Research in context
Evidence before this study
Osimertinib is a third-generation, CNS-active epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) that selectively inhibits EGFR-activating mutations, such as deletion in exon 19 or Leu858Arg, and resistance mutations, such as Thr790Met. Osimertinib is approved for the treatment of patients with non-small-cell lung cancer with the EGFR Thr790Met resistant mutation and previous resistance to EGFR TKIs. Progression-free survival with second-line osimertinib is superior to that achieved with gefitinib or erlotinib as first-line treatment for EGFR mutant non-small-cell lung cancer. Mechanisms underlying resistance to osimertinib and clinical outcomes after treatment with this drug are being intensively investigated. We searched PubMed for studies published in English between Jan 1, 2013, and July 31, 2017, using the term “osimertinib” OR “AZD9291” AND “non-small cell lung cancer” OR “NSCLC” AND “EGFR mutations” AND “T790M” AND “resistance”. We identified reports involving 31 patients in three case studies and five case series. None had accrued enough patients to assess distributions of specific resistance mechanisms or outcomes. We searched PubMed again with the term “osimertinib” OR “AZD9291” AND “non-small cell lung cancer” OR “NSCLC” AND “EGFR mutations” AND “liquid biopsy” OR “circulating tumor DNA”, but found no studies with serial measurements (before treatment or after disease progression) of circulating tumour DNA (ctDNA) in plasma to monitor osimertinib treatment outcomes.
Added value of this study
This retrospective analysis used tumour tissue and plasma samples taken from 53 patients from one centre in the AURA study who had data on EGFR-activating mutations and acquired Thr790Met mutations before and after osimertinib treatment. We investigated mechanisms of resistance, time to development of resistance, and clinical outcomes after development of osimertinib resistance, in enough patients to assess outcomes, and revealed genomic and clinical data not captured in the AURA study.
Implications of all the available evidence
We were able to assess mechanisms underlying resistance to osimertinib in patients with EGFR-mutant non-small-cell lung cancer who had acquired the Thr790Met mutation, and found that heterogeneous resistance mechanisms develop, even across different samples from individual patients. Testing of ctDNA for EGFR-activating mutations and the Thr790Met mutation has been widely used to identify patients who might benefit from treatment with EGFR TKIs. Our findings suggest that this approach could be used to follow up patients treated with osimertinib. We found that loss of Thr790Met but maintenance of EGFR-activating mutations in plasma correlated with shortened progression-free survival, which had not previously been reported. These patients should be assessed for the potential benefit of early intervention in future clinical trials. Testing for the presence of ctDNA after disease progression should be done with caution, because we found heterogeneity in resistance mechanisms and discordance in results between tumour tissue and plasma even within individual patients. Of ten patients tested for MET amplification, five were positive. Testing osimertinib combined with a c-MET inhibitor as preventive rather than salvage therapy in future clinical trials might be useful. We detected many known resistance mechanisms, such as the EGFR Cys797Ser mutation, MET amplification, and BRAF mutations, in tumour tissue. These data support serial testing of plasma for ctDNA in a broader gene panel in future clinical trials as a potential method to identify patients who will develop resistance, particularly because the discordant resistant mechanisms we noted in plasma and tumour samples suggest that repeat biopsy is necessary after disease progression. Combination of osimertinib plus another targeted therapy might be useful for these patients, but the anticancer efficacy of this approach needs to be shown in clinical trials. Since all the patients in this study had received multiple lines of treatment before osimertinib, our results need to be compared with resistance patterns after first-line osimertinib treatment; such information is being collected in the AURA and FLAURA studies. We hope that future studies will provide insight into the optimum time to use osimertinib, alone or in combination therapy, to prolong overall survival of patients with EGFR mutant non-small-cell cancer.