Study Supports Routine Lung Tumor Genotyping

Using multiplex genotyping to identify oncogenic drivers and match patients to individualized therapies has the potential to transform drug development and treatment for lung cancers, according to a recent study.

In the study, investigators at 14 U.S. hospitals participating in the Lung Cancer Mutation Consortium tested the tumors of 1,007 patients with metastatic lung adenocarcinomas for at least one driver mutation; 733 patients had their tumors fully genotyped and were tested for 10 driver mutations (JAMA 2014;311:1998–2006). Of the latter group, 64% had actionable drivers, and in 28% of those cases, physicians matched the patients to existing targeted therapies or clinical trials.

Although patients in the study with oncogenic drivers who received targeted therapy lived about a year longer than other patients, randomized trials would be needed to prove a causal link, says Mark G. Kris, MD, a thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, and co–lead investigator of the study. The significance of this study lies in proving that it's possible to look for multiple targets in a single tumor specimen at diagnosis and use those findings to select individualized therapies.

“This wasn't just a theoretical experiment,” says Kris. “We tested the tumor tissue of current patients and the results were sent to their physicians to aid in their care.”

The 10 drivers were selected based on a reported frequency of at least 1% in lung adenocarcinomas and the availability of targeted drugs—either approved or under development—when the trial began in 2009. Among the tumors that were evaluated for all 10 drivers, the most common drivers were KRAS (25%), EGFR (21%), and ALK (8%).

When the trial began, the only targeted drugs approved to treat lung cancers were EGFR inhibitors. However, the study helped in the development of other therapies, says Kris, by assigning patients to clinical trials of the ALK inhibitor crizotinib (Xalkori; Pfizer), which received accelerated approval in 2011, and the BRAF inhibitor dabrafenib (Tafinlar; GSK), which earned Breakthrough Therapy designation early this year.

“Clearly, these findings demonstrate the feasibility of prospectively incorporating genomic testing into clinical trial designs and, if effective, into clinical care,” write Boris Pasche, MD, PhD, and Stefan Grant, MD, JD, MBA, in an accompanying editorial (JAMA 2014;311:1975–6). “The study also highlights the need for a fundamental shift in how clinical trials are conducted in patients with lung cancers and, by extension, in an increasing number of other malignancies in which oncogenic drivers can be targeted.”

The FDA's approval late last year of the first next-generation genomic sequencer, Illumina's MiSeqDx, gave researchers and clinicians an even more powerful tool to search for genetic changes, Kris adds.

“By switching to next-generation platforms, we're able to test for hundreds of genes instead of just 10,” he says. “We're finding both unexpected genetic alterations that have targeted therapies available as well as new targets that will be researched to see how relevant they are to lung cancers and whether new therapies could be designed for them.”

The study also serves as a model for collaboration among government funders, researchers, and industry, says Kris.

“The study was funded by the National Cancer Institute but the trials were paid for by pharmaceutical companies,” he says. “It's a great example of using federal dollars as seed money and the resources of the pharmaceutical industry to act upon the targets our research found.”

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