The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria.

Safety and efficacy will also be measured.

Naïve patients ≥ 18 years of age with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation. Evidence of measurable or evaluable metastatic disease is required.

Primary objective:

• To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria.

Secondary objectives:

• To determine the safety and tolerability profile of osimertinib (AZD9291), measured using the number and severity of AEs entered into the Case Report Form (CRF); chemistry, blood count, vital signs, physical examination, weight, ECG and performance status (S).
• To determine other efficacy parameters such as progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), duration of response (DOR), disease control rate (DCR), and tumor shrinkage (TS).
• To correlate the parameters of clinical response efficacy documented with the EGFR mutational status.
• To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in plasma and serum.
• To determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to EGFR TKI response and determine whether they are predictors of treatment response.
• To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at the site of covalent binding to the drug (C797) or other mutations in tissue or blood.

Type of study: Multicenter, international, single-arm, open-label, non-controlled phase IIa clinical study.

Treatment: Patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily.

Inclusion Criteria:

• Patient aged 18 years or older

• Patients with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation who are not candidates for local curative treatment.

• Patients with a M1a stage according to the TNM version 7 including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease that is not a candidate for curative treatment (including patients who progress after chemoradiotherapy in stage III disease).

• Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally.

• ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2.

• Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients with asymptomatic and stable brain metastases are eligible for the study.

• Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the primary tumor or metastatic tumor tissue, within the 60 days prior to study entry.

• Life expectancy ≥12 weeks.

• Adequate hematologic function:

  • Absolute neutrophil count (ANC) > 1.5 x 109/L
  • platelet count > 100.0 x109/L
  • hemoglobin > 9.0 g/dL (> 6.2 mmol/L).

• Adequate coagulation: INR ≤ 1.5.

• Adequate liver function

• Adequate renal function.

• Capacity to swallow, patient capable of completing treatment and accessible, ensuring proper follow-up.

• Patients able to complete study and within geographical proximity allowing for adequate follow-up.

• Resolution of all acute toxic effects of previous anti-cancer therapy (which can only be adjuvant or neoadjuvant) or surgical interventions not exceeding grade ≤ 1 according to the NCI CTCAE version 4.0 (except for alopecia or other side effects that the investigator does not consider to be a risk to patient safety).

• All men or women of childbearing potential must use a contraception method during the study treatment and for at least 12 months after the last dose of the study drug.

• Signed and dated informed consent form

Exclusion Criteria:

• Locally advanced lung cancer candidate for curative treatment through radical surgery and/or radio(chemo)therapy.
• Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with predominantly squamous cell cancer, or with any small-cell lung cancer component.
• Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally.
• Patients who have received prior antineoplastic treatment for advanced disease.
• Second active neoplasia
• Patients with just one measurable or evaluable tumor lesion that has been resected or irradiated prior to their enrollment in the study.
• Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD.
• Corrected QT Interval (QTc) >470 msec, obtained from 3 ECGs at rest, using the QTc value determined according to the clinical screening ECG machine.
• Any clinically significant abnormality in ECG rhythm, conduction or morphology at rest.
• Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat or sudden inexplicable death under the age of 40 in first-degree relatives or any concomitant medications that prolong the QT interval.
• Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or progressive neoplasia. Patients with history of CNS metastasis or compression of the spinal cord are eligible if they have received local final treatment (e.g., radiotherapy, stereotactic surgery) and if they have remained clinically stable without using anticonvulsants and corticosteroids for a minimum of 4 weeks prior to the first day of study treatment.
• Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to swallow study drug or significant intestinal resection that restricts the adequate absorption of osimertinib (AZD9291).
• Patients who have had a surgical procedure unrelated to the study within 7 days prior to the administration of the drug or a significant traumatic lesion during the 4 weeks prior to starting the administration of the study drug, patients who have not recovered from the side effects of any major surgery or patients who might need major surgery during the course of the study.
• Pregnant or breastfeeding women. Women of childbearing potential, including women who had their last menstrual period within the last two years, must have a negative serum or urine pregnancy test in the 7 days prior to the start of the treatment.
• Patients who are not willing to use an adequate contraception method until 12 months after the last dose of study treatment.
• Patients with a serious concomitant systemic disorder (e.g., active infection, including HIV or heart disease) that is incompatible with the study (in the opinion of the investigator), history of bleeding diathesis or anticoagulant therapy (the use of low molecular weight heparin is permitted provided that it is used for prophylaxis).
• Patients with a history of cancer that has been completely treated, with no evidence of malignant disease currently cannot be enrolled in the study if their chemotherapy was completed less than 6 months prior and/or have received a bone marrow transplant less than 2 years before the first day of study treatment.
• Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months have elapsed between the end of chemotherapy and the first day of study treatment.
• Patients who have received prior EGFR treatments for lung cancer.
• Patients who have received treatment with an investigational drug within 3 weeks before the first day of study treatment.
• Treatment with prohibited drugs within 14 days before the first day of study treatment.

42 months

Regular investigator and local laboratory assessments were used to determine adverse events. Basic safety visits were performed on day 1 of each cycle every 2 cycles (every 6 weeks).