® titled “A New Wave of Progress in the Treatment of Hepatocellular Carcinoma.” I’m Anthony El-Khoueiry. I’m a GI [gastrointestinal] medical oncologist at the USC [University of Southern California] Norris Comprehensive Cancer Center in Los Angeles, California. I’m joined by 3 friends and colleagues who are experts in the field of treatment of hepatocellular carcinoma [HCC], and I ask them to introduce themselves. I’d like to start with Dr Nicole Rich.

 Hi. My name is Nicole Rich. I’m a transplant hepatologist at UT [University of Texas] Southwestern Medical Center in Dallas, Texas.

 My name is Pierre Gholam. I’m a professor of medicine at Case Western Reserve University School of Medicine, and I lead our multidisciplinary hepatobiliary tumor team at the NCI [National Cancer Institute]–designated Seidman Cancer Center in Cleveland, Ohio.

 Hi, everyone. I’m Daneng Li. I’m a GI medical oncologist, and I lead our hepatobiliary tumor program at City of Hope in Duarte, California.

 Welcome, everyone. We’re going to discuss a number of recent updates regarding the treatment of hepatocellular carcinoma, including some exciting abstracts and presentations from the 2022 ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium]. We’ll discuss the data in the context of other recent updates to the treatment landscape and their impact on clinical practice.

Let’s get started with our first topic, which is a review of the approved first-line systemic options for patients with advanced HCC. I’ll start by covering the data as of January 2022, and then ask some of my colleagues to update on other newer developments. I’ll start chronologically. For a long time, sorafenib was the only standard of care for advanced HCC. This was based on the SHARP trial as well as another international study known as the Asia-Pacific trial, both of which compared sorafenib with placebo. In the SHARP trial, sorafenib was superior to placebo with a median overall survival [OS] of between 10 and 11 months.

Then we had a long gap of close to 10 years of negative studies in which different compounds were either compared with sorafenib or added to sorafenib. They all failed until the REFLECT study was conducted, which was a noninferiority study comparing lenvatinib with sorafenib in patients with advanced HCC. These are patients with Child-Pugh A cirrhosis and good performance status. They had to be candidates for systemic therapy. Patients were randomized 1:1 to lenvatinib or sorafenib, and the study met its noninferiority end point. The median overall survival with lenvatinib was about 13 months, and with sorafenib, it was about 12 months. The confidence interval was below the threshold of 1.08, which was required to meet the noninferiority end point. Despite the median OS being quite similar, lenvatinib had a higher PFS [progression-free survival] and superior response rate compared with sorafenib. That may have influenced how it was used compared with sorafenib in the clinic.

After that came the data with single-agent anti–PD-1 therapy with nivolumab and pembrolizumab, with phase 1/2 studies showing promising response rates and durable responses. Those data led to the phase 3 study known as CheckMate 459. That study compared nivolumab with sorafenib in previously untreated patients with first-line advanced HCC. It was a superiority study. In that study, nivolumab led to a median overall survival of around 16 months, and sorafenib around 14 months, but the study didn’t meet the superiority end point. It wasn’t statistically significant. The response rate was confirmed. It was the same as what’s seen in the phase 1/2 data, with a response rate of around 16% or 17% for nivolumab. The responses were durable. The safety was confirmed as well. As a matter of fact, the quality-of-life data favored nivolumab for the duration of therapy in that trial. But it was a negative study, statistically speaking.

The next step was to add on to anti–PD-1 therapy. That brings us to the IMbrave150 study, in which atezolizumab, an anti-PD-L1 antibody, was combined with bevacizumab, the anti-VEGF antibody. Atezolizumab-bevacizumab was compared with sorafenib. This was a 2:1 randomization with Child-Pugh A patients, mostly BCLC [Barcelona Clinic Liver Cancer] stage C. The study was a positive trial at all levels. There was a superior overall survival, a superior PFS, and a superior response with the combination of atezolizumab and bevacizumab. The median overall survival was an unprecedented 19 months for the combination of atezolizumab-bevacizumab vs about 13 months with sorafenib. The PFS was about 6.9 months, and the response rate was about 30% with atezolizumab-bevacizumab.

Of note, because of the risk of bleeding with bevacizumab, this study required that patients undergo an endoscopy within 6 months prior to enrollment to ensure that if there were varices, the requirement was that they’d be treated based on institutional standard. It required variceal screening and therapy based on institutional standard. Those are the data as of January 2022. I focus mostly on efficacy, but based on this, atezolizumab-bevacizumab became the first-line standard for patients who have no contraindications to immunotherapy or bevacizumab. Otherwise, the options were to use TKIs [tyrosine kinase inhibitors], like sorafenib or lenvatinib.

Videos

Anthony B. El-Khoueiry, MD, provides insight on the evolution of care for frontline systemic therapy in advanced HCC and discusses currently approved first-line standard of care options.

First-Line Systemic Treatment for Advanced HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses research on biomarkers in hepatocellular carcinoma (HCC). 

An important area of research in HCC is on biomarkers, says El-Khoueiry. Given that patients with advanced HCC have access to multiple therapies, it would be beneficial to know which patients are going to respond to which agents. To that end, some preliminary research regarding biomarkers for anti—PD-1 agents have emerged, adds El-Khoueiry.

For example, in the phase I/II CheckMate-040 trial, which evaluated the safety and efficacy of nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in advanced HCC, investigators showed that PD-L1 expression was associated with a higher objective response rate. However, PD-L1 was not shown to be a definitive biomarker as there were responders in the PD-L1—negative group of the trial as well. Right now, it is an evolving area of research. As such, biomarkers should not be used to select patients for treatments in current practice, concludes El-Khoueiry.

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses research on biomarkers in hepatocellular carcinoma (HCC).

Dr. El-Khoueiry Discusses Research on Biomarkers in HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses immunotherapy combination in hepatocellular carcinoma (HCC).

There are several combinations of immuno-oncology (IO) agents plus other IO agents under investigation. One of the most promising combinations is PD-1/L1 inhibition with CTLA-4 inhibition. Additionally, there is the phase III HIMALAYA trial, which is combining durvalumab (Imfinzi) and tremelimumab versus durvalumab alone versus sorafenib (Sutent) in the frontline setting. Furthermore, data from a phase II cohort of nivolumab (Opdivo) plus ipilimumab (Yervoy) are anticipated.

There is also rationale to combine PD-1 inhibitors with anti-VEGF targeted therapies, says El-Khoueiry. For example, the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima), which has shown a promising early signal. There are also combinations of nivolumab and sorafenib as well as nivolumab and lenvatinib in ongoing trials. The combination of atezolizumab (Tecentriq) with bevacizumab (Avastin) is also worth mentioning, adds El-Khoueiry, as this combination has shown an objective response rate (ORR) of approximately 30%. Investigators are still working to determine whether the toxicity of these combinations is tolerable and whether the improvement in ORR will translate to improved overall survival.

Dr. El-Khoueiry on Immunotherapy Combinations in HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses choosing between immunotherapy agents and TKIs in hepatocellular carcinoma (HCC).

According to data from phase I/II studies, nivolumab (Opdivo) and pembrolizumab (Keytruda) can be used in the second-line setting as well as in the third-line setting. The trial eligibility did not limit the number of prior lines of therapy; however, patients must have had prior exposure to sorafenib (Nexavar), says El-Khoueiry. It can be difficult to decide between a TKI and a PD-1 inhibitor in the second-line setting as there are no head-to-head trials that have compared these agents directly. Therefore, a lot of the decision comes down to patient characteristics.

PD-1 inhibitors may induce a long-lasting response. However, not all patients will reach third- or fourth-line treatment. In those cases, giving these agents as second-line therapy may be the patient’s best chance of deriving benefit from them. For patients who are progressing rapidly or have high-risk disease, giving them immunotherapy may also be preferable in the second-line setting as opposed to a TKI. However, the TKIs are FDA approved based on phase III data and level 1 evidence. For example, data regarding the sequence of frontline sorafenib and second-line regorafenib (Stivarga) indicate a median overall survival of 26 months.

Dr. El-Khoueiry on Choosing Between Immunotherapy Agents and TKIs in HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses the role of ramucirumab (Cyramza) in advanced hepatocellular carcinoma (HCC).

Ramucirumab, a VEGFR-2 antibody, is one of several agents that has been tested in the second-line setting for patients who have previously been treated with sorafenib (Nexavar). The drug was first evaluated in the phase III REACH study, which was negative. However, a subgroup analysis indicated that patients with an alpha-fetoprotein (AFP) ≥400 benefitted from ramucirumab. Therefore, the phase III REACH-2 study was launched, homing in on this specific patient population.

REACH-2 was a positive study showing an improvement in overall survival (OS) with ramucirumab versus placebo in patients with AFP ≥400. The median OS of 8 months was a little bit less than what has been seen with the VEGF TKIs in this space, but cross-trial comparisons have caveats, El-Khoueiry says. In a joint analysis of REACH and REACH-2, it was determined that there was a 3-month improvement in OS with ramucirumab in this select population.

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses the role of ramucirumab in advanced hepatocellular carcinoma.

Dr. El-Khoueiry on the Role of Ramucirumab in Advanced HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, distinguishes between lenvatinib (Lenvima) and sorafenib (Nexavar) in the frontline treatment of advanced hepatocellular carcinoma (HCC).

Choosing between the 2 TKIs is challenging because the phase III REFLECT study, which led to the FDA approval of lenvatinib in the frontline setting, was a noninferiority study. Lenvatinib was successful in demonstrating noninferiority in terms of overall survival compared with sorafenib. The agent also demonstrated a superior progression-free survival (PFS) and overall response rate (ORR). However, PFS and ORR were secondary endpoints of the trial, and it’s difficult to make treatment decisions based on secondary endpoints, says El-Khoueiry.

Nevertheless, lenvatinib is a potent drug that targets VEGF and FGFR, creating a unique mechanism of action, El-Khoueiry says. The higher ORR and longer PFS may make lenvatinib an option for symptomatic patients who need an immediate response or who may not make it to subsequent lines of therapy.

With regards to safety, the 2 TKIs appear to have overlapping toxicities. However, there was higher risk of hypertension with lenvatinib and higher risk of hand-foot syndrome with sorafenib in the REFLECT study. This could be another factor in determining the right TKI to use, El-Khoueiry concludes.

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, distinguishes between lenvatinib and sorafenib for the frontline treatment of advanced hepatocellular carcinoma.

Dr. El-Khoueiry on Choosing Between Lenvatinib and Sorafenib in HCC

Anthony B. El-Khoueiry, MD, associate professor of Clinical Medicine, USC Norris Comprehensive Cancer Center, discusses the role that immunotherapy currently plays, and will continue to play, in the treatment landscape of hepatocellular carcinoma (HCC).

Currently, the only approved therapy in this space is sorafenib (Nexavar). Because of the tolerability of immunotherapy, as well as its mechanism of action, El-Khoueiry sees ample opportunity to incorporate such agents into earlier stages of disease.

El-Khoueiry expects that immunotherapy may be best evaluated in combination with loco-regional therapies in earlier stages of disease. Immunotherapy may also have a future role in the adjuvant setting, following resection.

Anthony B. El-Khoueiry, MD, associate professor of Clinical Medicine, USC Norris Comprehensive Cancer Center, discusses the role that immunotherapy currently plays, and will continue to play, in the treatment landscape of hepatocellular carcinoma (HCC). 

Dr. El-Khoueiry on Evolving Role of Immunotherapy in HCC

Anthony B. El-Khoueiry, MD, associate professor of Clinical Medicine, USC Norris Comprehensive Cancer Center, discusses the rationale for evaluating nivolumab in advanced hepatocellular carcinoma (HCC).

There is evidence that supports the evaluation of nivolumab in this setting, says El-Khoueiry. The evidence of CD8 and CD4 T-cell infiltration has been detected in some tumors with HCC. The expression of both inhibitory and stimulatory checkpoints have been expressed in HCC as well.

There are also data that demonstrate that a higher level of infiltration of CD8+ cytotoxic T lymphocytes is a good prognostic marker, and is associated with better outcomes for patients. On the other hand, says El-Khoueiry, expression of PD-L1 or PD-L2 on a tumor is associated with worse outcomes.

Anthony B. El-Khoueiry, MD

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