Author(s): Sehhoon Park, MD, PhD1; Richard Baldry, BSc2; Hyun Ae Jung, MD, PhD1; Jong-Mu Sun, MD, PhD1; Se-Hoon Lee, MD, PhD1; Jin Seok Ahn, MD, PhD1; Yu Jung Kim, MD, PhD2; Youngjoo Lee, MD, PhD3; Dong-Wan Kim, MD, PhD4; Sang-We Kim, MD, PhD5; Ki Hyeong Lee, MD, PhD6; Won Jae Lee, MD7; Jung Won Choi, MD, PhD7; Kyuha Chong, MD, PhD7; Jung-Il Lee, MD, PhD7; So-Hyeon Gwon, BS8; Nak-Hoon Son, PhD8; Myung-Ju Ahn, MD, PhD1
PURPOSE
Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs.
MATERIALS AND METHODS
In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6.
RESULTS
A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set—T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2.
CONCLUSION
The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.
Author Affiliations
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Clinical Pharmacology and Quantitative Pharmacology, Post Market and Lifecycle Management, AstraZeneca, Cambridge, United Kingdom; 2Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 3Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si Gyeonggi-do, Republic of Korea; 4Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; 5Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 6Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea; 7Department of Neurosurgery, Brain Tumor Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 8Department of Statistics, Keimyung University, Daegu, Republic of Korea
