Biomarkers, Patient Factors Inform HCC Treatment Decisions Beyond Frontline Setting

There are clear biomarkers available to guide treatment decisions in the second-line setting for patients with advanced hepatocellular carcinoma, Lipika Goyal, MD, Mphil, said during a presentation at the 2020 HCC-TAG Conference.

Lipika Goyal, MD, Mphil

There are clear biomarkers available to guide treatment decisions in the second-line setting for patients with advanced hepatocellular carcinoma (HCC), Lipika Goyal, MD, Mphil, said during a presentation at the 2020 HCC-TAG Conference. She added, however, that there are some patient characteristics to keep in mind when choosing an agent.

Goyal, an instructor at Harvard University Medical School, largely focused on patients who received upfront atezolizumab (Tecentriq) and bevacizumab (Avastin) in the phase III IMbrave150 trial. She called the regimen the "-1 line of therapy" because the combination has not been FDA approved in this patient population.

The combination is not appropriate for every patient with HCC. While there are no contraindications for atezolizumab, patients with severe underlying autoimmune disorders should likely not receive the PD-L1 inhibitor to reduce the risk for immune-related adverse events. For patients who have undergone surgery within the previous 28 days, have an open wound or fistula, uncontrolled hypertension, congestive heart failure, nephrotic syndrome, or have experienced recent bleeding, "you really want to think twice" before using bevacizumab, Goyal said.

For those who have already received the frontline combination of atezolizumab/bevacizumab, she said a clinical trial or Yttrium-90 (Y-90) embolization may be viable options before proceeding to sorafenib (Nexavar) or lenvatinib (Lenvima).

"Quality of life is a very important part of how we make decisions," she said. "If we can do liver-directed therapy as a way to spare people toxicity, we should think about it."

Making Second-Line Choices

For people who receive frontline sorafenib or lenvatinib, Goyal said she considers a second-line immunotherapy when patients have either has experienced rapid progression on treatment with a tyrosine kinase inhibitor (TKI), had poor tolerability to a TKI, or is unlikely to get to third-line treatment.

When selecting patients for the oral multikinase inhibitor regorafenib (Stivarga), the eligibility criteria in the phase III RESORCE trial required patients to demonstrate tolerance to >400 mg sorafenib daily for ≥20 of the previous 28 days. When the data were published online in 2016, RESORCE was the first phase III trial to demonstrate a survival benefit for a systemic therapy in the second-line setting for patients with advanced HCC who progressed on sorafenib.

Patients in RESORCE had Barcelona Clinic Liver Cancer stage B or C disease, ≥1 lesion by RECIST v1.1 criteria, unresectable disease, and progression on prior sorafenib. Patients from 152 centers across 21 countries were randomly assigned to 160 mg regorafenib or placebo in a 3-weeks-on/1-week-off schedule.

Regorafenib induced a median overall survival (OS) of 10.6 months (95% CI, 9.1-12.1) versus 7.8 months (95% CI, 6.3-8.8) with placebo. This result represented a 37% reduction in the risk for death (HR, 0.63; 95% CI, 0.50-0.79; one-sided P <.0001).1

"[The time] from day 1 of sorafenib until [patients] passed away on the RESORCE trial was 22 months, so you're selecting for the best actors, for people who tolerated sorafenib and potentially the people who are going to respond the best to regorafenib," Goyal said. She noted that regorafenib improved survival across subgroups, including those with alpha fetoprotein (AFP) >400 ng/mL.

Patients with AFP ≥400 ng/mL and who been previously treated with sorafenib are indicated for ramucirumab (Cyramza), according to results from the phase III REACH-2 trial. The FDA approved the VEGFR2 inhibitor in May 2019, based on findings from the international, double-blind, placebo-controlled, multicenter trial.

The median OS was 8.5 months with ramucirumab compared with 7.3 months with placebo (HR, 0.71; 95% CI, 0.53-0.95; P = .020) in patients who experienced progression on or intolerance to frontline sorafenib.2

There is no specific requirement for sorafenib tolerance or AFP level for cabozantinib (Cabometyx), Goyal said, and the drug is acceptable for use in the third-line setting. In January 2019, the FDA approved the multikinase inhibitor for patients who have previously received sorafenib, based on findings from the phase III CELESTIAL trial.

Results showed that the median OS favored the cabozantinib arm over placebo, at 10.2 vs 8.0 months, respectively (HR, 0.76; 95% CI, 0.63-0.92; P = .0049).3 By investigator assessment, the median PFS was 5.2 months for cabozantinib compared with 1.9 months with placebo (HR, 0.44, 95% CI, 0.36-0.52; P <.0001). The ORR was 4% with cabozantinib compared with 0.4% with placebo (P = .0086).


  1. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. doi: 10.1016/S0140-6736(16)32453-9.
  2. Zhu AX, Kang Y-K, Yen C-J, et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol. 2018;36 (suppl; abstr 4003).
  3. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Eng J Med. 2018;379(1):54-63. doi: 10.1056/NEJMoa1717002.

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