Although next-generation TKIs, such as osimertinib (Tagrisso), have helped to overcome resistance in EGFR-mutated non–small cell lung cancer (NSCLC), a more complete understanding of resistance mechanisms may lead to the ability to overcome resistance to the next generation of these drugs, as well, according to Roy S. Herbst, MD, PhD.1
“Everyone with an EGFR mutation gets an EGFR inhibitor, and we are moving them to the earliest setting,” Herbst, the Ensign Professor of Medicine, professor of Pharmacology, director of Center for Thoracic Cancers, and chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, said during the 16th Annual New York Lung Cancers Symposium, program developed by Physicians’ Education Resource® LLC. “There are a multitude of resistance mechanisms, and personalized therapy and upon resistance is probably going to be the norm going forward.”
Next Steps? Targeting Resistance
Currently, there are several ongoing trials further examining osimertinib, such the phase 3 NeoADAURA (NCT04351555) trial, and the phase 3 LAURA trial (NCT03521154), as well as other studies looking at combination strategies and other EGFR TKIs. However, one of the biggest areas of research going forward will be targeting mechanisms of resistance to these agents, Herbst says.
Mechanisms of acquired resistance to first- and second-generation TKIs include secondary mutations in the drug target, activation of bypass signaling pathways, mutations in downstream pathways, and phenotypic changes in the tumor.9
For patients who are TKI-naïve with an EGFR mutation and receive a first- or second-generation EGFR TKI, a physician would perform a biopsy upon progression to determine if the patient was T790M-postive, in which case the patient would move on to osimertinib. After progression on osimertinib, a clinical trial would likely be recommended, according to Herbst. For those who are T790M-negative after the repeated biopsy, a clinical trial would also be recommended, as well as for those who initially receive osimertinib and then develop resistance.
Most (30%-40%) mechanisms of resistance to second-line osimertinib are unknown. Known mechanisms include acquired EGFR mutations (10%-26%), acquired amplifications (5%-50%), transformations (4%-15%), acquired cell cycle gene alterations (12%), acquired oncogenic fusions (3%-10%), and acquired MAPK–PI3K mutations (2%-10%).
Similarly, mechanisms of resistance to first-line osimertinib are largely unknown (40%-50%). Known mechanisms include acquired EGFR mutations (6%-10%), acquired amplifications (8%-17%), transformations (15%), acquired cell cycle gene alterations (10%), acquired oncogenic fusions (1%-8%), and acquired MAPK–PI3K mutations (13%%-14%).
However, strategies for overcoming these mechanisms remain unclear. Read more.