Dr. Liu on Resistance Mechanisms in EGFR-Mutant Lung Cancer

Stephen Liu, MD, associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center, discusses resistance mechanisms in EGFR-mutant lung cancer.

A recent study looking at progression on second-line osimertinib (Tagrisso) revealed that the biology of patients who retain T790M and those who lose T790M is fundamentally different, explains Liu.

Those who retain T790M seem to develop another acquired mutation. About half of those patients will develop C797S. That acquired mutation prevents osimertinib from binding from the ATP cleft. Whereas, in tumors that lose T790M, patients develop a broad range of different resistance mechanisms. Some of these mechanisms include MET amplification and mutations in PI3 kinase. These patients may also develop KRAS mutations, fusions in RET, BRAF, FGFR3, as well as in ALK, NTRK, and ROS, says Liu.

Another difference lies in the time it takes to develop that resistance, says Liu. In tumors that retain T790, the time to treatment discontinuation exceeded 1 year. Patients who lost T790M came off osimertinib much quicker, suggesting that those competing mechanisms of resistance were already present in those patients when T790M was detected. If physicians can detect those early on, maybe frontline treatment can be tailored to the patient thereby eliminating those clones, says Liu.