Key Factors for Choosing Frontline Hepatocellular Carcinoma Therapy

Daneng Li, MD (Moderator)

Associate Professor

Department of Medical Oncology & Therapeutics Research

Co-Director, Neuroendocrine Tumor Program

City of Hope Comprehensive Cancer Center

Duarte, CA

CASE SUMMARY

A 77-year-old White woman presented to her primary care physician complaining of abdominal pain and fatigue.​ She had cirrhosis due to heavy alcohol use; Crohn’s disease, controlled with infliximab (Remicade); and a history of variceal bleeding, with banding 2 months ago​. She had an ECOG performance status of 1. A CT scan of the chest, abdomen, and pelvis with triphasic liver evaluation revealed a 4.5-cm LR5 [LI-RADS score of 5] hepatic mass in the right lobe and metastatic disease in the lung​. She had a Child-Pugh status of A. Her α-fetoprotein level was 380 ng/mL. ​Biopsy was obtained and confirmed the diagnosis of hepatocellular carcinoma (HCC).

DANENG LI, MD: [In] the National Comprehensive Cancer Network [NCCN] guidelines for first-line treatments…the preferred regimen is either atezolizumab [Tecentriq] plus bevacizumab [Avastin] or durvalumab [Imfinzi] plus tremelimumab [Imjudo] based off of the respective phase 3 studies IMbrave150 [NCT03434379] or HIMALAYA [NCT03298451].¹

We have other recommended regimens, including the tyrosine kinase inhibitors [TKIs] sorafenib [Nexavar] or lenvatinib [Lenvima], which are both category 1 recommendations, based off of phase 3 data. We also have additional level 2 evidence for single-agent immunotherapy with durvalumab based off of noninferiority data of durvalumab versus sorafenib, as well as pembrolizumab [Keytruda] in an accelerated cohort of first-line patients.

Nivolumab [Opdivo] is also being placed in this scenario as useful in certain situations. It has some Child-Pugh B data, so that can also be potentially considered in the respective scenarios.

LI: It is not surprising that survival as well as safety and tolerability are at the top of our decision making in terms of what we're choosing for our patients. Then response rate…in specific scenarios. I think that's completely reasonable, and I don't think that there's too much debate on this. Where the safety and tolerability issue comes up is that our patients with HCC are vulnerable. This patient [has] an autoimmune condition and variceal bleeding.

Would your recommendations change due to how old this patient was, due to etiology of their cirrhosis, meaning if it's [related to] hepatitis B, hepatitis C, or non-viral? Or does it change based off of performance status or convenience or even Child-Pugh score?

MUJAHID RIZVI, MD: It's probably a bit of everything, but Child-Pugh status and their performance status are key, and how old they are and what their support system is. I practice in a rural setting where patients sometimes drive 2 and a half hours to come and see us, but in that situation, that's always important as well…for an infusion versus oral medication.

LI: If someone had poor performance status, were more elderly and frail, or had Child-Pugh status that's lower, what type of agent are you thinking in those cases?

RIZVI: You could try a single-agent TKI.

LI: Do you have a preference of which one?

RIZVI: I’d look at up-to-date NCCN guidelines and [consider] sorafenib or lenvatinib.

YELENA KRIJANOVSKI, MD: Transplant makes a difference. You don't want to use immunotherapy. I agree with Child-Pugh stage—if it's B, you can use nivolumab.

LI: Yes, nivolumab has some Child-Pugh B data.²

KRIJANOVSKI: Sorafenib [has Child-Pugh B data as well].³

ANDY JANG, MD: The decision is going to be weighed for IMbrave150 versus HIMALAYA. It is important how quickly can you get your patient to see the gastroenterologist, get an EGD [esophagogastroduodenoscopy] done, and make sure there's no varices. If it's a tall task, maybe you should consider the HIMALAYA regimen first, because you can skip that part.

If I have a non-viral patient, I will probably lean towards the HIMALAYA approach. In IMbrave150, half of the patients were hepatitis B patients, so maybe that favored their response in the report.⁴

[Additionally, I consider] the antibody [toxicities] in the IMbrave150 trial. If you use single-agent immunotherapy or the HIMALAYA regimen, the number [of those toxicities] is going to be very low. So that's another factor that I'm thinking about to decide between these 2 regimens.

LI: Those are all valid points. Dr Jang, how would you choose between lenvatinib and durvalumab/tremelimumab since they haven't been compared head-to-head in that sense? I've heard that some will say “If I can't get an EGD soon enough, I'll just give them lenvatinib.” How do you choose between lenvatinib and durvalumab/tremelimumab if you're not going to choose atezolizumab/bevacizumab?

JANG: If you look at overall the combination regimens nowadays, if you look at the IMbrave150 and HIMALAYA [trial regimens], or maybe even the newer ones, the [trial of SHR-1210 plus apatinib; NCT03839550], the median overall survival [OS] is somewhere between 19 and 21 months,^4,5 so I think it consistently shows superiority over single-agent TKIs. If I can do the combination, that's the first thing I would do. I’d do a single-agent TKI if I have a contraindication, or the patient prefers oral therapy, or other issues.

LI: There are additional data that have come out [showing a similar OS for single-agent lenvatinib].⁶

CURTIS CHONG, MD: I always try to prefer immunotherapy, because you're never going to get long-term survival with the TKI.

LI: So for you, it’s durability for the patient population?

CHONG: Exactly.

LI: I’ve heard that comment as well. Certainly, I think TKIs are [leading to] faster responses and everything, but at the tail end of the Kaplan-Meier curve, maybe [they offer] a little bit less compared with the immunotherapy. Median and early response versus trying to go for the tail [is] that's also a potential factor to consider.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 5.2022. Accessed February 27, 2023. https://bit.ly/3SxjcoG}

_{2. Kudo M, Matilla A, Santoro A, et al. CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol. 2021;75(3):600-609. doi:10.1016/j.jhep.2021.04.047}

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

<sub>4. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
5. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):doi:10.1056/EVIDoa2100070</sub>

_{6. Finn RS, Kudo M, Merle P, et al. LBA34 - Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089}