Combination Therapies Outperform Sorafenib in Hepatocellular Carcinoma

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The superiority of the combination regimens for hepatocellular carcinoma treatment was demonstrated in results from the IMbrave150 and HIMALAYA trials, according to Josep M. Llovet, MD, PhD.

Josep M. Llovet, MD, PhD

Josep M. Llovet, MD, PhD

According to a presentation summarizing molecular targeted therapies in hepatocellular carcinoma (HCC) in the first and second line, frontline combination therapies including atezolizumab (Tecentriq) and bevacizumab (Avastin) or tremelimumab and durvalumab (Imfinzi) demonstrated superiority in overall survival (OS) compared with sorafenib (Nexavar) monotherapy. However, in patients for whom combination therapy is contraindicated, sorafenib or lenvatinib (Lenvima) are considered as first-line therapies, said Josep M. Llovet, MD, PhD, during the American Association for Cancer Research Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer in Boston, Massachusetts.1

The superiority of the combination regimens was demonstrated in results from the IMbrave150 (NCT03434379)2 and HIMALAYA (NCT03298451)3 trials, respectively. “Sorafenib became the gold standard of care based on the phase 3 [NCT00105443; SHARP]4 trial findings,” said Llovet, a full professor of medicine and director of the Liver Cancer Program at the Icahn School of Medicine at Mount Sinai, New York, New York.

After progression to first line, sorafenib and lenvatinib are recommended, with regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza) gaining second-line indications. Pembrolizumab (Keytruda) and the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) gained FDA approval based on phase 2 data.

First-line Therapies

In IMbrave150,2 which evaluated the combination of atezolizumab and bevacizumab, median OS was 19.2 months and median progression-free survival (PFS) was 6.8 months. Investigators reported 36% grade 3/4 treatment-related adverse events (TRAEs) with the most common being hypertension (10%), increased aspartate aminotransferase (AST; 4%), and proteinuria (3%). In addition, 2% of TRAEs led to death and AEs leading to drug withdrawal were 16% for any drug and 7% for both drugs (TABLE5).

The SHARP trial4 randomly assigned 602 patients with advanced HCC who had not been previously treated with systemic therapy to receive sorafenib or placebo. Median OS was 10.7 months in the treatment arm and 7.9 months in the control arm (HR, 0.69; 95% CI, 0.55-0.87; P < .001). Investigators noted no significant difference between the 2 groups in median time to symptomatic progression (4.1 months vs 4.9 months, respectively; P = .77). Also, 45% of patients reported grade 3/4 TRAEs with the most common being diarrhea (8%), hand-foot syndrome (HFS; 8%), and fatigue (4%).

The global, open-label, randomized phase 3 REFLECT study (NCT01761266) demonstrated the efficacy of lenvatinib.6 Llovet noted that REFLECT excluded patients with extrahepatic main portal vein invasion or who had greater than 50% liver involvement. Median OS was 13.6 months and median PFS was 7.4 months. Also, 57% of patients experienced grade 3/4 TRAEs with the most common being hypertension (23%) and weight loss (8%). Furthermore, 2% of TRAEs resulted in death and 9% of AEs led to drug withdrawal.

Second-line Therapies

Regorafenib was evaluated in patients with HCC who progressed on sorafenib treatment in the RESORCE trial (NCT01774344).7 A total of 843 patients were screened, of whom 573 were enrolled and randomized (379 received regorafenib and 194 received placebo) and 567 initiated treatment (374 received regorafenib and 193 received placebo). Investigators reported that the median OS was 10.6 months and median PFS was 3.1 months. The objective response rate was 11% in the treatment arm and 7% in the control arm. Half of the patients experienced grade 3/4 TRAEs with the most common being hypertension (13%), HFS (13%), and fatigue (9%). Also, 2% of patients who experienced TRAEs died and 10% of AEs led to drug withdrawal.

In the CELESTIAL trial (NCT01908426),8 707 patients were randomly assigned to receive 60 mg of cabozantinib once daily or matching placebo. Among patients with previously treated advanced HCC, treatment with cabozantinib resulted in longer OS (10.2 months) and PFS (5.2 months) compared with placebo.

Further, 68% of patients experienced grade 3/4 TRAEs with the most common being HFS (17%), hypertension (16%), and increased AST (12%). AEs led to drug withdrawal in 16% of patients.

Kudo et al evaluated ramucirumab after prior sorafenib in patients with advanced

HCC in the REACH-2 trial (NCT02435433).9 Investigators reported a longer OS for second-line ramucirumab vs placebo (HR, 0.710; 95% CI, 0.531-0.949; P = .0199) and an α-fetoprotein of 400 ng/mL or greater.

Druggable Targets

Identifying and targeting individual oncogenic drivers along with increased feasibility of sequencing tumor genomes, met with initial success.10 Turning to exome sequencing in HCC, Llovet said a meta-analysis of whole exome sequencing for 928 HCC cases resulted in the identification of 25% potential actionable targets, but none have resulted in FDA-approved agents.10

“When we look at melanoma, we have 80% druggable targets with 45% of drugs approved for this indication, [so comparatively], HCC is in a bad situation,” Llovet emphasized.

Noting the potential of linking targets with therapies in HCC, Llovet identified potential novel drivers and receptors.

Emerging data suggest that FGF19 could be a potential HCC driver and that its receptor, FGFR4, could be a novel therapeutic target. Fisogatinib (BLU-554), a selective oral FGFR4 inhibitor, was evaluated in a phase 1 dose-escalation and dose-expansion study (NCT02508467).11 The agent elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC.

An oral MEK inhibitor, refametinib, is undergoing evaluation in patients with RAS-mutated HCC in 2 phase 2 studies as monotherapy (NCT01915589) and in combination with sorafenib (NCT01915602).12 The investigators reported that prospective testing for RAS family mutations using circulating tumor DNA was a feasible, noninvasive approach in patients with HCC. The investigators reported a median OS of 12.7 months in the combination trial suggesting a synergistic effect, which should be explored further.


1. Llovet JM. Molecular targeted therapies for advanced RCC. Presented at: AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; May 5-8, 2022; Boston, MA. Accessed June 21, 2022.

2. Finn RS, Qin S, Ikeda M, et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(suppl 3):267. doi:10.1200/JCO.2021.39.3_suppl.267

3. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379

4. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

5. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3

6. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib infirst-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-

7. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. 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

8. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002

9. Kudo M, Okusaka T, Motomura K, et al. Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial. J Gastroenterol. 2020;55(6):627-639. doi:10.1007/s00535-020-01668-w

10. Hyman DM, Taylor BS, Baselga J. Implementing genome-driven oncology. Cell. 2017;168(4):584-599. doi:10.1016/j.cell.2016.12.015

11. Kim RD, Sarker D, Meyer T, et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 2019;9(12):1696-1707. doi:10.1158/2159-8290.CD-19-0555

12. Lim HY, Merle P, Weiss KH, et al. Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular carcinoma. Clin Cancer Res. 2018;24(19):4650-4661. doi:10.1158/1078-0432.CCR-17-3588

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