A New Approach for EGFR-Mutant Non-Small-Cell Lung Cancer?

In 2015, more people in the United States died from lung cancer than breast, colon and prostate cancer combined. Many of them developed brain metastases, the most common complication from lung cancer.

For years, oncologists have treated have these patients with surgery and radiation. That is changing with the advent of new drug therapies that can penetrate the blood-brain barrier, allowing physicians to experiment with targeted therapies alone or combined with radiation.

Now a ground-breaking study that includes Cleveland Clinic patients with a particular kind of lung cancer — EGFR-mutant non-small-cell lung cancer (NSCLC) — has shed new light on the effectiveness of such drugs when they are used alone or in combination with radiation.

“The results were very interesting,” says Manmeet Ahluwalia, MD, director of the Brain Metastasis Research Program of the Neurological Institute of Cleveland Clinic, of the multi-institutional study that was published in the April issue of the Journal of Oncology.

“We looked at a combination of radiation — either whole brain or a focused form of radiation approach employing stereotactic radiosurgery — used in combination with targeted therapies and whether the combined approach was any better than using the drugs alone.”

Stereotactic radio surgery and targeted drugs most effective

Dr. Ahluwalia was an author on the retrospective study that involved a total of 351 patients from six institutions. The study had three arms with about 100 patients in each, all with EGFR-mutant non-small-cell lung cancer (NSCLC). The EFGR mutation is found in in 10 to 15 percent of patients with lung adenocarcinoma in North America and up to 60 percent of patients in Asia.

Of the three arms: one received stereotactic radiosurgery (SRS) and the EGFR-tyrosine kinase inhibitor (TKIs) erlotinib. Another arm received whole brain radiotherapy (WBRT) and erlotinib. The third arm received erlotinib alone and used radiation at salvage.

Erlotinib targets EGFR-tyrosine kinase, which is overly expressed and sometimes mutated in various forms of cancer. Studies have shown it is effective in lung cancer patients with or without EGFR mutations, but it appears to be more effective in the former.

The median overall survival (OS) rate for the patients who were treated with SRS followed by erlotinib was 47 months. For the patients treated with WBRT followed by erlotinib, OS was 31 months. And for the patients treated with just erlotinib, it was 25 months.

Prospective clinical trial is next step

Dr. Ahluwalia says their study suggests that use of EGFR-tyrosine kinase inhibitor alone should not be the standard of care for NSCLC patients especially when using first generation TKIs. He also said the next step is a randomized prospective clinical trial testing whether patients do better if they receive TKIs alone or in combination with radiation. There has been more use of SRS in recent years in brain metastases patients, he says, compared to WBRT, especially for patients with better outcomes.

In addition, Dr. Ahluwalia and colleagues at Cleveland Clinic will now lead a new phase 1 clinical trial to determine the safety of combining osimertinib and SRS in patients with NSCLC and 1 to 10 brain metastases.

The newer generation TKIs such as osimertinib and alectinib that have excellent blood-brain barrier penetration are promising, Dr. Ahluwalia says, and such agents are being increasingly being used in the frontline management of patients with brain metastases. Still, he adds, trials are needed to test the combination of targeted therapies and radiation, particularly SRS, to evaluate efficacy and toxicity.