Ronan Flippot1, Pamela Biondani2, Edouard Auclin3, Dingyu Xiao4, Lizza Hendriks5, Emilie Le Rhun6, Charlotte Leduc7, Michèle Beau-Faller8, Radj Gervais4, Jordi Remon1, Julien Adam9, David Planchard1, Pernelle Lavaud1, Charles Naltet1, Caroline Caramella10, Cécile Le Pechoux11, Ludovic Lacroix12, Anas Gazzah1, Laura Mezquita1, Benjamin Besse13. 1. Department of Medical Oncology, Gustave Roussy, Villejuif, France. 2. Department of Medical Oncology, Paul Brousse Hospital, Villejuif, France. 3. Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France. 4. Department of Medical Oncology, Centre François Baclesse, Caen, France. 5. Department of Medical Oncology, Gustave Roussy, Villejuif, France; Department of Pulmonary Diseases, GROW - School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, Netherlands. 6. University of Lille, Lille, France; Neuro-oncology, General and Stereotaxic Neurosurgery Department, Lille University Hospital, Lille, France; Breast Cancer Department, Oscar Lambret Center, Lille, France; Department of Neurology & Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland. 7. Department of Pneumology, Strasbourg University Hospital, Strasbourg, France. 8. Department of Molecular Biology, Strasbourg University Hospital, Strasbourg, France. 9. Department of Pathology, Gustave Roussy, Villejuif, France. 10. Department of Radiology, Gustave Roussy, Villejuif, France. 11. Department of Radiotherapy, Gustave Roussy, Villejuif, France. 12. Department of Molecular Biology, Gustave Roussy, Villejuif, France. 13. Department of Medical Oncology, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address: benjamin.besse@gustaveroussy.fr.
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.
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.
Authors: Janna Josephus Anna Oda Schoenmaekers; Marthe Sentijna Paats; Anne-Marie Clasina Dingemans; Lizza Elisabeth Lucia Hendriks Journal: Transl Lung Cancer Res Date: 2020-12