Novel Agents, Including Immunotherapy, Look to Conquer Advanced Liver Cancer


A number of novel therapies are currently being explored as second-line treatments for patients with advanced hepatocellular carcinoma (HCC), including a host of targeted therapies and various immune checkpoint inhibitors.

A number of novel therapies are currently being explored as second-line treatments for patients with advanced hepatocellular carcinoma (HCC), including a host of targeted therapies and various immune checkpoint inhibitors. Ghassan Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, addressed this topic in a talk at the 1st Annual School of Gastrointestinal Oncology.

“Almost 15 years ago, there was very little interest in the disease, now there is a plethora of clinical trials that are readily available in the first-, second-, and third-line setting,” explained Abou-Alfa. “I highly encourage the physicians and their patients to seek clinical trials in those settings, because short of [Nexavar] there is nothing called 'standard of care.' There is diversity in regard to the targets, this is going to give a wealth of information.”

Nexavar (sorafenib) was approved based on the phase 3 SHARP trial,1 which randomized 602 patients to the multikinase inhibitor (299 patients) or placebo (303 patients). Median overall survival (OS) with Nexavar was 10.7 months compared with 7.9 months with placebo, representing the first and only systemic therapy to improve survival in a phase 3 study for patients with HCC. In the trial, there was a 31 percent reduction in the risk of death with Nexavar.

Following this demonstration of success, a number of studies were commenced in an attempt to build upon these results, including an investigation of adjuvant Nexavar for patients with HCC. Unfortunately, this study failed to show a benefit for Nexavar versus placebo.

In the trial,2 1,114 patients were randomized to Nexavar (556 patients) or placebo (558 patients) following ablation or resection. At the final analysis, the median recurrence-free survival (RFS) was 33.3 months with Nexavar versus 33.7 months with placebo. Median OS was not yet assessable from the study.

In a separate phase 2 study,3 Nexavar (154 patients) or placebo (153 patients) was added to transarterial chemoembolization (TACE) for patients with intermediate-stage HCC. Results were similar between the two arms for OS and for time to progression.

In further attempts to expand upon the use of Nexavar, studies have assessed combination approaches. In the phase 3 CALGB-80802 study4 patients with advanced HCC received frontline Nexavar alone (173 patients) or in combination with doxorubicin (173 patients). Median OS with the combination was 8.9 months compared with 10.5 months with single-agent Nexavar.

“There is not a role for adjuvant [Nexavar], and there is no role for peri-TACE [Nexavar],” said Abou-Alfa. “The role of [Nexavar] in the local regional setting was unfortunately negative, we didn't prove that additional [Nexavar] adds anything in that regard.”

Now, with Nexavar solidified as the frontline therapy for advanced HCC, phase 3 studies are exploring a host of second-line treatments, including the multikinase inhibitors Cabometyx (cabozantinib; NCT01908426) and regorafenib (NCT01774344), the MET inhibitor tivantinib (NCT01755767), and the VEGFR2 inhibitor Cyramza (ramucirumab; NCT02435433). Additionally, phase 2 studies are looking at immune-based approaches in the second-line setting.

Immunotherapy on Horizon for HCC

“Work in the second-line setting is multi-faceted—immunotherapeutics are under evaluation and the molecular understanding of HCC is underway,” said Abou-Alfa.PD-L1 is expressed in 45 percent to 100 percent of patients with HCC. This expression is demonstrated on the tumor itself and the microenvironment, in Kupffer cells and tumor associated monocytes. Murine models and early clinical studies have shown promising efficacy for PD-L1 blockade. Additionally, evidence suggests that CTLA-4 blockade could also be an effective option.In a phase 2 study,5 the CTLA-4 inhibitor tremelimumab showed signs of activity in 20 patients with HCC and chronic hepatitis C. The partial response rate was 17.6 percent with the immunotherapy and the disease control rate (DCR) was 76 percent. TTP was 6.5 months and a virologic response was indicated. However, grade 3 AST and ALT increases were seen in 45 percent of patients.

Adding to the early success seen with immunotherapy, the anti—PD-1 agent Opdivo (nivolumab) showed an objective response rate of 19 percent, which consisted of two complete responses for patients with pretreated advanced HCC.6 Stable disease was experienced by 48 percent of patients, for a DCR of 67 percent. These responses were observed regardless of hepatitis infection status.

“There are studies looking at anti—PD-L1 and anti–CTLA-4 and the combinations of the agents in a randomized, second-line setting,” said Abou-Alfa. “There is one other aspect that needs to be looked into, and that is the localized setting. This is an environment that is very poor inflammatory in nature, and probably adding an anti–PD-L1 in this setting would be of value.”

A phase 2 study is currently exploring the PD-L1 inhibitor durvalumab and tremelimumab alone or in combination for patients with unresectable HCC following prior Nexavar. The trial plans to enroll 120 patients, with an estimated completion date of April 2018.

A phase 3 study is also comparing Opdivo with Nexavar as a frontline therapy for patients with advanced HCC. This trial plans to enroll 726 patients with dual primary endpoints of OS and TTP. The primary completion date is July 2017 (NCT02576509).


  1. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med. 2008;359:378-390.
  2. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344—1354.
  3. Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. J Clin Oncol. 2012;30 (suppl 4; abstr LBA154^).
  4. Abou-Alfa GK, Niedzwieski D, Knox JJ, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). J Clin Oncol. 2016;34 (suppl 4S; abstr 192).
  5. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-88.
  6. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II Safety and Antitumor Activity of Nivolumab in Patients with Advanced Hepatocellular Carcinoma (HCC): CA209-040. J Clin Oncol. 2015;33 (suppl; abstr LBA101).
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