Diagnosis and Management of Unresectable HCC Using Clinical Criteria

The treatment landscape for hepatocellular carcinoma (HCC) has evolved significantly with multiple frontline systemic therapy options now available. Anthony B. El-Khoueiry, MD, an associate professor of clinical medicine in the Division of Medical Oncology and director of the phase I drug development clinical program at the Keck School of Medicine, University of Southern California, discussed the case of a patient with HCC in a virtual Case-Based Roundtable event with oncologists from the Pacific region. He covered the role of cirrhosis in confirming a radiologic diagnosis, downstaging strategies for transplant eligibility, and the evolution of frontline systemic therapies.

CASE SUMMARY

• A 62-year-old man presented to primary care physician with complaints of:
  • Early satiety, mild discomfort in right upper quadrant, & increasing fatigue (last 2-3 months)
  • Unintentional weight loss (~6 lbs) in last 1-2 months
• Relevant history
  • Medical history: type 2 diabetes well controlled (metformin) & hyperlipidemia, no prior upper gastrointestinal (GI) bleeding, coronary artery disease, or hypertension
  • Social history: Former smoker (quit 6 years ago), enjoys cycling & gardening with wife, works as engineer for city of Dallas with plans to retire in next 2 to 3 years
• Initial workup by primary care physician
  • Labs showed mild anemia, elevated liver enzymes:
    • Alanine aminotransferase 65 U/L, aspartate aminotransferase 72 U/L, alfa-fetoprotein 850 ng/mL
  • Additional staging:
    • Esophagogastroduodenoscopy: small varices, no banding required,
    • Child-Pugh class A
    • ECOG performance status: 0
• Referral to GI/Oncology
  • Diagnostics:
    • MRI of the abdomen demonstrated 2 lesions in the right lobe (4-5 cm), mild portal hypertension, splenomegaly
    • Chest CT showed multiple bilateral lung nodes, measuring 1 to 2 cm,
    • ECOG performance status: 1
• Diagnosis
  • Metastatic, unresectable HCC, non-viral etiology, Child-Pugh class A
  • Barcelona Clinic Liver Cancer C, albumin-bilirubin score 2

Targeted Oncology: How often are you able to downstage disease for patients with HCC so they are able to go for transplant?

Anthony B. El-Khoueiry, MD: The data varies; the traditional data, if you rely only on liver-directed therapy, it's a minority of patients, I would say 20% to 30%. Now that we are sometimes utilizing systemic therapy as part of the downstaging effort, the data are still evolving, but I'm suspecting it's going to start looking more like 30% to 40%. It also depends on what you're downstaging from. If somebody is just outside [the requirement], if you have 3 lesions, and one of them is 5 cm instead of 3 cm—the likelihood of downstaging if somebody has preserved liver function is very high. It's more than 50%. If we're talking multifocal disease, a lot of large lesions, the chance of downstaging with systemic therapy, you're going to have to have a strong partial response to downstage efficiently. So that's where it may be closer to 30%.

What do you think of the diagnosis of HCC for this patient?

The reason I'm OK to accept a radiologic diagnosis here is that we know the patient has cirrhosis. The endoscopy did show some small varices. We see portal hypertension on imaging. The radiologic diagnosis only applies if you have known cirrhosis or viral hepatitis. In the patients who have fatty liver disease or metabolic-associated fatty liver disease and a tumor without known cirrhosis, even if there is enhancement and washout, even if they call it LI-RADS 5, you cannot assume it's HCC. You still have to do a biopsy.

In this case, the uniqueness is the patient already has cirrhosis, which increases the positive predictive value of the imaging, [meeting] the criteria. Next-generation sequencing [NGS] is now still more reliable on tissue for HCC, but there are more and more data evolving that doing liquid biopsy is pretty consistent with what we see on tissue for HCC. The data lag behind other tumor types because we haven't historically done NGS as much on HCC, but as the data arise, it looks comparable.

If this patient had Child Pugh B disease, would that change your thinking on treatment?

There are prospective safety data for single-agent IO in Child Pugh B. For the doublets, whether it's IO/VEGF or IO/IO, there are only retrospective series and cohort series showing potentially that it's safe and maybe has some benefit. The problem is Child Pugh B is very heterogeneous, so you have some patients who are B7 or B8, just because their albumin is low, bilirubin is high, but they have good performance status; they don't have any other issues and have been stable like this for a while. In those patients, we tend to be more aggressive and treat, vs a patient who's B8 but is having paracentesis every other week and they're intermittently encephalopathic. You know they're not going to do well. Their mortality is definitely driven by their cirrhosis, and we wouldn't treat them. So there's a lot of art of medicine and subjective interpretation in this space.

What were the initial FDA approvals for systemic therapy in HCC?

We started with sorafenib [Nexavar], which reigned for 10 years. We could not beat it for a long time. In the SHARP trial [NCT00105443], it showed an improvement in overall survival of 10.7 months vs 7.9 months with placebo for advanced HCC.¹ And then after 10 years, lenvatinib [Lenvima] in the REFLECT trial [NCT01761266] was shown to be non-inferior to sorafenib, at 13.6 vs 12.3 months for overall survival, but with better progression-free survival and better response rate.²

The treatment field has evolved significantly. The second-line regimens approved post sorafenib started with single-agent nivolumab [Opdivo] initially and single-agent regorafenib [Stivarga], then pembrolizumab [Keytruda], cabozantinib [Cabometyx], ramucirumab [Cyramza] from REACH-2 [NCT02435433], and nivolumab/ipilimumab [Yervoy] from CheckMate 040 [NCT01658878]. The first-line regiments that came after the REFLECT trial were IMbrave150 [NCT03434379] with atezolizumab [Tecentriq]/bevacizumab [Avastin], the HIMALAYA trial with tremelimumab [Imjudo]/durvalumab [Imfinzi], and then, most recently, nivolumab/ipilimumab in CheckMate 9DW [NCT04039607].

Certainly, multiple first-line options are available. The second-line options are really all developed post-sorafenib, so we extrapolate and end up using them post-IO based on very limited data, and we use them in random sequences. This is an active area of drug development.

DISCLOSURES: El-Khoueiry previously reported receiving honoraria from Bayer, Bristol Myers Squibb, Roche/Genentech, Eisai, Merck, Agenus, Exelixis, AstraZeneca/MedImmune, ABL Bio, QED Therapeutics, Servier, Tallac Therapeutics, Senti Biosciences, and Qurient; and a consulting or advisory role with Bristol Myers Squibb, Bayer, Eisai, Roche, Merck, Exelixis, Pieris Pharmaceuticals, Agenus, Gilead Sciences, AstraZeneca/MedImmune, ABL Bio, QED Therapeutics, Servier, Tallac Therapeutics, Senti Biosciences, and Qurient.

REFERENCES:

1. 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

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