Tremelimumab Plus Durvalumab Receives FDA Approval for Unresectable Hepatocellular Carcinoma

Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York City, New York, discusses the Food and Drug Administration (FDA) approval of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma. Dr Abou-Alfa is the principal investigator of the phase 3 HIMALAYA trial, the results of which led to this approval.

In the phase 3 HIMALAYA trial, the median overall survival of those patients treated with tremelimumab plus durvalumab was 16.4 months compared to 13.8 months in those treated with the standard of care sorafenib. This represented a statistically significant improvement with tremelimumab plus durvalumab vs sorafenib.

On October 21, 2022, the FDA approved tremelimumab in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma, with a recommended dose of 300 mg tremelimumab intravenous in combination with 1500 mg durvalumab on day 1 of cycle 1, followed by the same dose of durvalumab every 4 weeks (for patients ≥30 kg).

Transcript:

Thanks again for having me. It was very delightful news this week, a new adjuvant therapy for our dear patients with hepatocellular carcinoma. This new approval is of the combination of 2 checkpoint inhibitors, durvalumab plus tremelimumab.

Before we go on, I think it's important for us to really understand what we’re trying to do, what's the mechanism of action of these 2 therapies together. As we know, durvalumab is another anti-PD-L1 therapy. Anti-PD-L1s work at the cellular brain level. It's offered as a comfortable seat for the T-cells so they don't attack the cancer, and the anti-PD-L1 is kicking that chair so the T-cells can fall onto the cancer.

Interestingly, we know this will not happen without an order from up the chain of command, that’s where CTLA4 comes into play. Tremelimumab is an anti-CTLA4, because as we know, CD28 talks to CD80/86 in all our lymph nodes, incites them to send the message all the way to the anti-PD-L1 to do their job. But this where CTLA4 come into play and hijacks the CD80/86, so they all fall asleep and nothing happens. Until an anti-CTLA4 comes into play, takes away CTLA4 to permit CD80/86 to send their message all the way to the cell membrane level for the anti-PD-L1 to do their job.

What was fascinating about the HIMALAYA study is that this anti-CTLA4, tremelimumab, is only needed for 1 dose. Wow. Why only one dose? Because it's so potent of an anti-CTLA4, enough that it is even 3 times more potent than CD28, that's at base in our body. And as such, you can think about it as a jump-start for your car when there’s cold weather and you want to jump start the battery: that’s tremelimumab. After that, pushing on the gas is the durvalumab, that you will give on a monthly basis. It's quite fascinating that now our dear patients can receive 1 therapy once a month with only 1 dose of tremelimumab at the start of the therapy. That's all that is needed.

In the study, the comparison was to standard of care, sorafenib. And sorafenib is a tyrosine kinase inhibitor.  And here we can see that there was an improvement in survival, up to 16.43 months compared to the sorafenib with 13.77 months. Clinically and statistically, this is significant, and more importantly, the combination is really very well tolerated. There has been understandably some adverse events, but thankfully nothing really of concern, short of the classic remedial reactions that we can see with the checkpoint inhibitors.

Where does this therapy come into play, in regard to all other therapies that we have for patients who had advanced hepatocellular carcinoma? Number 1, all the patients that have never had therapy. Anybody who doesn't have metastatic disease, anybody who does not have an incurable disease. Because when we have even locally advanced therapy, at some point the local therapy will unfortunately not help any further. At same time, we know very well that even patients with quite extensive locally advanced disease, they might benefit, as is reported in the literature from systemic therapy even further than from local therapy. And of course, patients with metastatic disease, sadly are most of the patients who will benefit from that treatment.

Durvalumab plus tremelimumab is a first-line therapy. There are other options of therapy that are available. Interestingly, I would say that we're entering with 2 categories of therapies. One of them is tyrosine kinase inhibitors, and we have 2 of them already available, sorafenib and lenvatinib as a single agent. And of course, we have got the combinations, 2 that are positive. One of them is the previously reported atezolizumab plus bevacizumab, and now with the recently reported durvalumab plus tremelimumab.

Is it fair to compare? No. Because as we know, we don't compare studies. But important also, we should not compare numbers, because the median survivals that we can see are really to be put in the perspective of the study itself. For example, in the atezolizumab plus bevacizumab, the median survival was 19 months. But we can look and see that 50% of patients had hepatitis B. While in the durvalumab tremelimumab trial, only 30% of the patients have hepatitis B. Why this is important? Because as we have seen in retrospective analysis that was done by our colleagues in UK recently, that was reported at ILCA, the International Liver Cancer Association meeting in Madrid in September, the patients that received atezolizumab plus bevacizumab as a first-line therapy in the real-world data analysis, the mean survival was only 15 months or so. Why is that? Because if you look at the demographics, there were more patients with non-viral than patients with hepatitis B. Again, the numbers are not to be compared across studies, but it's very important to look at the demographics and you'll see that ultimately everybody will benefit from the treatment.

There are certain conveniences offered with durvalumab-tremelimumab: no need for any evaluation for varices. We did not have any bleeding on this study for any varices. Number two is, there's no concern for antidrug antibody, which unfortunately some other checkpoint inhibitors have that problem. For example, with the atezolizumab up to 30% of patients had antidrug antibodies, while with durvalumab it was only 1.5%. And thirdly of course, the benefit of only needing the therapy once a month.

Where we go from there? The sky is the limit, and this is really what's the delightful thing for all of our dear patients here at Memorial Sloan Kettering. I am humbled to say that we witnessed the disease from really when this, sadly, the mean survival was barely 3 months. And look where we are today. And the potential for further improvement and outcome is definitely going forward.

We anticipate and we hope that we'll have access available for all patients with the disease wherever they are. We understand there are certain challenges, and certain requirements, and certain accessibility issues that might arise in certain parts of the world, but I'm sure working hand-in-hand, we'll be able to make sure that all our dear patients wherever they will be treated. Thanks again for having me.