Yarchoan Discusses New HCC Trials and Abstracts to be Presented at ESMO 2022

Mark Yarchoan, MD

Many trials are exploring immune-oncology (IO) therapies combined with VEGF antibodies, tyrosine kinase inhibitors (TKIs), and other IO agents aiming to develop new treatment options for patients with hepatocellular carcinoma (HCC).

According to Mark Yarchoan, MD, the current standard of care for this patient population is the combination of bevacizumab (Avastin) and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq).

Use of bevacizumab/atezolizumab is supported by findings of the IMbrave150 study (NCT03434379) which evaluated the efficacy and safety of atezolizumab in and bevacizumab vs sorafenib (Nexavar) in patients with locally advanced or metastatic HCC.

This study was the first to show that the combination demonstrated an improvement in overall survival (OS) vs the old standard of care, sorafenib alone.

Still, experts in the HCC field are always looking to find new regimens to further improve patient outcomes. This includes adding onto the standard-of-care regimens with new agents.

According to Yarchoan, an assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, the future will point towards new anti-VEGF and IO combinations as well as IO-IO combinations like durvalumab (Imfinzi) plus tremelimumab (Ticilimumab), or ipilimumab (Yervoy) and nivolumab (Opdivo).

“Although we made a lot of progress in the last couple of years, response rates to doublet therapies are in a range of 20% to 30%, and it would be great if we were starting to push response rates towards 50%. I think that what we must do is add in third agents. Already, you are starting to see some early clinical trials of triplet therapy. I think the goal should be to beat our current standard of care,” said Yarchoan in an interview with Targeted Oncology^TM.

In the interview, Yarchoan discusses the current HCC space as well as 3 late breaking abstracts that will be presented at the 2022 ESMO Congress.

Yarchoan: The most preferred frontline therapy for HCC is the combination of bevacizumab and atezolizumab, based on the IMbrave150 study. This was the first study to show an improvement in overall survival vs the old standard of care, sorafenib. At least right now, you need a reason not to give a patient that bevacizumab and atezolizumab in first-line therapy. There are many patients who don't qualify for this therapy, including patients at particular risk for bleeding, patients with active autoimmune disease, patients who've had a recent transplant, etc.

We also have a second regimen that has shown improved overall survival vs sorafenib. That's the combination of durvalumab and a single dose of tremelimumab. It is not yet FDA approved but we anticipating that this will soon be another first-line option for patients. Which patients should get bevacizumab/atezolizumab vs who should get durvalumab/tremelimumab remains unclear because we don't have a head-to-head study of these 2 active regimens. I think durvalumab and tremelimumab is going to be a great option for patients who are not candidates for anti-VEGF therapy. That may be where the regimen gets the most use.

Where do you think research in this field is pointing towards?

I can't perfectly predict the future, but I think we're going to get to a situation where we have multiple active regimens in the first-line setting, including anti-VEGF/IO combinations like bevacizumab and atezolizumab, and IO-IO combinations like durvalumab/tremelimumab and maybe soon, ipilimumab, and nivolumab. I think we need biomarkers to determine who should get IO-IO vs anti-VEGF IO. Right now, we don’t have biomarkers to guide therapy selection for most patients and the decision for first-line therapy is largely based on side effects and efficacy in unselected groups of patients.

More broadly, we've entered a stage where the majority of patients should be offered doublet therapy, and we're starting to think about triplet therapy. How can we improve upon the regimens that we already have? Response rates to doublet therapies are in a range of 20% to 30%, and it would be great if we were starting to push response rates towards 50%. I think what we have to do is identify new combinations that build on our current doublets. Already, you are starting to see some early clinical trials of triplet therapy. The goal should be to beat our current standard of care.

Can you explain the background of LBA34 that will be presented at ESMO which will discuss the primary results from the phase 3 LEAP-002 study?

At this point, I'm discussing this abstract without having seen the data yet. The LEAP-002 study reportedly missed its primary end point. This is the combination of lenvatinib [Lenvima] and pembrolizumab [Keytruda] vs lenvatinib as a monotherapy. Many of us were hopeful that the study would be positive because I think it's fair to say that lenvatinib and pembrolizumab are active in HCC. There was a phase 1B study that showed the highest response rate I've seen of a frontline study thus far..

I think the challenge is that lenvatinib alone is an effective agent. In this era, patients can essentially crossover from one lenvatinib to IO based therapies. Some of that may have hurt the study, and the study may have been a little bit underpowered. We will have to see what the data looks like. It wouldn't surprise me if LEAP-002 ends up showing an impressive response rate OS and PFS for the doublet, but just not enough to be the single agent because the single agent performed well. It's a trend we've seen with many frontline studies where the control arm, which is usually a TKI monotherapy control, seems to be doing better and better because of the availability of second-line therapies. So again, very interesting, and somewhat disappointing. Without seeing the data, its hard to speculate, but one wonders if lenvatinib/pembrolizumab would have beat sorafenib if the trial had been run concurrently with IMbrave150.

The combination of cabozantinib and atezolizumab was also a disappointing readout in the frontline setting. The combination met its PFS end point, but not the OS end point. It does raise a question whether TKI/IO is the best strategy or whether bevacizumab based combinations make more sense because of toxicity concerns. Again, its hard to speculate without seeing all of the data yet, but we must look at all these studies together to try to understand broad signals.

What can you tell us about LBA35 examining the phase 3 trial of camrelizumab [SHR1210] and rivoceranib [apatinib] vs sorafenib in the first-line for patients with unresectable hepatocellular carcinoma?

It is interesting that reportedly, the combination of camrelizumab and rivoceranib, which is another TKI/IO combination, was positive. This was a global study but done mostly outside of the United States. It's not clear if this regimen will get approved in the United States. Again, we have to look at the data, but there is at least 1 positive TKI/IO study in HCC.

Why was that positive while lenvatinib/pembrolizumab, and cabozantinib/atezolizumab were not positive or semi-positive for cabozantinib is unclear. It may have had more to do with where the studies were done and the availability of second-line therapy than anything else. At least that's my suspicion, without having seen the data.

What are you most excited to learn about at ESMO this year?

We learn more about HCC from each of these large, randomized studies. I'm interested to see what the curves look like for LEAP-002. Did everything go in the right direction and was it just underpowered for its end points?

One other study worth mentioning is the tislelizumab [BGB-A317], which is another single agent PD1 vs sorafenib study. This is a little bit less exciting for me. We already had nivolumab vs sorafenib in the frontline setting [Checkmate 459], which showed similar OS as sorafenib but failed to show superiority. Then we had durvalumab as a single-agent vs sorafenib, which formally hit non-inferiority. I don’t think we need to test this again but now we have another PD-1 agent showing non-inferiority versus sorafenib.

At this point, I think it's fair to say that PD-1 is active in HCC and is not worse than sorafenib and better tolerated than sorafenib. Unless there are big surprises in the data, I suspect that the RATIONALE-301 study will further boost our confidence in this conclusion.

What unmet needs still exist in the HCC space?

Although it's exciting that we've had so many large, randomized phase 3 studies reading out and patients are living longer than ever before with better quality of life than ever before, the survival for HCC still lags. As compared to many other tumor types, response rates are lower in HCC. I think it's fair to celebrate the work that's been done. I think we still need more effective regimens and there's a lot more work to do. In particular we need to understand immune resistance and why some of these tumors do not respond to immunotherapy, and we need biomarkers to identify these patients who should be treated with alternative regimens.

Another major unmet need right now are patients with impaired liver function, the Child Pugh B patients. All of these frontline studies that we've talked about are focused on patients with excellent liver function. For those of us who treat HCC in clinical practice, we have many patients who come in the door with borderline liver function. The optimal management of these patients is unclear. We need regimens that are safe for this population, and to better tease out which of these patients are likely to benefit from systemic therapy in the first place. This remains a major challenge.