Resistance Mechanisms to Osimertinib in Advanced T790M-Positive NSCLC

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is currently used to treat patients with EGFR-mutated metastatic non-small cell lung cancer (NSCLC), including those with acquired resistance to prior TKI therapy through development of the T790M resistance mutation. In patients with T790M mutations, osimertinib is associated with a high response rate and progression-free survival of 10.1 months. Unfortunately, the majority of patients will eventually develop resistance to osimertinib as the mechanisms underlying this resistance are not well understood. In an attempt to identify molecular and clinical biomarkers that may predict for osimertinib resistance, a two-part study utilized next-generation sequencing (NGS) technology to evaluate patients with advanced T790M-positive NSCLC who were treated with osimertinib and subsequently developed resistance.

Of the 143 patients included in the initial cohort study, 41 developed resistance to osimertinib, with a median time to treatment discontinuation (TTD) of 8 months. At the time of resistance, 13 patients (32%) maintained T790M and 28 patients (68%) had lost T790M. Among patients who maintained T790M at the time of resistance, 9 (22%) had developed the C797S resistance mutation. A range of resistance mechanisms were identified in the patients who lost T790M. Known EGFR TKI resistance mechanisms identified included small-cell lung cancer transformation, MET amplification, PIK3CA mutation, and BRAF mutations. In addition to known resistance mechanisms, several unexpected resistance mechanisms were identified, including RET, FGFR3, and BRAF fusions and KRAS mutations. Patients with loss of T790M had shorter TTD than patients who maintained T790M (6.1 months vs 15.2 months).

In the confirmatory analysis, plasma cell-free DNA genotyping was performed on 110 patients from the AURA trial who developed osimertinib resistance. Loss of T790M was observed in 52 patients (47%), while 58 patients (53%) maintained T790M. Patients with loss of T790M had a shorter TTD (5.5 months vs 12.6 months; P = .006). Resistance mechanisms in these patients were similar to those observed in the initial cohort study. Serial plasma genotyping in 19 patients revealed that those who lost T790M at resistance had smaller decrease in EGFR driver mutations after 1 to 3 weeks of osimertinib therapy than patients who maintained T790M at mutation (100% vs 83%; P = .01).

The investigators concluded that these data explain the heterogeneity of responses to osimertinib among patients with T790M mutations, highlighting the difference in duration of response and time to resistance in patients who lose T790M versus those who maintain T790M. Patients who develop osimertinib resistance should be retested for T790M in order to guide treatment decisions. Given the wide variety of resistance mechanisms identified in patients with loss of T790M, future studies aimed at overcoming osimertinib resistance will need to focus on strategies that can overcome multiple resistance mechanisms at once or prevent development of resistance through first-line combination therapy.

JAMA Oncol. 2018 Aug 2. [Epub ahead of print.]

Clinical Opinion Poll

What frontline therapy would you recommend for a 49 y/o woman diagnosed with low tumor burden metastatic ALK+ NSCLC (lung and liver metastases, normal brain MRI, PS0)?