MedPage Today brought together three leaders in the field of liver cancer to discuss the latest research and clinical advances. In this second of four exclusive episodes, moderator Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York City, is joined by Amit Singal, MD, of UT Southwestern Medical Center in Dallas, and Peter R. Galle, MD, PhD, of Mainz University Medical Center in Germany, for a roundtable discussion on the various combination therapies in hepatocellular carcinoma (HCC).
Following is a transcript of their remarks:
Abou-Alfa: Hello everybody, and thanks for joining us on this roundtable on liver cancer. It’s a great pleasure to have you on board and my name is Ghassan Abou-Alfa from Memorial Sloan Kettering Cancer Center, New York. I’m joined today by dear colleagues Dr. Peter Galle from University in Mainz, Germany, as well as Dr. Singal from University Texas Southwest in Dallas.
Let’s move on to a very important other subject as we already excited everybody, and we excited ourselves, about the different lines of therapy. And I’ll start with you, Peter. So, no doubt that the tyrosine kinase inhibitors played a role, no doubt that the check pointers were attempted, then we finally settled to a combination of therapies. Tell us about the combination of therapies, what does it mean to you? Give us examples, your experience.
Galle: Yeah, and sorafenib [Nexavar] entered the stage, we were excited. Systemic therapy started and it was supposed to be well tolerated. That’s what the study said. In reality, patients were suffering, and objectively there was not a lot to see; almost no objective response.
In this setting, there was some reluctance and systemic therapy was not taken over to the extent recommended by guidelines. Then as Amit earlier mentioned, there were all these trials negative in the end for the next 10 years, showing us something about toxicity and trial design, but no success. And then with the advent of immunotherapy, everybody got excited because then we saw responses, we saw all of a sudden 10-20% objective responses, and in individual patients, very durable, very deep responses. But in clinical trials, these monotherapeutic approaches actually failed. And then combination started, atezolizumab [Tecentriq], bevacizumab [Avastin], and this really was the breakthrough, six months more above sorafenib, objective response of 30%. This was exciting and this has changed the routine. And you can see that. If you go to the outpatient clinic, these patients earlier with their hand-foot disasters they were looking differently. Now patients are in good shape and tolerate therapy well. So it’s a dramatic difference. I feel privileged that I was part of this development.
Abou-Alfa: That’s right, and I totally agree with you. This is a great combination we start with. And of course there were other combinations that really people were excited about, and among which also the dual checkpoint inhibitors, like, for example, durvalumab [Imfinzi] plus tremelimumab [Imjudo] that also was showing positive outcome.
Interestingly though, in those two positive studies, there has been always a challenge in regard to who are the patients. And let’s go back to Dr. Singal and let us talk about etiology. As we know, HCC is really based on at least four main etiologies. How do these patients fare in regard to checkpoint inhibitors and is there any difference or any false in that regards?
Singal: Yeah, so Ghassan, as you’ve brought up, there’s different etiologies of the underlying liver disease, whether that’s viral hepatitis or non-viral hepatitis, predominantly non-alcoholic fatty liver disease [NAFLD] or alcohol-associated cirrhosis. This is an interesting debate in the field. And so there was a nice preclinical study that suggested patients with non-viral etiologies, particularly those with underlying NAFLD, may not have the same responses to immunotherapy as those patients who have viral liver disease, and there’s been subsequent post-hoc analyses of some of the clinical trials which suggest that this may actually be seen in patients.
However, we should remember that these are post-hoc analyses, not well adjusted, and so I think, at least my estimation is, that these sort of hypothesis-generating data are too premature for us to change our clinical practice at this time.
I think this needs further evaluation, but I think at this point, as Peter said, I mean these combination therapies significantly improve survival compared to the alternatives. So you’re taking a look at a median survival with atezolizumab and bevacizumab of 19 months compared to 13 months with sorafenib. Marked difference. And I can tell you when we see patients in clinical practice, we do not change, currently, our recommendations based on liver disease etiology. And if it was my mom or my dad who had HCC and needed a therapy, I would go with these combination therapies given the exciting survival we see in these settings.
Abou-Alfa: Well, thanks so much Dr. Singal, this is a very important message. And Peter you presented on this last year, and JAMA Oncology just had a great paper just yesterday about anti-drug antibody [ADA] and pretty much brought in that after all patients with anti-drug antibody exactly as you presented at ACR [American College of Rheumatology] last year. And now we have an article for the first time in JAMA Oncology talking about that these patients don’t fare that well. Your perspective with that, because especially you’re involved in the effort with the atezolizumab and bevacizumab.
Galle: Yeah, so first thing is it’s very difficult to generate evidence here because the development of ADA, is nothing you can stratify on. It’s something which is developing on trial. And that results in an uneven distribution with respect to prognostic factors. And that is something which is hard to differentiate, the presence of antibodies and these prognostic factors.
Then it’s very different to have a true time- and objective response-related assessment, because where did it start, ADAs? It started in rheumatology, in inflammatory bowel disease. That’s very clear. There is an increased inflammatory course, then there is a loss of activity, and then you have to do something about it.
A patient progressing with a tumor, that’s quite different. And that might be for various reason and not just attributed to ADAs. So at present, I don’t see a very solid evidence, and in particular with respect to liver disease patients, the option to add immune-suppressive or antiproliferative agents such as methotrexate, azathioprine, that and in particular corticoids, that might not be the way to deal with patients with liver disease. So we are stuck a bit.
Abou-Alfa: Well, that’s very important and so nice to hear from you as well. So to again summarize for our colleagues, no doubt that there’s a great excitement regard to the treatment of liver cancer. We heard about two important combinations that really showed positive outcome; one of them is atezolizumab plus bevacizumab. The other one is of durvalumab plus tremelimumab, which we’re waiting for the FDA approval of, even though the trial was already published and reported free.
On the other hand, we spoke about [that] etiology would not necessarily matter. Yes, maybe as Dr. Singal mentioned, the hepatitis B etiology patients might fare best in regard to checkpoint inhibitors, followed by the hep C [hepatitis C], followed by the non-viral. However, it does not mean that everybody should get the therapy, because even though it’s to a “lesser” extent of benefit, still there’s benefit. So no doubt that will depend on that as a reference point for the therapy.
And thirdly, we brought in the ADA. Admittedly, this is something that has been going on for a while with atezolizumab specific[ally], there is a certain data that suggested that ADA are more likely to occur with atezolizumab. Dr. Galle, as he showed us, he reported at the ACR last year, that about 30% patients might have the ADA. I kind of brought up that subject because interestingly, there was literally an article barely a day old, 23 hours old, looking into JAMA Oncology on the patients who received atezolizumab and how the ADA did impact regard to the survival outcome.
Watch episode one in this series: Recent Advances in Systemic Therapy for Hepatocellular Carcinoma