New & recent approved systemic treatments for Hepatocellular Carcinoma (HCC) Liver Cancer
Hepatocellular carcinoma (HCC) or primary liver cancer often presents in the advanced stage. It is an aggressive tumour that often occurs in the setting of chronic liver disease and cirrhosis of the liver. It is often discovered late, and the survival following diagnosis is often poor. Although the mainstay of treatment is surgical operation, many patients are not suitable because of extensive tumour or poor liver function. Systemic therapy is the main treatment for these cases. In Asia, liver cancer is listed as one of the most common malignancies, in view of endemic hepatitis B and C. Advances and understanding of the disease, have led to the recent development of new systemic therapeutic options. At OncoCare Cancer Centre, Singapore, we often see patients with advanced HCC for discussion of treatment. Currently only targeted therapy and immunotherapy are the only approved modalities for systemic therapy. Chemotherapy has not been shown to prolong survival of patients with advanced HCC. Some of these therapies used at OncoCare and how they work, are discussed here.
Sorafenib (Nexavar) is an oral multi–kinase inhibitor, blocking the activity of VEGF receptors 1, 2, and 3, as well as PDGF receptor-β, braf, c-kit and FLT-3. These are targets that affect liver cancer growth and proliferation. It is the first targeted therapy to demonstrate overall survival benefit in advanced HCC, and was approved for use since 2007. Two phase III studies, the SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial and the Asia-Pacific trial (Efficacy and Safety of Sorafenib in Patients in the Asia-Pacific Region with Advanced Hepatocellular Carcinoma), showed that Sorafenib in patients with Child’s Pugh A (CP-A) good liver function had improvement in median survival compared to placebo. However, both studies did not show any improvement of symptoms or improved quality of life. Patients with impaired liver function (CP-B8 and above) were excluded from these studies. A post marketing study in such patients demonstrated an increase in treatment related toxicities, with difficulties in ascertaining benefit. Therefore, the use of Sorafenib in patients with impaired liver function is currently not strongly supported.
Studies in the second-line setting, following disease progression on Sorafenib have been disappointing until recently. The phase III RESORCE (Regorafenib after Sorafenib in patients with Hepatocellular Carcinoma) trial found that patients taking Regorafenib, compared to placebo and best supportive care, had a better median overall survival. Regorafenib (Stivarga) is structurally similar to Sorafenib, but differs only by the addition of a fluorine atom in a centre phenyl ring. This difference results in a distinct biochemical profile, with higher potency. We would usually give Regorafenib continuously for 3 weeks, followed by 1 week of rest. Common side effects of both tyrosine kinase inhibitors include diarrhoea, hand-foot syndrome and fatigue. Regorafenib was approved for use by the United States FDA since April 2017.
In the first line setting, many oral anti-angiogenic tyrosine kinase inhibitors such as Sunitinib, Linafinib and Brivanib have been compared with Sorafenib with the end point of non-inferiority, but were all negative prior to Lenvatinib. Lenvatinib (Lenvima) is currently (April 2018) pending FDA approval for first line use after a strongly positive phase III study. Similar to Sorafenib, it blocks the activity of VEGF1, 2 and 3, but also has activity against FGFR, PDGFR and RET. Lenvatinib was compared against Sorafenib in the first line setting, and was deemed to be non-inferior to Sorafenib, the primary end point of the study. Notably, the progression free survival of Lenvatinib was nearly twice that of Sorafenib, and in our experience also shows seems better tolerated, with fewer hand-foot syndrome, although having a higher proportion of patients with hypertension.
Immunotherapy with anti-PD1 antibodies
The evolving field of immunotherapy in oncology has also generated interest in HCC. PD-L1 is expressed in the majority of patients with HCC, and is significantly associated with markers of tumour aggression, such as high α-fetoprotein levels, microvascular invasion and poorly differentiated tumours. Initial studies with CTLA-4 blockade showed partial response rates of ~15% and disease control rates of ~75%. However, this was associated with severe inflammation of the liver in half of the patients.
Anti-PD1 blockade with Nivolumab (Opdivo) showed a response rate of 19% and a disease control rate of 67%. More importantly, these responses were observed regardless of hepatitis infection status, and also demonstrated safety of its use. Sustained and durable response was also observed, including 2 complete responses and 7 partial responses in a small cohort of 39 patients. Based on this, the FDA has granted accelerated approval of Nivolumab in September 2017, for patients who have failed first line therapy with Sorafenib, or who are Sorafenib intolerant.
Recently, the safety and efficacy of another PD1 inhibitor, Pembrolizumab (Keytruda) was also shown to have similar results as Nivolumab. The main difference is that Pembrolizumab is given in a 3 weekly dose frequency compared to Nivolumab. In March 2018, Nivolumab was approved for 4-weekly use at a dose of 480mg as well. Multiple phase II/III studies are now underway, exploring the combination of CTLA-4 and PD-L1 blockade, as well as the use of anti-PD1 antibodies with Sorafenib. Our experience with these medications at OncoCare Cancer Centre, Singapore, is that although the drugs are well tolerated by most patients, care monitoring of the immune-related side effects is important.
For the longest of times, Sorafenib had been the only approved option for advanced hepatocellular carcinoma. There are now 3 new options that are approved or in the midst of approval for use in the past year alone. Many are now available with our centre and using them has benefited many patients. With many more in the pipeline, we hope that the median survival for this lethal cancer can be meaningfully prolonged.
“Expert knowledge means better care for cancer”
Dr Thomas Soh
MRCP (United Kingdom)