Finding New Ways to Overcome Resistant Lung Cancer

The identification of two mutations that cause resistance to a next-generation therapy may lead to new treatment options for patients with ALK-positive non-small cell lung cancer

Lung cancer is the most common cause of cancer death in the U.S. and worldwide. Each year more than 225,000 people across the country are expected to die due to lung cancer.

In the face of those grim statistics, we’ve made remarkable progress in developing new and effective treatments for lung cancer.

In recent years, scientists have identified distinct molecular characteristics in some forms of non-small cell lung cancer, leading to targeted therapies. For example, patients who have non-small cell lung cancer tumors with alterations in a gene called anaplastic lymphoma receptor tyrosine kinase (ALK) respond well to ALK inhibitors.

A major challenge in treating ALK-positive lung cancers, however, is acquired resistance to the ALK inhibitors such as crizotinib. Almost all patients with ALK-positive cancer develop resistance to crizotinib within a year.

Similarly, patients develop resistance to alectinib, a second-generation ALK inhibitor that is more potent than crizotinib and overcomes resistance to that drug.

A team of physician-scientists at the Massachusetts General Hospital Cancer Center in Boston and Memorial Sloan-Kettering Cancer Center in New York have identified two mutations that cause resistance to alectinib, and their findings may lead to new treatment regimens for ALK-positive patients.

“We were able to find a way to overcome this type of resistance, in our laboratory experiments as well as in a patient using another next-generation ALK inhibitor, ceritinib,” explains Alice T. Shaw, MD, PhD, a thoracic oncologist at Mass General and the senior author of the study published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).

“There are eight next-generation ALK inhibitors that have entered the clinic, and our results show that ALK-positive lung cancer patients may benefit from multiple, sequential ALK-inhibitor therapies depending on the underlying resistance mechanism,” she says.

About 85 percent of the more than 220,000 people diagnosed each year with lung cancer in the U.S. have non-small cell lung cancer. Some 3 percent to 5 percent of those patients have non-small cell lung cancers that are ALK positive.

James “Rocky” Lagno, 53, of Epping, N.H., who had never smoked, was
diagnosed with advanced ALK-positive lung cancer and given a year to live in July 2011.

“My oncologist told me I should probably think about a bucket list, but also suggested I get a second opinion,” said the realtor who had been married less than two years at the time of his diagnosis.

Rocky’s wife – who did extensive research after his diagnosis – insisted he get a second biopsy and genetic testing of his cancer, which found that he had the ALK mutation. He started taking crizotinib, which worked well for several months before the cancer developed resistance.

At that point Rocky’s oncologist referred him to Dr. Shaw in Boston. He was unable to join a clinical trial involving ceritinib because he already had a second primary cancer – thyroid cancer – and his lung cancer had spread to his brain. But Dr. Shaw was able to get a compassionate use exception for Rocky to receive ceritinib.

His cancer has been stable since the middle of 2013.

“I don’t have any expectation of going into remission or becoming cancer-free,” says Rocky, “but my quality of life is practically back to what I had before the diagnosis.”

Still for thousands of patients like Rocky the question remains of what happens after their cancer develops resistance to a particular ALK inhibitor.

“Fortunately, our study suggests that you may be able to use another next-generation ALK inhibitor as the next treatment,” says Dr. Shaw. “Depending on the resistance mechanisms the patients’ tumors develop, it may be possible for them to derive clinical benefit from a series of different ALK inhibitors.”