial, initially reported last year at ASCO [the American Society of Clinical Oncology Annual Meeting], I think at that time the successful response [in] patients was only 23 patients. But they were actually able to report a 60% response rate, which was really obviously [getting] everybody in the field very excited. And so you know that as we’re actually [getting] more patients, we’re following these patients longer, I think we’re still seeing very, very respectful response rate in the 30% range. But I think also more importantly, we need to see the mature data, how durable these responses are, and also the safety profile.

Suffice it to say, I think so far the safety profile seems to be manageable. I think this is really taking into consideration that we collectively in the field, we have learned both drugs reasonably well, particularly [the] bevacizumab-related safety profile. So I think each patient needs to be actually mandatory to have upper endoscopy, make sure they don’t have the bleeding risk. And for that reason I think the safety profile in that trial is actually incredibly respectful. But having said that, you know we still need to see the larger, more mature data set. But on the other hand, you know the study, as we know, the combination has been moved to the first-line setting comparison with sorafenib in a randomized phase III trial, right?

Ghassan K. Abou-Alfa, MD: Fair enough.

Andrew X. Zhu, MD, PhD: Yeah.

Ghassan K. Abou-Alfa, MD: Fair enough. And if anything, Rich, as we heard from Andrew, at ASCO last year, [in] 2018, we have seen the impressive response rate, which was even in some subgroups up to 72%. Then, however, the revision of this, which was presented at ESMO [the European Society of Medical Oncology 2018 Congress] back in October, did not show those responses. They kind of, like, were in a more realistic response rate. Your thoughts on that.

Richard S. Finn, MD: Well, I would still say 30%…in liver cancer, that’s a great response rate. And those were confirmed by independent review, by conventional RECIST criteria. So we’re really causing tumors to shrink. And this is not happening in a vacuum because this regimen also is active in lung cancer. In liver cancer it has a breakthrough therapy designation. The regimen seems to be well tolerated, and I don’t think anybody [is] surprised to see it drop. Just as we see exciting results in phase II, when we go to phase III the results are never as good in general in clinical research. And also when you go from 23 patients to over 50, I think now to 70 patients, you know you get a better distribution, right? Things are not by random chance. But I think we can say that this combination does have significant activity in liver cancer. The question is, like with CheckMate 459, will this activity be better than sorafenib?

Ghassan K. Abou-Alfa, MD: Fair enough. And if anything, by all means, I think we all agree that we are still highly intrigued by really the combination of a TKI [tyrosine kinase inhibitor] plus a checkpoint inhibitor. And as we already mentioned, there are many of them that are either being considered or in trial, or some reported data. And no doubt that the drugs authority we spoke about and we discussed, including the lenvatinib, including cabozantinib—and we didn’t hear yet about ramucirumab in that setting, but at least the lenvatinib and cabozantinib with their evaluation in combination with checkpoint inhibitors is definitely worth following—and see where this might take us at, of course, the atezo-bevacizumab that we heard about per se.

I go back to, however, something that actually Katie alluded to, which is, the anti-CTLA4. And you’re right, the story started there with the anti-CTLA4, intriguing responses, and then it kind of like metamorphosed into other things. And my understanding is that at the moment there is quite a bit of interest in combination of anti-CTLA4 plus anti-PD-L1. Tell us about that.

R. Kate Kelley, MD: Sure. So I think we often draw from experience in other tumor types to make progress in liver cancer following using examples in lung cancer or renal cell carcinoma historically. And I think in other tumor types, particularly lung cancer, we do see higher response rates with the combination of CTLA4 checkpoint inhibitor, combined with PD-1 [programmed cell death protein 1] or PD-L1 checkpoint inhibition. And so following upon that model, the combination of durvalumab and tremelimumab is now under study in the randomized phase III HIMALAYA trial. And likewise, nivolumab, the anti-PD-1 inhibitor, is being studied in an expanded phase II cohort as part of the original CheckMate040 study with ipilimumab, another CTLA4 inhibitor. And so we’ll look eagerly to those results to see is if we can also harness the combined checkpoint inhibition for higher response rates, higher efficacy as has been seen in other tumor types.

Ghassan K. Abou-Alfa, MD: Yeah, actually, there was another abstract that we saw at this GI ASCO [Gastrointestinal Cancers Symposium] 2019, which is about exactly the same combination that Katie is talking about, which is the tremelimumab plus durvalumab, which was reported by the NCI [National Cancer Institute] group. Dr [Charalampos] Floudas and colleagues showed it to be tolerated. And interestingly, we have seen the data, and actually some of it was reported by Katie at several of those meetings, that actually the combination is quite intriguing and definitely probably is valuable, as we saw in regard to the HIMALAYA study.

And I would say that my simplistic understanding of this is kind of like, they’re really fascinating because as we all know, in regard to the CTLA4, the story is that we have the CD80 and CD86, which are like 2 guys in regard to the immune system that are in the lymph nodes and they are actually talking to the CD28. And they hang out together. They go for coffee, and they are all active and energetic. But interestingly then, CTLA4 come and say, “Guys 80 and 86, why don’t you hang out with me.” But it appears to be what they drank made them asleep. And this is where anti-CTLA4 come into play.

But what really is fascinating [and] what’s intriguing is that CD28 itself, after this kind of, of course it will be upset [that] 80 and 86 are not talking to me anymore; they’re hanging with CTLA4. But CD28 itself can actually activate CTLA4. How would this go? Because it’s all about the clearing of our immune system to kind of create the right things.

And what’s fascinating is that this activity, and because especially of that and other retro feedbacks of CD28 activating CTLA4, is really where the anti-PD-L1 come into play available of the immune cells, which is really to try to shrink down that kind of bridge between the T cells and the tumor and cause that damage effect that the durvalumab, for example, will apply. And this really [is] the theory [that] is [now] being evaluated, exactly as Katie said, in the HIMALAYA study, looking at the combination of the tremelimumab plus durvalumab, compared [with] the durvalumab as a single agent, anti-PD-L1, exactly as we heard already about 2 of them from Rich and from Andy. And in addition to sorafenib as [a standard of] care, which will be the intriguing one because, interestingly, it goes back to what we just spoke about, the possible application of TKI followed by checkpoint inhibitor. This will be an important arm for the study. So that’s really [a] quite intriguing study, and we’ll see where this will take us per se.

Transcript Edited for Clarity

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Transcript: 

Ghassan K. Abou-Alfa, MD: Andrew, tell us a little bit about your interpretation of the atezo [atezolizumab] plus bevacizumab data that you have seen.

Andrew X. Zhu, MD, PhD: So the trial that you’re referring to is the combinations of a PD-L1 [programmed death-ligand 1] antibody.

Ghassan K. Abou-Alfa, MD: Correct.

Andrew X. Zhu, MD, PhD: Atezo in combination with a VEGF antibody, bevacizumab.

Ghassan K. Abou-Alfa, MD: Correct.

Andrew X. Zhu, MD, PhD: And in a very, very interestingly executed clinical trial, initially reported last year at ASCO [the American Society of Clinical Oncology Annual Meeting], I think at that time the successful response [in] patients was only 23 patients. But they were actually able to report a 60% response rate, which was really obviously [getting] everybody in the field very excited. And so you know that as we’re actually [getting] more patients, we’re following these patients longer, I think we’re still seeing very, very respectful response rate in the 30% range. But I think also more importantly, we need to see the mature data, how durable these responses are, and also the safety profile.

Suffice it to say, I think so far the safety profile seems to be manageable. I think this is really taking into consideration that we collectively in the field, we have learned both drugs reasonably well, particularly [the] bevacizumab-related safety profile. So I think each patient needs to be actually mandatory to have upper endoscopy, make sure they don’t have the bleeding risk. And for that reason I think the safety profile in that trial is actually incredibly respectful. But having said that, you know we still need to see the larger, more mature data set. But on the other hand, you know the study, as we know, the combination has been moved to the first-line setting comparison with sorafenib in a randomized phase III trial, right?

Ghassan K. Abou-Alfa, MD: Fair enough.

Andrew X. Zhu, MD, PhD: Yeah.

Ghassan K. Abou-Alfa, MD: Fair enough. And if anything, Rich, as we heard from Andrew, at ASCO last year, [in] 2018, we have seen the impressive response rate, which was even in some subgroups up to 72%. Then, however, the revision of this, which was presented at ESMO [the European Society of Medical Oncology 2018 Congress] back in October, did not show those responses. They kind of, like, were in a more realistic response rate. Your thoughts on that.

Richard S. Finn, MD: Well, I would still say 30%…in liver cancer, that’s a great response rate. And those were confirmed by independent review, by conventional RECIST criteria. So we’re really causing tumors to shrink. And this is not happening in a vacuum because this regimen also is active in lung cancer. In liver cancer it has a breakthrough therapy designation. The regimen seems to be well tolerated, and I don’t think anybody [is] surprised to see it drop. Just as we see exciting results in phase II, when we go to phase III the results are never as good in general in clinical research. And also when you go from 23 patients to over 50, I think now to 70 patients, you know you get a better distribution, right? Things are not by random chance. But I think we can say that this combination does have significant activity in liver cancer. The question is, like with CheckMate 459, will this activity be better than sorafenib?

Ghassan K. Abou-Alfa, MD: Fair enough. And if anything, by all means, I think we all agree that we are still highly intrigued by really the combination of a TKI [tyrosine kinase inhibitor] plus a checkpoint inhibitor. And as we already mentioned, there are many of them that are either being considered or in trial, or some reported data. And no doubt that the drugs authority we spoke about and we discussed, including the lenvatinib, including cabozantinib—and we didn’t hear yet about ramucirumab in that setting, but at least the lenvatinib and cabozantinib with their evaluation in combination with checkpoint inhibitors is definitely worth following—and see where this might take us at, of course, the atezo-bevacizumab that we heard about per se.

I go back to, however, something that actually Katie alluded to, which is, the anti-CTLA4. And you’re right, the story started there with the anti-CTLA4, intriguing responses, and then it kind of like metamorphosed into other things. And my understanding is that at the moment there is quite a bit of interest in combination of anti-CTLA4 plus anti-PD-L1. Tell us about that.

R. Kate Kelley, MD: Sure. So I think we often draw from experience in other tumor types to make progress in liver cancer following using examples in lung cancer or renal cell carcinoma historically. And I think in other tumor types, particularly lung cancer, we do see higher response rates with the combination of CTLA4 checkpoint inhibitor, combined with PD-1 [programmed cell death protein 1] or PD-L1 checkpoint inhibition. And so following upon that model, the combination of durvalumab and tremelimumab is now under study in the randomized phase III HIMALAYA trial. And likewise, nivolumab, the anti-PD-1 inhibitor, is being studied in an expanded phase II cohort as part of the original CheckMate040 study with ipilimumab, another CTLA4 inhibitor. And so we’ll look eagerly to those results to see is if we can also harness the combined checkpoint inhibition for higher response rates, higher efficacy as has been seen in other tumor types.

Ghassan K. Abou-Alfa, MD: Yeah, actually, there was another abstract that we saw at this GI ASCO [Gastrointestinal Cancers Symposium] 2019, which is about exactly the same combination that Katie is talking about, which is the tremelimumab plus durvalumab, which was reported by the NCI [National Cancer Institute] group. Dr [Charalampos] Floudas and colleagues showed it to be tolerated. And interestingly, we have seen the data, and actually some of it was reported by Katie at several of those meetings, that actually the combination is quite intriguing and definitely probably is valuable, as we saw in regard to the HIMALAYA study.

And I would say that my simplistic understanding of this is kind of like, they’re really fascinating because as we all know, in regard to the CTLA4, the story is that we have the CD80 and CD86, which are like 2 guys in regard to the immune system that are in the lymph nodes and they are actually talking to the CD28. And they hang out together. They go for coffee, and they are all active and energetic. But interestingly then, CTLA4 come and say, “Guys 80 and 86, why don’t you hang out with me.” But it appears to be what they drank made them asleep. And this is where anti-CTLA4 come into play.

But what really is fascinating [and] what’s intriguing is that CD28 itself, after this kind of, of course it will be upset [that] 80 and 86 are not talking to me anymore; they’re hanging with CTLA4. But CD28 itself can actually activate CTLA4. How would this go? Because it’s all about the clearing of our immune system to kind of create the right things.

And what’s fascinating is that this activity, and because especially of that and other retro feedbacks of CD28 activating CTLA4, is really where the anti-PD-L1 come into play available of the immune cells, which is really to try to shrink down that kind of bridge between the T cells and the tumor and cause that damage effect that the durvalumab, for example, will apply. And this really [is] the theory [that] is [now] being evaluated, exactly as Katie said, in the HIMALAYA study, looking at the combination of the tremelimumab plus durvalumab, compared [with] the durvalumab as a single agent, anti-PD-L1, exactly as we heard already about 2 of them from Rich and from Andy. And in addition to sorafenib as [a standard of] care, which will be the intriguing one because, interestingly, it goes back to what we just spoke about, the possible application of TKI followed by checkpoint inhibitor. This will be an important arm for the study. So that’s really [a] quite intriguing study, and we’ll see where this will take us per se.

Transcript Edited for Clarity
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