Mark Yarchoan, MD

During a Targeted Oncology Case-Based Roundtable event, Mark Yarchoan, MD, an assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, moderates a discussion about a 77-year-old woman with Child Pugh B and C hepatocellular carcinoma (HCC). 

According to the NCCN [National Comprehensive Cancer Network] guidelines, atezolizumab [Tecentriq] plus bevacizumab [Avastin] is the preferred first-line therapy regimen.

 Sorafenib [Nexavar] and lenvatinib [Lenvima] are both supported by category 1 data, and nivolumab [Opdivo] and FOLFOX [folinic acid, fluorouracil, and oxaliplatin] may be useful in select cases.

As an overview, the treatment landscape in HCC [hepa-tocellular carcinoma] has changed rapidly over the last couple of years. When I started treating this disease, sorafenib was the only approved therapy. Since then, we have gone from 1 to 9 therapies over 4 years. It is remarkable. Virtually every single trial we have is either a comparison with sorafenib or testing a new drug in sorafenib-treated patients. The biggest recent develop-ment is the positive IMbrave150 study [NCT03434379], which assessed the combination of atezolizumab plus bevacizumab.

 This combination had better results than sorafenib in terms of OS [overall survival] as well as some secondary end points. There are also a couple of trials of other therapies vs sorafenib that did not show superiority with regards to OS but showed some benefits with regard to secondary end points. These include the trials with lenvatinib, which had better PFS [progression-free survival] and ORR [objective response rate] than sorafenib. Then there was the trial with nivolumab, which is a technically negative study but I think is still useful as a front-line therapy in select cases.

What proportion of your patients with advanced HCC receive tyrosine kinase inhibitor (TKI) monotherapy as their first-line systemic therapy?

YARCHOAN: I would say that it is in the 11% to 25% range. This includes patients who have a history of transplant and probably should not get PD-L1 therapy, patients with active autoimmune disease, patients who need procedures where the use of bevacizumab is going to be problematic, and patients with a recent bleed or those for whom you are particularly worried about bleeding. These categories add up to quite a few patients. So there is a select group of patients who cannot get atezolizumab plus bevacizumab and for whom TKI monotherapy is an appropriate choice.

What is the evidence for the use of sorafenib for HCC?

YARCHOAN: Sorafenib was the first therapy to show a survival benefit in HCC. This is based on the SHARP [NCT00105443] and Asia-Pacific [NCT00492752] trials.

The SHARP study, a multicenter, phase 3 trial, was the definitive study in the United States.

 Sorafenib is a static drug; it does not tend to cause responses, but it did translate to an OS benefit

There was a survival benefit of almost 3 months with the sorafenib [10.7 months with sorafenib vs 7.9 months with placebo (HR, 0.69; P < .001)] but no significant difference in time to symptomatic progression [4.1 months vs 4.9 months; P = .77].

 The response rate was in the single digits. However, this was a very important landmark study because it was the first to show an OS benefit.

What is the evidence for the use of lenvatinib for HCC?

YARCHOAN:Much more recently, lenvatinib was the second therapy to be approved for frontline HCC treatment.

This approval was based on the phase 3 REFLECT study [NCT01761266]. This was a global study that was randomized against sorafenib and was set up as a noninferiority study. That means they were not trying to prove that lenvatinib was better; rather, that it was noninferior. There were multiple secondary end points such as PFS and ORR, and the study had standard enrollment criteria, and patients with unresectable disease, either BCLC stage B or not candidates for TACE [transarterial chemoembolization] or stage C.

The trial met its primary end point of demonstrating noninferiority.

 The median OS was similar for the lenvatinib and sorafenib arms [13.6 months vs 12.3 months, respectively (HR, 0.92; 95% CI, 079-1.06)]. There was a trend toward better survival in the lenvatinib arm, especially in patients with more aggressive disease, those with higher AFP levels, and other subgroups that have particularly aggressive biology.

Compared with sorafenib, lenvatinib did have better results in certain secondary end points. For example, PFS was basically double [7.4 months vs 3.7 months (HR, 0.66; 95% CI, 0.57-0.77; P < .0001)], and the ORR was 24% compared with 9% for sorafenib. So lenvatinib is clearly an active agent for HCC and some patients can get partial responses. I think it is worth noting that sorafenib performed well in this study. This is something we [have] observed with every single study since 2007. All studies used sorafenib as the control group, and sorafenib does a little bit better each time. For example, in this study the OS was 12 months, which is significantly better than the OS in the original SHARP study. The lenvatinib benefit was consistent in all subgroups. The poststudy systemic therapy was also similar between the 2 arms. However, PFS was a little longer in the lenvatinib arm; the patients switched over to secondary therapy less often and later than those on the sorafenib arm.

Since these drugs are both multitargeted TKIs, many of the AEs [adverse events] overlap.

 The thing to keep in mind with lenvatinib is that it tends to cause less hand-foot syndrome than sorafenib, which is a real plus. On the other hand, it does seem to cause a bit more hypertension than sorafenib does, probably due to more potent inhibition of VEGF.

How would you compare sorafenib and lenvatinib?

 Both sorafenib and lenvatinib are reason-able choices in the front-line setting. The sorafenib label says that it should be started at 400 mg twice a day.

However, many of us start it at 200 mg and work our way up. Lenvatinib is dosed by weight.8 So we start at 12 mg for patients who are over 60 kg and 8 mg for patients who weigh less than 60 kg. Lenvatinib comes in 4-mg tablets, which makes it easy to adjust the dose. We usually adjust the dose down by 4 mg per dose reduction, up to 3 dose reductions. I have had patients who seemed to be benefiting even from 4 mg. This is a potent drug and many patients require dose reductions, and that is OK. I do not think you should be nervous about going down on the dose. 

For patients with a Child-Pugh score B, I feel more comfortable with sorafenib because there are prospective data for sorafenib in that subgroup, while there are none for lenvatinib. Additionally, the REFLECT trial showed a little bit of an association with hepatic encephalopathy for lenvatinib.

I have a question regarding the etiology of cirrhosis. In the subset analysis for those with alcoholic cirrhosis there are impressive data with lenvatinib, while for those with hepatitis B and C there are good data with sorafenib but not so strong with lenvatinib. What do you think about that? Similarly, what are the data for dealing with cirrhosis due to the NASH [nonalcoholic steatohepatitis] type of hepatitis? This is important because it is going to become more prevalent as hepatitis B and C become a thing of the past. What is your opinion about this?

 The data suggest that sorafenib may be better for hepatitis C. But I do not think that difference is so striking in the clinical practice.

 All phase 3 trials in HCC break down the results based on the different etiologies. However, I am still not totally convinced that we should be changing our practice patterns that much based on etiology. In my experience, patients with hepatitis B usually have a little bit less cirrhosis and can often tolerate more intensive therapy. But aside from that, I don’t often change my management based on etiology because I do not think there is strong enough evidence to do so.

Another question I have is about something that was a hot topic many years ago. Say you discover a new hepatitis B or C infection during the work-up; do you hold up on treating it because it could lead to some kind of immune response that would interfere with the HCC?

That is a great question. There were some data, mostly from Spain, that showed that if you treat the hepatitis C, even if at the time of transplant, that the cancer might recur.

 So they suggested that the hepatitis C was some kind of neoantigen or antigen for the immune system to control the cancer. I have to say that story has not really panned out with subsequent data. It does not seem like the hepatitis C itself is an important antigen for controlling HCC because it is not only in the tumor but also in the tissues around it. So I do not get nervous about treating hepatitis C. That being said, the reason to treat hepatitis C is to prevent cirrhosis, to prevent HCC. So once they have HCC, I also do not know if it is necessary to treat the virus itself. I am not sure that there is a clear answer at this point. But I would not be nervous about treating the hepatitis C; I think it is a reasonable thing to do.

On the topic of etiology, liver cancer is now projected to be the number 3 cause of cancer deaths in the United States by 2040.

 There is a misconception that this problem is going away because we have drugs for hepatitis B and C. I think this NASH epidemic is translating into many more cases of HCC. Additionally, alcohol consumption has also increased, and that may be driving part of the epidemic that we are seeing.

I am always a little bit puzzled with NASH cirrhosis because of the lipid metabolites. Sometimes patients say that they don’t drink or only drink socially. However, I think that over several decades the alcohol has a role in NASH development.

The way patients are being referred to my practice is very interesting. A lot of the patients [with HCC] that I treat come from interventional radiologists who are holding them too long, or the patients feel that the treatment is not working and they want to see an oncologist. [However,] I still have a trickle from gastrointestinal doctors.

 I think this discussion of when patients should transition from interventional radiology to medical oncology is very interesting. It’s a controversial thing that every single practice and every group needs to deal with. We all have seen these patients who get repeated TACE until there is no liver left. It seems like it is becoming more often that the patients are the ones requesting to see a medical oncologist. So it seems that the patients are driving the referrals.

1. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 3.2021. Accessed August 10, 2021. https://bit.ly/3iVa7pC

2. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

3. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

4. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34. doi:10.1016/S1470-2045(08)70285-7

5. Cheng AL, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocel-lular carcinoma (uHCC). J Clin Oncol. 2017;35(suppl 15):4001. doi:10.1200/JCO.2017.35.15_suppl.4001

6. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treat-ment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1

7. Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2018. Accessed August 18, 2021. https://bit.ly/2W3NSF5

8. Lenvima. Prescribing information. Eisai Inc; 2021. Accessed August 18, 2021. https://bit.ly/2W0qQyK

9. Vinaixa C, Rubín A, Aguilera V, Berenguer M. Recurrence of hepatitis C after liver transplantation. Ann Gastroenterol. 2013;26(4):304-313.

10. Rahib L, Wehner M, Matrisian LM, Nead KT. Projection of cancer inci-dence and death to 2040 in the US: impact of cancer screening and a changing demographic. J Clin Oncol. 2020;38(suppl 15):1566. doi:10.1200/JCO.2020.38.15_suppl.1566

Articles

During a Targeted Oncology Case-Based Roundtable event, Mark Yarchoan, MD,  moderates a discussion about a 77-year-old woman with Child Pugh B and C hepatocellular carcinoma. 

Yarchoan Compares Lenvatinib and Sorafenib for Child Pugh B and C Hepatocellular Carcinoma

Mark Yarchoan, MD, medical oncologist, John Hopkins Medicine, explains his method for sequencing available treatment options for patients with hepatocellular carcinoma (HCC).

There is no correct answer to the question of what the best second-line treatment is for HCC. This is because more data are needed on most of the available agents. Previously, many of these drugs were studied when the only first-line drug available was sorafenib (Nexavar).

Immunotherapy will continue to play some role in the treatment of HCC because there is a group of patients who respond well to antiPD-1 therapy and some can have disease control for years. The majority of patients, however, do not respond to anti&ndash;PD-1 therapy, so it should only be considered for patients who progress on first-line therapy and are reluctant to take another tyrosine kinase inhibitor because of toxicity.

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Mark Yarchoan, MD, explains his method for sequencing available treatment options for patients with hepatocellular carcinoma.<br />
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Mark Yarchoan, MD | Authors

Articles

Yarchoan Compares Lenvatinib and Sorafenib for Child Pugh B and C Hepatocellular Carcinoma

Yarchoan Discusses Sequencing Treatment Options for Patients With HCC