LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non–Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both
Abstract
PURPOSE: New molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M. PATIENTS AND METHODS: This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after ≥ 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease. CONCLUSION: Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.
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As monotherapy, afatinib and dacomitinib fail to overcome T790M-mediated resistance in patients because effective preclinical concentrations cannot be reached due to wild-type EGFR toxicity.
“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 [29]
Afatinib monotherapy trials in patients with acquired resistance to erlotinib or gefitinib showed a response rate below 10% and progression-free survival of about 4 months.
“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 <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [15]
Afatinib failed to overcome EGFR T790M-mediated resistance in patients.
“However, for EGFR T790M mutated lung cancer, it failed to overcome EGFR T790M-mediated resistance in patients [36, 37].”
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“NSCLC patients who progressed during prior treatment with gefitinib or erlotinib was disappointing with only 7% to 8% (18, 40).”
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- Authors
- Katakami, N., Atagi, S., Goto, K., Hida, T., Horai, T., Inoue, A., Ichinose, Y., Koboyashi, K., Takeda, K., Kiura, K., Nishio, K., Seki, Y., Ebisawa, R., Shahidi, M., & Yamamoto, N.
- Affiliations
- Tohoku University Hospital (JP)
- Nobuyuki Katakami, Kobe City Medical Center General Hospital, Kobe; Shinji Atagi, National Hospital Organization Kinki-Chuo Chest Medical Center; Koji Takeda, Osaka City General Hospital; Kazuto Nishio, Kinki University, Osaka; Koichi Goto, National Cancer Center Hospital East, Chiba; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Takeshi Horai, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo; Akira Inoue, Tohoku University Hospital, Sendai; Yukito Ichinose, National...
- Boehringer Ingelheim (Germany) (DE)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2013-09-20
- Volume
- 31
- Issue
- 27
- Pages
- 3335-3341
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2132540363
- Cited by
- 326
- References
- 5
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 11 · 2023: 10 · 2022: 10 · 2021: 22 · 2020: 9 · 2019: 21 · 2018: 35 · 2017: 34 · 2016: 51 · 2015: 53 · 2014: 48 · 2013: 13
- FWCI
- 45.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (24240122)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- afatinib, non-small cell lung cancer, EGFR mutation, EGFR tyrosine kinase inhibitors, erlotinib, gefitinib, acquired drug resistance, T790M mutation, lung adenocarcinoma, third-line therapy, fourth-line treatment, objective response rate, progression-free survival, diarrhea, adverse events, L858R
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Adenocarcinoma of Lung, Afatinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Disease Progression, Disease-Free Survival
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