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

Patients diagnosed with advanced ALK+NSCLC who had baseline CNS metastases before the administration of alectinib were included from six hospitals in China from 2017 to 2020. MRI scans for intracranial lesions and CT scans for extracranial lesions at baseline and during the follow-up period were required; symptoms caused by BM were not mandatory, and patients could have received no or one or more prior ALK-TKIs before the initiation of alectinib; and prior CNS radiotherapy or surgery was allowed if the aforementioned criteria were met. Patients included in this study were divided into three cohorts based on the treatment history before the initiation 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 patients who developed progression only in CNS following treatment with other second-generation ALK inhibitors (ceritinib, CT707, WX-0593) were classified into cohort 3. The data cutoff date was June 1, 2021.

The definition and evaluation of intracranial or extracranial lesions were based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In other words, up to five target lesions (≥ 1 cm) in the whole body and up to two target lesions (≥ 1 cm) in each organ were included; ic-ORR, intracranial disease control rate, extracranial objective response rate (ex-ORR), and extracranial disease control rate were recorded; when taking intracranial and extracranial lesions together, overall objective response rate (o-ORR) and overall disease control rate were recorded; tumor shrinkage rate in CNS target lesions was also analyzed. The extent of improvement in CNS-related symptoms was mainly based on the subjective report from patients, which could be categorized into four different levels (significant improvement, moderate improvement, no improvement, deterioration); performance status and the proportions of patients who were in need of mannitol or corticosteroids before or after the initiation of alectinib were also recorded. Intracranial oligo-progression was defined as progression in one to three brain lesions, while patients who developed progression in more than three BMs were deemed as having intracranial multi-progression. Radiological assessment was obtained at baseline and then every 1 to 3 months.

Statistical analysis was conducted using the SPSS 26.0 statistical software (SPSS, Inc., Chicago, IL, USA). The distribution of patients and baseline demographic/clinical characteristics were described using frequency analysis. Objective response rate or disease control rate was estimated with 95% confidence interval (CI) based on the exact binomial distribution. Intracranial duration of response (ic-DOR) was defined as the time from the first CNS response (complete response [CR] + partial response [PR] in CNS target lesions and CR in CNS nontarget lesions) until CNS progression. CNS time to progression (CNS TTP) was calculated from the start date of administration of alectinib until CNS progression. Progression-free survival (PFS) was calculated from the start date of alectinib until progression or any death event. Overall survival (OS) was calculated from the start date of alectinib to any death event. Differences among groups were compared using Fisher exact test for categorical data and t-tests for continuous data. The survival curves were estimated using the Kaplan-Meier method, while differences in the variables were calculated using the log-rank test. A two-sided p value < 0.5 was considered statistically significant.

From July 2017 to September 2020, 65 patients (cohort 1: n = 20, cohort 2: n = 30, cohort 3: n = 13) with baseline CNS metastases treated with alectinib from six hospitals in China were included in our study. Patients’ baseline characteristics are described in Table 1. In each cohort, 11, 17, and 7 patients were found to have CNS target lesions; meanwhile, the median sums of maximum diameter of CNS target lesions were 2.7 cm (range 1 cm, 5.3 cm), 2.4 cm (range 1.2 cm, 5.1 cm), and 1.7 cm (range 1 cm, 3.2 cm) respectively. In each cohort, 8 (40%), 14 (43.7%), and 6 (46.2%) patients, respectively, were reported to develop symptoms attributable to CNS metastases. Headache (n = 22), dizziness (n = 13), vomiting (n = 12), and fatigue (n = 12) were more common, while hemiplegia (n = 2), diplopia (n = 1), and tinnitus (n = 1) were less frequently reported in these patients. In total, nine patients were diagnosed with LM with or without BM, of whom eight were reported to experience CNS-related symptoms. A total of 13 patients received brain radiotherapy or brain surgery before the initiation of alectinib; however, most patients enrolled in our study had uncontrolled CNS metastases before treatment with alectinib (cohort 1: n = 19, cohort 2: n = 30, cohort 3: n = 12) (uncontrolled CNS metastases meant: CNS metastases were not treated before the administration of alectinib or progressed following prior targeted therapy or local treatment). Extracranial lesions were found in 12, 29, and 12 patients in each cohort, respectively.

The ic-ORR was 55% (4CR + 7PR), 53.1% (6CR + 11PR), and 38.5% (3CR + 2PR) in patients with or without CNS target lesions in each cohort, respectively (Table 2), and all patients reached disease control in CNS. In these three cohorts, 81.8% (2CR + 7PR), 76.5% (2CR + 11PR), and 42.8% (1CR + 2PR) of patients with CNS target lesions achieved CNS response, respectively, the median intracranial tumor shrinkage rate was 53% (range 0%, 100%), 58% (range 14%, 100%), 28% (range 0%, 100%) in these patients (Fig. 1). At the time of data cutoff, CNS TTP was NE, 33.0 m (95% CI: 15.8–50.2 m), and NE in these three cohorts separately, with a median follow-up of 19.2 months (95% CI: 17.7–20.8 m), 22.5 months (95% CI: 18.8–26.1 m), and 15.8 months (95% CI: 10.1–21.6 m), respectively (Fig. 2a). Furthermore, ic-DOR was NE in the three cohorts with median follow-up of 18.7 months (95% CI: 17.0–20.3 m), 22.7 months (95% CI: 20.5–25.0 m), and 16.8 months (95% CI: 16.1–17.4 m), respectively (Fig. 2b). Figure 3 demonstrates typical examples of radiological changes in patients with symptomatic BM.

The ic-ORR was 52.6% (4CR + 6PR), 56.7% (6CR + 11PR), and 33.3% (2CR + 2PR) in each cohort and all patients achieved disease control in CNS. For patients with CNS target lesions in these three cohorts, 80% (2CR + 6PR), 86.7% (2CR + 11PR), and 33.3% (2PR) of them were reported to have CNS response; in the meantime, median intracranial tumor shrinkage rate was 55% (range 0%, 100%), 58% (range 14%, 100%), and 26% (range 0%, 80%) in these patients (Table 3). In total, 21 patients (21/25, 84%) experienced significant improvement in CNS-related symptoms following the treatment with alectinib, of whom 13 patients (13/17, 76.5%) had BM and 8 (8/8, 100%) had LM ± BM. With a median follow-up of 19.0 months (95% CI: 16.6–21.4 m), 22.6 months (95% CI: 20.4–24.8 m), and 12.3 months (95% CI: 5.0–19.6 m), CNS-TTP in patients with uncontrolled CNS metastases was NE, 33.0 months (95% CI: 15.7–50.3 m), NE (Fig. 2c).

Of 28 patients reported to have symptoms attributable to CNS metastases, 20 patients had symptomatic BM and 8 patients were diagnosed with symptomatic LM. Three patients who had received radiotherapy (RT) right before the initiation of alectinib were deemed to have controlled CNS metastases. Therefore, most patients (25/28) had uncontrolled CNS metastases before the administration of alectinib. For each cohort, 75% (6/8), 78.6% (11/14), and 83% (5/6) of patients experienced significant improvement in CNS-related symptoms (Table 4); the remaining proportion of these patients (2/8, 3/13, 1/6) was reported to have at least no deterioration in symptoms, and out of them, further salvage RT was only needed in two patients. Mannitol or corticosteroids were needed to alleviate symptoms in 18 patients before the initiation of alectinib, whereas only three patients were still in need of these drugs a half-month after the administration of alectinib; therefore, the number of patients who were in need of these drugs decreased remarkably following the treatment with alectinib (as was shown in the Fisher test p < 0.001) (Table 5). Over 70% of patients experienced improvement in ECOG by at least one point following the treatment with alectinib; furthermore, ECOG improved by two points was seen in one-fifth of patients with CNS-related symptoms (Table 6). Similarly, there was also a steep fall-over in the number of patients with ECOG ≥ 2 points before and after the administration of alectinib (as was shown in the Fisher test p = 0.003) (Table 7).

Nine patients were diagnosed with LM (four patients with LM, five patients with LM + BM), of whom seven patients presented with typical clinical symptoms and linear enhancement in MRI at the time of diagnosis, one patient only had linear enhancement in MRI without CNS-related symptoms, while another one patient was found to have tumor cells in CSF without typical manifestation in MRI. All patients had uncontrolled CNS metastases before the initiation of alectinib. A complete 100% (8/8) of patients were reported to have significant improvement in CNS-related symptoms; furthermore, all patients (7/7) were no longer in need of mannitol or corticosteroids following the administration of alectinib, and seven patients experienced improvement in ECOG by at least one point (Tables 8 and 9). With a median follow-up of 16.8 months (95% CI: 4.1–28.7 m), CNS-TTP for patients with LM was 408d (Additional file 1: Fig. S1).

In this part of the analysis, patients with LM and patients with controlled BM were excluded (cohort 1: n = 15, cohort 2: n = 28). In cohort 1, poor performance status (ECOG ≥ 2: 50% vs 0%, p = 0.057), measurable CNS lesions (100% vs 36.4%, p = 0.077), and multiple BM (≥ 4: (100% vs 27.3%, p = 0.026) were more often seen in patients with symptomatic BM (Additional file 2: Table S1a). No statistically significant difference was showed in CNS-TTP between patients with symptomatic and asymptomatic BM in cohort 1 (p = 0.394, HR = 3.1, 95% CI: 0.12–79.0) (Fig. 4a). In cohort 2, baseline characteristics were also described in Additional file 2: Table S1b; similarly, patients with symptomatic BM were found to have poor performance status (ECOG ≥ 2: 50% vs 11.1%, p = 0.063), measurable CNS lesions (70% vs 44.4%, p = 0.254), and multiple BM (90% vs 38.9%, p = 0.016) more frequently. Likewise, there was also no statistically significant difference in CNS-TTP between patients with symptomatic and asymptomatic BM in cohort 2 (p = 0.168, HR = 2.24, 95% CI: 0.65–7.7) (Fig. 4b).

In this part of the analysis, patients with LM and patients with controlled BM were excluded. Included patients were further categorized into two groups (≥ 4 BM vs 1–3 BM) in cohorts 1 and 2. No statistically significant difference was demonstrated in CNS-TTP between patients with different numbers of BM (cohort 1: NE vs NE, p = 0.0925, HR undefined; cohort 2: 33.5 m vs NE, p = 0.316, HR = 1.9, 95% CI: 0.58–6.4) (Additional file 1: Fig. S2).

The ex-ORR was 83.3%, 24.1%, and 33.3% in patients with or without extracranial target lesions and nearly all patients achieved disease control in extracranial lesions, with only one patient in cohort 2 evaluated as PD. For patients with extracranial target lesions, 90.9%, 50%, and 66.7% of patients demonstrated response. Taken together, o-ORR was found to be 70%, 53.1%, and 30.8% in each cohort (Additional file 2: Table S2). At the time of data cutoff, in these three cohorts, 5, 17, and 6 patients were reported to develop progression events. In cohort 1, three patients experienced intracranial progression, while another two patients had extracranial progression; in cohort 2, eight patients developed progression only in CNS, while six patients experienced extracranial progression, and three patients had intracranial and extracranial progression simultaneously; in cohort 3, two patients experienced CNS progression while four patients were reported to have extracranial progression; intracranial oligo-progression was the main progression pattern for patients who developed CNS progression (11/14). No patient died in cohort 1 while 5 death events related to tumor progression or complications were confirmed in cohort 2; in cohort 3, one patient committed suicide and the other died of myocardial infarction without evidence of a progression event, while another death event was relevant to tumor progression (Additional file 2: Table S3). PFS and OS in the three cohorts are described in Additional file 1: Fig. S3.