Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial

Wu, Yi‐Long; Zhou, Caicun; Hu, Chengping; Feng, Jifeng; Lü, Shun; Huang, Yunchao; Li, Wei; Hou, Mingxiao; Shi, Jianhua; Lee, Kye Young; Xu, Chong-Rui; Massey, Dan; Kim, Miyoung; Shi, Yang; Geater, Sarayut Lucien

doi:10.1016/s1470-2045(13)70604-1

Cited by 1,750 publications

(1,597 citation statements)

References 27 publications

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“…However we should take into account that such study has met two (PFS and TTF) of the three co-primary endpoints, overall showing a significant reduction of 25% in the risk of PD, with about ¼ of patients reaching a significant PFS benefit >6 months with afatinib. Both TTF and PFS as well as OS data reported in LL7 are similar and consistent to those observed in other randomized studies of afatinib in first-line (Sequist et al, 2013;Wu et al, 2014), suggesting a potential superiority of this drug. Furthermore we can't exclude that final OS data, including also late censored events, might reach the statistical significance, definitively confirming the benefit observed in both PFS and TTF, which usually are more informative about first-line treatment efficacy.…”

Section: Direct Comparisonssupporting

confidence: 87%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Passiglia

Listì

Castiglia

et al. 2017

Critical Reviews in Oncology/Hematology

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The targeted inhibition of epidermal growth factor receptor (EGFR) has represented a milestone in the treatment of lung cancer. Several studies convincingly and consistently demonstrated a significant superiority of EGFR-TKIs over standard platinum-chemotherapy in EGFR-mutated NSCLC patients, leading to the sequential approval of gefitinib, erlotinib and afatinib as new standard first-line clinical treatment. To date we are witnessing a second revolution in the management of EGFR-positive NSCLC thanks to the development of new treatment strategies aiming to overcome acquired resistance to TKIs and ultimately improve patients’ outcomes. In this review we summarize the most important recent findings regarding EGFR-inhibition in NSCLC, highlighting the current unsolved questions on the selection of the best TKI in first-line, which therapy can be combined with upfront EGFR-TKIs, how to overcome acquired resistance, and which are the clinical applications of liquid biopsy

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Section: Direct Comparisonssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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

Passiglia

Listì

Castiglia

et al. 2017

Critical Reviews in Oncology/Hematology

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“…The HR for PFS among former/current smokers in OPTIMAL was 0.21 (95% CI: 0.09-0.49) [3]. The HR for PFS among current or ex smokers in LL6 was 0.46 (95% CI: 0.22-1.00) [6].Two remaining trials (NEJ002 and ENSURE) have not reported univariate analysis by smoking status [2,7]. Given that up to one-third of EGFRm patients had a previous smoking history [8], we performed a meta-analysis to analyze the role of smoking status and other potential predictive factors that may influence clinical outcome in EGFRm patients receiving firstline EGFR TKIs.…”

Section: Introductionmentioning

confidence: 98%

“…Based on results from seven prospective phase III randomized trials comparingfirst-line epidermal growthfactor receptor(EGFR) tyrosine kinase inhibitors (TKIs) to platinum-doublet chemotherapy as first-line treatment of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations (EGFRm), it is now well-established that EGFR TKI offers superior improvement in progression-free survival (PFS) [1][2][3][4][5][6][7]. Exploratory univariate analyses of three of the seven clinical trials (WJTOG3405, EURTAC, and LUX-Lung-3 [LL3]) suggested that EGFRm NSCLC patients who had a previous smoking history (former or current smoker) did not seem to derive a statistical PFS improvement when EGFR TKI was compared with platinum-doublet chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

The Role of Smoking Status on the Progression-Free Survival of Non-Small Cell Lung Cancer Patients Harboring Activating Epidermal Growth Factor Receptor (EGFR) Mutations Receiving First-Line EGFR Tyrosine Kinase Inhibitor Versus Platinum Doublet Chemotherapy: A Meta-Analysis of Prospective Randomized Trials

et al. 2015

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Background. Univariate analyses from several randomized phase III trials seemed to suggest ever-smokers with advanced mutated epidermal growth factor receptor (EGFRm) non-small cell lung cancer (NSCLC) did not seem to benefit from EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment when compared with platinum-doublet chemotherapy as measured by progression-free survival (PFS). Methods. A literature-based meta-analysis of PFS outcomes as measured by log-transformed pooled hazard ratio (HR) was performed using a random-effect model. Pooled HRs for smoking status, age, gender, ethnicity, type of EGFR mutation, and EGFR TKI were obtained. Comparison of the pooled HR was performed by metaregression analysis. Results. Among the 1,649 EGFRm NSCLC patients analyzed from 7 prospective randomized trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, LUX Lung-3, LUX Lung-6, and ENSURE),

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“…Afatinib, an irreversible HER-family blocker (17,18), has a remarkable antitumor effect against EGFR-mutated non-small cell lung cancer (NSCLC; refs. 19,20). In addition, a recent phase III study showed the efficacy of afatinib in patients with recurrent or metastatic HNSCC after the failure of platinum-based therapy (21), and in a phase I study, one of 7 patients with esophageal cancer achieved a partial response with afatinib (22).…”

Section: Introductionmentioning

confidence: 99%

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.

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Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial

Cited by 1,750 publications

References 27 publications

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

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

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

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