Erlotinib 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 (LM) during or after treatment with a tyrosine kinase inhibitor (TKI). Findings supporting second-line TKI therapy in these patients were presented at the European Lung Cancer Congress (ELCC) 2018, held 11 to 14 April in Geneva, Switzerland.
The development of LM in patients with NSCLC is associated with poorer outcomes. Although TKIs are known to have activity in patients with EGFR mutated NSCLC and LM, the optimal management of these patients following failure of TKI treatment is unknown, according to Ronan Flippot, Medical Oncology, Gustave Roussy in Villejuif, France.
This study was conducted in 66 consecutive patients with EGFR mutated NSCLC who experienced LM progression during first-line EGFR TKI treatment at the Institute Gustave Roussy and Lille University Hospital from April 2003 to September 2016. LM progression was defined as a diagnosis of LM made during TKI treatment or progression of known LM after first-line TKI.
The patients´ clinical and pathological 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 non-smokers. The patients had received a median of 2 (range 1 to 7) previous lines of treatment and 19 (29%) patients had also received intrathecal treatment. Genetic analysis revealed that 23 (35%) of the patients´ tumours had exon 19 deletion, 23 (35%) tumours harboured L858R exon 21 mutation, and 10 (15%) tumours showed T790M mutation.
Second-line TKIs had been administered to 36 (55%) patients after LM progression; of these, treatment comprised erlotinib in 19 (53%) patients, 10 (28%) were treated with high dose erlotinib at 300 mg daily, 3 patients received osimertinib, and 4 patients received other first- or second-generation TKIs.
Median OS following second-line TKI was improved with erlotinib
In patients treated with second-line TKI, the median PFS from the time of LM 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 TKIs. Patients treated with second-line erlotinib were mostly pretreated by afatinib or gefitinib (79%), and had better OS compared to patients treated with other first- or second-generation TKI after LM progression (hazard ratio 0.28, p = 0.0237). Prolonged survival was also reported with osimertinib in 3 patients harbouring T790M mutation, in which the median OS was NR (95% CI 6, NR).
Figure 1. Survival of patients with NSCLC who received second-line EGFR-TKI after leptomeningeal progression.
NSCLC: non-small cell lung cancer, TKI: tyrosine kinase inhibitor, HD Erlotinib: Erlotinib 300mg daily
Survival of patients with NSCLC who received second-line EGFR-TKI after leptomeningeal progression. NSCLC: non-small cell lung cancer, TKI: tyrosine kinase inhibitor, HD Erlotinib: Erlotinib 300mg daily. © Ronan Flippot.
Of the 9 (25%) patients alive at 10 months, 6 had received erlotinib, one 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 and demonstrated a CRR of 40% and DCR of 60%.
Dr Els Wauters, who discussed the poster, said that the data are very interesting. In general, only a little prospective randomised data are available for EGFR TKIs in CNS disease. Care of these patients should be individualised within a multidisciplinary approach. The choice of treatment should be driven by symptoms/extent of CNS disease, treatment line, site(s) of progression, drug delivery to CNS and molecular profile of tumour.
Conclusions: Based on these findings, the investigators were able to conclude that second-line treatment with a TKI can increase survival in patients with LM and EGFR mutated NSCLC that had previously been treated with a TKI.
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.
Disclosure: No external funding was disclosed.
Reference
144PD – Flippot R, Auclin E, Biondani P, et al. Leptomeningeal metastases in EGFR-mutated non-small cell lung carcinoma: Management after tyrosine kinase inhibitors.