IFCT-1003 LADIE trial: Randomized phase II trial evaluating treatment with EGFR-TKI versus EGFR-TKI associated with anti-estrogen in women with non-squamous advanced stage NSCLC

Background

The incidence of lung cancer is increasing dramatically in women and displays some specific epidemiological, radiological, clinical and pathological characteristics. Two main mechanisms emerged from recent findings in the field of lung carcinogenesis in women: the preferential involvement of the EGFR pathway and the potential impact of hormonal factors. The interaction of estrogen receptors with growth factor receptor signalling has also been shown. Preclinical data have shown that the combination of an EGFR-Tyrosine Kinase Inhibitor (TKI) with an anti-estrogen could overcome resistance to EGFR-TKI by postponing the reactivation of the PI3K-AKT pathway through the estrogen-mediated non-genomic pathway.

Trial design

We launched an open-label phase II randomized trial dedicated to women with advanced stage adenocarcinoma. Patients are treated by gefitinib (250 mg/d) vs. gefitinib + fulvestrant 500 mg MI / month (with a supplementary dose at day 15) in the EGFR mutated group (EGFR +) in first or second line setting and by erlotinib (150 mg/d, according to marketing authorization at trial initiation) vs. erlotinib + fulvestrant in the EGFR wild-type group (EGFR WT) in second or third line setting. Treatments are given until progression or unacceptable toxicity. Follow-up is performed in both arms every month to minimize the potential bias due to monthly fulvestrant injection. Primary objective is progression-free survival (PFS) at 3 and 9 months for EGFR WT and EGFR + patients, respectively. Secondary objectives are safety, overall survival and quality of life. Exploratory objective is biomarkers analysis. The main inclusion criteria are histologically-confirmed non-squamous NSCLC, available tumor tissue for EGFR mutation analysis, post-menopausal women, PS 0-2. The study has been approved by all ethical committees. An ancillary study is ongoing in the EGFR mutated cohort to detect and monitor the EGFR T790M mutation in the serum. First patients have been enrolled in May 2012. To date, 326 patients (162 EGFR + , 164 EGFR WT) have been enrolled and 394 (204 EGFR +, 190 EGFR WT) are expected.

Clinical trial identification

NCT01556191

Legal entity responsible for the study

N/A

Funding

AstraZeneca, Ligue Nationale Contre le Cancer

Disclosure

All authors have declared no conflicts of interest.