Part 2: Managing Frontline Lenvatinib Therapy for High-Risk HCC

Pierre Gholam, MD (Moderator)

Professor, School of Medicine

Case Western Reserve University

Cleveland, Ohio

CASE SUMMARY:

A 77-year-old Caucasian woman presented to her primary care physician complaining of abdominal pain and fatigue.​ She had cirrhosis due to heavy alcohol use as well as Crohn’s disease controlled with infliximab. She had a history of variceal bleeding, with banding 2 months earlier. She was given an ECOG performance status of 1.

A CT of her chest, abdomen, and pelvis with triphasic liver evaluation discovered a 4.5 cm LI-RADS category 5 hepatic mass in the right lobe and metastasis in the lung. She had a Child-Pugh class of A and an alpha-fetoprotein level of 380 ng/mL.

The patient was given lenvatinib (Lenvima) at 12 mg daily, but experienced modest weight loss and reported loss of appetite leading to a dose reduction to 8 mg, and she was referred for nutritional therapy. Imaging at 16 weeks indicated a partial response. After 8 months of therapy, treatment was discontinued due to disease progression.

DISCUSSION QUESTIONS:

• Discuss the selection of lenvatinib for this patient and your own experiences with lenvatinib in this setting.​
• What is your experience with adverse event (AE) management with tyrosine kinase inhibitors (TKIs) and, specifically, lenvatinib?​

EVAN LANG, MD: I started using sorafenib [Nexavar] many years ago. I found that it was tough to manage the AEs, and gastrointestinal [GI] toxicity, diarrhea. So, I found that that was challenging. Even though the AEs are comparable with lenvatinib,¹ my real-world experience is that lenvatinib is more tolerable. You can pick and choose the dosage based on weight. You can also dose-adjust the sorafenib, but I think the lenvatinib is manageable.

ARUN SENDILNATHAN, MD: I had some issues with lenvatinib. I would say it’s probably patient-related. At least with sorafenib, I was able to reduce the dose to 200 mg twice a day, and I was able to manage that. With lenvatinib, my patient had a lot of GI AEs. I just had 1 patient with lenvatinib, so I don’t have a lot of experience with it. That 1 patient did not do well on the lower dose. But I think sorafenib was better tolerated in her case. I had other patients that I have treated before with sorafenib and they have done OK, though they required dose reductions when they were on it for more than 6 or 7 months.

TAREK SABAGH: I had more experience with sorafenib, and I found it hard to tolerate. Many times, patients have thrombocytopenia and leukopenia, and I have to cut down the dose to 200 mg instead of the 400 mg twice a day.² I used it a lot when it first came out and was the only drug on the market. Now, when I have a patient that’s suitable for first-line TKI, I would use lenvatinib just because of this. Also, the other patients I see probably have portal hypertension, have splenomegaly, have low platelets or borderline blood counts to start with. So, this is my experience with sorafenib. For the most part, I’ve been using 50% of the recommended dose.

PIERRE GHOLAM, MD: Dr Rhoades, what are your thoughts on AE management with TKIs in general, lenvatinib in particular?

CHRIS RHOADES, MD: I have more experience in lenvatinib in other disease states. I had a question for you. Most other disease states have a higher starting dose with lenvatinib than hepatocellular carcinoma [HCC].³ So, is there a reason behind that in [the REFLECT] clinical trial [NCT01761266]? Was it tolerability, or comorbid conditions?

In my experience with lenvatinib, it’s hard to control disease-related symptoms. A lot of patients end up discontinuing it. But again, in other diseases, that’s usually at a higher rate. And if you cut down the dose, then you usually cut down efficacy, and you end up at these doses that you have with HCC. So I wonder why the dose was lower in this trial.

GHOLAM: So, dose-ranging studies are done with disease specificity in mind. Since these drugs are metabolized by the liver, you probably have to factor that in when you dose them. So, you have to pick the lowest effective dose that does not cause burdensome toxicity. That’s probably 1 of the main reasons why this ended up being the dose it is.

But you are absolutely correct; for other disease states, the dose is higher.³

RHOADES: Does the presence of cirrhosis affect your decision on which TKI you use?

GHOLAM: So, 80% of patients with HCC have cirrhosis, if you’re asking me that question. That question is very much relegated to a minority of patients who have HCC and a non-cirrhotic liver. To answer that question specifically for that 20%, the absence of cirrhosis does not significantly shape my decision to pick 1 treatment over the other.

NEERAJ MAHAJAN, MD: Lenvatinib is not an easy drug. It may be slightly better than sorafenib, but it’s more like a lesser evil.

_References:

_{1. 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}

_{2. Sorafenib (Nexavar). Prescribing information. Bayer Health Care Pharmaceuticals, Inc.; 2018. Accessed March 4, 2022. https://bit.ly/3CcENL7}

_{3. Lenvatinib (Lenvima). Prescribing information. Eisai Inc.; 2021. Accessed March 4, 2022. https://bit.ly/3sRtp4l}