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Acquired Osimertinib Resistance in EGFR-Positive NSCLC

By: Kayci Reyer
Posted: Tuesday, October 9, 2018

Mechanisms resulting in acquired osimertinib resistance have been associated with the absence of the EGFR T790M mutation in patients with non–small cell lung cancer (NSCLC), according to a study published in JAMA Oncology. Geoffrey R. Oxnard, MD, of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, and colleagues found that the mutation, usually associated with EGFR tyrosine kinase inhibitor resistance, was also associated with osimertinib resistance in its absence.

According to the authors, 143 patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified took part in the study. Overall, 41 patients developing osimertinib resistance underwent next-generation tumor sequencing, 68% of whom were women. Of the 13 patients who retained T790M after acquiring resistance, 9 were found to have EGFR C797S. Researchers found multiple resistance mechanisms in the 28 patients with developed resistance and a loss of T790M, including unexpected mechanisms such as acquired KRAS mutations.

Patients with a loss of T790M experienced a comparatively abbreviated time to osimertinib discontinuation (6.1 vs. 15.2 months); the authors noted this may suggest the possible appearance of preexisting resistant clones. A validation cohort of 110 patients with osimertinib resistance who underwent plasma cell–free DNA genotyping confirmed an association between the loss of T790M and a lesser decrease in levels of the EGFR driver mutation assessed after between 1 and 3 weeks of treatment (100% vs. 83% decrease; P = .01).

“These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance,” the authors concluded.



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