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Combination Immunotherapy for Hepatocellular Carcinoma

Presenting their results at the ESMO Asia Congress in 2019, researchers of the IMbrave150 study show for the first time in a decade a new class of treatment for hepatocellular carcinoma. The study reveals phase III trial results of a form of combination immunotherapy comprising of the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab.

Liver cancer is one of the most common cancers in the world. It is the fifth most common cancer in men and the ninth most common in women. Types of primary liver cancer develop from different cells within the liver. The most common type is hepatocellular carcinoma (HCC) which accounts for 75 percent of all liver cancers. In 2018, there were 840,000 new liver cancer cases worldwide. However, there are presently few therapeutic options available and no efficacious systemic therapy that function as useful adjuvant therapy especially for unresectable HCC.

In light of this, the IMbrave150 study aimed to test the efficacy of combination immunotherapy by atezolizumab in combination with bevacizumab as a treatment for people with unresectable hepatocellular carcinoma (HCC) who have not received prior systemic therapy compared to the sorafenib which is the current standard of care.

To elucidate on the main points and challenges of this study as well as the clinical implications of this new combination immunotherapy on management of HCC are Dr. Sivabalan Sivanesan, Medical Director of Roche Singapore and Professor Pierce Chow, Senior Consultant, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore.

Dr. Sivabalan Sivanesan: The IMbrave150 is a global Phase III, multi-centre, open-label study of 501 people with unresectable Hepatocellular Carcinoma (HCC) who have not received prior systemic therapy. Participants were randomised 2:1 to receive the combination of atezolizumab (1200mg IV every three weeks) plus bevacizumab (15mg/kg IV every three weeks) or sorafenib (400mg twice daily). Patients continued their respective treatments until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Results showed statistically significant and clinically meaningful improvements in overall survival and progression-free survival, with a reduced risk of death by 42 percent and the risk of cancer progression by 41 percent compared to sorafenib, the current standard of care.


1. Liver cancer is often referred to as Asian Liver Disease due to its high prevalence in Asia, what was done to ensure that Asian populations were greatly represented in the study?

Dr. Sivabalan Sivanesan: Approximately 72 percent of all global liver cancer cases are diagnosed in Asia,1 making it commonly referred to as an Asian liver disease. The study has equal representation of Asians in both arms and made up about 40 percent of the patients. The study was also conducted in many countries in Asia including, but not limited to, China, Japan, Taiwan, South Korea and Singapore.


2. What were the most prominent challenges faced in the process of the trial?

Dr. Sivabalan Sivanesan: One of the most prominent challenges were that patients with HCC often have concomitant conditions that either co-exist or occur as a result of the liver diseases. As such, it may affect the applicability of certain treatment modalities since some treatments might cause collateral damage to the non-cancerous liver tissue and thereby potentially aggravate liver dysfunction.2


3. What will be the role of Roche in bringing the new class of therapy to patients after its approval by health authorities?

Dr. Sivabalan Sivanesan: For over 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. The IMbrave150 study is a testament to this – the new class of treatment i.e. combination immunotherapy, with the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab, has proven positive results by enhancing the potential of the immune system to combat HCC. This new class of treatment could significantly enhance the health outcomes of HCC patients as well as improve patient access to treatment options in a timely manner.


4. How will Roche be collaborating with health authorities, doctors, and healthcare systems in bringing this combination immunotherapy to patients?

Dr. Sivabalan Sivanesan: The IMbrave150 study data has been submitted to health authorities globally and will be submitted to the Health Sciences Authority of Singapore for approvals. We will continue to work closely with global health authorities, healthcare professionals and the relevant medical institutions to address underlying issues that can prevent, diagnose and treat diseases and make a positive contribution to society.


5. If approved, how will this new combination immunotherapy (atezolizumab and bevacizumab) affect current practices in management of HCC?

Professor Pierce Chow: The positive results of the recently completed Phase III trial of this combination immunotherapy presents a significant breakthrough as it showed superior overall survival and progression-free survival in patients with unresectable HCC compared to sorafenib, which until then was the standard of care of advanced HCC. From a scientific standpoint, this combination therapy will now replace sorafenib as first-line therapy for patients with advanced HCC, and sorafenib will become one of the second line therapies for advanced HCC. This study was done in patients with advanced HCC. The positive results of the study mean that there is an expectation that new clinical studies using this combination therapy in other groups of HCC will be similarly useful. This will include intermediate-stage HCC in combination with loco-regional therapy, such as TACE (Transarterial Chemoembolization) or SIRT (Selective Internal Radiation Therapy) In which case, is the current standard of care for these patients, or in early-stage HCC as adjuvant therapy after successful liver surgery, in order to prevent the cancer from coming back.


6. In what ways will an efficacious combination immunotherapy like the one in the IMbrave150 study allow for more HCC patients to be cured by surgery?

Professor Pierce Chow: There is currently no proven adjuvant therapy in HCC. In other words, after surgery, there is no systemic therapy available that can be administered to the patient after surgery today, that has been proven to reduce the chances of the cancer coming back. This is of course related to the general shortage of good systemic therapy in HCC. Sorafenib, the previous standard-of-care systemic therapy, has not proven to be useful as adjuvant therapy. Without a good adjuvant therapy, recurrences in HCC after surgical resection tend to be high and many patients with HCC are not cured by surgery. Now that we have an efficacious new combination immunotherapy, there is every hope that this new therapy will prove to be useful as adjuvant therapy after surgical resection in HCC as well. This will however need to be proven in a randomised controlled trial. A randomised controlled trial on the use of the new combination therapy as adjuvant therapy after surgical resection in HCC, has already commenced worldwide and would be ready to enrol patients in Singapore. Efficacious adjuvant therapy will significantly extend the indications of surgery and increase the proportion of patients who can be potentially cured by surgery. In addition, we are beginning to see significant down-staging of patients with advanced HCC treated with immunotherapy such that they have become resectable and we have surgically resected such cases with curative intent. Hence, we are witnessing a new era in the management of HCC particularly when it comes to significantly better clinical outcomes in patients with HCC. [APBN]


  1. World Health Organisation: Globocan 2018 – Liver cancer factsheet. (8 May 2019) Retrieved from World Health Organisation: http://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf
  2. Pinter, M., Trauner, M., Peck-Radosavljevic, M. and Sieghart, W. (2016). Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open, 1(2), p.e000042.

About the Interviewees

Dr. Sivabalan Sivanesan, Medical Director of Roche Singapore


Professor Pierce Chow, Senior Consultant, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore