Nick Mulcahy

May 29, 2015

CHICAGO — Liver cancer can be added to the tumor types that have responded to the immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb).

The programmed death-1 (PD-1) inhibitor demonstrated an unprecedented overall response rate for a systemic therapy in advanced liver cancer, according to phase 1/2 data presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

However, the results are early, the sample size is small, and the patient population had relatively high liver function, experts caution.

Nevertheless, eight of 42 (19%) evaluable patients responded to nivolumab (tumor reduction beyond 30%), including two with complete responses, reported lead study author Anthony B. El-Khoueiry, MD, from the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.

The results compare favorably with the only systemic treatment approved by the US Food and Drug Administration for advanced liver cancer, sorafenib (Nexavar, Onyx/Bayer), which is a multitargeted tyrosine kinase inhibitor. The response rate with sorafenib in this setting is only 2%.

In the study, nivolumab was given intravenously every 2 weeks for up to 2 years.

Notably, responses to nivolumab have been durable in six of eight responders, and have surpassed 12 months in four patients.

Also, 20 (48%) of the patients had stable disease, with the longest lasting 17 months.

The overall survival rate at 12 months was 62% with nivolumab. The average overall survival rate at 12 months is about 30% with sorafenib, Dr El-Khoueiry said during a press briefing.

He also gave a big-picture perspective of the results.

"While we have to verify this early signal in larger studies, this is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer," he said in a press statement.

Another medical oncologist echoed this perspective.

"PD-1 immunotherapies continue to break new ground in diseases where nothing else seems to work well. The fact that this drug might stop advanced liver cancer in its tracks for months, even a year, is great news for patients." said ASCO expert Lynn Schuchter, MD, a medical oncologist at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

PD-1 immunotherapies continue to break new ground.

Larger trials are needed to understand the full impact of immunotherapy in liver cancer, she added.

Closer Look: Child–Pugh Score

All the study patients had histologically confirmed advanced hepatocellular carcinoma (HCC) and a Child–Pugh score of B7 or below.

The exclusion of patients with higher Child–Pugh scores is important, said Arturo Loaiza-Bonilla, MD, who treats liver cancer patients at Penn and was asked for comment.

Essentially, the patients in the nivolumab study are Child–Pugh A, and thus "more fit and healthier," he told Medscape Medical News in an email.

Child–Pugh A patients have a better prognosis than other liver cancer patients.

The study is also unusual in that it required a confirmatory tissue biopsy of the liver. "Currently, most of the diagnosis of HCC is made with imaging studies and AFP levels," said Dr Loaiza-Bonilla.

Tissue biopsy is preferable, he explained, because it allows molecular and biomarker assessment, which are needed to move the field forward and eventually aid patient treatment selection.

Liver cancer is the second leading cause of cancer death worldwide, said Dr El-Khoueiry.

In this study, the population was largely pretreated, with 75% of the enrolled patients having received previous systemic therapy, including 68% who had received sorafenib.

The 47 patients were a mix of those infected with hepatitis B or C (n = 23) and those uninfected (n = 24).

The primary end point of the study was safety, and nivolumab was "safe and well tolerated" even in patients with ongoing hepatitis B or C infections, Dr El-Khoueiry reported.

There have not been any safety concerns related to flares of hepatitis B infection or worsening viral infection, according to meeting press materials.

Drug-related adverse events of any grade occurred in 68%, and 19% were grade 3/4.

Grade 3 and 4 adverse events that affected at least 5% of patients were aspartate aminotransferase increase (12%), alanine aminotransferase increase (10%), and lipase increase (5%).

Abnormal liver enzymes and elevated amylase and lipase of any grade occurred in less than 20% of patients; these were not accompanied by any significant clinical symptoms, Dr El-Khoueiry observed.

A dose-limiting toxicity occurred in an uninfected patient at 10 mg/kg, but no maximum tolerated dose was defined in any cohort in the dose-escalation study.

Nivolumab is currently approved in the United States for the treatment of non-small cell lung cancer and melanoma.

These new findings indicate that a new class of drugs works in liver cancer. The results "provide strong justification for more studies of nivolumab and other immunotherapy approaches for patients with advanced liver cancer," Dr El-Khoueiry said.

This study was funded by Bristol-Myers Squibb. Dr El-Khoueiry reports financial ties to multiple pharmaceutical companies, including Bristol-Myers Squibb. Some of his coauthors report financial relationships with pharmaceutical companies, and one is an employee of Bristol-Myers Squibb. Dr Schuchter reports receiving research funding from multiple pharmaceuticals, including Bristol-Myers Squibb.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA101. Presented May 30, 2015.


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