Multi-centre trial paves way for immunotherapy in advanced liver cancer

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  • Immunotherapy drug nivolumab shows potential to fight against advanced liver cancer
  • Study was conducted in 11 countries, including Singapore led by NCCS
  • Nivolumab is the first immune-oncology drug to be approved by US FDA for 2nd line therapy in advanced HCC after sorafenib as a result of this study
  • Phase 3 study comparing nivolumab with sorafenib, which is the current standard treatment in advanced HCC is underway

Promising results from an international clinical trial has revealed the efficacy of using immunotherapy against advanced liver cancer or hepatocellular carcinoma (HCC). The National Cancer Centre Singapore (NCCS), together with institutions from 10 other countries, conducted a multi-centre, non-comparative, open-label phase 1/2 trial to assess the efficacy and safety of nivolumab in 262 patients with advanced HCC. The study included HCC patients with and without hepatitis B or C infection and across all PDL-1 expression levels.

Nivolumab, an immunotherapy drug that is currently approved in other cancers like non-small cell lung, melanoma and kidney cancers, enhances the body’s immune response against cancer cells. In this study, the efficacy of nivolumab in advanced HCC was evaluated as a first-line treatment in patients who had not previously received sorafenib, a systemic treatment that is the current standard of care in advanced HCC, and as a second-line treatment in those with previous disease progression on sorafenib or who did not tolerate sorafenib.

Metastatic hepatocellular carcinoma. The production of bile by the tumor accounts for the yellowish color of the tumor nodules. Credit: Wikimedia commons

Based on 154 HCC patients who had prior sorafenib and were given nivolumab 3mg/kg, the overall response rate was 14.3% (95% CI: 9.2, 20.8), with 3 complete responses (i.e. complete disappearance of cancer). Response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or longer and 55% had responses lasting 12 months or longer.

Results from the study also showed that nivolumab has a manageable safety profile and acceptable tolerability among patients, demonstrating its potential as a treatment for advanced HCC, which currently has limited therapeutic options. The findings were published in The Lancet in April 2017.

Through this study, US FDA granted accelerated approval to nivolumab in advanced HCC following prior sorafenib on 22 September 2017.

Updated results from the study presented at the annual meeting of the American Society of Clinical Oncology in June 2017, showed that the median survival was 15.6 months in the sorafenib-treated patients and 28.6 months in the sorafenib naïve advanced HCC patients.

“For almost 10 years, sorafenib was the only approved drug in advanced liver cancer and there were no other treatment options after failure of sorafenib. This was despite many trials conducted in liver cancer, all of which failed to show a survival benefit. Now, with nivolumab, we finally have an alternative effective and tolerable option that is changing the prognosis in liver cancer,” said Dr Choo Su-Pin, who is a co-author in this study. Dr Choo is a Senior Consultant Medical Oncologist and Chief of Gastrointestinal Oncology at NCCS.

“While nivolumab does not work in everybody, when it does, the durability of response is particularly impressive,” said Dr Choo. “We have seen prolonged responses whether with actual shrinkage of tumours or stability of tumours. We have patients who were told that they had only 6 months to live and they are now still very well and alive with minimal cancer after more than 2 years because of this drug.”

Mr TKK, who was diagnosed with stage 4 HCC in 2012, had an expected lifespan of six months. After undergoing several treatments that saw little results, he was advised to go for treatment with nivolumab on this trial. 29 months into the trial, his tumour has shrunk from 11cm to less than 5cm. Other small tumours in his liver have disappeared. Best part is that he has minimal side effects, is still physically fit to travel and is leading a full life.

Mr PS was diagnosed with HCC in Feb 2015 and underwent an operation to remove his cancer. In June 2015, his cancer relapsed and had spread to the peritoneum, lungs and lymph nodes. He was enrolled into the nivolumab trial in September 2015 and has been on nivolumab therapy since. The cancer has disappeared in his lungs and liver. The largest tumour in the peritoneum which was originally 10cm is now only 1.8cm in size. Furthermore, he has had no side effects from nivolumab.

Dr Choo will be presenting the updated results of Asian patients in this study at the upcoming ESMO (European Society of Medical Oncology) Asia conference in November 2017.

“This has resulted in a paradigm shift in the treatment of liver cancers. Moving forward, apart from placing nivolumab in the earlier stages of liver cancer, there are various studies combining nivolumab with other immune-oncology agents, with target therapies or with other modalities like liver-directed radioembolisation, in hope of increasing the anti-cancer efficacy in more patients. There are also many other immune-oncology agents being developed by other drug companies,” said Dr Choo.

HCC is the second most common cause of cancer mortality in Southeast Asia and more than 70% cases of HCC in Southeast Asia are a consequence of chronic infection with Hepatitis B Virus (HBV). For patients with advanced HCC, oral sorafenib is the only approved drug as a 1L agent worldwide and outcomes remain poor. The treatment may be administered to prolong survival of patients by about 2.5 months over best supportive care. 3

Median survival with sorafenib is about 6 months in Asian patients and about 10.7 months in Western patients. After failure of sorafenib, the only other drug approved till recently was regorafenib, which showed modest 2.5 months survival benefit in patients who had previously tolerated sorafenib well and who had good liver function.

The team has moved on with a phase 3 randomised study to compare the effectiveness of nivolumab with sorafenib as a first-line treatment in patients with advanced HCC. The study is sponsored by Bristol-Myers Squibb and is expected to complete in October 2018.