Drug combination nearly doubles survival for subset of advanced non-small cell lung cancer patients

Erlotinib and Entinostat work together to target advanced non-small-cell lung cancer. Image: Flickr/buddawiggi cc license

THREE KEY POINTS:

  • Results of 30-center phase II clinical trial show that combination of erlotinib and entinostat nearly doubles survival in subset of advanced non-small-cell lung cancer patients
  • Entinostat increases the effectiveness of erlotinib in patients with high E-cadherin
  • Example of personalized cancer care, target at tumor’s genetic characteristics

The drug erlotinib is FDA-approved for the treatment of non-small cell lung cancer, “but we haven’t cured a patient yet,” says Fred R. Hirsch, MD, PhD, investigator at the University of Colorado Cancer Center. “And so the challenge is to improve its effectiveness.”

Combining erlotinib with the drug entinostat may do just that, according to a recent CU Cancer Center study published in the Journal of Clinical Oncology.

It’s a needed advance. “Despite significant improvement for subgroups of lung cancer patients, the outcome for the overall patient population with advanced non-small cell lung cancer (NSCLC) remains dismal,” Hirsch says.

These patients with advanced disease constitute about 55 percent of the new cases diagnosed with NSCLC, resulting in a total of more than 100,000 new cases of advanced NSCLC in the United States every year.

Erlotinib targets a cancer-causing genetic abnormality called an EGFR mutation, which in many lung cancers is stuck in the “on” position, leading to unregulated cell division. Lab work previously completed at the CU Cancer Center showed that people with high levels of another protein called E-cadherin are especially susceptible to drugs like erlotinib that target these EGFR mutations.

Importantly, Hirsch and his collaborators asked why these people with high E-cadherin responded well to erlotinib. They discovered this population’s strong response had to do with a process called histone deacetylation or HDAC. Stop HDAC and erlotinib works better.

That’s exactly what entinostat does – it’s an HDAC inhibitor – and when Hirsch, Paul Bunn, MD, professor of medical oncology at the University of Colorado School of Medicine, and other CU colleagues tested the rational combination of erlotinib and entinostat in cells and then in mice, they found what he calls, “a synergistic effect against tumor tissues.”

This lab work formed the basis of a 30-center phase II human clinical trial, the results of which are the basis of the recent report. Interestingly, the combination didn’t work with all advanced non-small-cell lung cancer patients. But it nearly doubled the median survival in patients with high E-cadherin, from 5.4 months to 9.4 months.

“This is a great example of research that we brought from the bench to the clinic,” says Hirsch, who is also a professor of medical oncology at the CU medical school. “But as promising as is this observation, we now need to test the drug combination prospectively, with the approximately 40 percent of NSCLC patients whose tumors have high E-cadherin.”

If these results hold in a larger, prospective trial, this drug combination could prove to be another strong example of personalized cancer therapy, targeted at a tumor’s specific genetic characteristics – in this case NSCLC that expresses high levels of E-cadherin.

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About the author: Garth Sundem

In addition to writing for the University of Colorado Cancer Center, Garth is the author of the books The Geeks' Guide to World Domination, Brain Candy, and Geek Logik. Contact him at garth.sundem [at] ucdenver.edu.

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