Immunotherapy may not help certain liver cancer patients, study finds

Until recently, the standard treatment for patients newly diagnosed with advanced liver cancer was a drug that blocks certain cell molecules. Unfortunately, Sorafenib has rough side effects and usually doesn’t work; only about 11% of late-stage patients survive five years.

Immune-boosting drugs called checkpoint inhibitors are improving that grim outlook. A year ago, results of a ground-breaking clinical trial led to the first approval in a dozen years of a new initial treatment regimen that includes Tecentriq, a checkpoint inhibitor.

But now, research by an international group suggests that the effectiveness of this pricey class of drugs depends on the roots of the liver malignancy — whether it is linked to a viral infection, alcohol abuse, or a severe form of non-alcoholic fatty liver disease.

The research, published last month in Nature, began with studies in animal models and human liver samples. That prompted a re-analysis of three clinical trials of checkpoint inhibitors.

The conclusion: Liver cancer patients with a history of hepatitis B or C infections had tumor shrinkage and extended survival with immunotherapy. The rest of the patients did not benefit, although the researchers could not distinguish cancers related to alcohol damage from cancers related to severe fatty liver disease.

Senior author Josep M. Llovet, who directs the liver cancer program at Mount Sinai Hospital’s Tisch Cancer Institute, said the implications are huge for several reasons.

At least five clinical trials are underway worldwide aimed at further expanding the role of checkpoint inhibitors in liver cancer treatment. Meanwhile, severe fatty liver disease is becoming more common because it is linked to a modern lifestyle affliction: obesity.

“Now, we have a new challenge,” Llovet said in an interview. “How are we going to distinguish and treat liver cancer patients” with a history of severe fatty liver disease?

Fox Chase Cancer Center oncologist Jason A. Castellanos, who specializes in liver cancer, agreed.

“We thought we had an [immunotherapy] breakthrough last year, but now we know we need to see if there are differences” related to the cause of the cancer, he said. “This will probably redefine how liver cancer clinical trials ask questions in the future.”

Currently, there is no simple blood or urine test that can classify liver cancer patients based on viral or non-viral causes.

What’s more, most people with excessive fat in their livers go undiagnosed because the condition usually has no symptoms — not even when it progresses to the severe form, called nonalcoholic steatohepatitis, which is marked by inflammation, scarring and liver cell injury. Diagnosis requires imaging or a biopsy, or both.

It is not clear why some liver damage progresses to cancer.

“However, more than half of all people diagnosed have cirrhosis, a scarring condition of the liver commonly caused by chronic alcohol abuse and viral hepatitis,” wrote Sapna Parmar, an oncology pharmacist at Oncology Analytics.

This year, an estimated 42,000 people will be diagnosed with liver cancer, in most cases linked to viral hepatitis.

But studies are tracking a shift. Hepatitis is now readily curable in mere months with powerful new drugs, so cancer can be averted. Fatty liver disease, meanwhile, affects up to 40% of U.S. adults, or 83 million people — and counting. More than a million of them will progress to steatohepatitis, and as many as 33,000 of those will ultimately be diagnosed with liver cancer.

Checkpoint inhibitors have transformed the outlook for numerous solid-tumor cancers. (Think of former President Jimmy Carter, who was cured by Keytruda after melanoma spread to the nonagenarian’s brain and liver in 2015.)

These revolutionary drugs work by removing a molecular brake, or “checkpoint,” that cancer exploits to evade T cells, the disease-fighting soldiers of the immune system.

Llovet’s team of 110 scientists discovered nuances. While a checkpoint inhibitor dramatically shrank tumors in a mouse model of viral-induced liver cancer, the drug actually promoted tumor growth in a mouse model of cancer that started with severe fatty liver disease.

“This was shocking and very provocative,” Llovet said. “So then we went to humans, to the three existing trials of checkpoint inhibitors.”

Their analysis found clear benefits for the 900 patients with viral-related cancers, but not for the 700 with non-viral origins.

The researchers acknowledged that their findings are limited because the three trials had varying treatment combinations and designs, and did not distinguish between cancers linked to alcohol vs. fatty liver disease.

Fox Chase’s Castellanos, for one, does not think that undercuts its significance.

“This is a very novel idea and finding,” he said. “You can only gain new questions and new insights.”