Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study

Abstract

Background: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings.

Methods: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1.

Results: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone.

Conclusions: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Keywords: ALK-positive non-small cell lung cancer; Alectinib; Brain metastases; Central nervous system metastases; Leptomeningeal metastases.

Fig. 1

Tumor shrinkage rate in CNS target lesions; 11, 17, and 7 patients had CNS target lesions in these three cohorts respectively; median intracranial tumor shrinkage rate was 53% (range 0, 100%), 58% (range 14%, 100%), and 28% (range 0, 100%)

Fig. 2

a CNS time to progression in three cohorts. With a median follow-up of 19.2 months, 22.5 months, and 15.8 months in these three cohorts respectively, CNS TTP was NE vs 33.0 m vs NE. b Intracranial duration of response in three cohorts. With median follow-up of 18.7 months, 22.7 months, and 16.8 months in these three cohorts respectively, ic-DOR was NE vs NE vs NE. c CNS TTP in patients with uncontrolled CNS metastases. With a median follow-up of 19.0 months, 22.6 months, and 12.3 months in these three cohorts respectively, CNS TTP was NE vs 33.0 m vs NE

Fig. 3

Typical examples in patients treated with alectinib. A Patient 1 who received first-line alectinib experienced significant alleviation in headache. B Headache and dizziness disappeared in patient 2 who received alectinib after the progression of crizotinib. C Headache and vomiting were largely improved in patient 3 who developed CNS progression following the treatment of ceritinib

Fig. 4

a CNS TTP in patients with symptomatic and asymptomatic BM in cohort 1. CNS TTP for patients with symptomatic BM and patients with asymptomatic BM in cohort 1was NE vs NE, p = 0.394, HR = 3.1(95% CI: 0.12 to 79.0). b CNS TTP in patients with symptomatic and asymptomatic BM in cohort 2. CNS TTP for patients with symptomatic BM and patients with asymptomatic BM in cohort 2 was 21.5 m vs NE, p = 0.168, HR = 2.24 (95% CI: 0.65 to 7.7)