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David S. Ettinger, MD, FACP, FCCP


NCCN 2023: Next-Generation Tyrosine Kinase Inhibitors in Treatment of Metastatic Lung Cancer

By: Lauren Velentzas
Posted: Tuesday, April 11, 2023

During the recent NCCN 2023 Annual Conference in Orlando, Florida, Gregory J. Riely, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, discussed the use of next-generation tyrosine kinase inhibitors (TKIs) in the treatment of patients with metastatic non–small cell lung cancer (NSCLC). The use of these newer targeted therapies has led to better progression-free survival, he stated, and given the speed at which targeted therapies are being developed, patients with NSCLC should undergo molecular testing for these mutations as well as ROS1, MET exon 14 alterations, and RET and NTRK gene rearrangements.

“NSCLC is not one disease; it’s a clinical syndrome that can be identified as multiple different diseases,” said Dr. Riely. “There are multiple molecular targets with agents approved in the first-line setting, including EGFR, ALK, ROS1, RET, MET exon 14, and BRAF mutations. And new targeted therapies are addressing targets that we’ve not been able to target before, now with data in the second-line setting.”

Specifically, Dr. Riely noted that EGFR mutations are identified in 20% of newly diagnosed patients. Multiple randomized trials have shown that EGFR-targeted TKIs appear to be more effective than platinum-based doublets in these tumors. TKIs that target the EGFR T790M resistance mutation and avoid targeting wild-type EGFR, such as osimertinib, have been shown to reduce the risk of disease progression by 54% and reduce mortality by 20%.

Furthermore, KRAS mutations have also occurred in 20% of patients with NSCLC; however, targeting them has proved to be more challenging, according to Dr. Riely. The oral drugs sotorasib and adagrasib yielded response rates of about 40%, and sotorasib reduced the risk of disease progression by 44% in a phase III trial, but there was no overall survival improvement, he noted.

“In the second-line setting, patients with EGFR exon 20 insertions, KRAS G12C mutations, and HER2 mutations have targeted therapies,” Dr. Riely said, “but they should not receive these drugs in the first line, because we don’t have the data.”

Disclosure: Dr. Riely has received grant or research support from Merck, Mirati Therapeutics, Novartis, Pfizer, Roche Laboratories, and Takeda Pharmaceuticals North America.

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