Afatinib (A) vs gefitinib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label, Phase IIb trial LUX-Lung 7 (LL7)

Aim

The irreversible ErbB family blocker A and the reversible EGFR tyrosine kinase inhibitor G are approved for first-line treatment of advanced EGFR-mutant (m+) NSCLC. We have conducted a global randomized Phase IIb trial to prospectively compare the efficacy and safety of first-line A vs G in pts with EGFRm+ NSCLC.

Methods

Pts with stage IIIb/IV EGFRm+ NSCLC (defined by either local or central test) were randomized (1:1) to daily A 40 mg or G 250 mg, stratified by mutation type (Del19 or L858R) and presence of brain metastases. Treatment continued until disease progression or beyond if deemed beneficial by investigator. Co-primary endpoints were: progression free survival (PFS) by independent review, time to treatment failure (TTF), and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate, tumor shrinkage, and safety.

Results

319 pts were randomized to A (n = 160) or G (n = 159). Except for a slight gender imbalance (female: 56.9% [A] vs 66.7% [G]), baseline characteristics were similar: race (Asian: 58.8% vs 55.3%), EGFR mutation type (Del19: 57.5% vs 58.5%). Afatinib significantly improved PFS (HR = 0.73; 95% CI, 0.57–0.95; p = 0.0165) and TTF (HR = 0.73; 95% CI, 0.58–0.92; p = 0.0073) compared to G. This effect was consistent for ORR (70% vs 56%, p = 0.0083), and for subgroups by mutation type and race. OS is not yet mature. The most common grade ≥3 related adverse events (AEs) were diarrhea (12.5%) and rash/acne (9.4%) with A and alanine aminotransferase increase (8.2%) with G. Drug-related interstitial lung disease was reported for 0 (A) vs 4 pts (G; 2.5%). Treatment discontinuation due to related AEs was the same in each arm (6.3%).

Conclusions

First-line afatinib significantly improved PFS vs gefitinib in EGFRm+ pts. Consistent benefit was seen with TTF and ORR. AEs were manageable with the same low discontinuation rates in both arms.

Clinical trial identification

2011-001814-33

Disclosure

K. Park: employment with Samsung Medical Center and advisory board involvement with Boehringer Ingelheim (uncompensated). E.-H. Tan: advisory board involvement with Boehringer Ingelheim, MSD and AstraZeneca and honoraria from Boehringer Ingelheim, MSD and AstraZeneca. L. Zhang: involvement with advisory boards for Boehringer Ingelheim and AstraZeneca. V. Hirsh: honoraria for a Boehringer Ingelheim advisory board. K. O'Byrne: involvement with an advisory board for Boehringer Ingelheim and honoraria from Boehringer Ingelheim. M. Boyer: corporate-sponsored research from Pfizer, Peregrine Pharmaceuticals and Genetech/Roche and corporate-sponsored research and honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharpe and Dohme, and Astra Zeneca. J.C.-H. Yang: advisory board participation for Astrazeneca, Roche/Genentech, Boehringer Ingelheim, MSD, Merck Serono, Novartis, Clovis Oncology, Eli Lilly, Bayer, Celgene, Astellas, Innopharma, and Ono Pharmaceutical; honoraria from Astrazeneca, Roche/Genentech, Boehringer Ingelheim, MSD, Merck Serono, Novartis, Clovis Oncology, Eli Lilly, Bayer, Celgene, Astellas, Innopharma, and Ono Pharmaceutical. T. Mok: Speaker's Bureau participant with AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, MSD, Amgen, Janssen, Clovis Oncology, GSK, and Novartis; advisory board participation for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, and ACEA Biosciences, Inc.; honoraria from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Amgen, Janssen, Clovis Oncology, GSK, and Novartis; and major stock shareholder in Sanomics Ltd. M. Kim: reports full-time employment with Boehringer Ingelheim. D. Massey: employment with Boehringer Ingelheim Ltd. V. Zazulina: employment with Boehringer Ingelheim. L. Paz-Ares: honoraria from Boehringer Ingelheim, Roche, Lilly, AstraZeneca, Pfizer, Clovis, and BMS.