HCC Therapies Rapidly Advance After a Decade of Disappointment

Bruno Sangro, MD, PhD

After a decade of little movement in the treatment of advanced hepatocellular carcinoma (HCC), there are promising developments on the horizon, according to recent study findings. These advancements include 1 new drug that was approved earlier this year, 2 agents pending FDA decisions, and later-stage clinical trials for multiple therapies.

The potential for new therapies comes at a time of continuing challenges in the treatment of patients with HCC. It is the second most common cause of cancer deaths across the globe, and the incidence of the disease continues to rise in the United States.¹ In 2000, there were 4.4 cases of HCC per 100,000 individuals; this number rose to 6.7 cases per 100,000 in 2012.² Although treatment for early HCC is often successful, advanced cases usually have a poor prognosis.

“The first systemic therapy with a survival benefit for HCC was introduced literally a decade ago,” said Amit G. Singal, MD, MS, associate professor of medicine, medical director of the Liver Tumor Program, and clinical chief of the Hepatology Division of Digestive and Liver Diseases at University of Texas Southwestern Medical Center in Dallas, in an interview with OncologyLive^®. In 2007, the FDA approved sorafenib (Nexavar), a multikinase inhibitor that targets angiogenesis, for the treatment of patients with unresectable HCC.³

The drug had previously been approved for patients with renal cell carcinoma and has gained an indication for differentiated thyroid cancer. In HCC, sorafenib provides a median survival and time to radiologic progression that was approximately 3 months longer compared with placebo.⁴ Unfortunately, this was the last new treatment to be moderately successful for the next 10 years.

“There were many other promising studies, but they all turned out to be negative,” said Tim F. Greten, MD, senior investigator in the Thoracic and Gastrointestinal Oncology Branch and head of the Gastrointestinal Malignancy Section at the National Cancer Institute.

Now, oncologists who treat patients with advanced HCC may have 3 new therapies to administer by the end of this year. In April, the FDA approved regorafenib (Stivarga), a small-molecule multikinase inhibitor, as a second-line treatment for patients with HCC who have previously received sorafenib. The agency is scheduled to decide by September 24 whether to approve a supplemental biologics license application for nivolumab (Opdivo), a PD-1 inhibitor, as second-line therapy for HCC. Additionally, an application is pending for lenvatinib (Lenvima) as a first-line therapy.

Table. Selected Phase III Trials in Hepatocellular Carcinoma

New Hope With Regorafenib

Given the disappointments from earlier trials, most clinicians remain somewhat guarded when considering current phase II studies that appear to have positive results. But there is room for a positive outlook when it comes to several emerging immunotherapy and targeted therapy agents, experts say, and clinical development has rapidly advanced into phase III trials (Table).The paradigm in HCC treatment started changing last year when the results of the phase III RESORCE trial demonstrated a survival benefit with regorafenib. The drug, which previously was approved for colorectal cancer and gastrointestinal stromal tumors, targets several kinases that promote tumor angiogenesis, such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), along with other kinases. Similarly, sorafenib also targets VEGFRs and PDGFR-beta.

The international, multicenter, randomized, double-blind, placebo-controlled RESORCE study investigated the use of regorafenib among 573 adult patients with advanced HCC who had progressed following treatment on sorafenib.^5,6 The study participants were randomized to receive oral regorafenib at 160 mg once daily during weeks 1 to 3 of each 4-week cycle plus best supportive care (BSC) or placebo plus BSC. The primary endpoint was overall survival (OS), with treatment continuing until disease progression or unacceptable toxicity.

The results showed that patients who received regorafenib had a median OS of 10.6 months compared with 7.8 months for patients who took the placebo (HR, 0.63; 95% CI, 0.50-0.79; P <.0001). There was also a statistically significant improvement in progression-free survival (PFS) based on modified RECIST criteria for HCC, with an estimated median PFS of 3.1 months for the regorafenib arm and 1.5 months for the placebo arm (HR, 0.46; 95% CI, 0.37-0.56; P <.0001). The overall response rate, also based on modified RECIST criteria, was 11% in the regorafenib arm and 4% in the placebo arm.

Updated findings presented at the 2017 World Gastrointestinal Conference in June revealed that OS was slightly improved over the primary analysis. The median OS with regorafenib was 10.7 months (95% CI, 9.1-12.2) compared with 7.9 months (95% CI, 6.4-9.0) with placebo (HR, 0.61; 95% CI, 0.50-0.75; P <.0001).⁷

Part of the significance of the updated results is that they more clearly show the effects of prolonged treatment with regorafenib, said Jordi Bruix, MD, head of the Barcelona Clinic Liver Cancer (BCLC) group at the University of Barcelona. Using a Swimmer plot to illustrate, he explained, “What you see here is that all of the events have shifted farther to the regorafenib side, demonstrating that any subgroup events of OS that were borderline in the primary analysis now firmly favor regorafenib.”

Adverse events (AEs) were more prevalent among patients in the regorafenib arm. In the primary analysis, 79.7% of patients in this cohort experienced grade 3 or higher AEs compared with 58.5% percent in the placebo arm, resulting in dose modifications for 68.2% in the regorafenib arm and 31.1% in the placebo arm. However, more deaths occurred in the placebo arm within 30 days of the last treatment (19.7% for placebo vs 13.4% for regorafenib).

The most common grade 3 or higher AEs associated with regorafenib were hypertension, hand-foot skin reaction (HFSR), fatigue, and diarrhea. Other common AEs included pain, decreased appetite, infection, dysphonia, elevated bilirubin, fever, mucositis, weight loss, rash, and nausea.

Immunotherapy Shows Potential

In the updated analysis, the occurrence of HFSR at any time during regorafenib treatment suggested that HFSR may be a marker for regorafenib activity. OS was significantly prolonged in patients developing HFSR: a median OS of 14.1 months (95% CI, 11.7-16.5) compared with a median OS of 6.6 months (95% CI, 5.0-8.5) for those who did not experience HFSR.7 Overall, the incidence of any-grade HFSR with regorafenib was 53% versus 8% with placebo; grade 3 HFSR incidence was 13% versus 1%, respectively.There is a strong rationale for pursuing immunotherapeutic strategies in HCC, according to Anthony B. El-Khoueiry, MD, an associate professor of medicine at USC Norris Comprehensive Cancer Center in Los Angeles.² A growing body of research shows that HCC employs immunosuppressive processes, including the upregulation of inhibitory immune checkpoint molecules and the production of cytokines and myeloid-derived suppressor cells, El-Khoueiry wrote recently in the American Society of Clinical Oncology 2017 Educational Book.

As a result, he said immune checkpoint blockade strategies, notably those targeting the PD-1/ PD-L1 pathway and CTLA-4, have shown promising early results in clinical and preclinical studies. He also noted that cytokine-induced killer cells and other forms of adoptive cell therapies, as well as oncolytic virus therapy, are strategies worth pursuing. Thus far, the PD-1 inhibitor nivolumab is the most advanced immunotherapy in the development process.

“Immuno-oncology seems to have caught the eye of HCC and found an opportunity there that is currently being worked up with several trials, among which nivolumab is one,” said Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, in an interview.

Singal agreed there is reason to be optimistic about upcoming results regarding nivolumab and the field of immunotherapy. “The early data for nivolumab as a second-line agent are very promising, and we are optimistically anticipating final results of the trial.”

Nivolumab Findings

The FDA is evaluating nivolumab under its priority review program based on the results of the phase I/II CheckMate 040 trial in which the checkpoint blockade agent provided a durable response with a manageable safety profile as a second-line therapy for patients previously treated with sorafenib.⁸

The trial accrued 262 patients with advanced HCC with or without hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. There were 48 patients in the dose-escalation phase and 214 patients in the dose-expansion phase. Seventy-seven percent of patients in the dose-escalation phase and 68% in the expansion phase had prior sorafenib.

The overall objective response rate (ORR) in the escalation phase was 15% (95% CI, 6%-28%), including 3 complete responses (CRs) and 4 partial responses (PRs). The median duration of response was 17 months (95% CI, 6-24), and the median time to progression was 3.4 months (95% CI, 1.6-6.9). The disease control rate was 58% (95% CI, 43%-72%).

In the expansion group, the ORR was 20% (42/214; 95% CI, 15%-26%), including 3 CRs and 39 PRs. Combining these responses with 96 (45%) patients who had stable disease, the disease control rate was 64% (138/214). The 3 CRs occurred in 2 patients without viral hepatitis and 1 patient with HBV infection. All 3 patients had prior sorafenib.

“This was the first time that any PD-1 inhibitor was tested in an HCC population,” Bruno Sangro, MD, PhD, an investigator on the study, said in an interview. “This is a [difficult] population, because apart from liver cancer, most of these patients have liver cirrhosis.

So, safety was one of the things that we wanted to observe very carefully from the beginning. In this regard, the result that we have observed is that nivolumab has a very similar, or even slightly better, profile in this population compared with what has been observed in other tumor types.”

Sangro, head of the Hepatology Unit in the Internal Medicine Department at Clinica Universidad de Navarra in Spain, said the median OS rate is typically much lower for secondline therapies than the rate observed in the CheckMate 040 trial.

Fresh Targeted Therapy Approaches

Nivolumab is being evaluated in comparison with sorafenib as a first-line therapy for patients with advanced HCC in the randomized phase III CheckMate 459 study (NCT02576509). Investigators are seeking to recruit 726 patients; global enrollment has been completed but is ongoing for a substudy taking place in China.While immunotherapy has injected a new modality into the evolving landscape of potential new HCC treatments, researchers are continuing to explore tyrosine kinase inhibitors (TKIs), with some recent successes.

Lenvatinib

First-line treatment with lenvatinib improved PFS by 3.7 months and was noninferior for OS compared with sorafenib for patients with unresectable HCC, according to results of a phase III trial, involving 954 patients, presented at the 2017 American Society of Clinical Oncology Annual Meeting in June.⁹

In the open-label REFLECT study, or Study 304, the median OS with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06). The median PFS with lenvatinib was 7.4 versus 3.7 months with sorafenib (HR, 0.66; 95% CI, 0.57-0.77; P <.00001).

Additionally, the median time to progression was 8.9 months with lenvatinib (95% CI, 7.4-9.2) and 3.7 months with sorafenib (95% CI, 3.6-5.4), representing a 37% reduction in the risk of progression (HR, 0.63; 95% CI, 0.53-0.73; P <.00001). The ORR was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio, 3.13; 95% CI, 2.15-4.56; P <.00001).

In July, Eisai Inc announced that it had submitted a supplemental new drug application for lenvatinib as a first-line therapy in HCC, based on the results of the REFLECT trial.¹⁰ Lenvatinib also is a multikinase inhibitor that targets angiogenic pathways, including VEGFRs and other processes that promote tumor growth and progression.

Cabozantinib

Cabozantinib, which inhibits multiple receptor kinases, is another promising agent for HCC that has already been approved by the FDA for the treatment of patients with renal cell carcinoma under the brand name Cabometyx and for medullary thyroid cancer under Cometriq. In preclinical studies, cabozantinib has been shown to suppress MET and VEGFR signaling, and its broad activity has prompted researchers to investigate its potential against multiple tumor types.

Recently published findings of a phase II trial involving 41 patients with advanced HCC showed a median PFS of 5.2 months and OS of 11.5 months, as well as a 78% tumor regression rate, 5% ORR, and reductions in alpha-fetoprotein. More than 70% of the patients had received at least 1 line of prior systemic therapy; 59% had received a prior TKI.¹¹

The most common AEs of grade 3 or greater severity included diarrhea (20%), HFSR (15%), thrombocytopenia (15%), hypertension (10%), and transaminase elevation (10%). No dose reductions were reported during the first 12 weeks of the study, although 59% of patients overall reduced their dosage.

Treatment Disappointments

The results support the continuing investigation of cabozantinib in HCC at a starting dose of 60 mg daily, investigators concluded. The ongoing phase III CELESTIAL trial is comparing cabozantinib monotherapy versus placebo in patients with HCC who already have received sorafenib (NCT01908426).Although development of new therapies for HCC is progressing rapidly this year, the field has seen several recent disappointments. Tivantinib, an oral MET receptor TKI, failed to meet its primary endpoint of OS in a phase III study that included 340 patients who had previously taken sorafenib.¹² They were given either tivantinib or placebo plus BSC.

A second phase III trial of this agent, conducted in Japan, also did not meet its primary PFS endpoint. The introducing of radioembolization with yttrium-90 (Y-90) microspheres has become part of the tool chest for locoregional HCC therapy. However, the SARAH trial, a prospective randomized study that compared the efficacy and safety of selective internal radiation therapy (SIRT) Y-90 resin microspheres with sorafenib found no advantage with SIRT in the advanced disease setting.¹³

“There was a lot of hope for radioembolization as a potential treatment for patients with advanced HCC,” said Singal. “But it unfortunately doesn’t have any benefit over systemic therapy.”

In the SARAH trial, 459 patients with locally advanced or inoperable HCC who did not respond to other treatments or had 2 failed rounds of transarterial chemoembolization were randomized to SIRT with Y-90 resin microspheres (n = 237) or oral sorafenib at 400 mg twice daily (n = 222).

The results showed that fewer patients in the SIRT arm experienced treatment-related AEs compared with the sorafenib arm: 76% versus 94%, respectively, (P < .001), including a lower rate of grade ≥3 events (40.7% vs 63.0%, respectively; P <.001). For the study’s primary endpoint, however, patients in both cohorts experienced a similar median OS of 8.0 months with SIRT versus 9.9 months with sorafenib (P = .179). Median PFS, a secondary endpoint, was 4.1 months versus 3.7 months in the SIRT and sorafenib groups, respectively (P = .765).

Early Identification of HCC Is Still Key

Despite the results, some researchers see a wider role for SIRT treatment in HCC. “What we have learned is that SIRT is a safe option for these patients with very advanced tumors, and the patients have a better tolerability, with a significantly lower number and intensity of adverse events,” said Sangro. “So, this means that SIRT could be a tool that we could consider in multidisciplinary discussions in the treatment of patients with advanced HCC.”As researchers work to identify new treatments for advanced HCC, it is important to remember that HCC is often treatable, with good, long-term outcomes in its earlier stages. “Overall, HCC has a poor prognosis,” Singal pointed out. “However, that’s driven by high rates of late-stage diagnosis. Something that is underrecognized is that HCC can have a good prognosis if we find it early. When the cancer is small, we have curative therapies available in surgical resection, liver transplantation, or ablation, and 5-year survival rates with those therapies exceed 60% to 70%. I think that gets lost because we focus on those with more advanced tumor burden. This highlights the importance of screening for HCC in high-risk patients.”

“I think one has to take away a little bit [of] this pessimism that there’s nothing we can do for patients with HCC,” Greten said.

Meanwhile, questions remain over whether broader adoption of HBV vaccinations and the availability of HCV treatments will lead to a decline in rates of HCC. Possibly, say experts, but hepatitis is not the only risk factor for HCC.

Most cases of HCC are caused by cirrhosis, but what causes the cirrhosis can vary. HBV is the cause of 50% of HCC cases, followed by HCV, which causes about 25%.¹⁴ The rest stem from damage to the liver through causes such as alcohol use, toxins in the liver, diabetes, and morbid obesity.

“There are published trends showing some kind of decline in the number of patients who have HCC related to hepatitis B with HCC, especially in America. But it does not mean this is affecting the whole number globally because there are at least half a million people with hepatitis B who get HCC every year in Asia, for example,” said Abou-Alfa.

The availability of treatment for HCV may also affect the number of patients diagnosed with HCC, but researchers do not have any data on this yet. Abou-Alfa pointed out that although HCV can be cured, there may still be damage to the liver after treatment, and this remains a risk factor for HCC.

Meanwhile, although a decline in hepatitisrelated HCC may be occurring, clinicians are starting to see a rise in HCC related to nonalcoholic fatty liver disease. “There are so many patients who have fatty liver disease and are obese; the absolute numbers are actually going to be potentially very high,” Greten said.

In the United States, it is estimated that between 80 to 100 million adults may be affected by nonalcoholic fatty liver disease, and approximately 3% to 12% of adults have nonalcoholic steatohepatitis.^15,16 “While it’s unclear if we’re going to see a true decline in the number of new HCC cases, we’re definitely going to see a change in its epidemiology or its causes. Nonalcoholic fatty liver-related HCC is going to be the future of this field,” explained Singal.

For patients diagnosed with advanced HCC, regardless of the reason, any internet search will turn up devastating news. Advanced HCC is difficult to treat, and the prognosis is not good. However, with new advancements in treatment, there is hope.

“We can tell patients now that there is certainly a secondline treatment available, which has been FDA approved, and there may be another first-line treatment,” said Greten. “I think that with the recent advances with interventional therapies as well as with systemic therapies, we now have enough treatment options in the first-line setting…The current trials that are out there have very good early data and preliminary data suggesting that the field may change in the near future.”

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