The last liver cancer drug, sorafenib was approved in 2007. After a decade, drugs like regorafenib, nivolumab and lenvatinib are showing potential in treating hepatocellular carcinoma.
by Dr Akhil Chopra
Viral hepatitis is a devastating public health issue and unlike HIV, malaria or tuberculosis, global deaths continue to rise.
The liver is a large, meaty organ situated in the right side of the belly, found only in vertebrates. Normally, one cannot feel the liver since it is situated behind the rib cage. The liver's main function is to filter the blood coming from the intestines, before passing it to the rest of the body. The liver performs hundreds of essential functions for the body including detoxifying chemicals, metabolising drugs, absorb nutrients, secrete bile etc.
Liver transplantation is the only option for complete liver failure. Terminology related to the liver often starts in hepat- from ńπ∝τo-, the Greek word for liver. Since the liver filters most of the blood in the body, it is particularly susceptible for spread of cancer cells from other parts of the body.
Cancer has existed for all of human history. Despite much of the progress in treatment of cancer over the past few decades, it remains a deadly disease. The word “cancer” also evokes a number of different emotions in a person such as fear, anxiety, anger, sadness, denial etc. It is associated with a physical, psychological, emotional and financial impact. Cancer affects both the patient and the family in a tremendous way.
Hepatocellular carcinoma (HCC) or liver cancer is an aggressive cancer that usually develops in the setting of chronic liver dysfunction or cirrhosis of the liver. It is the sixth most common cancer worldwide, but the highest incidence rates are noted in East Asia (North and South Korea, China, Japan and Vietnam), and sub-Saharan Africa, which accounts for 82 percent of liver cancer cases worldwide.
The cause of underlying liver damage is often due to either an infection with the hepatitis viruses –B or C; alcohol related liver damage or non-alcoholic fatty liver disease. There are two competing causes of death in these groups of patients- liver failure and liver cancer.
The treatment of advanced liver cancer is usually dictated by underlying liver function as assessed by the Child-Pugh scoring system. The Child-Pugh score can be easily calculated by routine blood tests such a bilirubin level, albumin level and prothrombin time and two clinical factors, namely the presence of ascites and encephalopathy. The cumulative score categorises the liver function into 3 classes - A, B or C with classes B and C reflecting poor underlying liver function. Patients with class B and C liver dysfunction do not generally benefit from conventional anti-cancer treatment.
Historically, the treatment of advanced liver cancer with cytotoxic chemotherapy has not been very effective. This is likely due to inherent resistance of liver cancer cells to chemotherapy, as well as a poor underlying liver reserve leading to significant toxicities from chemotherapy. Until 2007, no effective therapy existed for advanced liver cancer.
In Dec 2007, FDA approved sorafenib, a drug with a novel mechanism of action for the treatment of advanced liver cancer. The approval was based on the results of two large randomised clinical trials done in patients with advanced liver cancer with good underlying liver function. Results from both these trials showed that sorafenib improved survival of patients with advanced liver cancer, as compared to placebo. Sorafenib was one of the first multi-kinase inhibitors (molecularly targeted agents) to be approved in the treatment of advanced cancer.
Subsequently, for many years, there was not much progress in the treatment of advanced liver cancer. Multiple large clinical trials using novel agents failed to show superiority over sorafenib.
However, the last couple of years have been very encouraging in the treatment of this deadly disease. On 27 April 2017, the U.S. Food and Drug Administration (FDA) expanded the indications of regorafenib (STIVARGA, Bayer HealthCare Pharmaceuticals Inc.) to include the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This approval was based on a large international clinical trial of 573 patients with advanced liver cancer who had failed treatment with sorafenib. Patients taking regorafenib lived longer and had their cancer under control longer than those taking placebo. Toxicity of regorafenib was manageable.
On 22 September 2017, the FDA granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for the treatment of HCC in patients who have been previously treated with sorafenib. Nivolumab, a type of “immunotherapy drug”, is a fully human monoclonal immunoglobulin G4 antibody to PD-1 that essentially works by activating the patient’s own immune system to attack the cancer. It is one of the many new exciting drugs that work on the principle of immune checkpoint blockade in which drugs work by releasing the brakes on the immune system so it can destroy cancer cells. The 2018 Nobel Prize in Medicine was awarded to two scientists who pioneered the research work in cancer immunotherapy.
The approval was based on the CHECKMATE-040 trial in which nivolumab was given to patients with advanced liver cancers who had progressed or were intolerant to sorafenib. Nivolumab demonstrated impressive activity against liver cancer and a few patients on the trial were rendered cancer free with the drug. Immune related toxicities were manageable. Nivolumab is now being tested against sorafenib in the first-line treatment of advanced liver cancer.
Most recently, on 16 August 2018, the FDA approved lenvatinib capsules (Lenvima, Eisai Inc.) for first-line treatment of patients with unresectable HCC.
This approval was based on the REFLECT trial where almost 1000 patients with advanced liver cancer were treated with either sorafenib or lenvatinib as a head to head comparison.
The trial results essentially demonstrated that lenvatinib was not inferior to sorafenib and could be used as another option for this type of cancer.
Lenvatinib shrank the cancer by 41 percent as compared to 19 percent of the time with sorafenib and cancer growth was controlled for a longer time with lenvatinib. Side effect profile of the two drugs were slightly different, but toxicities were manageable.
Ramucirumab and cabozantinib are a couple of other exciting drugs awaiting approval in the second line treatment of advanced liver cancer.
In summary, the treatment options for patients suffering from advanced liver cancer have increased over the past couple of years and the world is eagerly awaiting results of ongoing clinical trials with new drugs and combinations. It is hoped that each patient will be offered a personalised management plan to effectively manage their pain, treatment, and improve their quality of life.
I have personally been involved in treating advanced liver cancer patients over the past decade and have witnessed and experienced the progress made in this area. Last year, a patient was diagnosed with advanced liver cancer when he had gone for a routine health check-up. This was a huge shock for my patient and his family, especially because he was very fit and healthy until that point. He was also the main breadwinner for the family. Since surgery/transplant or loco-regional therapies like TACE were not an option for his advanced stage of cancer; he was started on sorafenib. Unfortunately, within two months of starting the treatment, his cancer showed signs of progression. The U.S. FDA had just approved nivolumab for second-line treatment for liver cancer and after extensive discussion; he was started on this treatment. The treatment was quite expensive, and it was probably his last option. Fortunately, he had a very good response to the treatment and his cancer shrank significantly. His symptoms of pain, poor appetite with weight loss and fatigue; all resolved. The drug was able to control his tumour for almost a year, before his cancer progressed again and he eventually passed on. I was heartened to know that he was able to spend some pain-free quality time with his family towards the end.
Dr Akhil Chopra is a senior consultant in medical oncology at OncoCare Cancer Centre (Singapore)