Ten years ago researchers at Dana-Farber and in Japan published a study showing that lung cancer patients whose tumors had a malfunctioning version of a protein called Epidermal Growth Factor Receptor (EGFR) responded dramatically to a drug that specifically targets the EGFR protein. The findings launched the era of precision medicine for lung cancer, transforming the way the disease is treated in many patients.
Today, the arsenal of targeted therapies for lung adenocarcioma – the most common lung malignancy – includes more than a dozen agents, some of which have received Food and Drug Administration (FDA) approval and some of which are being tested in clinical trials. At the same time, researchers are developing “next-generation” targeted therapies that show promise of working when standard targeted agents fail.
Together, the new drugs have extended the lives of tens of thousands of lung adenocarcinoma patients around the world and demonstrated the effectiveness of an approach to cancer therapy that has become a staple in treating a variety of malignancies.
“Prior to this research, lung cancer treatment had not made much progress for more than a decade,” says Bruce Johnson, MD, chief clinical research officer at Dana-Farber, who co-led the 2004 study with colleagues Pasi Jänne, MD, PhD, Matthew Meyerson, MD, PhD, and William Sellers, MD (now of the Novartis Institutes for BioMedical Research). “For the 20 to 40 percent of patients with advanced lung cancer who responded to chemotherapy, remissions usually lasted four to six months, and average survival rates were about a year. Today, patients with EGFR mutations who are treated with targeted drugs have a year of remission and survive an average of two to three years, with some making it to five years or more.”
The story of targeted therapy’s application to lung cancer began in the early 2000s with clinical trials of a tantalizing – and baffling – new drug called gefitinib. The vast majority of patients with lung adenocarcinoma who received gefitinib had little or no response to it. In the small percentage of patients who did respond, however, the results were spectacular – complete or near-complete remissions that commonly lasted about a year or longer.
Doctors couldn’t predict which patients would be among the lucky few. Some experts argued that the drug shouldn’t be approved for lung cancer since it worked so infrequently.
Discoveries by a team of investigators at Dana-Farber – and a separate team at Massachusetts General Hospital – found a molecular explanation for the drug’s seemingly sporadic success. The researchers wove several strands of evidence together to link an EGFR mutation to gefitinib’s effectiveness.
“The 2004 study was the first demonstration that precision medicine could be successful in patients with lung cancer,” says Jänne, director of the Lowe Center for Thoracic Oncology at Dana-Farber. “It opened up the realization that not all lung cancers are created the same – that there are different subsets of the disease based on the molecular abnormalities that underlie it, and that treatment can be targeted at those abnormalities.” The study has been cited in more than 6,000 subsequent scientific studies.
Since the introduction of gefitinib and erlotinib, other targeted drugs have been developed for treating lung cancers with specific genetic abnormalities. Crizotinib, which targets an error in the ALK gene, has been approved by the FDA for use in non-small cell lung cancer patients. An array of new agents targeting specific mutated genes in lung adenocarcinoma are currently being tested in clinical trials, with more in earlier stages of development.
Researchers at Dana-Farber recently developed, and are currently testing, agents that target EGFR mutations when drugs like erlotinib lose their effectiveness. Such third-generation therapies may benefit patients who become resistant to Tarceva and similar drugs.
Today, when a patient with lung adenocarcinoma starts treatment at Dana-Farber/Brigham and Women’s Cancer Center, tissue from his or her tumor is scanned for nearly a dozen mutations that can potentially be blocked by targeted therapies. Approximately half of all lung cancer patients at the center are treated with targeted drugs, either as standard therapy or in a clinical trial.
“Since the early 2000s there has been a flood of discoveries of genomic abnormalities in lung cancer, which has quickly led to the development of an array of potential new therapies,” Meyerson says. “There will continue to be intensive development of agents that target single abnormalities, as well as agents that can overcome drug resistance.”