Rapid Progress in HCC Paradigm Shifts Standards, Sequencing Strategies

Bradley G. Somer, MD

Following a period of stagnation, rapid advances have been made in the treatment of patients with hepatocellular carcinoma (HCC), according to Bradley G. Somer, MD, but as more options emerge in all lines of treatment, sequencing approaches will require careful consideration.

“Several new therapies are available in HCC, which is a complicated disease that should be considered in a multidisciplinary setting. Since the field is evolving so rapidly, questions should be asked often,” said Somer, an associate professor in the Department of Hematology and Medical Oncology at the University of Tennessee Health Science Center.

In May 2020, the combination of atezolizumab plus bevacizumab was approved by the FDA for use in patients with unresectable or metastatic HCC who had not received previous systemic treatment based on data from the pivotal phase 3 IMbrave150 trial.

Results from the trial showed that the combination reduced the risk of death by 42% compared with sorafenib in this patient population (HR, 0.58; 95% CI, 0.42-0.79; P = .0006). The regimen was also found to reduce the risk of disease progression or death by 41% versus sorafenib (HR, 0.59; 95% CI, 0.47-0.76; P <.0001).

“The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is an excellent new standard of care in terms of systemic therapy, and several exciting second-line therapies have recently emerged, as well,” added Somer. “This is an exciting field, but it’s important to remember that this is a disease that requires careful thought prior to initiating therapy.”

In an interview with OncLive during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Somer, who is also a medical oncologist, a senior partner of the Executive Cancer Council, and the head of Strategic Expansion/Development in the West Cancer Center Research Program at West Cancer Center, discussed shifts in the HCC treatment paradigm, pivotal trials that have generated excitement, and sequencing approaches.

OncLive: Could you discuss some of the key advances recently made in HCC treatment?

Somer: HCC is a very complex disease. Many of these patients have underlying illnesses. However, new therapies [have emerged]. There is a new standard of care in the first-line setting based on data from the IMbrave150 trial. However, this also adds layers of complexity in terms of how to manage the next line of treatment. [It’s important to consider the] data [that have emerged in the] second- and third-line [settings] to [determine how to] best manage these patients.

Could you expand on IMbrave150 and the impact of this trial on the treatment paradigm?

Since 2008, the prior standard had been oral TKIs, specifically sorafenib (Nexavar), which was approved by the FDA in 2008. There was not much change [until 10 years later], in 2018, when lenvatinib (Lenvima) was FDA approved based on data from a noninferiority study. VEGF TKIs were the previous standard until recently.

The IMbrave150 study compared sorafenib with bevacizumab plus atezolizumab. This trial was powered for overall survival (OS) and progression-free survival (PFS); investigators also examined safety. A clear OS benefit was observed [with the combination]; survival was improved by approximately 42%. In addition, the toxicity profile of the regimen was found to very reasonable. When you look at the VEGF inhibitors, as a class effect, they tend to have some quality-of-life (QOL)–related adverse effects that make it very difficult in this patient population. These toxicities can include hand-foot syndrome, asthenia, diarrhea, and other QOL-related toxicities, but you don't see as much with atezolizumab plus bevacizumab. For the patients who are without a contraindication, this represents a new standard of care in the frontline setting.

Are there any patients for whom you would not recommend using this combination?

This therapy is clearly a new standard. [The combination has] a better OS, PFS, and a more favorable toxicity profile for most patients. That being said, for some patients, this might not necessarily be applicable. For example, this therapy may be less desirable for transplant patients, a checkpoint inhibitor might be relatively contraindicated or those who have other medical conditions. The caveat is that the trial enrolled patients with Child-Pugh A disease. In the real world, some of those patients may be Child-Pugh B or C. Then, you would have to consider that before making a decision.

Beyond this trial, what are some of the other approaches that have emerged in HCC? How are you approaching sequencing in practice?

The field is changing very rapidly. Many phase 3 trials are currently in development. In 1 trial, investigators examined the combination of lenvatinib plus pembrolizumab, which had [received breakthrough therapy] status. However, since atezolizumab plus bevacizumab came out, [this] was put on hold until the randomized, controlled, phase 3 LEAP-002 study [read] out. Other combination phase 3 studies are maturing; these could potentially alter the treatment landscape again in the first-line setting. This could happen in the next year or so. Stay tuned, because it’s likely that the story will continue to evolve.

In the second-line setting, multiple FDA approved drugs [are available]; they are all for patients who [progressed] on sorafenib or were intolerant to it; again, this is largely the Child-Pugh A population. We don't necessarily have a standard for those who progress on the atezolizumab/bevacizumab combination so it’s open for interpretation. You must decide on what to do next based on the frontline therapy that was received along with any underlying medical conditions they may have. You also must consider any toxicities they may have previously experienced, their performance status, etc. This can all help determine the next line of therapy. Also, the efficacy and toxicity profile of each drug also plays an important role in the decision-making process.

In the past couple of years, many options have emerged, largely in [those who progressed on] sorafenib. We must now determine how to sort this out in the post–atezolizumab/bevacizumab era. There is a couple of ways to approach this. For example, regorafenib (Stivarga) and cabozantinib (Cabometyx) are options. Ramucirumab (Cyramza) is another option, specifically for patient populations with alpha-fetoprotein–high disease, defined by greater than 400 ng/mL. The combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) was recently FDA approved, so this regimen is also an option. These are all possibilities. You have to think tactically and strategically.

In the third-line setting, the only drug with data is cabozantinib and potentially some of the checkpoint inhibitors.

You could possibly use cabozantinib in the third-line setting, and in the second line you are left with the others. When you look at alpha-fetoprotein of greater than 400 ng/mL, you've got a biomarker that will help select patients for therapy. If patients have levels that are over 400 ng/mL, you have ramucirumab as an option, since there are survival data in that biomarker-selected patient population.

In addition, while all of these drugs can cause hypertension, you don't have the hand-foot syndrome with ramucirumab that you have with the VEGF inhibitors. In the other group of patients, you may consider VEGF inhibitors, or potentially the combination of ipilimumab and nivolumab, depending on the patient given the high response rates seen with this approach.

Notably, we do not have a head-to-head comparison to drive the ipilimumab/nivolumab combination. The approach is exciting, and I believe it’s a great option, especially if you are looking for high response rates and long-term benefit; however, it would be interesting to see that analyzed against 1 of the current standards.

Could you further highlight the role of alpha-fetoprotein (AFP) as a biomarker in this space?

AFP clearly has prognostic information and you can also use it to help monitor therapy and to define the disease. In terms of selection of therapy, we don't have a great way to select patients for any kind of therapy through a biomarker.

Initially, the pivotal trial with ramucirumab, which was compared the agent with sorafenib, [patients were] stratified by AFP high and low and the benefit was seen in the patients who had AFP of greater than 400 ng/mL. In this pivotal study, AFP over 400 ng/mL was utilized as a biomarker.

All patients had to have alpha-fetoprotein over 400 ng/mL and that's where we saw the survival benefit [with the approach]. This proved that in this specific patient population, you do have the survival benefit and it wasn’t just a post-hoc analysis; it was a prospectively designed biomarker. I believe that it's an important piece of information to help guide therapy because we really don't have any.

Is there anything else that you would like to add?

This is an extremely rapidly evolving field. In the past 2 years, we have seen several FDA approvals in the second-line setting. A few exciting studies are ongoing, including the 1 assessing the combination of lenvatinib and pembrolizumab in the frontline setting. Emerging data with the VEGF inhibitor apatinib (YN968D1) in the second-line setting have also looked good. Data are also looking promising with immunotherapy combinations.

Historically, there was not much to offer to patients with this disease, but now there are many options. There's an enormous amount of thought that goes into deciding which therapy to use in which setting. It’s a very multi-dimensional and multidisciplinary disease. The issues with this disease should be considered as part of a collaborative effort, incorporating other colleagues such as those in hepatology, interventional radiology, and surgery.

Reference

FDA approves Genentech’s Tecentriq in combination with Avastin for people with the most common form of liver cancer. News release. Genentech. May 29, 2020. Accessed August 19, 2020. https://bit.ly/2Aneztc.