Sequencing Challenges, Novel Research Efforts Come to Forefront in HCC


Benjamin Leon Musher, MD, discusses sequencing challenges and research efforts needed regarding immunotherapy in hepatocellular carcinoma before it becomes a standard approach for patients.

Benjamin Leon Musher, MD

Benjamin Leon Musher, MD

Benjamin Leon Musher, MD

With the approval of the frontline combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) on the horizon in hepatocellular carcinoma (HCC), other research efforts are exploring the optimal sequence of therapies and further refining the role of immunotherapy in this disease, explained Benjamin Leon Musher, MD.

For example, the multiarm, phase I/II CheckMate-040 trial is evaluating the combination of nivolumab (Opdivo) in combination with other agents in patients with HCC who were previously treated with sorafenib (Nexavar). Updated findings of the arm combining nivolumab with ipilimumab (Yervoy) were presented during the 2020 Gastrointestinal Cancers Symposium.

For patients who received prior treatment with sorafenib for ≤6 months, the combination led to a median overall survival (OS) of 19.2 months (95% CI, 8.3—not reached [NR]).1 For those who had prior sorafenib for >6 months, the median OS was 25.5 months (95%, CI, 9.4—NR). Researchers concluded that this combination could be a potential treatment option for patients, independent of prior duration of sorafenib.

A subanalysis of an additional arm of CheckMate-040, evaluating the triplet of nivolumab, ipilimumab, and cabozantinib (Cabometyx), was presented at the 2020 Gastrointestinal Cancers Symposium. The 3-drug regimen induced higher response rates, progression-free survival (PFS), and OS compared with nivolumab/cabozantinib in patients with advanced HCC who were either sorafenib-naïve or received prior treatment with the TKI.2

“There are 2 very important principles in treating patients with HCC,” Musher said. “First, we need to find the right patients to treat because a lot of these patients already have livers that are not functioning well. Secondly, the last thing we want to do, as clinicians, is shorten somebody's life or make them miserable without any benefit from other therapies.”

In an interview during the 2020 OncLive® State of the Science Summit™ on Gastrointestinal Malignancies, Musher, associate professor of medicine, hematology and oncology, Baylor College of Medicine, discussed sequencing challenges and research efforts needed regarding immunotherapy in HCC before it becomes a standard approach for patients.

OncLive: How do you determine the optimal sequence in HCC treatment?

Musher: There are many options for second- and third-line therapy, which has made the field quite confusing. We have 2 drugs approved for first-line use, and we will probably have the combination of atezolizumab and bevacizumab approved soon based on reported phase III data.

The problem is that the trials that have been reported on second- and later-line therapies were based on patients having been treated with frontline sorafenib. The sequencing is going to become a problem. As long as you are not giving the same class of agents twice, it makes sense to sequence the options that one thinks are best while taking [factors into account, such as] comorbidities, performance status, liver function, prior transplant, oral or intravenous medication, and alpha-fetoprotein (AFP) levels. There is not one answer for all patients.

Is ramucirumab (Cyramza) the optimal treatment for patients with HCC who have high levels of AFP?

I am more likely to use it in patients with a higher AFP who [were previously treated with] immunotherapy. Most oncologists want patients to have the opportunity to get immunotherapy at a certain point because of the possibility of a longer-term response.

What TKI options are available in HCC?

The options for TKIs past the first-line setting are regorafenib (Stivarga), cabozantinib, and ramucirumab. If you use frontline sorafenib followed by lenvatinib (Lenvima) as second-line therapy, or vice versa, most would consider those acceptable.

As far as which one to choose, it is really a matter of comorbidities and patient preferences. For example, we know that lenvatinib causes more hypertension and sorafenib tends to cause more fatigue and hand-foot syndrome. A lot of this is looking at the patient, determining what they have, and what the physician is most concerned about.

Do patients prefer immunotherapy over TKIs?

Immunotherapy is a very hot area and people love to think of their immune systems as being activated and attacking their cancer. Oncologists realize that if these drugs work, they may work for longer periods of time. That being said, [there are] many patients who respond and sometimes even tolerate TKIs better [than immunotherapy]. Immunotherapy does have its problems, especially if patients have [compromised liver function].

Again, patients do like the idea of immunotherapy but there are also infusions and pills. There are patients who might be concerned about compliance and adverse events (AEs) from pills rather than immunotherapy. It involves a realistic conversation with patients about all of their options.

We do not have good data to tell us exactly which one to use when. For example, there is no reason to believe that nivolumab is any more or less effective after sorafenib/lenvatinib. We need to regard pembrolizumab (Keytruda) and nivolumab as being interchangeable and we need to consider TKIs as options to use in the first-, second-, and third-line settings.

When it comes to data gaps in the field, what area would you like to see addressed first?

The atezolizumab and bevacizumab first-line option has confused the field that much more. As we know, several of these agents have some VEGF activity, but we do not know if, for example, [a patient receives] frontline bevacizumab, whether or not if that will decrease the possibility of other agents working in later-line settings.

We have to look into these questions. There has also been a lot of biomarker investigations, but we do not have any good biomarkers thus far.

What other trials would you like to highlight?

The CheckMate-040 trial is a complicated study with several cohorts. There was one part of the trial comparing 3 different combinations: ipilimumab, nivolumab, and cabozantinib. Those data are a bit premature at this point. The combination of ipilimumab and nivolumab produces more immunological AEs. I do not use that combination for HCC, but it does warrant investigation.

What additional areas would you like to highlight?

A controversial but evolving question that arises is, “How much local therapy should we be giving patients before we get into systemic therapy?” We have to remember that we have transarterial chemoembolization, radiofrequency ablation, and yttrium-90, but those are not addressing the biological problem of HCC which tends to be multi-focal.

What we sometimes see is too much local therapy [being given] and then we do not have systemic options for some of these patients. This involves good multidisciplinary tumor boards and conversations between medical oncology, hepatology, interventional radiology, and liver transplantation to figure out the best way to approach cancer and liver disease at the same time.

An important question we need to ask ourselves is, "Should we be treating a patient at all?" A lot of these patients cannot be cured, but there is such a temptation to treat cancer because it is a loaded word. We have to understand that some of them will not benefit from shrinking or controlling their cancer.


  1. He AR, Yau T, Hsu C, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): subgroup analyses from CheckMate 040. J Clin Oncol. 2020;38(suppl 512; abstr 512). doi: 10.1200/JCO.2020.38.4_suppl512
  2. Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2020;38(suppl_4; abstr 478). doi: 10.1200/JCO.2020.38.4_suppl.478
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