Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial

Abstract

BackgroundIn LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.Patients and methodsLUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.ResultsTwo-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.ConclusionIn LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifierNCT01466660.

Optimizing outcomes in EGFR Mutation-Positive Nsclc: Which Tyrosine Kinase Inhibitor and When?

“…Median OS was not significantly different between treatment arms (27.9 months with afatinib vs 24.5 months with gefitinib; HR: 0.86; p = 0.2580). However, LUX-Lung 7 was not powered for OS, as the sample size was based on controlling the width of the CI for the HR of PFS [29]. As in LUX-Lung 3 and LUX-Lung 6, the efficacy findings were generally consistent across patient subgroups of gender, age and ethnicity.…”

EGFR inhibition in NSCLC: New findings…. and opened questions?

“…However it has not been translated into an OS benefit. Indeed at a median follow-up of 42.6 months only a trend toward a better OS has been observed in patients receiving afatinib (27.9 vs 24.5 months) which did not reach statistical significance (HR: 0.86, 95%CI: 0.66-1.12) (Paz-Ares et al, 2017b). Even if OS data are still immature, LL7 can be formally defined as a negative trial.…”

“…Since the approval of the first EGFR-TKI gefitinib in clinical setting, several other compounds have been developed by pharma, which may be classified as first, second, and third-generation EGFR-TKIs. About eight phase III randomized clinical trials compared EGFR-TKI Gefitinib, Erlotinib, or Afatinib vs platinum-based chemotherapy as first-line treatment for EGFR-mutated NSCLC patients (Reis-Filho and Pusztai, 2011;Mitsudomi et al, 2010;Maemondo et al, 2010;Paz-Ares et al, 2017a;Network CGA, 2012;Zhou et al, 2011;Sequist et al, 2011;Wu et al, 2014). The results of all such studies convincingly and consistently demonstrated a significant superiority of EGFR-TKIs over standard platinum-chemotherapy, improving both response rate (RR), progression free survival (PFS) and quality of life (QoL) of EGFR-mutated NSCLC patients.…”

Algorithms for Management of Patients With Adverse Events on Therapy With Tyrosine Kinase Inhibitors Egfr

“…Частота любых НЯ ≥ 3 степени тяжести составляла 56,9% и 53,5%, а частота связанных с лечением НЯ ≥ 3 степени тяжести составляла 31,3% и 19,5% при лечении афатинибом и гефитинибом соответственно [70]. Такая же тенденция была замечена и при проведении другого сравнительного исследования ИТК-EGFR первого и второго поколений (эрлотиниба и афатиниба) LUX-Lung 8 в качестве второй линии терапии плоскоклеточного рака легкого.…”