Study Identifies Acquired Resistance After Treatment for Patients with NSCLC

Acquired resistance after treatment for non-small cell lung cancer (NSCLC) with third- generation EGFR tyrosine kinase inhibitors (TKI) was associated with diverse pathways, according to a recent study published in Cancer.

Moreover, the treatment with osimertinib was associated with loss of EGFR T790M and emergence of EGFR-independent resistance mechanisms.

“Our data reveal the unique characteristic of resistance mechanisms acquired after treatment with third-generation EGFR TKIs in patients who have advanced NSCLC harboring the EGFR T790M mutation,” wrote the researchers.

In the population, there were 36 patients with posttreatment biopsies, of which EGFR-dependent mechanisms were observed in 10 patients (5 in the osimertinib group and 5 in the olmutinib group). EGFR-independent mechanisms were found in 21 patients (11 in the osimertinib group and 10 in the olmutinib group). Further, EGFR T790M disappeared in 14 total patients (10 in the osimertinib group and 4 in the olmutinib group). This group of patients were also found to show EGFR-independent pathways as a secondary resistance mechanism.

Using targeted sequencing on 113 specimens obtained via tissue biopsy, this study analyzed a total of 98 patients with advanced EGFR-mutant NSCLC treated with third generation TKIs from January 2014 to July 2018. Of that sample, 53 were treated with osimertinib and 45 treated with olmutinib.

“To the best of our knowledge, this is the first comprehensive data with an integrated genomic landscape to analyze the resistance mechanism of progression after osimertinib and olmutinib therapy,” wrote the researchers. While the resistance mechanisms to EGFR TKIs have been studied extensively, a focus on specific third-generation drugs is an area of ongoing investigation.”

The researchers were quick to note the complexities in resistance evolution, stressing the need for serial biopsy after disease progression. They continued that different somatic mutations were detected from a single sample, but is likely the result of separate clones.

A significant limitation of the survival outcomes according to post-treatment T790M status deals with the treatment of a handful of patients. According to the researchers, 2 patients who were originally treated with olmutinib were subsequently treated with osimertinib. More, 2 other patients treated with osimertinib were subsequently treated with a combination therapy. That, coupled with the small sample of patients (98), are the reason the researchers stress that the data from the study be taken with caution.

The purpose of the above study was to “investigate the mechanism of acquired resistance after treatment with third- generation EGFR TKIs.”

“While this research was conducted on a small data subset and should be interpreted with caution, the report provides a comprehensive insight into genomic alterations to guide subsequent treatment strategies, especially in an era where the use of third-generation EGFR TKIs continues to increase,” wrote the researchers.

Reference:

Lee J, Kim HS, Lee B, et al. Genomic Landscape of Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR T790M-Mutant Non–Small Cell Lung Cancer. Cancer. DOI: 10.1002/cncr.32809.