Lung cancer is the most common of all malignant tumors worldwide (1, 2). The proportion of non-small cell lung cancer (NSCLC) in all lung cancer is about 80%, and 30% − 43% of patients will have brain metastasis (BM) in the process of the disease (3–5). The proportion of small cell lung cancer (SCLC) in all lung cancer is about 15% − 20%, in which about 80% of SCLC patients will have BM in the process of the disease (4–6). The prognosis of lung cancer patients with BM is poor, and the median survival time (mOS) of patients that do not receive treatment is only 1–3 months (1, 3).
In recent years, significantly improved prognosis has been achieved for lung cancer patients by treatment using small molecular targeted tyrosine kinase inhibitors (TKIs) to target anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and C-ros oncogene 1-receptor tyrosine kinase (ROS1) (1, 3, 7–10). Patients with BM from NSCLC receiving these treatments also showed significantly improved survival. The response rate of brain lesions from NSCLC BM patients with EGFR mutation to first generation TKIs reached 60.0% − 80.0%, with complete remission (CR) rate of 40.0% and mOS of 15–20 months (11). A meta-analysis study also showed that the first generation TKIs had significant effect on BM in patients with EGFR/ALK gene mutations, with median progression free survival (mPFS) of 7.4 months and mOS of 11.9 months (7, 12). Compared with first generation TKIs, second generation TKIs such as afatinib can simultaneously inhibit several ErbB family members (including EGFR, ErbB3, ErbB4, and human epidermal growth factor receptor-2) (13). The use of afatinib for initial treatment of advanced NSCLC patients is better than use for gefitinib with increased time to treatment failure (TTF), median duration of response (mDOR), and progression free survival (PFS) (12–15). However, the ability of afatinib to cross the blood-brain barrier (BBB) to reach the effective concentration in the central nervous system has not been demonstrated (16).
In patients with the EGFR T790M mutation, the distribution of osimertinib (AZD9291) in brain tissue was significantly higher than that of the first and second generation EGFR/ALK-TKIs (17, 18). AURA3 trial was a phase III clinical study, which tested AZD9291 (80 mg/d) vs standard dual drug chemotherapy (containing platinum), and found that AZD9291 significantly prolonged PFS (mPFS: 11.7 vs 5.6 months; hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.15–0.69; p = 0.004), with objective response rate (ORR) of the central nervous system of 70% vs 31% for AZD9291 treatment vs standard dual drug chemotherapy, respectively (19). In FLAURA trial, the intracranial CR rate of AZD9291-treated BM patients with NSCLC was 18%, with 88% of patients experiencing remission times of more than half a year (20). However, for advanced NSCLC and SCLC patients with non-gene mutation or resistance to EGFR/ALK-TKIs, alternative TKIs are not available, so it is urgent to develop specific targeted drugs.
Anlotinib hydrochloride was independently developed in China as a new orally administered, multi-target TKI (21). Anlotinib can inhibit tumor cell proliferation and tumor angiogenesis by inhibiting tumor related kinases, such as VEGFR, FGFR, PDGFR α/β, c-kit, and RET (22, 23). The ALTER1202 trial was a double-blind, randomized, multicenter, phase II clinical trial involving 119 NSCLC patients with measurable lesions and no gene mutation, who were treated with at least two chemotherapy regimens but progressed or relapsed. A total of 81 patients were included in the anlotinib group and the remaining patients received placebo treatment. Of the 119 patients, the mPFS of the anlotinib group was 4.1 months (95% CI 2.8–4.2) and that of the placebo group was 0.7 months (95% CI 0.7–0.8). The HR of tumor recurrence was reduced by 80.8% for the anlotinib treatment group, and this difference was statistically significant (HR 0.192, 95% CI 0.117–0.315, p < 0.0001). The mOS was 7.3 months for the anlotinib group (95% CI 6.5–10.5) and 4.9 months for the placebo group (95% CI 2.6–6.7), with a statistically significant 47.2% reduction in the death risk (HR 0.528, 95% CI 0.304–0.918, p = 0.021) (24). Moreover, ALTER1202 was also study the the treatment effects of anlotinib for third- and further-line treatment of SCLC (anlotinib group 46 patients, placebo group 22 patients), it indicated the mPFS of anlotinib group vs placebo group (4.1 vs 0.7 months, HR 0.19, 95% CI 2.4–5.8, p < 0.0001), and mOS of anlotinib group vs placebo group (7.3 vs 4.9 months, HR 0.53, 95% CI 0.34–0.81, p < 0.0029) (25).
The ALTER0302 trial was a double-blind, randomized, multicenter, phase II clinical trial with 117 enrolled patients. The patients had received two or more chemotherapy regimens, and EGFR/ALK gene mutation positive patients had received at least two chemotherapy regimens after EGFR/ALK-TKIs treatment (21, 26). The patients were randomized into two groups at a ratio of 1:1. The PFS of the anlotinib group (mPFS: 4.8 months, 95% CI 3.5–6.4) was significantly better than that of the placebo (mPFS: 1.2 months, 95% CI 0.7–1.6) (21, 26).
The ALTER0303 double-blind, randomized, phase III clinical trial included 31 medical centers in China. A total of 437 advanced NSCLC patients were included in the trial, and were randomly allocated into the placebo group (n = 143) or the anlotinib group (n = 294) at a ratio of 1:2. These results showed that anlotinib prolonged the mOS by 3.3 months (9.6 vs 6.3 months, HR 0.68, 95% CI 0.54–0.87, p = 0.0018) and the mPFS by 4.0 months (5.4 vs 1.4 months, HR 0.25, 95% CI 0.19–0.31, p < 0.0001) (27–29). In the ALTER0303 trial, the efficacy of anlotinib for the treatment of BM was also evaluated, as 97 (22.2%) patients had BM at baseline. For these patients with BM at baseline, the mPFS for anlotinib treatment was 4.17, considerable higher than the 1.3 months for placebo treatment, and 8.57 for mOS for anlotinib treatment compared to 4.55 months for placebo treatment. The patients in the anlotinib group had a longer time to brain progression (TTBP) than the placebo group, indicating that anlotinib delays the progression of intracranial lesions from advanced NSCLC patients (30). The exploratory subgroup analysis of the ALTER0303 trials showed that patients with either EGFR gene mutation or wild-type exhibited improved PFS and OS with anlotinib treatment (27, 28, 30). Related clinical studies show that both NSCLC and SCLC can significantly prolong PFS and OS (25–28, 30). Therefore, in May 2018 and June 2019, China Food and Drug Administration (CFDA) officially approved anlotinib for single drug treatment for the third-line or higher treatment of advanced NSCLC patients and SCLC patients with non-gene mutation or EGFR/ALK-TKIs resistance.
Clinical studies have confirmed that anlotinib can effectively treat some patients with advanced lung cancer, including patients with BM (27, 28, 30). However, for NSCLC patients with no gene mutation or EGFR/ALK-TKIs resistance, as well as SCLC patients with BM, cranial radiotherapy (CRT) is still considered the standard treatment regime, as this treatment can quickly relieve central nervous system the symptoms and improve the survival time of patients (31). CRT can increase the permeability of the BBB, which may increase the content of anlotinib in brain tissue, so the curative effect of CRT combined with anlotinib may be better than that of CRT alone for NSCLC patients with no gene mutation or EGFR/ALK-TKIs resistance or for SCLC patients with BM (32, 33). In this study, we retrospectively analyzed the effects of CRT combined with anlotinib treatment compared with CRT alone for patients with lung cancer BM and multi-line chemotherapy failure or patients with EGFR/ALK-TKIs resistance or patients with non-EGFR/ALK mutations or intolerable chemotherapy.