Repeat T790M Testing Recommended for TKI-resistant Patients With NSCLC

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Researchers analyzed the resistance biopsies and plasma specimens of 119 patients with T790M-positive NSCLC treated with osimertinib.
Researchers analyzed the resistance biopsies and plasma specimens of 119 patients with T790M-positive NSCLC treated with osimertinib.
The following article features coverage from the IASLC 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan. Click here to read more of Cancer Therapy Advisor's conference coverage.

Repeat testing for T790M mutation status among tyrosine kinase inhibitor (TKI)-resistant patients with non–small cell lung (NSCLC) may help to elucidate the individual patient's disease pathology, according to a study presented at the International Association for the Study of Lung Cancer (IASLC) 18th Annual World Conference on Lung Cancer (WCLC) in Japan.1

Researchers analyzed the resistance biopsies and plasma specimens of 119 patients with T790M-positive NSCLC treated with osimertinib. Patients included in the study previously exhibited resistance to TKI therapy.

At resistance, 11 patients maintained T790M, of whom 7 acquired the EGFR C797S mutation and 1 patient had a PIK3CA mutation.

Twenty-two patients lost the T790M mutation at resistance, of whom 14 had competing resistance mechanisms such as MET amplification, fusions in RET or GFGR, mutations in BRAF, PIK3CA, or KRAS, or histologic transformations of small-cell lung cancer.  Patients who lost T790M had a median time to treatment failure (TTF) of 3 months vs 15 months in patients who maintained T790M.

To verify the findings, investigators studied plasma samples from patients treated with osimertinib who took part in the AURA trial (ClinicalTrials.gov Identifier: NCT01802632).

Of the 157 patients, only 110 patients had detectable tumor DNA in plasma and were eligible for analysis.

At resistance, 58 (53%) patients maintained T790M, of whom 24 acquired the C797S mutation.

Fifty-two patients lost T790M at resistance and did not acquire C797S. Median TTF was 5.7 months and 12.5 months in patients with T790M loss compared with patients who maintained T790M at resistance.

At time of resistance, patients who lost T790M had a greater T790M response than driver response (median difference 16%), suggesting that competing resistance mechanisms led to incomplete driver suppression.

The authors concluded that “patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.”

Read more of Cancer Therapy Advisor's coverage of the IASLC 18th World Conference on Lung Cancer (WCLC) by visiting the conference page.

Reference

  1. Oxnard GR, Hu Y, Mileham KF, et al. Osimertinib resistance mediated by loss of EGFR T790M is associated with early resistance and competing resistance mechanisms. Presented at: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; October 2017; Yokohama, Japan. Abstract OA 09.02.

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