Expert Provides Clarity on Treatment of Advanced HCC

Partner | Cancer Centers | <b>Mayo Clinic Cancer Center</b>

Mitesh J. Borad, MD, discusses liver-directed therapies, systemic therapy, and the management of liver cancer.

Mitesh J. Borad, MD

Although hepatocellular carcinoma is less frequent in the United States with less than 40,000 cases per year, the global incidence per year is estimated to be 782,000 cases, said Mitesh J. Borad, MD.

In a presentation during the 2018 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, Borad, an associate professor of medicine in the Division of Hematology/Oncology at Mayo Clinic, discussed liver-directed therapies, systemic therapy, and the management of liver cancer.

HCC is the most common primary cancer of the liver; typical etiologies for HCC include hepatitis B or C, metabolic syndrome, and alcoholic liver disease.

“This is a dual disease,” said Borad. “You are not only dealing with the tumor, but the background in which it arises such as cirrhosis or fibrosis—which can drive outcomes in patients. Both things really need to be considered.”

Liver-Directed Therapies

Borad says that patients can be broadly categorized into 3 stages: early-, intermediate-, and advanced-stage disease. In early-stage disease, surgery or transplant is a viable option, and in intermediate- and advanced-stage disease, locoregional therapy or systemic therapy should be considered.Liver-directed therapies include embolization, radiofrequency ablation, cryoablation, radioembolization, alcohol ablation, and external beam radiation.

The SARAH study evaluated the safety and efficacy of selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) resin microspheres compared with sorafenib (Nexavar) in patients with locally advanced and inoperable HCC. The results of this randomized phase III trial did not show significant differences in outcomes in overall survival (OS); OS for patients who received SIRT was 8.0 versus 9.9 months with sorafenib (P = .179).1 Responses were somewhat higher in the radioembolization arm, says Borad, but that did not translate into survival advantage.

SIRveNIB was an Asian-Pacific study with a similar question as SARAH: Can patients do better with sorafenib? Almost 500 patients with advanced-stage HCC were treated with either SIRT or sorafenib. This was also considered a negative study, with similar results in both arms. Although there was a higher tumor response rate with SIRT, Borad said that unless these responses translate into survival differences, they are not impactful in the advanced setting.

Systemic Therapy

Borad said that the take-home message from these 2 studies is that Y-90 remains a reasonable modality to treat HCC, despite the negative studies. Future studies should focus on liver-limited cases and earlier-stage disease to potentially optimize the use of Y-90.In the first-line setting, patients with advanced HCC should be treated systemically with either sorafenib or lenvatinib (Lenvima), Borad says.

Sorafenib was the rst FDA-approved systemic therapy for the treatment of patients with HCC, and up until recently, it was the only agents to show a significant improvement in OS in this field. This approval was based on results from the SHARP study.

The phase III REFLECT study, updated results of which were presented at the 11th Annual Conference of the International Liver Cancer Association, compared lenvatinib versus sorafenib in the first-line setting. The median OS with lenvatinib was 13.6 versus 12.3 months for sorafenib, and there was an improvement in progression-free survival (PFS) by 3.7 months compared with sorafenib.2 In the 954-patient study, median PFS with lenvatinib was 7.4 versus 3.7 months with sorafenib (HR, 0.66; 95% CI, 0.57-0.77; P <.00001).

A supplemental new drug application for lenvatinib in this setting has been accepted by the FDA. Under the Prescription Drug User Fee Act, the agency will decide on the approval by August 24, 2018. “While downstaging is generally not a major objective in advanced disease in patients, higher response rates with lenvatinib are provocative and should be studied in a formal prospective study in borderline resectable patients,” said Borad.

Borad concluded that either of these options are viable, but the hand-foot toxicities with sorafenib are dreaded by most patients and physicians. Although sorafenib might become generic in the near future, so that may be a factor in terms of cost, he adds.

In the second-line setting, there are more options for treatment. There are 2 antiangiogenics, regorafenib (Stivarga) and cabozantinib (Cabometyx), as well as the PD-1 inhibitor nivolumab (Opdivo).

In April 2017, the FDA approved regorafenib as a second-line treatment for patients with HCC who have previously received sorafenib. This approval was based off findings from the phase III RESORCE trial, which evaluated the safety and efficacy of regorafenib versus placebo in patients with HCC who had progressed on sorafenib.

With a primary endpoint of OS, 573 patients from 152 centers in 21 countries in North and South America, Europe, Australia, and Asia were treated with either regorafenib at 160 mg once daily (n = 379) or placebo (n = 194) and best supportive care. The median OS was 10.6 months with regorafenib compared with 7.8 months with placebo,3 meaning that the reduction in the risk of death with regorafenib was 38% (HR, 0.63; 95% CI, 0.50-0.79; P <.001).

The randomized phase III CELESTIAL trial, findings of which were presented at the 2017 Gastrointestinal Cancers Symposium, showed that cabozantinib improved OS and PFS compared with placebo for patients with previously treated advanced HCC. The median OS with cabozantinib was 10.2 months versus 8.0 months with placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92; P = .0049).4

In May 2018, the FDA accepted a supplemental new drug application for cabozantinib as a treatment for patients with previously treated advanced HCC based on the preliminary results of this trial.

“Both regorafenib and cabozantinib are suitable choices for patients who previously progressed on sorafenib,” said Borad. “[The] choice of antiangiogenics will need to be considered in the setting of nivolumab and other immune checkpoint inhibitors.”

In September 2017, nivolumab was approved by the FDA following treatment with sorafenib in patients with HCC, regardless of PD-L1 status.

This approval was based on findings from the phase I/II CheckMate-040 trial of 154 patients with advanced HCC. The overall response rate (ORR) by blinded independent central review was 18.2%, and 3.2% of patients experienced a complete response.5

“We saw early responses mostly, some delayed. They are durable in nature, which makes [nivolumab] very appealing in terms of what a patient desires,” said Borad. “Responses can persist, even after you stop therapy.”

Liver Dysfunction

Toxicities were mostly autoimmune-related and manageable. However, Borad said it is important to follow any liver-related toxicities closely. Hepatotoxicity may be higher in HCC than what has been observed with nivolumab in other tumor types.Liver dysfunction is broken down into 3 factors: liver function, patient, and tumor.

Specifically with liver function, in a study of patients with HCC, the albumin-bilirubin (ALBI) grade approach was established as a way to assess the degree of liver function. This distilled what was already in the Child-Pugh scoring system, explained Borad.

With ALBI, the scoring is objective, Borad said. The ALBI score is calculated by (log10 bilirubin x 0.66) plus (albumin x -0.085). Bilirubin is measured in μmol/L and albumin, g/L. There are 3 classes—ALBI Grade 1, which is ≤-2.6; ALBI Grade 2, which is >-2.6 ≤ 2.6 ≤ -1.39; and ALBI Grade 3, which is >-1.39.

“[ALBI] is a robust measure if used properly,” said Borad.

Borad concluded his presentation by saying that after a decade without any advancements in the treatment of patients with HCC, there are new options approved and more coming down the pike, arming oncologists with the tools to fight this malignancy.


  1. Vilgrain V, Bouattour M, Sibert A, et al. SARAH: a randomised controlled trial comparing efficacy and safety of selective internal radiation therapy (with yttrium-90 microspheres) and sorafenib in patients with locally advanced hepatocellular carcinoma. Presented at: 2017 International Liver Congress; April 19-23, 2017; Amsterdam, Netherlands. Abstract GS-012.
  2. Cheng A-L, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2017;35 (suppl; abstr 4001).
  3. Bruix J, Merle P, Granito A, et al. E cacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract LBA03.
  4. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2018;36 (suppl 4S; abstr 208).
  5. Crocenzi TS, El-Khoueiry AB, Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. J Clin Oncol. 2017;35 (suppl; abstr 4013).