What are the FDA approved second-line treatments for hepatocellular carcinoma (HCC)?

Updated: Jan 31, 2021
  • Author: Luca Cicalese, MD, FACS; Chief Editor: John Geibel, MD, MSc, DSc, AGAF  more...
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Answer

Regorafenib

In April 2017, regorafenib was approved by the FDA for use in patients with HCC who have been previously treated with sorafenib. Approval was based on the RESORCE trial results (N = 573) in patients with progressive HCC who had undergone treatment with sorafenib. [67] In this trial, regorafenib improved overall survival (OS) in comparison with placebo (10.6 vs 7.8 months). Median PFS was also significantly better with regorafenib than with placebo (3.1 vs 1.5 months), as were the disease control rate (65.2% vs 36.1%) and the complete or partial response rate (10.6% vs 4.1%).

Nivolumab

In September 2017, nivolumab (Opdivo) was approved by the FDA for patients with HCC who have been previously treated with sorafenib. Accelerated approval was based on the CheckMate-040 trial, a phase 1/2, open-label, multicenter trial evaluating nivolumab in patients with advanced HCC who progressed on or were intolerant of sorafenib. [68] Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In the CheckMate-040 trial, 154 patients received nivolumab 3 mg/kg IV every 2 weeks. Of the 154 patients, 22 (14.3%) responded to nivolumab, with complete response seen in 3 (1.9%). [68] The duration of response ranged from 3.2 months to greater than 38.2 months. In those who responded, 91% had responses lasting at least 6 months, and 55% had responses lasting at least 12 months. Common adverse reactions occurring in greater than 20% of patients in nivolumab clinical trials include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.

Lenvatinib

In August 2018, the FDA approved lenvatinib, a vascular endothelial growth factor (VEGF) inhibitor, for first-line treatment of unresectable HCC. Approval was based on the phase III REFLECT trial, which showed that lenvatinib was noninferior to sorafenib for first-line treatment of HCC. [69]  Median OS was 13.6 months with lenvatinib vs 12.3 months with sorafenib. Median PFS was 7.4 months for lenvatinib versus 3.7 months for sorafenib. Time to progression was 8.9 months for lenvatinib vs 3.7 months for sorafenib.

Pembrolizumab

In November 2018, the FDA granted pembrolizumab an accelerated approval for patients with HCC previously treated with sorafenib. Approval was based on the KEYNOTE-224 trial, in which single-agent pembrolizumab induced an objective response of 17% among 104 patients with advanced HCC previously treated with sorafenib. [70] The overall response rate was 1%, and the partial response rate was 16%; meanwhile, 44% of patients had stable disease, 33% had progressive disease, and 6% were considered not assessable. Pembrolizumab treatment resulted in durable responses and favorable PFS and OS in patients with advanced HCC previously treated with sorafenib.

Cabozantinib

In January 2019, cabozantinib was approved for HCC in patients previously treated with sorafenib. Cabozantinib is an inhibitor of multiple tyrosine kinases, including RET, MET, and VEGFR-2. Approval was based on the phase III CELESTIAL trial (N = 707). OS was improved by 2.2 months with cabozantinib (10.2 months) as compared with placebo (8.0 months). The improvement in median OS with cabozantinib represented a 24% reduction in the risk of death (HR, 0.76). [71]

Ramucirumab

In May 2019, ramucirumab, a VEGFR2 antagonist, was approved by the FDA for HCC. It is indicated as monotherapy in patients with HCC who have an alpha fetoprotein (AFP) level of 400 ng/mL or higher and have been previously treated with sorafenib. Approval was based on the REACH‑2 randomized double-blind placebo-controlled study (N = 292). [72] Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Estimated median OS was 8.5 months (range, 7.0-10.6) for ramucirumab and 7.3 months (range, 5.4-9.1) for placebo (HR 0.71).

Atezolizumab plus bevacizumab

In IMbrave150, a global, open-label, phase III trial in systemic treatment–naïve patients with unresectable HCC, both OS and PFS were better with atezolizumab plus bevacizumab than with sorafenib. OS at 12 months was 67.2% (95% CI, 61.3 to 73.1) in patients (n = 329) treated with atezolizumab–bevacizumab and 54.6% (95% CI, 45.2 to 64.0) in patients (n = 156) treated with sorafenib. Median PFS was 6.8 months (95% CI, 5.7 to 8.3) versus 4.3 months (95% CI, 4.0 to 5.6), respectively. The hazard ratio for disease progression or death with atezolizumab–bevacizumab compared with sorafenib was 0.59 (95% CI, 0.47 to 0.76; P < 0.001). [73] On the basis of the IMbrave150 results, in May 2020 the FDA approved atezolizumab in combination with bevacizumab for systemic treatment–naïve patients with unresectable or metastatic HCC. [74]

 


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