Newly Identified Mutation in NSCLC Suggests Novel Treatment Option

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Approximately 5% of patients with non-small cell lung cancers (NSCLCs) may respond well to a class of targeted therapies called MET inhibitors due to the presence of a specific genetic mutation, according to a study published in The Oncologist on March 24, 2016.

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Approximately 5% of patients with non-small cell lung cancers (NSCLCs) may respond well to a class of targeted therapies called MET inhibitors due to the presence of a specific genetic mutation, according to a study published in The Oncologist on March 24, 2016. Based on these findings, all patients with NSCLC may benefit from genetic testing to determine whether MET inhibitor therapy is an option.

Genetic testing to identify potentially drug-targetable mutations is now the standard of care for NSCLC. In current practice, NSCLC tumors are screened for more than 50 potential genetic abnormalities, including EGFR mutations and ALK or ROS1 translocations. However, approximately 40% to 50% of NSCLCs will not test positive for any of these known mutations.

To find novel NSCLC mutations, a research team led by Rebecca S. Heist, MD, MPH, Assistant Professor in Medicine, MGH Cancer Center, Massachusetts General Hospital, identified 54 never-smokers with NSCLC whose tumors tested negative for known driver mutations. Using an advanced form of genetic screening called next-generation sequencing (NGS), the researchers examined tumor samples from these patients to detect any other commonly occurring abnormalities.

“Lung cancers that harbor specific genetic mutations can be highly sensitive to targeted therapies,” said study co-author A. John Iafrate, MD, PhD, Associate Pathologist, Massachusetts General Hospital. “The overall goal of our research is to find new genetic drivers in NSCLC that might lead to new targets for therapy.”

Among the original group of 54 patients, 10 tumors exhibited a mutation called MET exon 14 skipping. The research team then tested a second group of tumor samples from 89 patients with NSCLC treated at the MGH Cancer Center. This group represented the full spectrum of NSCLC, with a range of disease stages (IA to IV), histology types (adenocarcinoma and squamous cell carcinoma), and smoking histories (0 to 60 pack years). Overall, 5.6% of cancers exhibited the MET exon 14 skipping abnormality.

Treatment with a MET inhibitor such as crizotinib is a promising strategy for patients with this mutation. As an example, Dr. Heist and colleagues described one patient with squamous cell lung carcinoma, extensive metastatic disease, and MET exon 14 skipping. After 4 weeks of twice daily treatment with crizotinib, the patient experienced near-complete resolution of a soft tissue mass around a lytic rib lesion, resolution of adrenal and liver lesions, and a decreased thrombus in the right main pulmonary artery. Now starting in the seventh month of treatment with crizotinib, the patient’s initial response has been maintained.

“Molecular testing for MET exon 14 skipping should be performed on all lung cancers because this alteration is targetable with currently available therapy,” Dr. Iafrate said. “Patients with this alteration appear to respond well to MET inhibition, including patients with NSCLC whose cancers do not exhibit any other known drug-targetable mutations.”

Nate Pennell, a medical oncologist at the Cleveland Clinic and an Editor of The Oncologist commented, commented, “The prevalence of MET exon 14 skipping mutations in approximately 5% of NSCLC cases which would make MET mutations the second most common actionable mutation in lung cancer after EGFR mutations. More importantly, these mutations are present in both smokers and nonsmokers, in both adenocarcinoma and squamous cell carcinoma, and appear to be responsive to already commercially available MET inhibitors, potentially broadening the exciting field of personalized medicine into a much broader segment of lung cancer patients than previously recognized.”

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Article: “MET Exon 14 Skipping in Non-Small Cell Lung Cancer,” Heist RS, Shim HS, Gingipally S, et al. (DOI: DOI: 10.1634/theoncologist.2015-0510). The article can be accessed at http://www.theoncologist.com.

About The Oncologist: Now celebrating its 21st edition, this internationally peer-reviewed journal focuses on clear and concise interpretation addressing the multimodality diagnosis, treatment, and quality of life of the cancer patient. Each issue is meant to impact the practice of oncology and to facilitate significant communication in the introduction of new medical treatments and technologies. The Oncologist is the official journal of the Society for Translational Oncology (STO).

About AlphaMed Press: Established in 1983, AlphaMed Press, which has offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, is the publisher of three internationally renowned peer-reviewed journals: The Oncologist® (http://www.TheOncologist.com), which is entering its 21st year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. STEM CELLS Translational Medicine® (http://www.StemCellsTM.com), currently in its 5th year, is dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. STEM CELLS® (http://www.StemCells.com), celebrating its 34th year, is the world's first journal devoted to this fast paced field of research.

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