Clinical Trial Results Allude to New Options for Patients With HCC

The hepatocellular carcinoma (HCC) space has been presented with a number of trials exploring immune-oncology (IO) therapies combined with VEGF antibodies, tyrosine kinase inhibitors (TKIs), and more over the past 5 years.

Currently, more than 1 standard-of-care option exists in this space, including the combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) or regorafenib (Stivarga) in the first-line setting, and camrelizumab (AiRuiK), or nivolumab (Opdivo), ipilimumab (Yervoy), and ramucirumab (Cyramza) in the second-line setting.

Even though many options are available, investigators continue to look for better outcomes for their patients. This includes investigating novel therapies alone and adding onto the standard-of-care regimens.

Updated data from trials evaluating new options in HCC were discussed in 3 late breaking abstracts presented at the European Society for Medical Oncology (ESMO) Congress 2022.

These trials included the phase 3 RATIONALE-301 (NCT03412773) study of frontline tislelizumab vs sorafenib, a phase 3 study (NCT03764293) examining the PD-1 inhibitor camrelizumab combined with rivoceranib, and the phase 3 LEAP-002 study (NCT03713593) of lenvatinib plus pembrolizumab (Keytruda).

In an interview with Targeted Oncology^TM, Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed 3 late breaking abstracts in the HCC space currently influencing the field.

Targeted Oncology: Can you discuss some abstracts presented at ESMO 2022 that sparked interest in the HCC space?

Abou-Alfa: There was great excitement at an oral session with 3 late breaking abstracts that really help us shape our thoughts regarding the treatment of advanced hepatocellular carcinoma or liver cancer. We were all excited about the LEAP-002 study which evaluated the combination of pembrolizumab plus lenvatinib, an anti PD-1 plus anti-EGFR vs lenvatinib as a standard of care as a TKI. It is a drug that we all use and have used. That study carried on with high anticipation because of the concept of combining a checkpoint inhibitor plus an anti-TKI or specifically, an anti-MGF, per se, especially because the phase 1B study of the combination was promising within the limitation of it being phase 1 study. It had been a median survival of 22 months. However, the LEAP-002 study of pembrolizumab plus lenvatinib vs lenvatinib was negative.

It showed that the median survival did not differ much between the lenvatinib plus pembrolizumab arm which was a total of 21 months vs lenvatinib at 19 months. If anything, the hazard ratio did not favor that improved survival that we're all looking for which was 0.84. The question is why. Understandably, that could be the design of the study. It could be, did people get second-line therapy after the lenvatinib? If anything, yes, at least a certain percentage of them, not all of them, but about 20% or more did receive second-line checkpoint inhibitors. Number 3 is, could the population be in particular regard to that. A very important point over here, that the hepatitis B patients were close to at about 50%, where we know that checkpoint inhibitors favor best regard to the patients with hepatitis B.

Could it be that the lenvatinib did well because of some particular or what they received afterwards as a second-line therapy. We can argue that maybe the completion does not work. But also, we need to find out how much and why lenvatinib as a single agent got to that setting. We're very delighted with it, it is an easy drug to use and very easy to manage, so this brings a lot of questions, and frankly, more questions than answers.

What did you think about the data presented regarding the phase 2 trial evaluating camrelizumab and rivoceranib vs sorafenib in the first-line for unresectable HCC?

Camrelizumab and rivoceranib is again, an anti-PD1 plus anti-VEGF, which was evaluated vs sorafenib. This study was positive, showing a clear improvement in survival in favor of the combination therapy of Camrelizumab plus rivoceranib at 22 months vs sorafenib at 15 months. What's going on over here? Lenvatinib is 19 months and here, sorafenib is at 15. I think the 15 months with sorafenib has already been reported in studies, and this is just how much it can do. Could it be that the anti-MGF of the lenvatinib favors its improved survival in LEAP-002? Time will tell.

In the camrelizumab and rivoceranib study, it is also important to recall that the patients with hepatitis B were the majority. About 75% of the patients were those with hepatitis B, which is expected with the study running mainly in Asia, specifically in China.

It was a positive study, and we are excited about the drugs. We don't have as much experience in regard to those drugs in the Western Hemisphere, but there will definitely be further input into guiding us and defining the role of that therapy. But at the same time, it's going to pose a little bit of a question about the comparator arm, as we just heard, even though I will still say legit comparator on per se.

What are your thoughts on the 3rd abstract which was presented during this session regarding the phase 3 RATIONALE-301 trial?

The third study was another intriguing point for all of us. This is another anti-PD-1, tislelizumab, vs sorafenib in an inferiority study looking for equivalency between the 2, which is fair and an appropriate question as we have seen from other alternative studies like nivolumab vs sorafenib, pembrolizumab vs placebo, and recently, the HIMALAYA study [NCT03298451] of durvalumab [Imfinzi] single-agent vs sorafenib, which was looked at also for inferiority. Intriguingly, that study was positive, because it did not show any non-inferiority and it showed a clear non-separation between the 2 arms of the study, bringing up an important point in regard to what is the role of single-agent, anti-PD-1in regard to HCC.

These are great results, but we have to build the story together. Interestingly, it appears to be that they're not all equal in regard to either single-agent or combination therapies. Number 2, we're getting a sense that some of them are probably better than others. Of course, number 3 is that the dynamics in the field are evolving so fast that even comparisons among studies is not correct, not necessarily fair. On top of this, we now have the combination of camrelizumab and rivoceranib with again, 22 months vs sorafenib. Also, we have the lenvatinib plus pembrolizumab, which again is a negative study, but close to 22 months as well.

What would you say is the key takeaway from this study?

It's all about the geology. Number 1 in the real-world data from the atezolizumab and bevacizumab, there were less than 50% of patients in the IMbrave-150 [NCT03434379] that were positive for hepatitis B. Number 2 is the very robust results that we have seen for the camrelizumab plus rivoceranib is dependent on 75% of the patients with hepatitis B and to add to this, 50% of the patients had hepatitis B in regard to the lenvatinib plus pembrolizumab. Interestingly, it is real-world data. However, the percentage with hepatitis B was only about 30%-40%. Interestingly, the same thing applies for the patients in the HIMALAYA study which was only 30%.

What are the implications of these findings?

Clearly, it tells you that it does play a role. You can get more benefits here and there. For the future, we have a dynamic field, and we have to settle for what would be a good reference point for us. As an example, durvalumab/tremelimumab is because it's a global study with 1400 patients. It includes 30% with hepatitis B, 30% with hepatitis C, and 40% non-viral, which is a good representation. Number 2, could it be that we have to start delineating the patients based on the specific etiology and do different trials? Time will tell. Number 3 could be the immune microenvironment with other variables could be analyzed, and of course, this something to think of as well.

So, how can we pass on this information to all patients so they benefit from all over the world? As we all know, in the continent of Africa, hepatitis B related to HCC has the highest incidence in the world and sadly as we have studied last year, part of the effort that was led by Memorial Sloan Kettering Cancer Center in regard to the guidelines with liver cancer in Africa, 84% of the physicians only have access to sorafenib. The question is, could some of those kinds of studies be started and vetted into regard to different technologies, different ethnicities, and different parts of the world? Time will tell.