Spotlight

For Lung Cancer, a New Drug and a Way Forward

The phone call that would change Dr. Michael Weitz’s life came from his mother. In June 2009, she tuned in to the evening news and learned about an experimental cancer drug that had made a patient’s lung tumors all but disappear. She phoned her son to say that the drug, a pill called crizotinib, might help him.

Dr. Michael Weitz, an emergency room physician from Santa Monica, CA, was diagnosed with lung cancer at age 49. (Image courtesy of the Los Angeles Daily News)

Dr. Weitz, an emergency room physician from California who had never smoked cigarettes, needed all the help he could get. Three years earlier, at age 49, the father of three boys had been diagnosed with non-small cell lung cancer (NSCLC), and the disease would eventually invade his bones and his brain. Chemotherapy, surgery, radiation, and erlotinib (Tarceva) had kept him alive, but he never knew when the latest treatment would stop working.

The new drug, however, was a long shot. Fewer than five lung cancers in 100 had the specific genetic change targeted by crizotinib. But because his left lung had been removed, Dr. Weitz had plenty of tumor tissue available for testing. His doctors sent a sample to Massachusetts General Hospital for analysis, and the test came back positive, making him eligible for the treatment.

Dr. Weitz’s tumor cells harbored a fusion of two genes (EML4 and ALK) that appears to drive the disease in some patients. He enrolled in the trial, and 2 months later scans showed a striking reduction in his cancer. By the next round of testing, the tumors had disappeared to the point where doctors described it as “minimal disease.”

“The results were dramatic,” Dr. Weitz said recently. “This was a game-changer.” Compared with his other treatments, he has experienced few, if any, side effects. The beauty of this targeted therapy, he noted, “is that you’re not killing off healthy cells—you’re just going after the bad guys.”

Back to Work

Patients with a rare genetic change in their lung tumors have responded to treatment with the drug crizotinib.

Although he knows the disease could return at any time, Dr. Weitz has returned to work and is once again exercising. He has also joined the scientific advisory board of the Lung Cancer Foundation of America, an organization dedicated to funding research. In part because of this advocacy work, Dr. Weitz traveled to Chicago earlier this month for the annual meeting of the American Society of Clinical Oncology (ASCO).

He was also there to hear a presentation on the crizotinib trial in which he had been participating. The results were featured in the plenary session, which is unusual for small, early-stage trials. But the results were impressive: 87 percent of the 82 patients in the trial responded and many saw their tumors shrink or their disease stabilize after 8 weeks of therapy, the researchers reported.

“This trial confirms what we have known from the very first patient—that this drug is a great option for these patients,” said Dr. Alice Shaw of the Massachusetts General Hospital Cancer Center and an author of the findings. She cautioned, however, that little is known about the natural history of this particular type of lung cancer and additional research is needed.

More than 100 patients have received crizotinib after testing positive for the EML4/ALK fusion gene. Because most patients are still being treated, the trial does not yet have data on survival, noted Dr. Yung-Jue Bang of Seoul National University College of Medicine in Korea, who presented the findings.

In a discussion of the results at the plenary session, Dr. Martin Edelman of the University of Maryland Greenebaum Cancer Center noted the drug’s “striking activity” and the “durable” responses in patients who had already received multiple therapies. “It’s hard to imagine that these early results will change over time,” he said.

Biological Markers

Dr. Edelman also provided some historical context. Six years ago, when doctors first observed dramatic responses to gefitinib (Iressa) in patients with lung cancer, there were no molecular markers for identifying likely responders. It was only by analyzing patient samples retrospectively that researchers discovered biomarkers of response (mutations in the EGFR gene).

Crizotinib has followed a different path. The EML4/ALK fusion gene, which produces an aberrantly activated ALK protein, is used as a marker to select patients. The drug was initially developed to inhibit a signaling protein called c-Met, but it also proved to be active against the ALK protein, another signaling protein and, like c-Met, a tyrosine kinase.

When Japanese researchers reported the presence of the fusion gene in lung tumors in August 2007, the drug was already being evaluated in other cancers. Researchers at Massachusetts General Hospital quickly developed a test for the fusion gene. Within months, they had enrolled a patient with lung cancer into the trial, and in less than 3 years, preliminary results from the trial were making news.

“This study demonstrates the power of understanding the biology of cancer,” said Dr. Mark Kris, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center, who was not involved in the study. Crizotinib, he continued, is an example of what doctors have always wanted to give their patients—a drug that is tailored to the specific features of a given patient’s disease.

At the ASCO meeting, some lung cancer experts were discussing crizotinib as a model for moving forward in this deadly disease. By discovering genetic alterations underlying subtypes of lung cancer and developing therapies against these changes, the researchers hoped to make progress against this leading cause of cancer death worldwide.

In the case of crizotinib, testing patient tumors was critical for uncovering the drug’s dramatic effects in selected patients. Had the drug been tested in 100 unselected patients with lung cancer, researchers might have concluded that the drug had little or no activity in the disease.

Dr. Edelman stressed the importance of selecting patients in trials of targeted drugs by showing a slide with a long list of disappointing lung cancer trials. “If targeted drugs had been employed in targeted populations, how many of these trials would have been positive?” he asked.

Larger crizotinib trials are planned or underway, including a phase III study called PROFILE 1007. This will compare crizotinib with standard second-line chemotherapy for patients with ALK fusion gene-positive recurrent NSCLC.

A Unique Disease

Last year, Dr. Shaw and her colleagues reported that patients with the EML4/ALK fusion gene had a distinct subtype of NSCLC with identifiable clinical characteristics. These patients, like Dr. Weitz, tend to be much younger than other patients with lung cancer, to be nonsmokers, and to have the adenocarcinoma form of the disease.

The patients also have a high likelihood of responding to ALK-targeted agents, although not all patients with the fusion gene respond to crizotinib. In addition, some patients with the gene fusion have developed resistance to the drug, the researchers said.

Still, many patients are doing well (at least one patient has been on the drug for 20 months). With more than 200,000 new lung cancers diagnosed in the United States each year, an estimated 10,000 patients could be eligible for these agents. “It’s our job as oncologists to find these patients,” said Dr. Kris.

A project launched last fall called the Lung Cancer Mutation Consortium could play a role. Fourteen sites around the country will test patients free of charge for a panel of 10 genetic changes for which there are drugs available, including the EML4/ALK fusion gene. Patients will be referred to the appropriate clinical trials based on their particular tumor types.

The 2-year consortium project, funded with a $5.2 million grant from the American Recovery and Reinvestment Act, aims to determine the frequencies of certain mutations in 1,000 patients with advanced lung adenocarcinomas. Investigators will also collect clinical information to uncover links between specific mutations and clinical features and outcomes.

“The consortium is how we will translate findings from our research on the human genome into medicines for patients,” said Dr. Paul Bunn, former director of the University of Colorado Cancer Center and a project leader. He noted that The Cancer Genome Atlas project, for instance, is characterizing genomic changes in two types of lung cancer and that these results will be used to develop biomarker-driven therapies.

“A Future Again”

In his work advocating for lung cancer research, Dr. Weitz urges patients to have their tumors tested, saying that this can help them develop a strategy for trying to manage the disease in a way that other chronic diseases are managed.

He compares being a patient to playing chess. “You have to think several steps ahead,” he explained. “And you always need several therapies in your back pocket in case the current one doesn’t work out.”

These days, though, he has more than just cancer on his mind. “My friends and family have been so supportive,” he said. “For more than 3 years, there’s been an outpouring of love and affection. I now have energy and can think about planning trips. I have a future again.”

—Edward R. Winstead

See also: Common Cancers May Involve Fused Genes
Trial Makes Push Toward More Individualized Lung Cancer Therapy