A Phase I open-label multicenter study was initiated to evaluate the association of T-cell lymphocyte-4 (CTLA-4) inhibitor Trem with Gef in progressing EGFR-mut NSCLC (NCT02040064).
Key inclusion criteria included advanced NSCLC with an EGFR-mut, progression after a response on any prior EGFR TKI (first line or beyond), adequate PS (0-1). 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 (DLT) period of 42 days were applied. Three escalating doses of Trem were pre-planned (3, 6 and 10mg/kg).
Between January, 2014 and March, 2015, 26 stage IV pts (20pts in the escalating dose cohorts and 6 in expansion cohort pts at RP2D) received at least one dose of Trem (median age of 66 years, female 65%, never smoker 61% and 61% had received ≥2 lines). Previous line was an EGFR-TKI in 77% of pts. DLTs occurred in 5 pts, 1 at 3mg/Kg (grade 3 colitis), 2 at 6mg/Kg (one grade 3 colitis and one AST-ALT increase grade 3 in expansion cohort) and 2 at 10mg/Kg (one grade 3 diarrhea and one AST-ALT increase grade 3) of Trem. All toxicities were reversible with discontinuation of Trem. Most common (≥20%) adverse events (AEs/grade 3-4 AEs) were diarrhea (92%/27%), asthenia (77%/4%), dry skin (54%/4%), nausea (38%/4%), anorexia (27%/8%), dyspnea (42%/0%), colitis (19%/4%), and vomiting (27%/4%). No pneumonitis or increases in cutaneous toxicity related to treatments were observed. Twenty four pts were evaluable for response. The best overall response was stable disease in 67% of pts (18/24pts, 69% at 3mg/Kg, 50% at 6mg/Kg and 80% at 10mg/Kg). All pts discontinued treatment after median duration of 8 weeks (range: 2 to 77 weeks), most frequently due to disease progression (60% of pts).
The recommended dose of Trem in phased combination with Gef in EGFR-mut pts with NSCLC was identified as 3mg/kg. Antitumor activity was stable disease in two thirds of pts. The safety profile was consistent with the previously defined AE profile.
Clinical trial identification
Legal entity responsible for the study
Gustave Roussy was the sponsor and coordinator of this trial. This research was conducted with support from AstraZeneca.
D. Planchard: Advisory Board : Astrazeneca, Boehringer, Pfizer, Roche, BMS, Merck, Novartis, Sanofi-aventis, Lilly, Clovis. F. Barlesi: Astrazeneca. C. Gomez-Roca: advisory board Sanofi and Novartis. J. Mazieres, L. Greillier: advisory board Atrazeneca. A. Varga, J-C. Soria: advisory board Atrazeneca and Clovis. B. Besse: Research grants from Astrazeneca. All other authors have declared no conflicts of interest.