ELCC 2018: Second-Line Tyrosine Kinase Inhibitor Therapy Demonstrates Clinical Benefit in EGFR-Mutated NSCLC With Leptomeningeal Metastasis
Erlotinib (Tarceva) or high-dose erlotinib provides benefit in patients with epidermal growth factor receptor (EGFR) mutated non–small cell lung cancer (NSCLC) who develop leptomeningeal metastasis during or after treatment with a tyrosine kinase inhibitor. Findings supporting second-line tyrosine kinase inhibitor therapy in these patients were presented by Flippot et al at the European Lung Cancer Congress (ELCC), in Geneva, Switzerland (Abstract 144PD).
The development of leptomeningeal metastasis in patients with NSCLC is associated with poorer outcomes. Although tyrosine kinase inhibitors are known to have activity in patients with EGFR-mutated NSCLC and leptomeningeal metastasis, the optimal management of these patients following failure of tyrosine kinase inhibitor treatment is unknown, according to Ronan Flippot, MD, of Gustave Roussy in Villejuif, France.
This study was conducted in 66 consecutive patients with EGFR-mutated NSCLC who experienced leptomeningeal metastasis progression during first-line EGFR tyrosine kinase inhibitor treatment at the Institute Gustave Roussy and Lille University Hospital from April 2003 to September 2016. Leptomeningeal metastasis progression was defined as a diagnosis of leptomeningeal metastasis made during tyrosine kinase inhibitor treatment or progression of known leptomeningeal metastasis after first-line tyrosine kinase inhibitor.
The patients’ clinical and pathologic data were retrospectively collected and the investigators assessed overall survival (OS), progression-free survival (PFS), clinical response rate (CRR), and disease control rate (DCR) following second-line treatment. The DCR was defined as clinical response or stable disease lasting > 2 months.
The median age of the patients was 54 (range 26 to 79) years. Fifty-one (77%) patients were female and 56 (85%) were nonsmokers. The patients had received a median of 2 (range, 1–7) previous lines of treatment and 19 (29%) patients had also received intrathecal treatment. Genetic analysis revealed that 23 (35%) of the patients’ tumors had exon 19 deletion, 23 (35%) tumors harbored L858R exon 21 mutation, and 10 (15%) tumors showed T790M mutation.
Second-line tyrosine kinase inhibitors had been administered to 36 (55%) patients after leptomeningeal metastasis progression; of these, treatment comprised erlotinib in 19 (53%) patients. Ten (28%) were treated with high-dose erlotinib at 300 mg daily, 3 patients received osimertinib (Tagrisso), and 4 patients received other first- or second-generation tyrosine kinase inhibitors.
Findings
In patients treated with a second-line tyrosine kinase inhibitor, the median PFS from the time of leptomeningeal metastasis progression was 3 months (95% confidence interval [CI] = 2–3) and median OS was 7 months (95% CI = 3–10). The CRR was 43% and the DCR was 77%.
The median OS was 8 months (95% CI 7, 10) with second-line erlotinib, 2 months (95% CI 1,5) with high-dose erlotinib, and 2 months (95% CI = 0–2) in patients treated with other first- or second-generation tyrosine kinase inhibitors. Patients treated with second-line erlotinib were mostly pretreated by afatinib (Gilotrif) or gefitinib (Iressa; 79%), and had better OS compared to patients treated with other first- or second-generation tyrosine kinase inhibitor after leptomeningeal metastasis progression (hazard ratio = 0.28, P = .0237). Prolonged survival was also reported with osimertinib in 3 patients harboring T790M mutation, in which the median OS was NR (95% CI = 6 to NR).
Of the 9 (25%) patients alive at 10 months, 6 had received erlotinib, 1 had been treated with high-dose erlotinib, and 2 patients received osimertinib.
Eighty percent of patients receiving high-dose erlotinib had received prior erlotinib as first-line therapy and demonstrated a CRR of 40% and DCR of 60%.
Conclusions
Based on these findings, the investigators were able to conclude that second-line treatment with a tyrosine kinase inhibitor can increase survival in patients with leptomeningeal metastasis and EGFR-mutated NSCLC that had previously been treated with a tyrosine kinase inhibitor. They further concluded that erlotinib administered after prior gefitinib or afatinib is a suitable treatment strategy and that clinical benefit in this patient population could also be attained by increasing the erlotinib dose in the second line.
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