El-Khoueiry Elucidates Recent Updates in the Rapidly Evolving HCC Treatment Paradigm

Anthony B. El-Khoueiry, MD, discusses the evolution of HCC treatment, paradigm-shifting trials, and where future research is headed.

Treatment for advanced hepatocellular carcinoma (HCC) continues to evolve, according to Anthony B. El-Khoueiry, MD, who adds that one of the key advances came in the form of the IMbrave150 trial, which was the first to show superiority of atezolizumab (Tecentriq) and bevacizumab (Avastin) over sorafenib (Nexavar), which was once the only standard of care.

“A massive evolution has occurred in the treatment of patients with HCC over the past couple of years. Multiple new agents have received approval, and with these approvals, the landscape continues to shift,” said El-Khoueiry, medical director of the Clinical Investigations Support Office at the University of Southern California Norris Comprehensive Cancer Center. “Among the most momentous changes has been the most recent data from the trial IMbrave150, which compared the combination of atezolizumab and bevacizumab with sorafenib; this was the first phase 3 trial to show superiority with the combination over sorafenib. As such, this approach has become the standard of care of the first-line treatment of patients with Child–Pugh A HCC.”

Results from the phase 3 IMbrave150 trial showed that atezolizumab plus bevacizumab resulted in a 42% reduction in the risk of death compared with sorafenib (HR, 0.58; 95% CI, 0.42-0.79; P = .0006); the regimen was also associated with a 41% reduction in the risk of disease progression or death versus sorafenib (HR, 0.59; 95% CI, 0.47-0.76; P <.0001). These data led to the May 2020 FDA approval of the combination for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic treatment.

In an interview with OncLive during the 2020 International Perspectives in Cancer on Gastrointestinal Cancer, El-Khoueiry, an associate professor of clinical medicine and director of the phase 1 drug development clinical program at the Keck School of Medicine at USC, discussed the evolution of HCC treatment, paradigm-shifting trials, and where future research is headed.

OncLive: What does frontline treatment for patients with HCC currently look like?

El-Khoueiry: For a long time, sorafenib was the only standard, first-line systemic therapy and has shown improved overall survival (OS) compared with placebo with a median OS of 10 to 11 months. Then, came the REFLECT trial, which was a noninferiority study comparing lenvatinib (Lenvima) with sorafenib. This was a large, international trial, with over 900 patients, and lenvatinib is another multitargeted TKI inhibitor that has more potent inhibition of the VEGF receptors, but it also inhibits the fibroblast growth factor receptor family.

Lenvatinib was shown to be noninferior to sorafenib, but with a superior progression-free survival (PFS) and response rate. Lenvatinib became a second first-line treatment option and we were able to choose between sorafenib and lenvatinib, until the atezolizumab and bevacizumab combination showed superiority to sorafenib and became the new standard of care.

Could you expand on the data reported from the pivotal IMbrave150 trial that led to this shift in the paradigm?

With regard to the IMbrave150 trial, which compared atezolizumab/bevacizumab with sorafenib, it's important to note that the eligibility criteria limited accrual to patients with Child–Pugh A, so well-preserved liver function. All patients also had to undergo an endoscopy prior to enrollment to ensure that, if there were varices, they were treated as per institutional standard. This is important, given the increased risk of bleeding that we’ve seen in other tumor types with bevacizumab, as well as in prior smaller studies with HCC.

With these precautions taken, the safety profile of atezolizumab plus bevacizumab was quite manageable. Overall, the combination was very well tolerated. We definitely saw less adverse effects that are commonly seen with sorafenib, such as less skin toxicity and diarrhea. There were a few instances of bleeding; however, for the most part, they were manageable. Moreover, grade 3 and 4 toxicities were slightly higher with sorafenib compared with the combination.

In terms of efficacy, the median OS was not reached, but we saw a hazard ratio of 0.58, which reflects a 42% reduction in the risk of death. With the combination, we saw an improved median PFS of 6.8 months versus 4.3 months with sorafenib and a RECIST response rate of 28%. Again, there was a respectable reduction in tumor size with this combination in the phase 3 setting.

I do believe that this combination will become the standard first-line regimen, but it's critical that it’s used in the right patients with the right safety parameters. I would be very careful by extrapolating the usage of this combination to patients with more advanced cirrhosis because their risk of hypertension and bleeding becomes higher. As such, until there are more safety data beyond Child–Pugh A, I would restrict the usage of this regimen to these patients.

Sorafenib was also compared with nivolumab (Opdivo) in the first-line setting in the CheckMate-459 trial. What lessons were learned from that research?

Prior to the combination of atezolizumab and bevacizumab, there was another attempt to bring immunotherapy, specifically checkpoint inhibitors targeting PD-1, as single agents to the first-line space. In the CheckMate-459 trial, which compared nivolumab with sorafenib. The trial did not reach statistical significance in that it did not show an improvement in median OS with nivolumab compared with sorafenib.

Now, there are some caveats to this study. For example, there was a high rate of crossover from the sorafenib arm. Approximately 20% of patients went on to receive a checkpoint inhibitor in the second-line, post sorafenib progression. Another 10% or 11% of patients received an experimental therapy, many of which were actually immunotherapy agents. This high crossover rate may have diluted the impact of single-agent nivolumab in that setting.

Are any other notable first-line combinations under investigation right now?

Several other first-line combinations are being looked at, mostly based on the concept of combining anti–PD-1/PD-L1 agents with either monoclonal antibodies against VEGF, such as bevacizumab, or TKIs that are multitargeted but include targeting of the VEGF axis. This is based on preclinical evidence suggesting that anti-VEGF inhibition does potentiate anti–PD-L1 activity through reduction in both activity and the number of myeloid-derived suppressor cells through the recruitment of cytotoxic T cells into the tumor and through the upregulation of PD-L1 expression.

Some trials that are worth mentioning include the combinations of pembrolizumab (Keytruda) with lenvatinib. We saw updated data during the 2020 ASCO Virtual Scientific Program with this combination, with a promising response rate of 36% by RECIST criteria in approximately 100 patients and an intriguing median OS.

We are looking forward to the phase 3 data from the [COSMIC-312] study, which is an ongoing phase 3 trial comparing cabozantinib (Cabometyx) in combination with atezolizumab versus sorafenib alone. This trial is either completed or nearing completion of accrual. Another phase 1b study is combining pembrolizumab with regorafenib (Stivarga), [and this] was presented at the 2020 Gastrointestinal Cancers Symposium. We're looking forward to seeing the outcomes of all these studies.

Another category of trials, are immunotherapy combinations, which include combining anti–PD-1/PD-L1 agents with anti–CTLA-4 inhibition. We know that the combinations of nivolumab plus ipilimumab (Yervoy) have shown promising efficacy in the second-line setting and have received accelerated FDA approval. Based on that, there is a study comparing the combination of nivolumab plus ipilimumab in first-line setting versus sorafenib, lenvatinib, or physician’s choice.

There's also the HIMALAYA trial, which compared the combination of durvalumab (Imfinzi) and tremelimumab versus durvalumab monotherapy versus sorafenib in the first-line setting. We are still awaiting the results of this [trial]. An update from this phase 1b study was presented at the past ASCO meeting, with a single priming high dose of tremelimumab at 300 mg [plus durvalumab]; that [regimen] showed a manageable safety profile with promising efficacy. We are excited to see the final results from that research.

What do you hope to see investigated further in future research?

We have a challenge in the second- and third-line settings because all the approved second- and third-line agents came out of data in the post-sorafenib era. As such, all the second- and third-line trials were designed for patients who had progressed on sorafenib. What to do with patients who progress on atezolizumab and bevacizumab,or other doublets that may get approved in the first-line space is unknown. We do not have definitive data. In the meantime, we will be extrapolating and using various TKIs, potentially post-progression on these combinations in the first-line setting.

However, limited data are available on how to sequence them and which should go first. There is some need for better assessment of the second- and third-line existing options. There are also opportunities for novel therapies in the second- and third-line settings. Finally, we need to improve patient selection. Hopefully some biomarker-driven trials may facilitate the selection of the best therapy for the right patient, especially since we may have more combinations receiving approval; it will be hard to choose between them without a definitive biomarker.

It is truly a new dawn for the treatment of advanced HCC with multiple systemic therapies being available. It's critical that physicians are familiar with the various options and the AEs, so they can optimally sequence these agents for patients. We are seeing very promising OS in advanced disease, whether you’re looking at the emerging data from first-line trials, which show a median OS [of more than] 20 months, or the exploratory analysis from prior trials, looking at the sequence of sorafenib followed by regorafenib, where the median OS in that select patient population was 26 months. The OS is looking much better in advanced disease.

My last message is that, because we have more systemic therapy options available, it is critical that patients are transitioned from liver-directed therapy to systemic therapy at the right time. Overtreating patients with liver-directed therapy has risks of decompensation of the liver function, the liver cirrhosis, and missing the opportunity to receive effective systemic agents in sequence, which has a different impact on OS.


  1. 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 July 30, 2020. https://bit.ly/2Aneztc.