Phase I Study of Tremelimumab (Trem) in Combination with Gefitinib (Gef) in Epidermal Growth Factor Receptor Mutant (Egfr-Mut) Non-Small Cell Lung Cancer (Nsclc)

Background: Treatment options for patients (pts) with EGFR-mut NSCLC who have failed standard chemotherapy and first generation tyrosine kinase inhibitors (TKIs) are limited. Treatment with EGFR TKIs influences the release of chemokines leading to increased T cell recruitment, and tumor cell death induced by TKIs leads to increased antigen release and immune priming. Trem is a human immunoglobulin G2 (IgG2) kappa monoclonal antibody (mAb) that is directed against the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4). This trial is aimed at elucidating whether or not adding anti-CTLA-4 therapy to existing Gef would complement and enhance its effects. Trial design: This phase I multicenter, single-arm study is designed to evaluate Gef (oral 250mg once-daily) plus Trem (starting dose of 3mg/kg IV every 4 weeks for 6 cycles and beyond every 12 weeks) in pts with EGFR-mut advanced NSCLC who have failed EGFR TKI. A rolling 6-cycle design and a dose limiting toxicity period of 42 days will be implemented. Three escalating doses of Trem are planned (3, 6 and 10mg/kg). Six pts will be enrolled for each dose level (up to 24 evaluable pts will be enrolled). Pts may have received chemotherapy between the EGFR TKI and inclusion in this study but must present a systemic objective progression. To prevent a tumor flare when starting Gef + Trem therapy, pts not previously treated with Gef will receive Gef treatment for 2 weeks before the addition of Trem. Pts with ECOG performance status ≥2, history of chronic inflammatory or autoimmune disease, untreated brain metastases or requiring systemic steroids are not eligible. The primary objective is to determine the safety and tolerability of the combination and to establish a recommended phase 2 dose. Secondary/exploratory objectives include evaluating response endpoints (overall response rate, progression free survival according to RECIST 1.1), determining immunogenicity and identifying immune biomarkers of this combination (peripheral blood mononuclear cell, sera and sequential tumor biopsies), and describing the pharmacokinetics for each agent in combination. The study is recruiting in 3 sites in France since February 2014. ClinicalTrials.gov identifier NCT02040064. Disclosure: D. Planchard: Advisory board with Astra-Zeneca to disclose; F. Barlesi: Consultant or advisory relationship with AstraZeneca to disclose; N. Byrne: Nathalie Byrne is an employee of AstraZeneca and owns stock/stock options in AstraZeneca; Besse: research grants from AstraZeneca; A. Nash: Anthony Nash is an employee of AstraZeneca and owns stock/stock options in AstraZeneca; A. Di Pietro: Alessandra DiPietro is an employee of MedImmune and owns stock/stock options in AstraZeneca; J. Soria: JC Soria have honoraria from AstraZeneca to disclose. All other authors have declared no conflicts of interest.