Burst of Targeted Agents Leads to Transformed HCC Paradigm

Richard S. Finn, MD, reflects on data from the phase III REFLECT, RESORCE, CELESTIAL, and REACH-2 trials in hepatocellular carcinoma.

Richard S. Finn, MD

Sorafenib (Nexavar) was approved for patients with unresectable hepatocellular carcinoma (HCC) in 2007 and for the next decade, it was the only oral therapeutic agent for this patient population. Since 2017, physicians treating patients with this disease have seen 4 positive phase III studies demonstrating an improvement in survival, said Richard S. Finn, MD, in a presentation during the 2020 HCC-TAG Conference.

“If we're going to get patients to second-line [treatment], we have to get them to frontline. That has to do with transitioning patients from locoregional therapy appropriately,” Finn explained. “I don't want to stop locoregional therapy—it’s very important in managing a majority of patients we see. But it doesn’t cure them, and to keep doing it after progression will limit our ability to maximize what we can do.”

Finn, an assistant professor of medicine at the University of California, Los Angeles, reflected on data from the phase III REFLECT, RESORCE, CELESTIAL, and REACH-2 trials.

The FDA approved the oral multikinase inhibitor lenvatinib (Lenvima) in August 2018 as a frontline treatment for patients with unresectable HCC based on data from the phase III REFLECT trial. In the international, multicenter, randomized, open-label, non-inferiority study, lenvatinib was found to be noninferior to the established first-line standard of care, sorafenib. Patients with unresectable HCC were randomized to lenvatinib (n = 478) or sorafenib (n = 476). The primary endpoint of the study was OS noninferiority.

Results showed that the median overall survival (OS) by investigator review with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06). The median OS for patients who responded to lenvatinib was 22.4 months compared with 11.4 months for nonresponders (HR, 0.61; 95% CI, 0.49-0.70; P <.001).1

As assessed by investigator review using mRECIST criteria, the objective response rate (ORR) was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio [OR], 3.13; 95% CI, 2.15-4.56; P <.00001). By independent review, the ORR benefit with lenvatinib was even stronger (40.6% vs 12.4%; OR, 5.01; 95% CI, 3.59-7.01; P <.0001). As assessed by independent review using RECIST v1.1 criteria, the ORR with lenvatinib was 18.8% (OR, 3.34; 95% CI, 2.17-5.14).

The noninferiority results was also consistent across patient subgroups in REFLECT, including age, gender, body weight, ECOG performance status, and posttreatment anti-cancer therapy. Moreover, lenvatinib significantly improved progression-free survival, time to progression, and ORR in this patient population.

“For the first time with a TKI, we're starting to see significant response rates,” Finn said. “By mRECIST, the ORR by investigator review is 24%. By experts in the field, it was 41%, but even by RECIST, it was 19%. That's a real response rate when compared with sorafenib, which historically has always given us single-agent responses of 6.5%.”

Targeted Agents in Second-Line Setting

In the RESORCE trial, patients with radiologic progression during sorafenib treatment who had Child-Pugh A status and Barcelona Clinic Liver Cancer (BCLC) stage B or C disease not amenable to resection or locoregional therapy were randomized to receive regorafenib (Stivarga; n = 379) or placebo (n = 194) until disease progression, death, or unacceptable toxicity.

In the primary analysis, the median OS with regorafenib was 10.6 months (95% CI, 9.1-12.1) versus 7.8 months (95% CI, 6.3-8.8) with placebo (HR, 0.62; 95% CI, 0.50-0.78; 2-sided P <.001).2

The multikinase inhibitor cabozantinib (Cabometyx) was evaluated in HCC in the CELESTIAL trial. Here, 707 patients with previously treated advanced HCC were randomized to 60 mg of once-daily cabozantinib (n = 470) or placebo (n = 237). All patients had an ECOG performance status of 0 or 1, a Child-Pugh score of A, and had progressed on ≥1 prior systemic therapy for advanced HCC. Seventy percent of patients in the trial had only received prior sorafenib.

Results showed that the median OS favored the cabozantinib arm over placebo at 10.2 months versus 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).

Finn noted that the results for cabozantinib were very similar to those observed with regorafenib in this patient population. “I don’t think we can look at hazard ratios that differ by a few points and say that, in reality, that it means anything—unless you do a head-to-head [trial],” he said.

Ramucirumab (Cyramza), a fully humanized monoclonal VEGFR2 inhibitor, was granted FDA approval in May 2019 for the treatment of patients with HCC who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been previously treated with sorafenib. The decision was based on results from the phase III REACH-2 trial.

In this study, patients were randomized to receive best supportive care and ramucirumab (n = 197) or placebo (n = 95) until disease progression or unacceptable toxicity. Eligible patients were required to have a diagnosis of HCC and BCLC stage B or C, Child-Pugh score of A, AFP ≥400 ng/mL, disease progression with first-line sorafenib, and disease that was refractory to or not amenable to local treatment.

Because REACH-2 investigators selected patients based on AFP, it was the first positive biomarker-driven study in HCC, Finn said.

In the overall population, 8.5 months compared with 7.3 months with placebo (HR, 0.710; 95% CI, 0.531-0.949, P = .0199) in patients who experienced disease progression on or intolerance to frontline sorafenib. The OS rates both favored ramucirumab over best supportive care at 12 months (36.8 vs 30.3%, respectively) and 18 months (24.5% vs 11.3%).4 The median durations of follow-up were 7.9 months for ramucirumab and 6.6 months for placebo.

A subgroup analysis showed that, in patients with AFP ≥400 ng/mL, the median OS in the ramucirumab arm was 7.8 months compared with 4.2 months for placebo (HR, .67; 95% CI, 0.51-0.90; P = .006).


  1. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
  2. Bruix J, Merle P, Granito A, et al. Overall survival (OS) update: 2-year follow-up from the phase 3 RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) progressing on sorafenib. Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. O-023. ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.
  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.
  4. 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). doi: 10.1200/JCO.2018.36.15_suppl.4003.

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