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Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial
Abstract
Background Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors.Methods In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136.Findings Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group.Interpretation Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment.Funding Boehringer Ingelheim Inc.
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“However, as monotherapy, they have failed to overcome T790M-mediated resistance in patients (28, 29), because concentrations at which these irreversible TKIs overcome T790M activity pre-clinically are not achievable in humans due to dose-limiting toxicity related to non-selective inhibition of wild-type EGFR (30).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [28]
In the citing paper
“However, we know from clinical experience that afatinib is unable to inhibit T790M in the clinic due to a lack of a therapeutic window”
In the citing paper
“For example, studies of afatinib monotherapy showed a response rate of less than 10% among patients with acquired resistance to erlotinib or gefitinib, with a progression-free survival of approximately 4 months.13,15”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [13]
In the citing paper
“However, in lung cancer patients, afatinib is only effective in EGFR TKI naive EGFR mutant cancers and has a RR of < 10% in patients with NSCLC that have developed resistance to gefitinib or erlotinib (13).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [13]
In the citing paper
“neither Afatinib [76] nor Neratinib [77] nor Dacomitinib [78] demonstrated significant activity as single agent in patients harboring the T790M mutations.”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [76]
In the citing paper
“However, for EGFR T790M mutated lung cancer, it failed to overcome EGFR T790M-mediated resistance in patients [36, 37].”
In the citing paper
“Sixty-three percent of the patients in the afatinib group and 76% in the control group received ≥ one subsequent regimen (all mutation statuses).15”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In the citing paper
“Response rate was 7% versus 0.5%.”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In the citing paper
“In a prespecified analysis, participants with a complete or partial response to a first-line EGFR TKI whose tumors also had known EGFR mutation test results (58 [88%] of 66), the HR for PFS was significant (0.23), but the HR for OS was not (0.90) in the afatinib arm.”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In the citing paper
“Some of the second-line studies included patients who had received > two previous regimens.15,23,47,48,51,65”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In the citing paper
“The study found no improvement in the primary end point of OS between patients randomly assigned to afatinib and those randomly assigned to placebo, although PFS was longer in the afatinib group (3.3 v 1.1 months; HR, 0.38; 95% CI, 0.31 to 0.48; P < .001).”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
In the citing paper
“Among these 96 patients, PFS was 3.3 months for those who received afatinib and 1.0 month for those who received placebo (HR, 0.55; 95% CI, 0.31 to 0.85; P = .009).15”
From Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update (2015) · cites this paper as [15]
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Metadata
- Authors
- Miller, V. A., Hirsh, V., Cadranel, J., Chen, Y.-M., Park, K., Kim, S.-W., Zhou, C., Su, W.-C., Wang, M., Sun, Y., Heo, D. S., Crino, L., Tan, E.-H., Chao, T.-Y., Shahidi, M., Cong, X. J., Lorence, R. M., & Yang, J. C.-H.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- McGill University Health Centre (CA)
- Assistance Publique – Hôpitaux de Paris (FR)
- Taipei Veterans General Hospital (TW)
- Samsung Medical Center (KR)
- Asan Medical Center (KR)
- Tongji University (CN)
- National Cheng Kung University Hospital (TW)
- Peking Union Medical College Hospital (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Seoul National University Hospital (KR)
- National Cancer Centre Singapore (SG)
- Taipei Medical University-Shuang Ho Hospital (TW)
- Boehringer Ingelheim (United Kingdom) (GB)
- Boehringer Ingelheim (United States) (US)
- National Taiwan University (TW)
- Corresponding author
- Yang, James Chih-Hsin
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 13
- Issue
- 5
- Pages
- 528-538
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2152905269
- Cited by
- 961
- References
- 29
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 28 · 2023: 38 · 2022: 33 · 2021: 46 · 2020: 50 · 2019: 57 · 2018: 70 · 2017: 103 · 2016: 99 · 2015: 125 · 2014: 139 · 2013: 107 · 2012: 37
- FWCI
- 105.26
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-05-01)
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- afatinib, non-small cell lung cancer, lung adenocarcinoma, EGFR tyrosine kinase inhibitors, erlotinib, gefitinib, EGFR mutation, EGFR inhibitor resistance, second-line therapy, overall survival, progression-free survival, best supportive care, targeted therapy
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Afatinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Protein Kinase Inhibitors
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