Time-to-treatment failure (TTF) with first-line afatinib (A) vs gefitinib (G) in patients (pts) with EGFR mutation-positive (EGFRm+) advanced non-small-cell lung cancer (NSCLC): Randomized phase IIb LUX-lung 7 (LL7) trial

Background

LL7 compared the efficacy/safety of the irreversible ErbB family blocker A with the reversible EGFR TKI G in pts with treatment (tx)-naïve EGFRm+ advanced NSCLC. Co-primary endpoints were PFS, TTF and OS. PFS was significantly improved with A vs G, with manageable tolerability (Park et al. Lancet Oncol 2016). TTF was included as an endpoint to reflect real-world clinical practice of continuing TKI tx beyond radiologic progression in the absence of clinical deterioration. Detailed analysis of TTF is reported here.

Methods

Pts with stage IIIb/IV adenocarcinoma and an activating EGFRm (Del19/L858R) were randomized (stratified by EGFRm type and brain metastases [BM]) to A 40mg/day or G 250mg/day until progressive disease (PD) or beyond if deemed beneficial. TTF was analyzed using a stratified log-rank test; data were summarized with Cox-regression models/Kaplan-Meier methods.

Results

319 pts were randomized (160 A, 159 G). At data cut-off (21 Aug 15), 87.5% A and 93.7% G pts had discontinued tx, mostly due to radiological PD (69.4 vs 74.8%) or toxicity (11.3 vs 10.7%). 35.0% A and 29.6% G pts with clinical benefit continued tx beyond radiologic PD; these pts had similar baseline characteristics to the overall pt population. Pts remained on tx significantly longer with A vs G (median TTF 13.7 vs 11.5 mos, HR 0.73 [95% CI 0.58–0.92], p = 0.007; pts on tx at 2 yrs: 25.0 vs 13.2%). Prespecified TTF subgroup analyses including age, gender, ECOG PS, EGFRm type, and race also favored A. Risk of tx failure was reduced to a similar degree with A vs G regardless of EGFRm type (Del19: HR 0.73 [0.54–0.99], p = 0.044; L858R: HR 0.75 [0.53–1.06], p = 0.104) or race (non-Asian: HR 0.66 [0.46–0.95], p = 0.024; Asian: HR 0.82 [0.60–1.11], p = 0.19). Median tx duration beyond PD was 2.7 and 2.0 mos, respectively.

Conclusions

TTF was significantly improved with first-line A vs G in EGFRm+ advanced NSCLC, complementing PFS findings. Improved TTF with A testifies to its general tolerability and manageability of AEs and suggests that it may confer additional clinical benefit in pts who continue tx beyond radiologic PD.

Clinical trial identification

NCT01466660

Legal entity responsible for the study

Boehringer Ingelheim

Funding

Boehringer Ingelheim

Disclosure

M. Schuler: Advisory board/board of directors: AZ, BI, BMS, Celgene, IQWig, Lilly, Novartis Corporate-sponsored research: BI, BMS, Novartis Other: Lecure Fees received from Alexion, BI, Celgene, GSK, Lilly, Novartis Patents (University Duisburg-Essen). L. Zhang: Advisory board/board of directors: AZ, Lilly. M. Boyer: Advisory board/board of directors: AZ Corporate-sponsored research: AZ, BI, Clovis, Roche. T.S.K. Mok: Stock (Sanomics Ltd); advisory board (AZ, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Aveo & Biodesix, BMS, geneDecode Co., Ltd, OncoGenex Technologies Inc.); board of directors (IASLC, Chinese Lung Cancer Research Foundation Ltd, CSCO, HKCTS); corporate-sponsored research (AZ, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS). V. Hirsh: Advisory board (honorarium): BI. J.C-H. Yang: Advisory board/board of directors: BI, Lilly, Bayer, Roche/Genentech/Chugai, AZ, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene, innopharma, Merrimack. D. Massey, J. Fan: Employed by Boehringer Ingelheim. K. Park: Advisory board: BI Corporate-sponsored research: AZ. All other authors have declared no conflicts of interest.