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ASCO 2015: PD-1 Checkpoint Inhibitor Nivolumab Shows Promise against Liver Cancer

Bristol-Myers Squibb's PD-1 immune checkpoint inhibitor nivolumab (Opdivo) was a star of the show at the American Society of Clinical Oncology (ASCO) annual meeting this week in Chicago, with study results showing that the drug demonstrated anti-tumor activity against hepatocellular carcinoma in a Phase 1/2 study, along with further Phase 3 evidence of its effectiveness against lung cancer and melanoma.

Over years or decades, chronic hepatitis B or C virus (HBV or HCV) infection, heavy alcohol use, and other factors can lead to advanced liver disease including cirrhosis (accumulation of scar tissue) and hepatocellular carcinoma (HCC), a type of liver cancer.

HCC is often diagnosed late, remains difficult to treat, and is a leading cause of cancer death worldwide. The tyrosine kinase inhibitor sorafenib (Nexavar) is currently the only FDA-approved drug for liver cancer that cannot be surgically removed, but it typically only extends survival by a few months and more effective therapies are needed.

Anthony El-Khoueiry from the Norris Comprehensive Cancer Center at the University of Southern California and colleagues evaluated nivolumab for patients with advanced hepatocellular carcinoma in a Phase 1/2 trial (CA209-040/ NCT01658878).

Nivolumab is a human monoclonal antibody that targets PD-1(programmed death protein 1), a cell signaling molecule expressed on immune cells. PD-1 plays a role in regulating immune response by dampening excessive immune activation. By blocking PD-1 or its ligand (binding partner) PD-L1, checkpoint inhibitors like nivolumab can release or re-enable immune responses against cancerous cells. Prior research has shown that HCC tumors that express high levels of PD-L1 have poor prognosis. Nivolumab is currently FDA-approved for advanced melanoma and non-small cell lung cancer.

This multiple ascending dose trial enrolled 47 participants with histologically confirmed advanced HCC, of whom 11 had active hepatitis B and 12 had hepatitis C. They had progressive disease with Child-Pugh Class B scores of 5 or 6 (indicating relatively good liver function) and ECOG scores of 0 (asymptomatic) or 1 (some symptoms but fully ambulatory). Most had portal vein tumor invasion or metastasis beyond the liver. About 75% had previously been treated for HCC, including 68% with prior sorafenib.

All participants were treated with intravenous infusions of nivolumab at doses of 0.1 to 10.0 mg/kg every other week for up to 2 years; there was no comparator drug or placebo in this early clinical trial. The primary endpoint was safety, with a secondary endpoint of anti-tumor activity.

Results

• At the time of this interim analysis 17 patients remained on treatment, while the rest had discontinued therapy due to disease progression (26 patients), adverse events (2 with drug-related events), or complete response.
• Among the 42 participants who could be evaluated for efficacy, 8 (19%) showed anti-tumor responses with tumor reduction of at least 30%.
• 2 of these patients (5%) experienced complete responses, while 6 patients (14%) had partial responses.
• Response duration ranged from 1.4 to 12.5 months
• The overall survival rate was 62% at 12 months. 
• Treatment with nivolumab was generally safe and well-tolerated.
• 32 participants (68%) experienced any drug-related adverse events, including 19% with grade 3/4 events.
• Adverse events reported by at least 15% of patients included skin rash (17%) and ALT, AST, lipase, and amylase elevations.
• There was no evidence of liver "flares" or worsening of HBV or HCV infection.
• No maximum tolerated dose of nivolumab was determined.

"Nivolumab monotherapy has a manageable safety profile in patients with HCC, including those with HBV or HCV infection," and "durable responses were observed across all dose levels and etiologic cohorts," the researchers concluded. "Encouraging 12-month overall survival was observed."

The response rates with nivolumab in this study compare favorably with a complete response rate of around 2% and a 1-year overall survival rate of about 30% with sorafenib.

"These preliminary data are encouraging and support the ongoing evaluation of nivolumab in this patient population, as they show promising preliminary survival data, and durable partial or complete response in 1 out of 5 nivolumab-treated patients, with many others experiencing stable disease," El-Khoueiry stated in a Bristol-Myers Squibb press release.

Commenting on the findings, Lawrence Fong from the University of California at San Francisco said, "For this disease with limited treatment options, nivolumab shows that patients can achieve a durable response." He added that the study allays concerns that immune checkpoint inhibitors may not be safe for people with viral infections such as HBV or HCV. 

6/10/15

Reference

Anthony El-Khoueiry, I Melero, TS Crocenzi, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. Chicago, May29-June 2, 2015. Abstract LBA101.

Other Sources

Bristol-Myers Squibb. Phase I/II Opdivo (nivolumab) Trial Shows Bristol-Myers Squibb’s PD-1 Immune Checkpoint Inhibitor is First to Demonstrate Anti-Tumor Activity In Patients With Hepatocellular Carcinoma. Press release. May 29, 2015.

ASCO. Nivolumab in HCC and Pembrolizumab in Tumors with Mismatch Repair Deficiency. ASCO Daily News. May 31, 2015.