Therapeutic Options Continue to Grow for HCC

Tanios Bekaii-Saab, MD

The treatment landscape of hepatocellular carcinoma (HCC) continues to expand, with some of the biggest approvals yet occurring in the past year, including the multikinase inhibitor regorafenib (Stivarga) and the PD-1 antibody nivolumab (Opdivo). “Before 2009, I would struggle to find a reasonable option,” said Tanios Bekaii-Saab, MD. “We used so many things that did not make sense, but we were so desperate because there were absolutely no therapies.”

2009 brought the approval of sorafenib (Nexavar), which prolonged survival in some patients. Sorafenib is still a mainstay in the frontline treatment of patients with HCC, although it remains a tough drug, according to Bekaii-Saab. In a presentation during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Bekaii-Saab, a professor of medicine at Mayo Clinic, discussed the evolving treatment of patients with HCC.

Embolization

Current options for patients with early-stage disease include surgery or transplantation. For those with intermediate-risk disease, transarterial chemoembolization (TACE) is the optimal option, with a survival rate of 40% to 60% at 2 years. For patients with high-risk HCC, treatment with sorafenib or enrollment on clinical trials is the best avenue, Bekaii-Saab said.In advanced HCC, liver embolotherapy techniques include TAE, which is the induction of ischemic necrosis at the arteriolar level using a permanent embolic.¹ While this option is low-cost and there are no chemotherapeutic adverse events, there is the risk for postembolization syndrome as well as pulmonary emboli.

TACE, which is intrahepatic chemotherapy combined with embolization, is a stronger supported option, based on randomized controlled trial data. Drug-eluting bead TACE is a more standardized form of conventional TACE, but it is more expensive.

Lastly there is radioembolization, which is radiation necrosis from beta-emitting Yttrium-90 microspheres. This technique may improve time to progression with some observational data; fewer treatment sessions are required, there is no post-embolization syndrome, and radiation segmentectomy may be potentially curative. This is an expensive option, however, and requires coordination between nuclear medicine, interventional radiology, and a radiation safety officer.

Systemic Therapy

As for these techniques in clinical trials, the multicenter, open-label, randomized phase III trial of selective internal radiation therapy (SIRT) versus sorafenib in locally advanced HCC, and the phase III SARAH study of SIRT versus sorafenib in locally advanced and inoperable HCC who failed after 2 rounds of TACE, were both negative. Bekaii-Saab said that these results indicate that the next challenge is second-line randomized trials.One of the most impactful trials of 2017 was the phase III RESORCE study, which investigated second-line regorafenib versus placebo in patients with HCC who had progressed on sorafenib. The median overall survival (OS) for regorafenib plus best supportive care was 10.6 months compared with 7.8 months for placebo plus best supportive care.² This represented a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.50- 0.78; P <.001). Results from this trial led to the FDA approval in April 2017 of regorafenib as a second-line treatment for patients with HCC who previously received sorafenib.

Immunotherapy

More recently, the phase III CELESTIAL trial of cabozantinib (Cabometyx) versus placebo in patients with HCC who progressed on sorafenib showed a 2.2-month improvement in OS with cabozantinib versus placebo for patients with previously treated advanced HCC.³ The median OS with cabozantinib was 10.2 months compared with 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).Nivolumab was granted an accelerated approval by the FDA in September 2017 for the treatment of patients with HCC following prior sorafenib, regardless of PD-L1 status. This approval was based on findings from the CheckMate-040 study, which evaluated patients with advanced HCC with or without hepatitis C virus or hepatitis B virus infection.⁴ The overall response rate by blinded independent central review was 18.2% per modified RECIST criteria for patients who had been previously treated with sorafenib.

Currently, there are a handful of ongoing trials with immunotherapy in HCC. There is a first-line trial, CheckMate-459, of nivolumab versus sorafenib (NCT02576509). In the secondline setting, there is pembrolizumab (Keytruda) versus best supportive care in the KEYNOTE-240 trial (NCT02702401), and durvalumab (Imfinzi) plus tremelimumab (NCT02519348).

Bekaii-Saab says that sequencing questions remain for clinicians treating patients with advanced disease.

References

1. Kishore S, Friedman T, Madoff DC. Update on embolization therapies for hepatocellular carcinoma. Curr Oncol Rep. 2017;19(6):40. doi: 10.1007/s11912-017-0597-2.
2. Bruix J, Merle P, Granito A, et al. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Ann Oncol. 2016;27(suppl 2):ii140- ii141. academic.oup.com/annonc/article/27/suppl_2/ii140/2475563. Published June 27, 2016. Accessed April 2, 2018.
3. 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). doi: 10.1200/JCO.2018.36.4_suppl.207.
4. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet Oncol. 2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2.