“At present, there is a 30% to 70% risk of relapse after surgery for even early-stage lung cancers so evaluating effective agents such as crizotinib and erlotinib in a collaborative national clinical trial setting is a step forward in finding out if these agents may actually help cure some patients with earlier-stage disease,” said medical oncologist Patrick Forde, MD, who is with the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.

Studies have shown that only about 10% of patients with lung adenocarcinoma and other lung cancers will have tumors with alterations in the EGFR gene and 5% will have alterations of the ALK gene.

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However, other researchers have now identified the novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Investigators at The Cancer Genome Atlas Research Network examined the genomes, RNA, and some protein from 230 lung adenocarcinoma samples. They identified mutations that put the RTK/RAS/RAF pathway into overdrive.1

Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. However, there are agents already currently available that curb aberrant activity of the RTK/RAS/RAF pathway and prompt therapeutic responses in patients. “For those patients who do not have tumors driven by EGFR or ALK, we know that a significant proportion will have other, less common, driver mutations and preliminary reports suggest that these abnormalities may also be selectively targeted,” Dr. Forde told Cancer Therapy Advisor.

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“The ongoing discovery and targeting of driver mutations is a very important avenue of investigation in non-small cell lung cancer (NSCLC). In addition to EGFR and ALK, abnormalities in MET, HER2, RET, ROS1 and others have been described in subsets of NSCLC tumors and trials that aim to selectively target these aberrations are ongoing.”

Sally York, MD, PhD, who is an assistant professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said exciting advances are now occurring in lung cancer research and clinical practice will be changing significantly over the next 12 to 24 months.

“There are second- and third-generation EGFR and ALK inhibitors in development. There are other tumor mutations being targeted with candidate drugs, and there is important research into how to overcome resistance to targeted therapies that have stopped working for a patient,” Dr. York told Cancer Therapy Advisor.

Dr. York and Dr. Forde also noted that immunotherapy is also showing considerable promise for a number of patients. Dr. Forde said that immunotherapy, which employs antibodies targeting immune checkpoints such as PD-1 and PD-L1, have delivered durable remissions for approximately 20% of advanced NSCLC patients in early-phase clinical trials and phase 3 trial results should be available in the near future.


  1. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550.