Abou-Alfa Explores Second-Generation Tyrosine Kinase Inhibitors in HCC

Ghasson K. Abou-Alfa, MD

During a Targeted Oncology Case Based Peer Perspectives event, Ghasson K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, New York, reviewed the case of a 77-year old woman with hepatocellular carcinoma (HCC). Abou-Alfa discussed his initial thoughts for this patient case, the National Comprehensive Cancer Network (NCCN) guideline recommendations for treating patients with HCC and the role of lenvatinib (Lenvima) as treatment of this patient population.

TARGETED ONCOLOGY: Would you recommend a biopsy for this patient?

Abou-Alfa: In this case, the patient has LI-RADS [Liver Imaging Reporting and Data System] 5, which includes radiologic components such as course, dimensions, location, necrosis component, nonnecrosis component, and blood flow. The other factor is the AFP; however, AFP is not specific, and it’s never diagnostic for HCC. This can be inhibited in many cancers, including cholangiocarcinoma and gastric cancer. Even inflammatory components in the liver can cause the inhibition of the AFP.

Now, with this said, there might be the concern or the fear that a biopsy might cause bleeding. That’s valid, and this would be on the consent form. But the fact that the patient had Child- Pugh score A, which, even though [the liver is] cirrhotic, [means] it’s minimal cirrhosis. In other words, it’s something that will not affect functionality of the liver in any way, shape, or form, so a biopsy is not going to be that much of a critical concern.

Personally, I [would] definitely do a biopsy, because the diagnosis is going to be critical. How many times have we seen that [symptoms such as this can be] cholangiocarcinoma mixed with HCC? I don’t want to undermine that component in the treatment regimen.

Also, I am a supporter of genetic analysis. I like that, but the genetic analysis is not so applicable yet for HCC. It’s probably good for research, good for analyses, good that we do it, but we’re not yet ready to decide on a therapy based on the genetic analyses per se.

I can understand the decision to not go ahead with biopsy, but at Sloan Kettering, where I practice, our institution will require me to do a biopsy for anybody you want to give systemic therapy to. Of course, I can understand why you don’t want to do it. But my recommendation from a solid experience with this is that a biopsy will be appropriate and justified.

TARGETED ONCOLOGY: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend with this Child-Pugh score?

Abou-Alfa: The NCCN guidelines list sorafenib [Nexavar], lenvatinib, and the combination of atezolizumab [Tecentriq] and bevacizumab [Avastin] as preferred treatment. The guidelines also state that nivolumab [Opdivo] and FOLFOX [folinic acid, fluorouracil, and oxaliplatin] may be useful under certain circumstances.¹

TARGETED ONCOLOGY: Please explain the rationale for the use of lenvatinib in HCC.

Abou-Alfa: Lenvatinib is a multiple kinase inhibitor that has better responses. A phase 3 noninferiority trial randomized patients to lenvatinib versus sorafenib [NCT01761266].2 The investigators conducted the trial to find out whether lenvatinib was as good as sorafenib, not whether lenvatinib is better than sorafenib. You can argue that this is a little bit of a quick, cheap way to get that. I respectfully disagree, because the statistics for noninferiority are totally different from a “superiority.” It will affect a lot of nuances of the detail for the therapy.

The Kaplan-Meier curves for sorafenib and lenvatinib closely follow each other. In overall survival, lenvatinib was reported as 13.6 months compared with sorafenib at 12.3 months [HR, 0.92; 95% CI, 0.79-1.06]. This was a positive sign of noninferiority.

Progression-free survival was better for the lenvatinib group at 7.4 months versus 3.7 months for the sorafenib group [HR, 0.66; 95% CI, 0.57-0.77; P < .0001].

This positive outcome is attributed to an impressive response rate for lenvatinib, which was 25% based on RECIST 1.1 criteria. Traditionally, the response rate for sorafenib is between 3% and 5%. Further, by modified RECIST, which accounts for the necrosis component, lenvatinib response is close to 42%.

By the way, if the patient has bone metastases, lenvatinib is the optimal choice. I have noticed in my experience that lenvatinib is a perfect therapy for the patients who have those kinds of symptomatic things, because of the excellent response that this agent provides.

TARGETED ONCOLOGY: How do the toxicity profiles of lenvatinib and sorafenib differ in unresectable HCC?

Abou-Alfa: Hand-foot syndrome has been a big concern for all of us, and it appears to be more common in regard to sorafenib compared with lenvatinib [FIGURE²]. This is a challenge with sorafenib. Other adverse effects include diarrhea, which is slightly higher for sorafenib, but it’s not as serious as grade 3. Hypertension is associated with lenvatinib, but it can be managed with antihypertensives. There are more cases of appetite loss and weight loss associated with lenvatinib than sorafenib, as well.

Some clinicians report fatigue being an adverse effect with lenvatinib. One way to alleviate it is to consider lowering the dose of lenvatinib, from 14 mg to 8 mg.…But overall, the bigger challenges are hand-foot syndrome for sorafenib, and similarly, hypertension for lenvatinib.

_References

1. _{NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 5.2020. Accessed August 27, 2020. https://bit.ly/2YGXWlA}
2. _{Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment 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}