Epidermal growth factor receptor tyrosine kinase inhibitor for treating EGFR mutation positive non-small cell lung cancer with brain metastasis

Abstract

The invention discloses treatment of EGFR mutation positive non-small cell lung cancer brain metastasis by administering an effective dose of an EGFR inhibitor. The EGFR inhibitor is N-(2-((2-(dimethylamine) ethyl) (methyl) amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl) pyrimidine-N '-2-yl) amine) phenyl) acrylamide mesylate.

Description

Technical Field

[0001] This application generally falls within the pharmaceutical field, specifically relating to the treatment of EGFR mutation-positive non-small cell lung cancer (such as brain metastases of non-small cell lung cancer) by administering an effective dose of an EGFR inhibitor, wherein the EGFR inhibitor is N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide. Background Technology

[0002] Lung cancer is the most common primary malignant tumor of the lung. It originates from the epithelial cells of the bronchial or bronchiolar bronchioles. From a pathological and therapeutic perspective, it can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 80%–85% of cases. Histologically, it can be classified into subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma according to the 2021 WHO classification of lung tumors. Common oncogenic driver genes detected by molecular biology include EGFR, ALK, ROS1, and RET. EGFR mutation is the most common type of lung cancer gene mutation in Asian populations, accounting for approximately 50%.

[0003] Brain metastasis in EGFR-mutant non-small cell lung cancer (NSCLC) is a life-threatening disease that severely impacts quality of life and is one of the most common distant metastases in advanced lung cancer. The incidence of brain metastasis is approximately 20% in newly diagnosed NSCLC patients, and as high as 57% in advanced NSCLC. During disease progression, approximately 20%-40% of patients develop brain metastases. The incidence of brain metastasis is even higher in lung cancer patients with driver gene positivity; evidence suggests that the incidence is 39.2% in EGFR-mutant patients and 28.2% in wild-type patients. Brain metastasis in EGFR-mutant advanced lung adenocarcinoma is as high as 44%-63%. Brain metastases include parenchymal and meningeal metastases. The most common site of parenchymal metastasis is the cerebral hemispheres, followed by the cerebellum and brainstem. Clinical manifestations of parenchymal brain metastases mainly include common increased intracranial pressure and specific focal symptoms and signs. Increased intracranial pressure primarily manifests as headache, vomiting, and papilledema, and may also include decreased vision, altered consciousness, and urinary and fecal incontinence; symptoms often progressively worsen. Early-stage metastatic tumors near the functional areas of the cerebral hemispheres may present with local irritation symptoms, while late-stage metastatic tumors may present with neurological dysfunction symptoms, including (1) mental symptoms: manifested as slow reaction, dementia, etc.; (2) epileptic seizures; (3) sensory disturbances; (4) motor disturbances: manifested as weakness of contralateral limbs or muscles or complete upper motor neuron paralysis; (5) aphasia; (6) visual field defects. Cerebellar metastases clinically manifest as limb coordination disorders, difficulty walking, and backward tilting when standing, etc. Brainstem metastases mostly present with crossed paralysis. In addition to common symptoms, lung cancer brain metastases may cause increased blood pressure, slowed pulse, and in severe cases, brain herniation due to tumor compression may lead to respiratory arrest, endangering the patient's life.

[0004] Currently, treatments for brain metastases from EGFR mutation-positive non-small cell lung cancer can alleviate symptoms, prolong life, and improve quality of life. These treatments include local and systemic therapies, such as surgery, whole-brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), chemotherapy, and targeted therapy. Surgery and radiation therapy (RT) have long been the standard treatments for brain metastases. Surgical resection requires a comprehensive assessment of the number, size, and location of tumors, as well as the patient's overall condition. Since brain metastases are typically advanced-stage, surgical selection requires even greater caution. WBRT has some control effect on subclinical intracranial lesions, but due to dose limitations in normal brain tissue, it is difficult to completely cure intracranial lesions. Approximately one-third of patients with brain metastases do not experience control of intracranial lesions after WBRT, and some even develop new intracranial metastases during the WBRT process. About 50% of patients with brain metastases die from progression of intracranial lesions. The median survival time for untreated brain metastases is less than 3 months. Reports indicate that the median survival time for patients receiving WBRT is only extended to 4-6 months, while increasing the risk of cognitive impairment and reducing quality of life. Chemotherapy drugs or first / second-generation EGFR TKIs (tyrosine kinase inhibitors) have limited blood-brain barrier penetration, resulting in limited efficacy against intracranial lesions. Studies of third-generation EGFR-TKIs (including osimertinib, ametinib, and vormetinib) have not calculated sample sizes for the brain metastasis subgroup, lacking sufficient statistical power to draw conclusive conclusions on this subgroup. Each of these methods has one or more drawbacks, such as lack of efficacy, severe side effects, and low patient compliance. Therefore, better methods for treating brain metastases in EGFR mutation-positive non-small cell lung cancer are needed. Summary of the Invention

[0005] One or more embodiments of this application provide the use of N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of brain metastases in EGFR mutation-positive non-small cell lung cancer.

[0006] In one or more embodiments, the EGFR mutation-positive non-small cell lung cancer brain metastasis is either an EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis or an EGFR-insensitive mutation-positive non-small cell lung cancer brain metastasis.

[0007] In one or more embodiments, the EGFR-sensitive mutation-positive non-small cell lung cancer brain metastases are either EGFR-sensitive mutation-positive non-small cell lung cancer brain metastases that have not previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer, or EGFR-sensitive mutation-positive non-small cell lung cancer brain metastases that have previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer.

[0008] In one or more embodiments, the EGFR-insensitive mutation-positive non-small cell lung cancer brain metastases are either EGFR-insensitive mutation-positive non-small cell lung cancer brain metastases in patients who have not previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer, or EGFR-insensitive mutation-positive non-small cell lung cancer brain metastases in patients who have previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer.

[0009] In one or more embodiments, the systemic antitumor treatment is a first- or second-generation EGFR tyrosine kinase inhibitor or other systemic antitumor treatment.

[0010] In one or more embodiments, the EGFR tyrosine kinase inhibitor is gefitinib, erlotinib, icotinib, afatinib, or dacomitinib.

[0011] In one or more embodiments, the other systemic antitumor treatment is chemotherapy.

[0012] In one or more embodiments, the EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis is either an EGFR exon 19 deletion mutation-positive non-small cell lung cancer brain metastasis or an EGFR exon 21 L858R mutation-positive non-small cell lung cancer brain metastasis.

[0013] In one or more embodiments, the EGFR 19 exon deletion mutation-positive non-small cell lung cancer brain metastasis refers to non-small cell lung cancer brain metastasis that is either EGFR 19 exon deletion mutation-positive alone or coexisting with other EGFR site mutations.

[0014] In one or more embodiments, the EGFR21 exon L858R mutation-positive non-small cell lung cancer brain metastasis refers to non-small cell lung cancer brain metastasis with EGFR21 exon L858R mutation alone or in coexistence with other EGFR site mutations.

[0015] In one or more embodiments, the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof is administered in combination with other anticancer drugs.

[0016] In one or more embodiments, the other anticancer drugs are platinum-based drugs and / or pemetrexed.

[0017] In one or more embodiments, the platinum-based drug is cisplatin or carboplatin.

[0018] In one or more embodiments, the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof is administered in combination with brain radiotherapy.

[0019] In one or more embodiments, the brain radiotherapy is whole-brain radiotherapy (WBRT) and / or stereotactic radiotherapy (SRS).

[0020] In one or more embodiments, the pharmaceutically acceptable salt is a methanesulfonate.

[0021] In one or more embodiments, EGFR-insensitive mutation-positive non-small cell lung cancer brain metastases are EGFR gene mutation-positive non-small cell lung cancer brain metastases other than EGFR exon 19 deletion and exon 21 L858R mutation.

[0022] One or more embodiments of this application provide a method for treating brain metastases of EGFR mutation-positive non-small cell lung cancer and other related diseases and conditions by administering an effective dose of an EGFR inhibitor.

[0023] One or more embodiments of this application provide methods for preventing and / or treating brain metastases from EGFR mutation-positive non-small cell lung cancer, comprising administering to a subject in need a therapeutically effective amount of N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof.

[0024] One or more embodiments of this application provide N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof, which is used as a medicament.

[0025] One or more embodiments of this application provide N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of brain metastases in EGFR mutation-positive non-small cell lung cancer.

[0026] In one or more embodiments, the structure of N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide methanesulfonate is as follows:

[0027]

[0028] In one or more embodiments, the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide methanesulfonate is prepared as an oral formulation, an injectable formulation, or a topical formulation.

[0029] In one or more embodiments, the oral preparation may be a tablet, capsule, or powder.

[0030] In one or more embodiments, the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide methanesulfonate is prepared as a tablet (without other active ingredients, hereinafter referred to as "the tablet of this application").

[0031] In one or more embodiments, the term "treatment" and its derivatives refer to preventive treatment or therapeutic treatment. Preventive treatment is appropriate, for example, when a patient is considered to be at high risk of developing cancer or cancer metastasis.

[0032] In one or more embodiments, the terms “treatment,” “therapeutic effective amount,” or their derivatives, unless otherwise defined, refer to an amount sought by, for example, an investigator or clinician, to elicit a biological or medical response in a tissue, system, animal, or human. Furthermore, the term “therapeutic effective amount” refers to any amount that results in improved treatment, healing, prevention, reduction in severity, or improvement of cancer compared to a corresponding patient who did not receive that amount.

[0033] In one or more embodiments, the tablets of this application may also be used to treat cancers for which the precipitating factors are unknown or must be identified, and a skilled physician will be able to determine the appropriate circumstances for administration of this application (where the patient is susceptible to or at risk of, for example, cancer or cancer metastasis).

[0034] In one or more embodiments, the terms "co-administration," "common administration," or their derivatives refer to the simultaneous or sequential administration, in any way, of the epidermal growth factor receptor tyrosine kinase inhibitor and one or more other anticancer active ingredients described herein, including, for example, simultaneous administration or administration at close intervals. Furthermore, it is not important whether they are administered in the same dosage form; for example, one compound may be administered orally while another compound may be administered by injection. The active ingredients are known to be used for the treatment of cancer, including chemotherapy and radiation therapy.

[0035] In one or more implementations, the terms "object" or "patient" can refer to mammals, such as humans. Attached Figure Description

[0036] Figure 1 This is a waterfall plot showing the change in the sum of the longest diameters of intracranial target lesions relative to the baseline in Example 1.

[0037] Figure 2 This is a spider diagram showing the changes in the sum of the longest diameters of intracranial target lesions relative to the baseline in Example 1, where different colors represent different subjects.

[0038] Figure 3 This is a swimlane plot of the overall assessment of intracranial tumors over time in Example 1.

[0039] Figure 4 This is a waterfall plot showing the change in the sum of the longest diameters of target lesions throughout the body relative to the baseline in Example 1.

[0040] Figure 5 This is a spider diagram showing the changes in the sum of the longest diameters of target lesions throughout the body relative to the baseline in Example 1, where different colors represent different subjects.

[0041] Figure 6 This is a lane diagram of the whole-body overall assessment-time in Example 1.

[0042] Figure 7 The waterfall plot of the total long diameter of the intracranial target lesion relative to the baseline in Example 2 is shown (cEFR (CNSevaluable-for-response set), which is a set of efficacy analyses of brain metastasis patients with measurable brain metastases who have received at least two tumor assessments).

[0043] Figure 8 This is a spider plot (cEFR) showing the percentage change in the total long diameter of the intracranial target lesion compared to the baseline in Example 2.

[0044] Figure 9 This is a pool diagram (cEFR) for evaluating the overall efficacy of intracranial tumor treatment in Example 2.

[0045] Figure 10 This is a waterfall plot (cEFR) showing the best change in the sum of the long diameters of the target lesions throughout the body compared to the baseline in Example 2.

[0046] Figure 11 This is a spider plot (cEFR) showing the percentage change in the total long diameter of the target lesions throughout the body compared to the baseline in Example 2.

[0047] Figure 12 This is a pool diagram (cEFR) for evaluating the overall efficacy of systemic tumor treatment in Example 2.

[0048] Among them, CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = inevaluable. Detailed Implementation

[0049] Example 1: Clinical study on the efficacy and safety of the tablet formulation of this application in treating EGFR mutation-positive NCSLC brain metastases.

[0050] Scheme Design

[0051] This protocol is a single-arm, open-label, multicenter phase II clinical trial in China to evaluate the efficacy and safety of the tablet formulation applied for in treating patients with brain metastases from EGFR-sensitive mutation-positive non-small cell lung cancer.

[0052] This study plans to recruit 30-40 patients with brain metastases (BM). Patients with EGFR-sensitive mutation-positive non-small cell lung cancer (NSCLC) with brain metastases who have not previously received systemic antitumor therapy or whose disease has progressed after receiving systemic antitumor therapy with first- or second-generation EGFR TKIs and who are T790M mutation-positive are eligible. The dosage is 160 mg once daily for 21 consecutive days as one cycle, until disease progression, meeting the criteria for discontinuation of treatment, withdrawal criteria, or study termination (whichever occurs first). The primary endpoints are intracranial objective response rate (iORR) and extracranial objective response rate (eORR). Secondary endpoints include overall objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).

[0053] Data statistics

[0054] In the BM group, 22 subjects completed at least two tumor assessments (20 of whom were patients who had not previously received systemic antitumor therapy, and 2 of whom had disease progression and were T790M mutation positive after previous systemic antitumor therapy with 1st / 2nd generation EGFR TKIs). Data showed that all 22 patients achieved effective remission of intracranial tumors, with 20 patients (90.9%) achieving partial remission (PR) and 2 patients (9.1%) achieving complete remission (CR). The confirmed intracranial objective response rate (iORR) was 100% (22 / 22, 95% CI: 84.56-100.00), and the median depth of intracranial response was 62.0%. Meanwhile, 20 patients (90.9%) achieved partial response (PR) based on systemic tumor assessment, and 2 patients (9.1%) had stable disease (SD). The overall objective response rate (ORR) was 90.9% (20 / 22, 95% CI: 70.84-98.88), and the disease control rate was 100% (22 / 22, 95% CI: 84.56-100.00). See details. Figure 1-6 .

[0055] The tablets described in this application did not generate any new safety signals, and no related deaths occurred; overall safety is manageable.

[0056] in conclusion

[0057] This study confirms that the tablets described in this application are effective for brain metastases of EGFR-sensitive mutation-positive non-small cell lung cancer that have progressed after receiving systemic antitumor therapy or systemic antitumor therapy with 1st / 2nd generation EGFR TKIs and have a T790M mutation.

[0058] Example 2: Safety, tolerability, pharmacokinetics, and pharmacodynamics of the tablet formulation of this application in treating EGFR mutation-positive NCSLC patients (including patients with baseline brain metastases).

[0059] Scheme Design

[0060] This study is a phase I clinical trial in patients with advanced NSCLC who are EGFR mutation-positive (including EGFR-sensitive and insensitive mutations) and have progressed after failure of previous systemic antitumor therapy or standard therapy with first- or second-generation EGFR TKIs and are T790M mutation-positive. The study is divided into two phases: Phase Ia (dose escalation) and Phase Ib (dose expansion). Phase Ia consists of six dose groups: 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, and 200 mg once daily, with a planned enrollment of 16–36 subjects. Phase Ib consists of three expansion dose groups: 80 mg, 120 mg, and 160 mg once daily, with a planned enrollment of 10–30 subjects in each group. Dosing is administered for 21 consecutive days as one cycle, until disease progression, meeting of discontinuation criteria, withdrawal criteria, or study termination (whichever occurs first). The aim is to determine the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of the tablet formulation described in this application for the treatment of EGFR mutation-positive advanced NSCLC patients, as well as its preliminary antitumor efficacy.

[0061] Data statistics

[0062] In the Phase Ib extension study, a total of 36 patients with EGFR-sensitive mutation NSCLC brain metastases who had not previously received systemic antitumor therapy were observed. 7, 19, and 10 patients, respectively, received 80 mg, 120 mg, and 160 mg of the tablets described in this application once daily (9 of the 36 patients had measurable intracranial lesions, of whom 2 received 120 mg of the tablets described in this application once daily and 7 received 160 mg of the tablets described in this application once daily).

[0063] Of the 36 patients with brain metastases, 7 patients in the 80mg dose group and 10 patients in the 160mg dose group achieved partial remission (PR) in systemic tumor assessment, with an overall objective response rate (ORR) of 100%. In the 120mg dose group, 18 of the 19 patients with brain metastases achieved PR, with an overall ORR of 94.7%. A total of 35 patients across the three dose groups achieved PR in systemic tumor assessment, resulting in an overall ORR of 97.2% (35 / 36).

[0064] After two cycles of treatment with the drug described in this study, all 36 patients with brain metastases showed varying degrees of reduction in systemic target lesions compared to baseline, with the first remission achieved in 6 weeks. The remission deepened further with prolonged treatment, with a median depth of systemic tumor response of 53%. Among the 36 patients, 18 remained in continuous remission, with the longest duration of remission being approximately 22 months.

[0065] Of the 36 patients with measurable intracranial brain metastases, 2 (22.2%) achieved complete remission (CR) of the intracranial lesions, and the remaining 7 (77.8%) achieved partial remission (PR) based on intracranial tumor assessment. All 9 patients also achieved PR based on systemic efficacy assessment, resulting in a confirmed intracranial objective response rate (iORR) and an overall objective response rate (ORR) of 100%. The median depth of response for intracranial tumors was 64%, and the median depth of response for systemic tumors was 55%. See appendix for details. Figure 7-12 .

[0066] In the phase Ib extension study, a patient with a T790M mutation-positive EGFR-sensitive mutation who had experienced disease progression after failure of standard treatment with first- or second-generation EGFR TKIs received 160 mg of the tablets described in this application once daily. The patient's systemic tumor assessment indicated partial response (PR).

[0067] In the phase Ib extension study, four patients with EGFR-insensitive mutation NSCLC brain metastases who had not previously received systemic antitumor therapy were observed (EGFR exon 21 L861Q mutation, EGFR exon 21 L861Q mutation, EGFR exon 18 G719X combined with exon 20 S768I mutation, and EGFR exon 21 L861Q mutation combined with exon 20 insertion, respectively). Two patients from each group received 120 mg and 160 mg of the tablets described in this application once daily. In the 120 mg dose group, the two patients with brain metastases achieved partial response (PR) and stable disease (SD), respectively, while in the 160 mg dose group, both patients achieved partial response (PR).

[0068] The tablets described in this application did not generate any new safety signals, and no related deaths occurred; overall safety is manageable.

[0069] The tablets in this application are administered orally, but the absorption and elimination rates are slow, and the time T for the parent drug to reach peak plasma concentration is short. max The half-life (t1 / 2) is greater than 50 hours (4-6 hours). After continuous administration for 15-21 days, the plasma concentrations of both the parent drug and metabolites reach steady-state levels, with some degree of accumulation. At doses between 20 mg and 200 mg, the C60 of both the parent drug and metabolites... max AUC increases with increasing dose.

[0070] in conclusion

[0071] This study confirms that the tablets described in this application are effective for brain metastases of EGFR-sensitive or non-sensitive mutation-positive non-small cell lung cancer that have progressed after failure of previous systemic antitumor therapy or standard treatment with 1st / 2nd generation EGFR TKIs and have T790M mutation positivity.

Claims

1. Use of N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of brain metastases in EGFR mutation-positive non-small cell lung cancer.

2. The use as described in claim 1, wherein the EGFR mutation-positive non-small cell lung cancer brain metastasis is either EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis or EGFR-insensitive mutation-positive non-small cell lung cancer brain metastasis.

3. The use as described in claim 2, wherein the EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis is either EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis in patients who have not previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer, or EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis in patients who have previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer.

4. The use as described in claim 2, wherein the EGFR-insensitive mutation-positive non-small cell lung cancer brain metastasis is either EGFR-insensitive mutation-positive non-small cell lung cancer brain metastasis in which the patient has not previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer, or EGFR-insensitive mutation-positive non-small cell lung cancer brain metastasis in which the patient has previously received systemic antitumor therapy for locally advanced or metastatic non-small cell lung cancer.

5. The use as described in claim 3 or 4, wherein the systemic antitumor treatment is a first- or second-generation EGFR tyrosine kinase inhibitor or other systemic antitumor treatment.

6. The use as described in claim 5, wherein the EGFR tyrosine kinase inhibitor is gefitinib, erlotinib, icotinib, afatinib, or dacomitinib; preferably, the other systemic antitumor treatment is chemotherapy.

7. The use as described in claim 2, wherein the EGFR-sensitive mutation-positive non-small cell lung cancer brain metastasis is an EGFR exon 19 deletion mutation-positive non-small cell lung cancer brain metastasis or an EGFR exon 21 L858R mutation-positive non-small cell lung cancer brain metastasis; preferably, the EGFR exon 19 deletion mutation-positive non-small cell lung cancer brain metastasis is an EGFR exon 19 deletion mutation-positive non-small cell lung cancer brain metastasis with or without other EGFR site mutations; preferably, the EGFR exon 21 L858R mutation-positive non-small cell lung cancer brain metastasis is an EGFR exon 21 L858R mutation-positive non-small cell lung cancer brain metastasis with or without other EGFR site mutations.

8. The use as claimed in claim 1, wherein the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof is administered in combination with other anticancer drugs; preferably, the other anticancer drugs are platinum-based drugs and / or pemetrexed; more preferably, the platinum-based drugs are cisplatin or carboplatin.

9. The use as claimed in claim 1, wherein the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide or a pharmaceutically acceptable salt thereof is administered in combination with brain radiotherapy; preferably, the brain radiotherapy is whole-brain radiotherapy (WBRT) and / or stereotactic radiotherapy (SRS).

10. The use as claimed in any one of claims 1-9, wherein the pharmaceutically acceptable salt is a methanesulfonate.

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