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

Abstract

The present application discloses a treatment of EGFR mutation-positive non-small cell lung cancer with brain metastasis by administering an effective dose of an EGFR inhibitor. The EGFR inhibitor is N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-deuteriomethyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amino)phenyl)acrylamide methanesulfonate.

Description

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

[0001] The present application generally belongs to the field of medicine, and specifically relates to treating EGFR mutation-positive non-small cell lung cancer (such as non-small cell lung cancer brain metastasis) by administering an effective dose of an EGFR inhibitor, which is N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indole-3-yl)pyrimidine-N'-2-yl)amine)phenyl)acrylamide. BACKGROUND

[0002] Lung cancer is the most common primary malignant tumor of the lung, which is a primary malignant tumor from bronchial or bronchiolar epithelial cells. From the pathological and therapeutic perspectives, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Non-small cell lung cancer accounts for about 80% to 85%, and can be divided into histological subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma according to the 2021 edition of WHO lung tumor histological classification standard. Common oncogenic driver genes detected by molecular biology are EGFR, ALK, ROS1, RET, etc. EGFR mutation is the main lung cancer gene mutation type in Asian population, accounting for about 50%.

[0003] Brain metastasis from EGFR-mutant non-small cell lung cancer (NSCLC) is a disease that seriously affects the quality of life and threatens life, and is one of the most common distant metastases in advanced lung cancer. The incidence of brain metastasis in patients with newly diagnosed NSCLC is about 20%, and the incidence of brain metastasis in advanced NSCLC is as high as 57%. About 20%-40% of patients will develop brain metastasis during the progression of the disease. The incidence of brain metastasis in patients with lung cancer with driver gene is higher. There is evidence that the incidence of brain metastasis in patients with EGFR-mutant and wild-type is 39.2% and 28.2%, respectively. The incidence of brain metastasis in patients with EGFR-mutant advanced lung adenocarcinoma is as high as 44%-63%. Brain metastatic tumors include brain parenchymal metastases and meningeal metastases. The most common site of brain parenchymal metastases is the cerebral hemisphere, followed by the cerebellum and brainstem. The clinical manifestations of brain parenchymal metastases mainly include common intracranial hypertension, specific focal symptoms and signs. The main manifestations of intracranial hypertension are headache, vomiting, optic nerve head edema, and can also appear visual impairment, disturbance of consciousness, incontinence, etc. The symptoms often progress. Early metastases near the functional area of the cerebral hemisphere can cause local irritation symptoms, and late metastases can cause neurologic damage symptoms, including (1) mental symptoms: manifested as slow response, dementia, etc.; (2) seizures; (3) sensory disorders; (4) motor disorders: manifested as contralateral limb or muscle weakness or complete upper motor neuron paralysis; (5) aphasia; (6) visual field impairment. The clinical manifestations of cerebellar metastases are limb coordination disorders, walking difficulties, and standing backward, etc. Most brainstem metastases appear to be crossed paralysis. In addition to the common symptoms, lung cancer brain metastasis can also cause increased blood pressure, decreased pulse, and in severe cases, brain hernia due to tumor compression can cause respiratory arrest, endangering the patient's life.

[0004] Current treatments for EGFR mutation-positive non-small cell lung cancer brain metastasis can be used to alleviate symptoms and prolong patient life and improve quality of life. Such treatment methods include local treatment and systemic treatment, such as surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), chemotherapy, targeted therapy, etc. Surgery and radiation therapy (RT) have been the standard treatment for brain metastasis. Surgical resection requires comprehensive evaluation of tumor number, size, location, and patient overall condition, etc. factors, and brain metastasis patients are all in the advanced stage, so surgical selection needs to be more cautious. WBRT has a certain control effect on intracranial subclinical lesions, but due to the dose limit of normal brain tissue, it is difficult to eradicate intracranial lesions, and about 1 / 3 of brain metastasis patients have uncontrolled intracranial lesions after WBRT, and even some patients develop new intracranial metastases during WBRT. About 50% of brain metastasis patients die of intracranial lesion progression. Brain metastasis patients who have not received any treatment have a median survival time of less than 3 months. It has been reported that the median survival time of patients receiving WBRT is only extended to 4-6 months, while increasing the risk of cognitive dysfunction and reducing the quality of life of patients. Chemotherapy drugs or first / second generation EGFR TKI (tyrosine kinase inhibitors) have low blood-brain barrier penetration ability, and limited efficacy on intracranial lesions. The sample size of the third generation EGFR-TKI (including osimertinib, amuvatinib and fostamatinib) related research does not target the brain metastasis subgroup, and there is a lack of sufficient test power to make confirmatory conclusions for the brain metastasis subgroup. Each of the above methods has one or more drawbacks, such as lack of effectiveness, severe side effects, and low patient compliance. Therefore, better methods for treating EGFR mutation-positive non-small cell lung cancer brain metastasis are needed. SUMMARY

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

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

[0007] In one or more embodiments, the EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis is an EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis that has not previously received systemic anti-neoplastic treatment for locally advanced or metastatic non-small cell lung cancer or an EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis that has previously received systemic anti-neoplastic treatment for locally advanced or metastatic non-small cell lung cancer.

[0008] In one or more embodiments, the EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis is an EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis that has not previously received systemic anti-neoplastic treatment for locally advanced or metastatic non-small cell lung cancer or an EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis that has previously received systemic anti-neoplastic treatment for locally advanced or metastatic non-small cell lung cancer.

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

[0012] In one or more embodiments, the EGFR-sensitizing mutation-positive non-small cell lung cancer brain metastasis is an EGFR 19 exon deletion mutation-positive non-small cell lung cancer brain metastasis or an EGFR 21 exon 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 is an EGFR 19 exon deletion mutation-positive non-small cell lung cancer brain metastasis that is present alone or coexists with other EGFR site mutations.

[0014] In one or more embodiments, the EGFR 21 exon L858R mutation-positive non-small cell lung cancer brain metastasis is an EGFR 21 exon L858R mutation-positive non-small cell lung cancer brain metastasis that is present alone or coexists with other EGFR site mutations.

[0015] In one or more embodiments, the N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amino)phenyl)acrylamide or a pharmaceutically acceptable salt thereof is administered in combination with another anti-cancer drug.

[0016] In one or more embodiments, the other anti-cancer drug is a platinum-based drug 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-(dimethylamino)ethyl)(methyl)amino)-4- methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amino)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 radiosurgery (SRS).

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

[0021] In one or more embodiments, the EGFR non-sensitizing mutation positive non-small cell lung cancer brain metastasis is an EGFR gene mutation positive non-small cell lung cancer brain metastasis other than an EGFR 19 exon deletion, 21 exon L858R mutation.

[0022] One or more embodiments of the present application provide methods of treating EGFR mutation positive non-small cell lung cancer brain metastasis and other related diseases and conditions by administering an effective dose of an EGFR inhibitor.

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

[0024] One or more embodiments of the present application provide N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amino)phenyl)acrylamide or a pharmaceutically acceptable salt thereof for use as a medicament.

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

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

[0027] In one or more embodiments, the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide methanesulfonic acid salt is prepared as an oral preparation, an injection preparation, or a topical preparation.

[0028] In one or more embodiments, the oral preparation can be a tablet, a capsule, a powder.

[0029] In one or more embodiments, the N-(2-((2-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amine)phenyl)acrylamide methanesulfonic acid salt is prepared as a tablet (containing no other active ingredients, hereinafter "the tablet of the present application").

[0030] In one or more embodiments, the term "treatment" and its derivatives refer to prophylactic treatment or therapeutic treatment. Prophylactic treatment is appropriate, for example, when a patient is considered to be at high risk of developing cancer or cancer metastasis.

[0031] In one or more embodiments, the term "treatment", "therapeutically effective amount", or its derivatives, unless otherwise defined, refer to an amount that will elicit a biological or medical response of a tissue, system, animal, or human by, for example, a researcher or clinician. Also, the term "therapeutically effective amount" refers to any amount that results in improvement of cancer, healing, prevention, lessening of severity, or amelioration compared to a corresponding patient who does not receive the amount.

[0032] In one or more embodiments, the tablet of the present application can also be used for the treatment of cancer whose inducing factor of the symptoms is unknown or must also be identified, and a skilled physician will be able to determine appropriate cases for administration of the present application (where a patient is susceptible to or at risk of, for example, cancer or cancer metastasis).

[0033] In one or more embodiments, the term "administered in combination," "co-administered," or derivatives thereof means that the epidermal growth factor receptor tyrosine kinase inhibitor described herein and the other anticancer active ingredient(s) are administered simultaneously or sequentially in any order in any manner, including, for example, simultaneously, in close proximity to each other. Also, it is not important whether the same dosage form is administered, for example, one compound can be administered orally and the other compound can be administered by injection. The active ingredients can be known to be useful in the treatment of cancer, including chemotherapy and radiation therapy.

[0034] In one or more embodiments, the term "subject," "patient" can be a mammal, for example, a human. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 is a waterfall plot of the sum of the longest diameters of intracranial target lesions relative to baseline change in Example 1.

[0036] Figure 2 is a spider plot of the sum of the longest diameters of intracranial target lesions relative to baseline change in Example 1, where different colors represent different subjects.

[0037] Figure 3 is a swim lane plot of the overall assessment of intracranial tumors over time in Example 1.

[0038] Figure 4 is a waterfall plot of the sum of the longest diameters of systemic target lesions relative to baseline change in Example 1.

[0039] Figure 5 is a spider plot of the sum of the longest diameters of systemic target lesions relative to baseline change in Example 1, where different colors represent different subjects.

[0040] Figure 6 is a swim lane plot of the overall assessment of systemic tumors over time in Example 1.

[0041] Figure 7 is a waterfall plot of the sum of the longest diameters of intracranial target lesions relative to baseline change in Example 2 (cEFR (CNS evaluable-for-response set), which is a set of brain metastatic patients with measurable brain metastatic lesions and who have received at least two prior lines of therapy for their brain metastatic disease).

[0042] Figure 8 is a spider plot of the percent change from baseline of the sum of the longest diameters of intracranial target lesions relative to baseline in Example 2 (cEFR).

[0043] Figure 9 is a swim lane plot of the overall assessment of intracranial tumors in Example 2 (cEFR).

[0044] Figure 10 is a waterfall plot of the best change from baseline of the sum of the longest diameters of systemic target lesions relative to baseline in Example 2 (cEFR).

[0045] Figure 11 is a spider plot of the percent change from baseline of the sum of the longest diameters of systemic target lesions relative to baseline in Example 2 (cEFR).

[0046] Figure 12 is a cEFR plot of the overall tumor efficacy evaluation in Example 2.

[0047] Wherein, CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = unevaluable. DETAILED DESCRIPTION

[0048] Example 1: Clinical study on efficacy and safety of the tablet of the present application in treating patients with EGFR mutation-positive NCSLC brain metastasis

[0049] Study design

[0050] This study is a single-arm, open, domestic multi-center phase II clinical study, which evaluates the efficacy and safety of the tablet of the present application in treating patients with EGFR mutation-positive non-small cell lung cancer brain metastasis.

[0051] In this study, 30-40 cases of BM (brain metastasis) subjects are planned to be recruited, including patients with EGFR mutation-positive non-small cell lung cancer brain metastasis who have not received systemic anti-tumor treatment or have received 1 / 2 generation EGFR TKIs systemic anti-tumor treatment and then developed disease progression and T790M mutation-positive. The administration dose is 160 mg once a day, and continuous administration for 21 days is a cycle, until disease progression, meeting the termination criteria, withdrawal criteria or termination of the study (whichever occurs first). The primary endpoint indicators are intracranial objective response rate (iORR) and extracranial objective response rate (eORR), and the secondary endpoint indicators include systemic objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), etc.

[0052] Data statistics

[0053] 22 patients in the BM group completed at least 2 tumor assessments (20 patients were previously untreated and 2 patients were previously treated with 1 / 2 generation EGFR TKIs and had disease progression and T790M mutation positive), and the data showed that the intracranial tumors of 22 patients were effectively relieved, among which 20 patients (90.9%) had partial remission (PR) of intracranial lesions, 2 patients (9.1%) had complete remission (CR) of intracranial lesions, the confirmed intracranial objective remission rate (iORR) was 100% (22 / 22, 95% CI: 84.56-100.00), and the median intracranial remission depth was 62.0%. At the same time, 20 patients (90.9%) had PR of systemic tumor assessment, 2 patients (9.1%) had stable disease (SD), the systemic objective remission 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 Figures 1-6.

[0054] The tablets of the present application did not produce new safety signals, and no related death cases occurred, and the overall safety was controllable.

[0055] Conclusion

[0056] The present study confirmed that the tablets of the present application had efficacy for EGFR sensitive mutation positive non-small cell lung cancer brain metastasis patients who had not received systemic anti-tumor treatment or had disease progression after receiving 1 / 2 generation EGFR TKIs systemic anti-tumor treatment and T790M mutation positive.

[0057] Example 2: Safety, tolerability, pharmacokinetics and pharmacodynamics of the tablets of the present application in the treatment of EGFR mutation positive NCSLC patients (including patients with baseline brain metastasis)

[0058] Design of the scheme

[0059] This study is a phase I clinical study in advanced NSCLC patients with EGFR mutation positive (including EGFR sensitive mutation and non-sensitive mutation) who have not received systemic anti-tumor therapy or have disease progression after failure of standard treatment of 1 / 2 generation EGFR TKIs and T790M mutation positive. It is divided into two stages of Ia dose climbing and Ib dose expansion. The six dose groups of Ia stage are 20mg, 40mg, 80mg, 120mg, 160mg and 200mg once a day, and 16-36 subjects are planned to be included; the three expansion dose groups of Ib stage are 80mg, 120mg and 160mg once a day, and 10-30 subjects are planned to be included in each group. Continuous administration for 21 days is a cycle, and the study is terminated until disease progression, termination criteria, withdrawal criteria or study termination (whichever occurs first). The purpose is to determine the safety, tolerability, pharmacokinetics and pharmacodynamics characteristics and preliminary anti-tumor efficacy of the tablet of the present application in the treatment of advanced NSCLC patients with EGFR mutation positive.

[0060] Data statistics

[0061] In the Ib phase expansion study, a total of 36 EGFR sensitive mutation NSCLC patients with brain metastasis who have not received systemic anti-tumor therapy were observed, and 7, 19 and 10 patients received the tablet of the present application once a day at doses of 80mg, 120mg and 160mg respectively (9 of the 36 patients had intracranial measurable lesions, of which 2 patients received the tablet of the present application once a day at a dose of 120mg, and 7 patients received the tablet of the present application once a day at a dose of 160mg).

[0062] Among the 36 patients with brain metastasis, 7 patients with brain metastasis in the 80mg dose group and 10 patients in the 160mg dose group had partial remission (PR) in the assessment of whole body lesions, and the optimal objective remission rate (OPR) was 100%; among the 19 patients with brain metastasis in the 120mg dose group, 18 patients had PR as the best remission, and the whole body objective remission rate (ORR) was 94.7%. The best whole body tumor evaluation of a total of 35 patients in the three dose groups was PR, and the overall objective remission rate (ORR) was as high as 97.2% (35 / 36).

[0063] After 2 cycles of treatment with the drug of the present application, the whole body target lesions of the 36 patients with brain metastasis were reduced to varying degrees compared with the baseline, the time to first remission was 6 weeks, and the remission was further deepened as the treatment time was prolonged, and the median whole body tumor remission depth was 53%. Among the 36 patients, 18 patients were still in sustained remission, and the longest remission duration was about 22 months.

[0064] Among the 36 cases, 9 cases of patients with measurable intracranial lesions brain metastasis, 2 cases (22.2%) appeared intracranial lesions complete remission (CR), the remaining 7 cases (77.8%) intracranial tumor evaluation were PR, while the 9 patients systemic efficacy evaluation were PR, confirmed intracranial objective remission rate (iORR) and systemic objective remission rate (ORR) were as high as 100%. The median remission depth of intracranial tumor was 64%, and the median remission depth of systemic tumor was 55%. See Figures 7-12.

[0065] In the Ib expansion study, 1 case of EGFR sensitive mutation patient who had previously received 1 / 2 generation EGFR TKIs standard treatment failure and T790M mutation positive after disease progression received 160m once daily tablets of the application. The patient's systemic lesion tumor evaluation was partial remission (PR).

[0066] In the Ib expansion study, 4 cases of EGFR non-sensitive mutation NSCLC brain metastasis patients (EGFR 21 exon L861Q mutation, EGFR 21 exon L861Q mutation, EGFR 18 exon G719X combined with 20 exon S768I mutation, and EGFR 21 exon L861Q mutation combined with 20 exon insertion, respectively) who had not previously received systemic anti-tumor treatment each had 2 patients receiving 120mg and 160m once daily tablets of the application. The 2 brain metastasis patients in the 120mg dose group had systemic lesion tumor evaluations of partial remission (PR) and stable disease (SD), respectively, and the 2 patients in the 160mg dose group had systemic lesion tumor evaluations of partial remission (PR).

[0067] The tablets of the application did not produce new safety signals, and there were no related deaths. The overall safety was controllable.

[0068] The tablets of the application are slowly absorbed and eliminated after oral administration, and the peak time T max of the original drug in the blood is 4-6h, and the half-life t 1 / 2 >50h. After 15-21 days of continuous administration, the blood concentrations of the original drug and metabolites can reach steady state levels, and there is a certain degree of accumulation. When the dose is between 20mg and 200mg, the C max and AUC of the original drug and metabolites increase with the increase of the dose.

[0069] Conclusion

[0070] This study confirms that the tablets of the application have efficacy for EGFR sensitive or non-sensitive mutation positive non-small cell lung cancer brain metastasis patients who have not previously received systemic anti-tumor treatment or have disease progression after 1 / 2 generation EGFR TKIs standard treatment failure and T790M mutation positive.

Claims

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

2. The use according to claim 1, wherein the EGFR mutation-positive non-small cell lung cancer brain metastasis is EGFR sensitive mutation-positive non-small cell lung cancer brain metastasis or EGFR non-sensitive mutation-positive non-small cell lung cancer brain metastasis.

3. The use according to claim 2, wherein the EGFR sensitive mutation-positive non-small cell lung cancer brain metastasis is EGFR sensitive mutation-positive non-small cell lung cancer brain metastasis that has not been previously treated with systemic anti-tumor therapy for locally advanced or metastatic non-small cell lung cancer or EGFR sensitive mutation-positive non-small cell lung cancer brain metastasis that has been previously treated with systemic anti-tumor therapy for locally advanced or metastatic non-small cell lung cancer.

4. The use according to claim 2, wherein the EGFR non-sensitive mutation-positive non-small cell lung cancer brain metastasis is EGFR non-sensitive mutation-positive non-small cell lung cancer brain metastasis that has not been previously treated with systemic anti-tumor therapy for locally advanced or metastatic non-small cell lung cancer or EGFR non-sensitive mutation-positive non-small cell lung cancer brain metastasis that has been previously treated with systemic anti-tumor therapy for locally advanced or metastatic non-small cell lung cancer.

5. The use according to claim 3 or 4, wherein the systemic anti-tumor therapy is a first or second generation EGFR tyrosine kinase inhibitor therapy or other systemic anti-tumor therapy.

6. The use according to claim 5, wherein the EGFR tyrosine kinase inhibitor is gefitinib, erlotinib, icotinib, afatinib, or dacomitinib; preferably, the other systemic anti-tumor therapy is chemotherapy.

7. The use according to claim 2, wherein the EGFR sensitive mutation-positive non-small cell lung cancer brain metastasis is EGFR 19 exon deletion mutation-positive non-small cell lung cancer brain metastasis or EGFR 21 exon L858R mutation-positive non-small cell lung cancer brain metastasis; preferably, the EGFR 19 exon deletion mutation-positive non-small cell lung cancer brain metastasis is EGFR 19 exon deletion mutation-positive non-small cell lung cancer brain metastasis that is present alone or coexists with other EGFR site mutations; preferably, wherein the EGFR 21 exon L858R mutation-positive non-small cell lung cancer brain metastasis is EGFR 21 exon L858R mutation-positive non-small cell lung cancer brain metastasis that is present alone or coexists with other EGFR site mutations.

8. The use of claim 1, wherein the N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amino)phenyl)acrylamide or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer drug; preferably, the other anticancer drug is a platinum drug and / or pemetrexed; more preferably, the platinum drug is cisplatin or carboplatin.

9. The use of claim 1, wherein the N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxy-5-((4-(1-deutero-methyl-1H-indol-3-yl)pyrimidin-N'-2-yl)amino)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 radiosurgery (SRS).

10. The use of any one of claims 1-9, wherein the pharmaceutically acceptable salt is a mesylate salt.

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