Data from real world to evaluate the efficacy of osimertinib in non-small cell lung cancer patients with central nervous system metastasis

Clinical and Translational Oncology https://doi.org/10.1007/s12094-019-02071-5 RESEARCH ARTICLE Data from real world to evaluate the efficacy of osimertinib in non‑small cell lung cancer patients with central nervous system metastasis P. Xing1 · Y. Mu1 · X. Hao1 · Y. Wang1 · J. Li1 Received: 5 December 2018 / Accepted: 23 February 2019 © The Author(s) 2019 Abstract Objectives Central nervous system (CNS) metastases are very common in patients with non-small-cell lung cancer (NSCLC). We aimed to explore the clinical impact of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on CNS metastases in patients with advanced NSCLC in real-world setting. Methods Patients with advanced NSCLC who received osimertinib after progression of early-generation EGFR-TKIs and CNS metastases on baseline brain scan were retrospectively collected. Primary outcomes were disease control rate (DCR) and progression-free survival (PFS), and secondary objectives were objective response rate (ORR), time to tumor response, median best percentage change from baseline in CNS target lesion (TL) size and safety. Results Between Apr 1, 2017, and Dec 30, 2017, 22 patients met selection criteria, 15 with ≥ 1 measurable CNS lesion (RECIST 1.1) were included in CNS evaluable for response (cEFR) set. Among the 22 patients, ORR and DCR were 40.9% and 86.4%, respectively, with median PFS of 8.5 months (95% CI 4.1, 13.0). Median intracranial PFS was not reached. Of 15 patients in cEFR set, CNS DCR was 80.0% with complete response reported in 3 patients (20.0%). Median best percentage change from baseline in CNS TL size was − 40% (range − 100 to + 60%) and median time to CNS tumor response was 1.3 months. CNS ORR was 53.3%. The safety profile was acceptable and no new unexpected findings were found. Conclusion This real-world analysis further confirmed that osimertinib indeed demonstrated clinically meaningful efficacy against CNS metastases in Chinese patients with advanced NSCLC. Keywords Osimertinib · Non-small cell lung cancer · Central nervous system · Brain metastases · Efficacy Introduction Central nervous system (CNS) metastases, such as leptomeningeal metastasis (LM) and brain metastasis (BM), are very common in non-small cell lung cancer (NSCLC) patients and are associated with a significant neurological deficit [1]. CNS metastases accounts for 10–15% at the time of P. Xing and Y. Mu have contributed equally to this work and should be considered co-first authors. * J. Li ; 1 National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Number 17 Panjiayuan Nan Li, Chao Yang District, Beijing 100021, China diagnosis and affects 30–50% of NSCLC patients throughout the course of the disease [2]. For advanced NSCLC patients with epidermal growth factor receptor (EGFR) activating mutations, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib, erlotinib, and afatinib are now considered to be standard first-line therapy based on evidence from several trials [3–5]. Although several researchers have demonstrated a certain activity of first- or second-generation EGFR-TKIs in EGFR-mutated NSCLC patients with CNS metastases [6], it was demonstrated that EGFR + NSCLC patients have a much higher risk of developing CNS metastases [7]. Treatment options for CNS metastases during or after first- or second-generation EGFR-TKIs include surgical resection, stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT) and chemotherapy, but with severe adverse effects or limited inability to cross the blood–brain barrier (BBB) [8–11]. These observations suggest that a drug with much better 13 Vol.:(0123456789) Clinical and Translational Oncology CNS penetration and acceptable safety profile is needed to effectively treat patients with CNS metastases. Osimertinib is a third-generation EGFR-TKI, which inhibits both EGFR and T790M mutations [12]. It demonstrated greater penetration of the BBB than gefitinib or afatinib in preclinical studies [13], and promising intracranial efficacy in patients with advanced NSCLC from several large-scale randomized control trials [14–16]. Among advanced NSCLC patients who have progressed on early-generation EGFR-TKI treatment, the CNS objective response rate (ORR) from those trials range from 50 to 70%, which showed significantly greater efficacy than chemotherapy [17]. However, there was lack of real-world evidence to illustrate the effectiveness and safety of osimertinib on the CNS metastases. Therefore, we retrospectively assessed the real-world clinical impact of osimertinib on CNS metastases in patients with advanced NSCLC in our cancer center. Materials and methods Data source and study population Patients with advanced NSCLC who received osimertinib after progression of early-generation EGFR-TKIs and CNS metastases were retrospectively collected in our cancer center between Apr 1, 2017, and Dec 30, 2017. Eligible patients were required to have histologically or cytologically confirmed NSCLC, stage IV cancer based on the AJCC Cancer Staging Manual (7th Edition) with CNS metastatic lesion on baseline brain CT or MRI scan, treated with osimertinib after progression of early-generation EGFR-TKIs and/or chemotherapy. And only patients with ≥ 1 measurable lesion on baseline brain scan were included in CNS evaluable for response (cEFR) set. A total of 22 patients met selection criteria, and 15 were included in the cEFR set. Assessments Primary outcomes were disease control rate (DCR) and progression-free survival (PFS), and secondary objectives were ORR, time to tumor response, median best percentage change from baseline in the sum of CNS target lesion (TL) size and safety. Disease response to treatment and tumor shrinkage was assessed according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria (version 1.1). DCR was defined as the occurrence of complete response (CR), partial response (PR), or stable disease (SD) ≥ 6 weeks, while ORR pointed to CR or PR. PFS was defined as the time interval from the start of the treatment until progressive disease (PD) or death from any other causes, whichever occurs first. Time to tumor response refers to the time from the date of first dose until first response. 13 CNS response evaluation of cEFR set included evaluable metastatic lesions in the brain only, regardless of extracranial response. Adverse events (AEs) were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Statistics analysis Statistical analyses were carried out by the SPSS 23.0 statistical software (SPSS, Inc., Chicago, IL, USA) and alpha = 0.05 was used as significant level for all statistical testing. The distribution of patients’ baseline demographic/ clinical characteristics and treatment patterns were (...truncated)