• The Phase I (n = 253) study of AZD9291 in patients with EGFR-mutant non-small cell lung cancer (NSCLC) resistant to an EGFR TKI demonstrated an objective response rate (ORR) of 51% overall and 61% in patients with T790M mutation-positive disease.
• The ORR in the Phase I/II study of first-line AZD9291 (n = 60) was 73%. The ongoing Phase III FLAURA trial is evaluating first-line AZD9291 versus erlotinib or gefitinib.

Approximately 60% of patients with disease progression on an EGFR TKI have acquired the T790M tumor mutation as the primary means of resistance. AZD9291 — or osimertinib — a third-generation EGFR TKI, results in tumor shrinkage in almost all patients with a T790M resistance mutation whose disease has progressed on a first-generation TKI. Responses are much less common in patients without a T790M mutation, and investigators often opt for chemotherapy in those patients. The remarkable feature of the third-generation EGFR TKIs is that these agents have less effect on normal cells with wild-type expression of EGFR, and, as a result, rash and GI toxicity are much less common than with the first-generation TKIs.

The critical need to establish when the T790M mutation is responsible for clinical resistance has now made rebiopsy critical in patients with disease progression on an EGFR TKI, but encouraging findings with serologic assays suggest that these modalities may replace tumor biopsy in the future.