A phase II, noncomparative, open label, multicentre, study of AZD9291 in patients with locally advanced or metastatic EGFR mutated “T790M undetectable or unknown” non-small cell lung cancer (stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

TPS9107 Background: Osimertinib (OSI), is an oral, potent, irreversible inhibitor of both epidermal growth factor receptor (EGFR) sensitizing and resistance mutations (T790M) indicated for the treatment of pts with advanced EGFR T790M mutation-positive NSCLC. In the AURA study, OSI was associated with an ORR of 21% (13/61) among all patients with T790M negative mutation. Response rate broken down by immediate versus no immediate prior EGFR TKI was 11% (4/36 pts) versus 36% (9/25) respectively. This better activity with deferred OSI, drug able to inhibit also the EGFR sensitizing mutations, could be explained by a selection of sensitive tumor cells during chemotherapy (re-challenge strategy). Aim of the current study is prospective evaluate the efficacy of OSI in EGFR mutated, T790M “undetectable or unknown” patients as third-line therapy after a first-line EGFR TKI and a subsequent chemotherapy. Methods: OSIRIS study is a prospective single-arm, phase 2, open label, italian multicenter study. T790M “undetectable or unknown" is defined by the following conditions: inconclusive/negative tumor test result for T790M at the time of disease progression or medical inaccessible/contraindications/declined tumor biopsy or insufficient tumor tissue for testing. Pts are treated with OSI 80 mg once daily until disease progression or unacceptable toxicity. The single-arm design is appropriate, as there is no accepted standard therapy for these pts after chemotherapy. The primary endpoint is ORR according to RECIST version 1.1. The null hypothesis that the true response rate is 9% will be tested against a one-sided alternative. In the first stage, 32 pts will be accrued. If there are 3 or fewer responses in these 32 pts, the study will be stopped. Otherwise, 49 additional pts will be accrued for a total of 81. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 19%. Secondary endpoints are PFS, OS and safety. Exploratory: mutational analysis of a panel of genes involved in resistance to EGFR-TKIs is planned. Clinical trial information: 2016-002555-17.