Abstract A51: Phase I, safety, tolerability and preliminary efficacy study of Tremelimumab (Trem) in combination with Gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM)
Authors: Planchard David , Barlesi Fabrice , Gomez-Roca Carlos , Mazieres Julien , Varga Andrea , Greillier Laurent , Chaput-Gras Nathalie , Lanoy Emilie , Parlavecchio Cedric , Malekzadeh Katty , Ngocamus Maud , ZAHI Sarah , Besse Benjamin , Poterie Audrey , Soria Jean-Charles 
Published: May 2016

Abstract
Background: Robust advances in our understanding of NSCLC molecular biology and host immunity have expanded the field of cancer therapy with new immunotherapeutic approaches that unlock the immune response, such as blockade of the T-cell lymphocyte-4 (CTLA-4) obtained with Trem, and molecularly targeted agents, including EGFR tyrosine kinase inhibitors (TKI) such as Gef. A Phase I open-label multicenter study was initiated to evaluate the association of Trem with Gef in EGFR-mut NSCLC (NCT02040064).
Methods: Key inclusion criteria included advanced/metastatic lung cancer with an activating mutation of EGFR (i.e., exon 19 deletion or exon 21 L858R point mutation), progression on any prior EGFR TKI (first line or beyond), measurable disease, adequate PS (0-1) and organ function. Patients (pts) may have received chemotherapy between EGFR TKI and inclusion. The primary objective was to determine the safety and tolerability of the combination of Gef (oral 250mg once-daily) with escalating doses of Trem (starting dose of 3mg/kg IV every 4 weeks for 6 cycles and beyond every 12 weeks) and to establish a recommended phase 2 dose (RP2D). A rolling 6 design and a dose limiting toxicity period of 42 days were applied. Three escalating doses of Trem were pre-planned (3, 6 and 10mg/kg). Data included here are preliminary and will be updated for presentation.
Results: Between January, 2014 and March, 2015, 20 stage IV pts received at least one dose of Trem (median age of 66 years, female 70%, never smoker 65% and 60% had received ≥2 lines). Seventeen pts were evaluable for dose-limiting toxicities (DLT). DLTs occurred in 4 pts, 1 at 3mg/Kg (grade 3 colitis, cycle 1), 1 at 6mg/Kg (grade 3 colitis, cycle 1) and 2 at 10mg/Kg (one grade 3 diarrhea and one AST-ALT increase grade 3, cycle 2) of Trem. All toxicities were reversible with discontinuation of Trem. Consequently, Trem 10mg/Kg plus Gef 250mg daily exceeded the maximum tolerable dosage. Most common (≥20%) adverse events (AEs/grade 3-4 AEs) were diarrhea (90%/30%), asthenia (55%/5%), dry skin (55%/5%), nausea (25%/0%), decreased of appetite (25%/10%), dyspnea (25%/0%), colitis (25%/15%), and vomiting (20%/0%). No pneumonitis or increases in cutaneous toxicity related to treatments were observed. To date, 3 pts remain on therapy (past cycles 4, 6 and 9) and 5 patients experienced long-term benefit (≥4months). Longest duration of treatment is 12 months thus far. A translational research program on biomarkers and PK data is currently being performed.
Conclusions: The recommended dose of Trem in phased combination with Gef in EGFR-mut pts with NSCLC was identified as 3mg/kg. The safety profile was consistent with the previously defined AE profile. An expansion cohort is enrolling pts at RP2D.
Citation Format: David Planchard, Fabrice Barlesi, Carlos Gomez-Roca, Julien Mazieres, Andrea Varga, Laurent Greillier, Nathalie Chaput-Gras, Emilie Lanoy, Cedric Parlavecchio, Katty Malekzadeh, Maud Ngocamus, Sarah ZAHI, Benjamin Besse, Audrey Poterie, Jean-Charles Soria. Phase I, safety, tolerability and preliminary efficacy study of Tremelimumab (Trem) in combination with Gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A51.