Importance of Using Multiplex Testing for Oncogenic Drivers to Select Targeted Drugs in Lung Cancer


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Paul A. Bunn, Jr, MD

The LCMC findings … demonstrate the critical importance of simultaneous testing for multiple genetic driver alterations before instituting therapy for patients with advanced lung cancer.

—Paul A. Bunn, Jr, MD

Lung cancer is the leading cause of cancer death in the world as well as in the United States, where it is the leading cancer killer in both men and women. The majority of lung cancer patients present with metastatic (stage IV) disease that cannot be cured with current therapies. Standard cytotoxic chemotherapy prolongs life by an average of a few months but at a cost of considerable toxicity.

In 2004, investigators reported that mutations in the epidermal growth factor receptor (EGFR) oncogene could activate the receptor, causing uncontrolled cell growth, but also rendered the cells susceptible to oral EGFR tyrosine kinase inhibitors. Several such EGFR tyrosine kinase inhibitors were shown to produce superior outcomes compared to cytotoxic chemotherapy with much reduced toxicity.

In subsequent years, other genetic alterations were shown to activate certain oncogenes, and these alterations also drove the growth of those cancers. Tyrosine kinase inhibitors specific for these altered oncogenes were also superior to cytotoxic chemotherapy.

Consortium Aims

The Lung Cancer Mutation Consortium (LCMC) was formed to determine the frequency of driver genetic alterations in 10 oncogenes, identify the clinical features and outcomes associated with these oncogenic changes and the outcome, determine whether multiple genetic tests could be performed on the same small biopsy, and assess whether specific oral tyrosine kinase inhibitors could improve outcomes for patients with these genetic changes.

Thus far, the LCMC has had two studies. The recently published JAMA article reviewed in this issue of The ASCO Post describes the results from the first study, funded by the National Cancer Institute and conducted at 11 institutions.1 (In the ongoing second study, there are 14 institutions studying a larger number of genes.) Those 11 institutions performed the panel testing of the 10 oncogenes in small biopsies from 1,000 patients with stage IV adenocarcinoma of the lung. The study found that 64% of the patients had one or more genetic driver alterations (3% had more than one).

Specific oral tyrosine kinase inhibitors were given to about half of the patients with a genetic driver. The median survival was 3.5 years for patients with a driver who were treated with a driver-specific tyrosine kinase inhibitor, 2.4 years for patients who had a driver change but did not receive a specific tyrosine kinase inhibitor, and 2.0 years for those without a driver treated with conventional therapies.

Conclusions

The LCMC findings demonstrate the critical importance of simultaneous testing for multiple genetic driver alterations before instituting therapy for patients with advanced lung cancer. Such multiplex testing can be performed on small biopsies in many academic and commercial laboratories and results in a personalized or precision therapy that improves outcomes and reduces toxicity compared to standard chemotherapy for advanced lung cancer patients. ■

Disclosure: Dr. Bunn is a Lung Cancer Mutation Consortium investigator and author of the Lung Cancer Mutation Consortium study published in JAMA and reviewed in this issue of The ASCO Post.

Reference

1. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014.

 


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