Efficacy and safety of osimertinib for leptomeningeal metastases from EGFR-mutant non-small cell lung cancer: a pooled analysis

Leptomeningeal metastases (LM), the spread of tumor cells into the leptomeninges and cerebrospinal fluid, represents one of the most deleterious complications of advanced non-small cell lung cancer (NSCLC) [1]. LM is associated with dismal prognosis due to poor response to cytotoxic agents and radiation treatment [2]. Of note, with emergence of modern treatment options such as targeted therapy and immunotherapy, considerably prolonged survival was achieved in patients with NSCLC. Owning to the rapid advances in imaging techniques and particularly tyrosine kinase inhibitors (TKIs) for patients harboring epidermal growth factor receptor (EGFR) mutations, recent years saw increasing incidence of LM from NSCLC [3].

Osimertinib is a third-generation EGFR TKI that inhibits both EGFR sensitizing and T790M mutations in NSCLC. Compared with first- and second-generation EGFR TKIs, osimertinib is more effectively cross the blood–brain barrier (BBB) and therefore with a superior cerebrospinal fluid (CSF) plasma concentration [4]. The phase III FLAURA study demonstrated higher efficacy of osimertinib compared to gefitinib or erlotinib for advanced NSCLC patients harboring EGFR-sensitizing mutations, including patients with central nervous system (CNS) metastases [5, 6]. However, the FLAURA study included only five patients with LM but not the patients with unstable neurological conditions. The AURA LM study reported the activity of osimertinib (80 mg) for the treatment of LM from NSCLC in a retrospective pooled analysis of four prospective studies within the AURA program (AURA extension, AURA2, AURA17, and AURA3) [7]. The included 22 LM patients, and the LM objective response rate (ORR), median LM progression-free survival (PFS) and overall survival (OS) were 55%, 11.1 months, and 18.8 months, respectively. The phase I BLOOM study evaluated the efficacy and safety of double dosage of osimertinib (160 mg qd) in forty-one NSCLC patients with LM [8]. The LM ORR assessed by the Response Assessment in Neuro-Oncology LM (RANO-LM) criteria was 62%. The median investigator-assessed PFS was 8.6 months, and the median OS was 11.0 months. Preliminary conclusions from these studies outlined a promising role of osimertinib for the treatment of LM from EGFR-mutant (EGFRm) NSCLC.

Nevertheless, many published articles or meeting abstracts on osimertinib for the treatment of LM from NSCLC enrolled a relatively small number of patients (< 50 patients in most studies), which weakens the persuasiveness of the conclusions from a single study. Furthermore, those studies vary in study design (prospective versus retrospective), dosages (80 mg versus 160 mg), race (Asian versus Caucasian), or LM response assessment criteria (RANO-LM versus Response Evaluation Criteria in Solid Tumors (RECIST)). Herein, an aggregate analysis of the currently available reports is highly demanded to clarify the role of osimertinib in management of LM from EGFRm NSCLC. In our study, we synthesized the outcomes from different studies with a particular focus on LM ORR, LM DCR, PFS, OS, and AEs, providing more insights for the optimal clinical use of osimertinib. This systematic review and meta-analysis was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [9].

In this pooled analysis, we included 11 studies consisting of 353 patients, and the pooled results showed that the ORR, DCR, and one-year OS rate of osimertinib for the treatment of EGFR-mutant NSCLC with LM were 42% (95% CI 24% to 59%), 93% (95% CI 88% to 97%), and 59% (95% CI 53% to 65%), respectively. The ORR data were numerically lower than another pooled study of osimertinib for advanced NSCLC with metastasis to any site (ORR 79%, 95% CI 75–84%) [21], and lower than two meta-analyses of osimertinib for NSCLC with CNS metastases (mainly brain metastases, ORR was 64% and 70%, respectively) [11, 22]. Nonetheless, considering the refractory characteristics of LM, an ORR of 42% was acceptable or even satisfactory when compared with cytotoxic agents, radiotherapy or first- and second-generation EGFR TKIs [23‐25].

The incidence of LM is considerably higher in EGFR-mutated NSCLC patients than EGFR wild-type ones (9.4% vs. 1.7%, P < 0.001) [26]. The third-generation TKI osimertinib was a favorable treatment option for patients with LM after resistance to first- or second-generation EGFR TKIs for two reasons. First of all, osimertinib is effective against the EGFR T790M mutation, which accounts for approximately 50% of the resistance from first- or second-generation EGFR TKIs [27]. Secondly, osimertinib is associated with a superior blood–brain barrier penetration capacity than other EGFR TKIs [6, 28]. Notably, disease progression in many patients was confined to LM with stable extracranial disease attributing to the poor penetration ability of gefitinib or erlotinib to the CNS system; whereas osimertinib is particularly highlighted for these patients. For treatment-naïve NSCLC LM patients, osimertinib is also recommended as an effective first-line treatment. In the FLAURA study, five patients in the osimertinib arm with LM, four of whom had a complete radiographic response and one had radiographic non-CR, non-PD response [6].

Whether increased doses (e.g., 160 mg) could enhance the efficacy of osimertinib for LM is indeed a question deserves further discussions. In a phase II study including forty NSCLC patients with LM treated with 160 mg osimertinib, a 92.5% disease control rate and 12.5% complete response rate according to RECIST 1.1, a median PFS of 8.0 months, and median OS of 13.3 months were reported [14]. These data were encouraging and repeated by the BLOOM phase I study (ORR 62%, DCR 78%, PFS 8.6 months, and OS 11.0 months). The clinical use of osimertinib 80 mg once daily in patients with LM is effective and widely recommended. A retrospective study from Zheng et al. reported an LM ORR of 38.2% (13/34), and the median intracranial PFS was 15.6 months for EGFR T790M mutation patients who received 80 mg Osimertinib [16]. The AURA phase I study compared a wide range of osimertinib doses (20–240 mg) but did not reveal significant difference in efficacy, e.g., 80 mg vs. 160 mg [29]. In our subgroup analysis, the pooled ORR was 47% for patients treated with 80 mg osimertinib, compared with 37% for patients treated with 160 mg osimertinib. To be noticed, studies of osimertinib 80 mg were either retrospective cohorts or studies with a small number of subjects (n = 13), or retrospective analyses of FLAURA and AURA series, which included only LM patients with stable neurological conditions. Further prospective studies for dosage specified efficacy and safety profiles of osimertinib are highly warranted.

The tolerance and safety are critical issues for NSCLC patients with LM since many patients have neurological impairment symptoms and progressively worsening. In our pooled analysis, rash (53%) and diarrhea (45%) of any grades were the most frequently reported AEs induced by osimertinib. This is in accordance with another meta-analysis on osimertinib for the treatment of advanced NSCLC with metastasis to any site (42% rash, 44% diarrhea). In the present study, pneumonia (5%) was the most frequently reported grade 3 or higher AE. No new safety concerns were identified in this study. No osimertinib-related death event was reported in the 4 included studies. The BLOOM study reported that all patients had at least 1 AE, 27 patients (66%) had an AE grade of 3 or higher, and 10 (24%) had AEs possibly causally related to osimertinib, as judged by the investigator. EGFR TKI-induced intestinal lung disease and pneumonia were frequent fatal AEs in a study based on 53 cohorts of 9569 participants [30].

Several limitations must be appreciated in this study. Among the first was the relatively small patient size in most included studies. Ten out of eleven included studies enrolled less than 50 patients. Second, all included studies were retrospective (n = 6) or phase I/II prospective (n = 5) studies, and no phase III randomized control trials were currently available. Third, the criteria of LM response assessment differed with different reports. Among the 11 studies, 3 studies defined treatment response by RANO-LM, 4 studies by RECIST or radiological response, and 4 studies did not report definitions of LM response. There is still a lack of suitable response assessment criteria for LM. RECIST is widely used for solid tumors; however, it is not appropriate for LM assessment since the presence of LM in imaging is usually linear but not bulk. RANO-LM was proposed to specifically evaluate the response assessment of LM in 2016 by incorporating several factors: standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation [31]. RANO-LM is superior to RECIST for the response assessment of LM however still needs to be optimized [32]. Fourth, a meta-analysis of median PFS and OS was not conducted due to insufficient data available. Although we have previously shown that EGFR-mutated LM patients are likely to gain limited benefits from WBRT [2], the potential role of osimertinib in combinations with other treatment modalities such as WBRT or intrathecal chemotherapy for specific EGFR-mutated patients was yet to be elucidated, i.e., co-existed with brain metastasis [33] or recurrent LM patients.

In conclusion, our systematic review and meta-analysis found that osimertinib showed meaningful CNS efficacy in terms of radiologic response and a manageable safety profile in patients with LM from EGFR-mutant NSCLC.