The checkpoint inhibitor nivolumab (Opdivo) produced durable responses, prolonged overall survival, and was generally well-tolerated as a treatment for advanced liver cancer that did not respond to standard therapy, researchers reported at the at the EASL International Liver Congress this week in Amsterdam.
Over years or decades chronic hepatitis B or C virus infection, heavy alcohol use, or other causes of liver injury can lead to development of liver cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer. People with hepatitis C who have progressed to cirrhosis remain at risk for HCC even after being cured with antiviral therapy.
HCC is often detected late and is difficult to treat. The only current treatment, the multikinase inhibitor sorafenib (Nexavar), does not work for many people with HCC, and a large majority experience disease progression. Several other therapy candidates have failed in clinical trials.
Nivolumab is a humanized monoclonal antibody that blocks the PD-1 (programmed death) protein expressed on T-cells. PD-1 triggers cell exhaustion as a way of curbing excessive immune response. Blocking this process can restore T-cell activity against tumor cells.
Nivolumab and other checkpoint inhibitors are important in the burgeoning field of immune oncology, which aims to enhance immune responses against cancer rather than attacking it with poorly tolerated therapies such as chemotherapy or radiation. It is approved in the U.S. and Europe for the treatment of advanced melanoma and lung and kidney cancers.
Jörg Trojan from Goethe University Hospital and Cancer Centre in Frankfurt presented findings from Bristol-Myers Squibb’s Phase 1/2 CheckMate 040 trial (NCT01658878), which evaluated nivolumab in people with advanced HCC who were not eligible for surgical resection. Bruno Sangro from Clinica Universidad de Navarra in Pamplona, Spain, gave an overview of the results at an EASL press conference.
The study enrolled a total of 262 patients. A small cohort first participated in a dose-escalation phase, testing intravenous infusions of nivolumab at doses ranging from 0.1 to 10 mg/kg. A 3 mg/kg dose given every 2 weeks was selected and additional patients were then added.
Trojan and Sangro presented findings from a cohort of 145 treatment-experienced patients who received the 3 mg/kg dose. There was no placebo or comparator drug arm. Most participants were men, with a median age of approximately 60 years. About 20% had hepatitis C, nearly 30% had hepatitis B, and the rest were uninfected.
Participants had tried at least one previous systemic cancer therapy. Almost all had progressed on sorafenib and a majority had undergone prior surgical resection. More than half had metastases beyond the liver. However, they had generally well-preserved liver function with Child-Pugh scores of 5 or 6.
More than 60% of sorafenib-experienced patients showed some level of HCC disease control. Overall, 19% demonstrated an objective response to nivolumab as assessed by study investigators, while 44% had stable disease and 32% experienced disease progression.
There were 3 people (2%) who had a complete response and 25 (17%) who had a partial response. Broken down by cause of HCC, objective response rates were 27% for hepatitis C, 14% for hepatitis B, and 19% for uninfected patients. Objective response occurred regardless of whether patients had high or low expression of PD-L1 — the ligand or binding partner of PD-1 — on their T-cells.
The median time to response ranged from 2 to 4 months, with 57% responding within 3 months. Responses to nivolumab were quite durable. By one criterion, the median duration of response was 12.4 months, but by another the median duration could not be determined because more than half of patients still showed on-going response. A few people sustained responses through 3 years of follow-up, according to Sangro.
The median overall survival was 16.7 months — a notable improvement over the current standard of care for people with advanced liver cancer. The overall survival rate at 12 months was 60%, and was similar in hepatitis C, hepatitis B, and uninfected patients.
Treatment with 3 mg/kg nivolumab was generally safe and well-tolerated. Grade 3/4 adverse events were uncommon (17%). The most frequently reported treatment-related adverse events were fatigue (24%), itching (19%), rash (16%), and diarrhea (14%). Side effects were similar in the hepatitis C, hepatitis B, and uninfected groups. Nivolumab had a minimal effect on HCV or HBV viral load overall, though a small number of people did see substantial decreases.
“In patients with advanced HCC who were previously treated with sorafenib, nivolumab increased survival and demonstrated durable and sustainable response,” Sangro summarized. “Responses were demonstrated across HCV-infected, HBV-infected, and uninfected patients.”
“The safety profile of nivolumab was manageable, and no new safety signals were observed,” he continued. “These results suggest nivolumab is a valuable treatment option for patients with HCC who progress on or are intolerant of sorafenib.”
A randomized phase 3 study, CheckMate 459, is now underway comparing nivolumab versus sorafenib for first-line treatment of people with advanced HCC.
“The reported median survival of 16.7 months in patients previously treated with sorafenib is promising and it encourages the evaluation of nivolumab in patients affected with hepatocellular carcinoma, EASL governing board member Alejandro Forner from Hospital Clinic Barcelona stated in an EASL press release.
By Liz Highleyman
B Sangro, T Yau, C Hsu, J Trojan, et al. Nivolumab in sorafenib-experienced patients with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis: CheckMate 040 study. EASL International Liver Congress. Amsterdam, April 19-23, 2017. Abstract GS-010.
AB El-Khoueiry, B Sangro, T Yau, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet, April 20, 2017 (online ahead of print).
EASL. ILC 2017: Nivolumab produces durable responses with long- term survival in sorafenib-experienced patients with advanced liver cancer. Press release. April 21, 2017.