ASCO Releases Guideline on Systemic Therapy for Advanced Hepatocellular Carcinoma

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ASCO has released a new evidence-based clinical practice guideline to assist in clinical decision-making for patients with advanced hepatocellular carcinoma.1

“Advanced hepatocellular carcinoma has transitioned from a disease where we had a single approved therapy for patients to one where we now have upward of nine options,” said John D. Gordan, MD, PhD, of the University of California, San Francisco, and Guideline Co-Chair. Additionally, the incidence of liver cancer is the most rapidly increasing cancer in the United States, noted Michal G. Rose, MD, of Yale Cancer Center and VA Connecticut Healthcare System in West Haven, Connecticut, and Guideline Co-Chair.

John D. Gordan, MD, PhD

John D. Gordan, MD, PhD

Michal G. Rose, MD

Michal G. Rose, MD

“There is a strong need for a guideline to help clinicians decide how to sequence treatment and how to select appropriate treatment for individual patients among the multiple good choices we now have,” Dr. Rose said.

ASCO convened an expert panel to develop clinical practice guideline recommendations based on a systematic review of studies published from 2007 to 2020. Nine phase III randomized clinical studies were included: eight were published and one was presented as an abstract. This review resulted in a series of recommendations for first- and second-line therapies.

First-Line Treatment

The first recommendation calls for the combination of atezolizumab/bevacizumab to be offered as a first-line treatment for most patients with advanced hepatocellular carcinoma, Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 to 1, and following management of esophageal varices, when present.

This recommendation was based on results from the IMbrave150 trial, which compared atezolizumab/bevacizumab with sorafenib. It showed improved overall survival for the combination (hazard ratio for survival = 0.58, 95% confidence interval [CI] = 0.42–0.79; P = .0006).

“Practitioners have to be aware that the trial had many exclusion criteria for this treatment,” Dr. Rose added.

The trial excluded patients who had myocardial infarction or stroke in the previous 3 months, those with a history of autoimmune disease, those who were on therapeutic anticoagulation, or those who had co-infection with hepatitis B virus or hepatitis C virus.

“Besides the exclusion criteria related to individual toxicities of bevacizumab and atezolizumab, one of the exclusion criteria to emphasize is that patients had to have screening for varices within several months of starting treatment,” Dr. Rose said. “In patients who do not have controlled varices or other contraindications, the physician should consider either sorafenib or lenvatinib.”

The second recommendation said that patients who may be ineligible for atezolizumab/bevacizumab can be offered sorafenib or lenvatinib as a first-line treatment. “The approval of front-line atezolizumab/bevacizumab caused quite a big shift in how we manage these patients,” Dr. Gordan said. He added that because data on atezolizumab/bevacizumab are so new, the best options for second-line therapy are still being explored.

Second-Line Treatment

After first-line treatment with atezolizumab/bevacizumab, patients can receive second-line treatment with the tyrosine kinase inhibitors sorafenib, lenvatinib, cabozantinib, or regorafenib. If patients receive first-line therapy with sorafenib or lenvatinib, second-line treatment with another tyrosine kinase inhibitor such as cabozantinib or regorafenib, or the VEGFR2 inhibitor ramucirumab is recommended for appropriate candidates. If atezolizumab/bevacizumab was not available when a patient started first-line treatment, it may be considered at this point as well.

Additionally, pembrolizumab or nivolumab may be reasonable second-line options for patients who received first-line treatment with sorafenib or lenvatinib. Specifically, these immune checkpoint inhibitors may be especially beneficial in patients who have contraindications to or cannot tolerate treatment with tyrosine kinase inhibitors.

Team Approach

Dr. Gordan noted that one of the most significant challenges in the treatment of hepatocellular carcinoma is the interface between treatment toxicity and patients’ baseline liver function. “Physicians must be aware that these recommendations are subject to a patient’s liver function and the precise comorbidities of the patient in a way that is not typical in most oncology guidelines,” Dr. Gordan said. “Participation of hepatology in the multidisciplinary care of these patients is critically important.”

The guideline authors noted that the majority of patients included in the randomized clinical trials of systemic therapy were relatively healthy with preserved liver function. They agreed “on a cautious approach to systemic therapy in patients with advanced hepatocellular carcinoma who are Child-Pugh class B with a good performance status, considering underlying liver function, bleed risk, presence of portal hypertension, extent of extrahepatic spread, tumor burden, and major vascular invasion.”

Moving forward, Dr. Gordan expects that updates to this guideline will be driven by additional approvals of therapy for patients with advanced hepatocellular carcinoma, specifically data on additional options for combination therapy. Until the results of randomized trials are published, the only combination therapy that is available to patients is atezolizumab/

DISCLOSURE: Dr. Gordan has served as a consultant or advisor to Genentech/Roche; has received institutional research funding from ShangPharma Innovation; holds patents or other intellectual property in “a small molecule patent…for a tool compound”; and has been reimbursed for travel, accommodations, or other expenses by Genentech/Roche. Dr. Rose has received institutional research funding from Bristol Myers Squibb, EpicentRx, Lilly, and Oncocyte.


1. Gordan JD, Kennedy EB, Abou-Alfa GK, et al: Systemic therapy for advanced hepatocellular carcinoma: ASCO Guideline. J Clin Oncol. November 16, 2020 (early release online).

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, November 18, 2020. All rights reserved.