Abstract
Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.
Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.
Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [ CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first-and second-generation TKI experienced clinical benefit.
Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Original language | English |
---|---|
Pages (from-to) | 1400-1407 |
Number of pages | 8 |
Journal | Journal of Thoracic Oncology |
Volume | 14 |
Issue number | 8 |
DOIs | |
Publication status | Published - Aug 2019 |
Keywords
- NSCLC
- EGFR
- Tyrosine kinase inhibitor
- Leptomeningeal metastases
- CELL LUNG-CANCER
- DOSE WEEKLY ERLOTINIB
- BRAIN METASTASES
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In: Journal of Thoracic Oncology, Vol. 14, No. 8, 08.2019, p. 1400-1407.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases
AU - Flippot, Ronan
AU - Biondani, Pamela
AU - Auclin, Edouard
AU - Xiao, Dingyu
AU - Hendriks, Lizza
AU - Le Rhun, Emilie
AU - Leduc, Charlotte
AU - Beau-Faller, Michele
AU - Gervais, Radj
AU - Remon, Jordi
AU - Adam, Julien
AU - Planchard, David
AU - Lavaud, Pernelle
AU - Naltet, Charles
AU - Caramella, Caroline
AU - Le Pechoux, Cecile
AU - Lacroix, Ludovic
AU - Gazzah, Anas
AU - Mezquita, Laura
AU - Besse, Benjamin
N1 - Funding Information: Disclosure: Dr. Flippot has received personal fees from Pfizer. Dr. Hendriks has received grants from Roche, Boehringer Ingelheim; and has received personal fees from Bristol-Myers Squibb, Roche, Quadia, and Boehringer Ingelheim; and has received nonfinancial support from Astra Zeneca. Dr. Le Rhun has received grants from Amgen and Mundi Pharma; and has received personal fees from Mundi Pharma, AbbVie, Daiichi Sankyo, and Novartis. Dr. Remon has received grants from Ose Immunotherapeutics; and has received personal fees from Osi Immunotherapeutics, MSD, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Astra Zeneca, and Roche. Dr. Adam has received grants from MSD, Sanofi, and Pierre Fabre; and has received personal fees from Astra Zeneca, Bristol-Myers Squibb, MSD, and Roche. Dr. Planchard has received personal fees from Astra Zeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Celgene, Novartis, Roche, and Pfizer. Dr. Lavaud has received personal fees from Pfizer. Dr. Caramella has received personal fees from Bristol-Myers Squibb and Pfizer. Dr. Pechoux has received personal fees from Astra Zeneca. Dr. Mezquita has received grants from Roche; and has received personal fees from Bristol-Myers Squibb, TecnoPharma, Roche, Astra Zeneca, and Chugai. Dr. Besse has received grants from AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Lilly, GlaxoSmithKline, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma. The remaining authors declare no conflict of interest. Disclosure: Dr. Flippot has received personal fees from Pfizer. Dr. Hendriks has received grants from Roche, Boehringer Ingelheim; and has received personal fees from Bristol-Myers Squibb, Roche, Quadia, and Boehringer Ingelheim; and has received nonfinancial support from Astra Zeneca. Dr. Le Rhun has received grants from Amgen and Mundi Pharma; and has received personal fees from Mundi Pharma, AbbVie, Daiichi Sankyo, and Novartis. Dr. Remon has received grants from Ose Immunotherapeutics; and has received personal fees from Osi Immunotherapeutics, MSD, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Astra Zeneca, and Roche. Dr. Adam has received grants from MSD, Sanofi, and Pierre Fabre; and has received personal fees from Astra Zeneca, Bristol-Myers Squibb, MSD, and Roche. Dr. Planchard has received personal fees from Astra Zeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Celgene, Novartis, Roche, and Pfizer. Dr. Lavaud has received personal fees from Pfizer. Dr. Caramella has received personal fees from Bristol-Myers Squibb and Pfizer. Dr. Pechoux has received personal fees from Astra Zeneca. Dr. Mezquita has received grants from Roche; and has received personal fees from Bristol-Myers Squibb, TecnoPharma, Roche, Astra Zeneca, and Chugai. Dr. Besse has received grants from AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Lilly, GlaxoSmithKline, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma. The remaining authors declare no conflict of interest. Funding Information: Disclosure: Dr. Flippot has received personal fees from Pfizer. Dr. Hendriks has received grants from Roche, Boehringer Ingelheim; and has received personal fees from Bristol-Myers Squibb, Roche, Quadia, and Boehringer Ingelheim; and has received nonfinancial support from Astra Zeneca. Dr. Le Rhun has received grants from Amgen and Mundi Pharma; and has received personal fees from Mundi Pharma, AbbVie, Daiichi Sankyo, and Novartis. Dr. Remon has received grants from Ose Immunotherapeutics; and has received personal fees from Osi Immunotherapeutics, MSD, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Astra Zeneca, and Roche. Dr. Adam has received grants from MSD, Sanofi, and Pierre Fabre; and has received personal fees from Astra Zeneca, Bristol-Myers Squibb, MSD, and Roche. Dr. Planchard has received personal fees from Astra Zeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Celgene, Novartis, Roche, and Pfizer. Dr. Lavaud has received personal fees from Pfizer. Dr. Caramella has received personal fees from Bristol-Myers Squibb and Pfizer. Dr. Pechoux has received personal fees from Astra Zeneca. Dr. Mezquita has received grants from Roche; and has received personal fees from Bristol-Myers Squibb, TecnoPharma, Roche, Astra Zeneca, and Chugai. Dr. Besse has received grants from AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Lilly, GlaxoSmithKline, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma. The remaining authors declare no conflict of interest. Publisher Copyright: © 2019 International Association for the Study of Lung Cancer
PY - 2019/8
Y1 - 2019/8
N2 - Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [ CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first-and second-generation TKI experienced clinical benefit.Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
AB - Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [ CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first-and second-generation TKI experienced clinical benefit.Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
KW - NSCLC
KW - EGFR
KW - Tyrosine kinase inhibitor
KW - Leptomeningeal metastases
KW - CELL LUNG-CANCER
KW - DOSE WEEKLY ERLOTINIB
KW - BRAIN METASTASES
U2 - 10.1016/j.jtho.2019.05.007
DO - 10.1016/j.jtho.2019.05.007
M3 - Article
C2 - 31108248
SN - 1556-0864
VL - 14
SP - 1400
EP - 1407
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 8
ER -