First-line osimertinib for leptomeningeal metastasis from lung adenocarcinoma with EGFR mutation as the initial and solitary site of postoperative recurrence

Abstract

Leptomeningeal metastasis (LM) from lung cancer has poor prognosis, and effective therapy has not been established. We present the case of a 54-year-old man with LM from lung adenocarcinoma harboring EGFR L858R point mutation, who received osimertinib as first-line therapy. He had previously undergone left lower lobectomy and lymph node dissection for lung adenocarcinoma. Five years and 9 months after the operation, he developed symptoms of dizziness, lightheadedness, and headache. Magnetic resonance imaging showed high signal intensity in the cerebral sulcus and meninges, and cerebrospinal fluid (CSF) cytology indicated adenocarcinoma with EGFR L858R point mutation, which suggested LM. After CSF drainage and administration of corticosteroid and glycerol, the patient received osimertinib (80 mg/day) as first-line therapy. These symptoms including dizziness, lightheadedness, and headache were relieved and the MRI appearance was normal, and he survived for 19 months with no disease progression. Osimertinib is considered to be an effective therapeutic option for LM from lung adenocarcinoma harboring EGFR mutation.

Introduction

EGFR mutation is one of the major driver mutations in lung adenocarcinoma and is known to be a therapeutic target. However, therapy has not been established for leptomeningeal metastasis (LM) from lung adenocarcinoma with EGFR mutation. To date, the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have been effective for LM with EGFR mutation [1, 2]. The third-generation EGFR-TKI osimertinib has been effective as second-line therapy for LM with EGFR T790M mutation [3]. We present a case of LM from lung adenocarcinoma harboring EGFR mutation that received osimertinib as first-line therapy.

Case

A 54-year-old man with a history of smoking was referred to our hospital for X-ray examination of a thoracic mass (Fig. 1a). Computed tomography (CT) scan showed a 10-mm nodule in the left lower lung lobe (Fig. 1b), and positron emission tomography—CT scan demonstrated high accumulation of fluorodeoxyglucose, with maximum standardized uptake value of 2.7 (Fig. 1c). Although a malignant growth was not diagnosed by bronchoscopy, we performed video-assisted, left lower lobectomy (ND2a-1) because of the possibility of lung cancer. The postoperative pathological diagnosis was invasive adenocarcinoma, papillary predominant type with stage IA1, harboring EGFR L858R point mutation (Fig. 1d).

Fig. 1.

Preoperative images and postoperative pathological findings. a Chest X-ray; b computed tomography (CT); c positron emission tomography–CT; and d hematoxylin–eosin staining of the tumor. Scale bar: 100 µm

He was followed up regularly at our hospital with no recurrence. However, he noticed dizziness, lightheadedness, and headache, and consulted another hospital at 69 months after surgery. Gadolinium-enhanced magnetic resonance imaging (MRI) showed diffuse hyperintensity in the cerebral sulcus and meninges (Fig. 2a). Cerebrospinal fluid (CSF) drainage was performed, and immunohistochemical staining of CSF showed thyroid transcription factor-1 (Fig. 2b). The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method revealed EGFR L858R point mutation. Therefore, the patient was diagnosed with recurrent lung adenocarcinoma with LM but no brain metastasis. A second cerebrospinal fluid drainage was performed, and dexamethasone (13.2 mg/day) and glycerol (400 ml/day) were administered for decompression. At the same time, osimertinib (80 mg/day) was administered as first-line therapy for recurrent lung adenocarcinoma harboring EGFR mutation. The symptoms including dizziness, lightheadedness, and headache disappeared within a few weeks, and gadolinium-enhanced MRI confirmed that high signals in the sulci and meninges disappeared within 2 and 4 months after administration of osimertinib (Fig. 2c and d). He did not have any recurrence of symptoms and was alive at 19 months after initiation of osimertinib. Figure 3 summarizes the clinical timeline of the patient.

Fig. 2.

Magnetic resonance imaging a before and c 2 and d 4 months after initiation of osimertinib. Arrowheads indicate high signal intensity in cerebral sulcus and arrows show leptomeningeal metastatic lesion. b Positive cytological staining for thyroid transcription factor-1 in cerebrospinal fluid, indicating metastasis from lung cancer

Fig. 3.

Clinical timelines of this patient

Discussion

This patient was diagnosed with postoperative LM from lung adenocarcinoma harboring EGFR mutation, and treated with the third-generation EGFR-TKI osimertinib. His symptoms of dizziness, headache, and wobble disappeared, and MRI features returned to normal soon after administration of osimertinib.

Although lung adenocarcinoma with EGFR mutation has been treated by EGFR-TKIs [4, 5], LM from lung cancer is known to have poor prognosis [6]. It is reported that the incidence of LM from lung adenocarcinoma with EGFR mutation is higher than that from lung adenocarcinoma without EGFR mutation [7]. Kwon et al. reported that most patients with LM already had other metastases, including brain, bone, and pleura [8]. The time of occurrence of postoperative LM was not clear in our patient, and in this rare case, LM was the initial and solitary site of postoperative metastasis.

There is no curative treatment for LM, but there are some reports that EGFR-TKIs may have some therapeutic effect on LM from lung adenocarcinoma harboring EGFR mutation (Table 1) [9-13, 3, 14, 15]. It is also reported that the third-generation TKI osimertinib might have an antitumor effect on LM from lung adenocarcinoma with EGFR mutation. The BLOOM and AURA3 trials demonstrated that osimertinib prolonged median progression-free survival of patients with central nervous system metastasis from lung adenocarcinoma harboring EGFR mutation that had become resistant to prior EGFR-TKI [16]. According to subset analysis of the FLAURA trial, osimertinib prolonged median progression-free survival compared with first-generation EGFR-TKI in patients with central nervous system lesions including LM (not reached versus 13.9 months; hazard ratio, 0.48; 95% CI 0.26–0.86; p = 0.014) [17].

Table 1.

Summary of the previous reports about outcome of the patients with leptomeningeal metastasis treated by osimertinib as second-line TKI

Author	N	T790M positive	Pre EGFR-TKI	Outcome
Chalmers A et al. Lung cancer. 2017; 114: 68–9 [9]	1	Negative	Erlotinib	PFS; 12 months
Niu H et al. Rep Oncol. 2017; 10: 840–5 [10]	1	Positive	Gefitinib	PFS; 12 months
Sakai H et al. ESMO Open. 2017; 2: e000104 [11]	1	Positive	Gefitinib and subsequently erlotinib	PFS; 7 weeks
Takeda T et al. Respiro Case Rep. 2017; 5: e00241 [12]	1	Positive	Gefitinib and subsequently erlotinib	PFS; 10 months
Chen J et al. Chin Clin Oncol. 2019; 8: 29 [13]	1	Positive	Erlotinib	PFS; 12 months
Nanjo S et al. Br J Cancer. 2018; 118: 32–7 [3]	13	2 Patients	Unknown	Median PFS; 7.2 months
Yang JCH et al. J Clin Oncol. 2020; 38: 538–547 [14]	41	20 Patients	Gefitinib: 31 patients Erlotinib: 7 patients Afatinib: 2 patients Dacomitinib: 1 patients	Median PFS; 8.6 months
Ahn MJ et al. J Thorac Oncol. 2020; 15: 637–48 [15]	22	22 Patients	Unknown	Median PFS; 11.1 months

EGFR epidermal growth factor receptor, PFS progression-free survival, TKI tyrosin kinase inhibitor

There are two factors that may contribute to the antitumor effect of osimertinib on LM. First, the molecular structure of osimertinib. Osimertinib has a pyrimidine structure in contrast to the first- and second-generation EGFR-TKIs [18]. EGFR-TKIs such as gefitinib and erlotinib usually bind to the ATP pocket of EGFR and exert their antitumor effect by inhibiting signal transduction [18]. Although the first- and second-generation EGFR-TKIs have reduced specificity for EGFR with the T790M mutation, osimertinib maintains its high specificity, because the pyrimidine structure irreversibly binds to EGFR [18]. Second, high permeability across the blood–brain barrier is important. It has been reported that osimertinib showed higher CSF transferability than first- or second-generation EGFR-TKI (brain/plasma concentration maximum ratio; osimertinib: 3.41, afatinib: < 0.36) [19], and another study reported that osimertinib had a stronger antitumor effect than erlotinib in a mouse model of LM [20]. Therefore, owing to its molecular structure and permeability, osimertinib may have stronger antitumor efficacy than first- or second-generation EGFR-TKI for LM from lung adenocarcinoma harboring EGFR mutation, and we selected osimertinib as first-line therapy for this patient.

In conclusion, we present a case of LM from lung adenocarcinoma harboring EGFR mutation treated with first-line osimertinib. Osimertinib may have a greater antitumor effect than gefitinib, erlotinib, and afatinib on LM from lung adenocarcinoma harboring EGFR mutation.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest in relation to this article.