Nivolumab demonstrates good safety and promising response rates in liver cancer study

Nivolumab (Opdivo), an antibody that blocks the PD-1 receptor and restores T-cell anti-tumour activity, appeared safe and was associated with disease control and stabilisation in a phase 1/2 study of people with hepatocellular carcinoma, according to late-breaking results from the CheckMate 040 study presented at the 2016 AASLD Liver Meeting last November in Boston.

Hepatocellular carcinoma (HCC), a type of primary liver cancer, can develop over years or decades in people with chronic hepatitis B or C virus (HBV or HCV) infection, heavy alcohol use or other causes of liver damage. People with hepatitis C who have progressed to liver cirrhosis remain at risk for HCC even after being cured with effective antiviral therapy.

HCC is often diagnosed late when it is difficult to treat, and it is a leading cause of cancer death worldwide. Sorafenib (Nexavar), a multikinase inhibitor, is the standard of care for HCC that cannot be surgically removed or resected, but it typically extends survival by only a few months and more effective therapies are urgently needed.

Bruno Sangro of Clinica Universidad de Navarra in Pamplona, Spain, presented findings from Bristol-Myers Squibb's CheckMate 040 trial, evaluating different doses of nivolumab in people with advanced HCC, including those with chronic HBV or HCV infection.

Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1 (programmed death protein 1), a cell-signalling molecule expressed on immune cells. PD-1 regulates immune response by suppressing excessive immune activation. By blocking the PD-1 receptor or its ligand (binding partner) PD-L1, checkpoint inhibitors like nivolumab can re-enable immune responses against tumour cells.

"PD-1 puts a brake on immune response, and nivolumab releases the brake," Sangro explained.

Nivolumab is currently approved by the EMA for treatment of advanced melanoma, non-small cell lung cancer and renal cell carcinoma, and also for head and neck cancers and Hodgkin lymphoma in the US.

CheckMate 040 included a phase 1 dose escalation segment that enrolled 48 participants and a phase 2 dose expansion segment that enrolled 214 people. Individuals in the first part received ascending doses of 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg nivolumab given by intravenous infusion every two weeks. In the second part everyone received the selected 3.0 mg/kg dose. There were no placebo or comparator drug arms in this early trial.

Participants had biopsy-confirmed advanced HCC not amenable to curative surgical resection. They had Child-Pugh scores < 7 (escalation) or < 6 (expansion), and AST and ALT liver enzyme levels < 5 times the upper limit of normal. They had experienced disease progression despite prior treatment or were intolerant of or unwilling to take sorafenib.

Looking at the escalation and expansion cohorts together, about 80% were men, half were white, 45% were Asian and the median age was 63 years. A quarter had hepatitis B (and had to be on suppressive antiviral therapy), 23% had hepatitis C and 51% did not have infection with either virus; people with HBV/HCV co-infection were excluded.

Most participants (76%) had cancer metastases beyond the liver. Prior treatment included surgical resection (61%); local treatment such as transcatheter arterial chemoembolization, radiofrequency ablation or percutaneous ethanol injection (60%); and radiation therapy (19%). Three-quarters had received prior systemic therapy, mostly with sorafenib (67%).

The primary study endpoints were safety and tolerability in the escalation segment and objective response in the expansion segment. Secondary endpoints included time to response, duration of response and overall survival. Preliminary results from the dose escalation cohort were previously presented at the 2015 American Society of Clinical Oncology annual meeting.

Overall, 68% of people experienced some level of HCC disease control.

In the escalation cohort, seven people (15%) had a protocol-defined objective response, and this was seen at all dose levels. Two people in the uninfected group and one in the HCV group achieved complete response (6%); 8% experienced partial response, with this being more common in the HCV group. Half had stable disease that neither improved nor worsened, while nearly a third had progressive or worsening HCC.

In the expansion cohort, 35 people (16%) had an objective response. Two people in the uninfected group achieved complete response (1%), while 15% overall experienced partial response. Again, about half (52%) had stable disease and 29% had progressive disease.

Responses usually occurred within the first three months of treatment and the median duration of response in the escalation cohort was 17 months. In the expansion cohort 30 people had ongoing responses for up to about 10 months of follow-up.

Median overall survival was 14.3 months in the escalation cohort. Survival rates were 66% at six and nine months, 59% at 12 months and 44% at 18 months. In the expansion cohort, survival was 83% at six months and 71% at nine months, with the later time points not yet reached.

Responses did not differ significantly based on PD-L1 expression on tumour cells. Some people (20%) in the HCV group saw transient vial load declines of > 1 log₁₀, but no one achieved sustained virological response. Likewise, a few people (5%) in the HBV group had a decline in hepatitis B surface antigen (HBsAg) levels.

Treatment was generally safe and well tolerated. Most people (83%) in the escalation cohort and 43% in the expansion cohort discontinued study treatment due to disease progression. One person (2%) in the escalation cohort and eight people (4%) in the expansion cohort stopped due to treatment-related adverse events or toxicity. Overall, 19 participants (7%) experienced treatment-related serious adverse events. The most common treatment-related side-effects were fatigue (18%), pruritus (15%), skin rash (14%), diarrhoea (9%) and nausea (6%).

Objective responses to nivolumab monotherapy in people with HCC "occurred early and were durable irrespective of infection status, were observed regardless of prior sorafenib treatment, and occurred in patients irrespective of PD-L1 expression on tumour cells," the researchers concluded.

"The overall survival rate was encouraging and notable disease stabilization was observed, including in some patients who progressed on prior sorafenib therapy," they added. "The manageable safety profile was similar to what has been observed in other tumour types without any new safety signals."

This study "challenges the assumption that immune therapy cannot be effective for patients with a high tumour burden," Sangro said.

A randomised phase 3 study, CheckMate 459, comparing nivolumab versus sorafenib for first-line treatment of people with advanced HCC is now enrolling.