Cara Yap , 7 January 2021
The Phase III, multi-centre, randomised, open-label study will evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus bevacizumab compared with active surveillance in participants with completely resected or ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence. It is being conducted across multiple locations in the Asia Pacific, Europe, North America, South America and Turkey.
About the principal investigator: Assoc Prof Toh Han Chong, BSc (London), MB BCHIR (Cambridge), MRCP (UK), FRCP (Edin), FAMS, Senior Consultant, Deputy Medical Director (Strategic Partnerships), National Cancer Centre Singapore
Assoc Prof Toh is Senior Consultant and former Head at the Division of Medical Oncology and now Deputy Medical Director (Strategic Partnerships), National Cancer Centre, Singapore. He is a recipient of the National Clinician Scientist Award for his pioneering work in cell therapy for cancer. He conducted the first cancer vaccine and T cell therapy clinical trials in Singapore, and continues to work actively in the field of cancer immunotherapy, immunology and inflammation. He also has a strong interest in drug development for gastrointestinal cancers including colon and liver cancer.
*Intended readers: healthcare and industry professionals
The previous FDA IND Phase III clinical trial (IMBRAVE150) combined two drugs - Atezolizumab plus Bevacizumab - as a first line of treatment for advanced liver cancer. We know that the antibody Atezolizumab activates T-cells and other immune cells via its anti PD-L1 activity in the local area around the liver cancer mass, while Bevacizumab is anti-angiogenic, meaning it blocks the leaky unhealthy cancer blood vessels and thereby creates a more robust immune environment around the cancer. As this drug combination produced striking survival and response benefit in the advanced setting, it is now being introduced in the adjuvant setting to prevent relapse - of which there is a high chance of approximately more than 50 per cent risk of recurrence within 2-3 years - in earlier stage liver cancer patients who have undergone surgery.
Here, patients rest for a couple of weeks or more after surgery, before the drugs are administered every 3 weeks for a total of 12 months. Currently, the standard drug used to treat advanced liver cancer is Sorafenib. Notably, over many years, there hasn’t been a successful trial with any strong evidence showing that you can reduce the risk of liver cancer relapse after resection. There is currently no standard of care using drugs to treat liver cancer after resection by the surgeon.
This is not a biomarker driven trial. Anybody who has had their liver cancer removed is eligible. Having said that, there is a fairly long list of eligibility criteria, which takes into consideration factors such as tumour size and liver function. Also, those with a history of autoimmune disease are not eligible for the trial. Otherwise, the trial is similar to the landmark IMBRAVE150 trial in metastatic liver cancer. The inclusion criteria is fairly broad, therefore a substantial number of patients should be able to enrol in it.
On average, it is about 50 per cent at two years or more, which is very significant - this is a highly aggressive cancer. It is very common in Asia because of the prevalence of Hepatitis B. This carrier status is commonly passed from a Hepatitis B carrier mother to foetus through blood transmission otherwise called vertical transmission. Hepatitis B has been the leading cause of liver cancer in Singapore and across Asia (except for Japan, which has more Hepatitis C related liver cancer), and can be attributed to over 70 per cent of liver cancers in Singapore. Another increasingly common risk factor for liver cancer is non-alcoholic steatohepatitis (NASH) which has become prevalent because of the modern urban dietary patterns.
While the risk of relapse will never go down to zero, we hope that this drug combination can bring it down significantly to make a real difference.
It was activated in December 2019, just before Covid-19 and put on hold for months because of the pandemic. The trial is now active.
It’s important for patients to have a good overall understanding of the drugs, their potential benefit and side effects. This is an adjuvant trial, which means these patients are cancer-free but still at real risk of relapse. Data from the published IMBRAVE150 trial - which is the first-line setting in advanced liver cancer - shows that the drugs are overall safe when compared to the control drug sorafenib. As two types of drugs are used instead of one, we take stringent precautions to ensure patient safety. For example, there’s a small risk that Bevacizumab may cause bleeding especially from pre-existing stomach ulcers or swollen blood vessels in the gut (varices), so patients will have to undergo a gastroscopy to ensure they do not have active varices of any serious significance before they can join the trial.
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*The content in this article is purely educational and written for healthcare professionals. It does not contain forward-looking statements, or those specific to commercial enterprise.