Medicine for treating meningeal metastasis of malignant tumor with NTRK and / or ROS1 mutation, application and preparation method of medicine

Abstract

The invention belongs to the field of biological medicines, and particularly relates to a medicine for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutations and a preparation method, and the medicine is a freeze-dried powder preparation or injection for subarachnoid space injection of NTRK / ROS1-TKIs. The invention also provides an application of the NTRK / ROS1-TKIs in preparation of a medicine for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutation. The prepared NTRK / ROS1-TKIs injection can be directly injected into the subarachnoid space of a patient, the drug concentration in cerebrospinal fluid of the patient is greatly improved, the cerebrospinal fluid / plasma concentration ratio can reach 20 times or more, the problem of insufficient dosage caused by the blood-brain barrier after the targeted drug is orally taken can be completely solved, and the drug has the advantages of fast effect taking, no toxic or side effect and no toxic or side effect. The treatment effect on meningeal metastasis of malignant tumors such as lung cancer can be obviously improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and particularly relates to a drug for treating meningeal metastasis of malignant tumor with NTRK and / or ROS1 mutation, application and preparation method of the drug. BACKGROUND

[0002] Meningeal metastasis of malignant tumor is a difficult and complicated clinical treatment, and the prognosis is extremely poor. If there is no effective treatment, the natural survival period is only about 1 month. Central nervous system is a common metastatic site of malignant tumor, but meningeal metastasis is substantially different from brain parenchymal metastasis, and needs to be treated differently. The current treatment methods have not achieved satisfactory results. Intrathecal chemotherapy is an important palliative treatment for meningeal metastasis, and the selection of chemotherapy drugs can include pemetrexed, methotrexate, thiotepa and cytarabine, and the specific dose and course of treatment need to be determined according to the individual condition of the patient.

[0003] NTRK gene fusion is a clear oncogenic driver mutation, NTRK is neurotrophic factor receptor tyrosine kinase, the incidence of NTRK gene fusion in some rare tumors such as secretory breast cancer and infantile fibrosarcoma is more than 90%, other tumors involved include central nervous system tumors, neuroendocrine tumors, salivary gland tumors, pancreatic cancer, non-small cell lung cancer, thyroid cancer, sarcoma, colorectal cancer, salivary gland tumor, bile duct cancer, ductal tumor, breast cancer, breast malignant melanoma and other gynecological tumors, etc. ROS1 gene fusion is oncogenic, ROS1 is a proto-oncogene, full name is c-ROS sarcoma oncogene-receptor tyrosine kinase, ROS1 gene fusion has been found in many cancers, first found in glioblastoma, then found in non-small cell lung cancer, about 0.9%-2% of all lung cancer patients have ROS1 fusion, 3.1% of lung adenocarcinoma patients have ROS1 fusion, a small number of squamous cell carcinoma patients have ROS1 fusion, and other cancers including bile duct cancer, ovarian cancer, gastric cancer, colorectal cancer, etc. can also have ROS1 gene fusion. Meningeal metastasis of malignant tumor with NTRK or ROS1 fusion mutation is relatively rare in clinical practice, but as the number of patients using NTRK / ROS1-TKIs increases, such special metastasis will be more common. NTRK / ROS1-TKIs include NTRK and ROS1-TKIs, NTRK-TKIs, and ROS1-TKIs.

[0004] NTRK and ROS1-TKIs usually include entrectinib and repotrectinib, which are pan-tumor targeted drugs. For malignant tumors with NTRK and ROS1 fusion mutations, these drugs have significant oral efficacy in clinical application and become the standard treatment options for advanced NTRK and ROS1 fusion malignant tumors. Other single-target NTRK-TKIs include larotrectinib and solitrexin, and single-target ROS1-TKIs include crizotinib, seritrexin, anakinra, tarloxin, loratadine, complex rexin, NVL-520, JYP0322 and other drugs.

[0005] NTRK / ROS1-TKIs are all orally administered, and their ability to pass through the blood-brain barrier is poor. The cerebrospinal fluid concentration of the conventional dose is less than 10-20% of the blood drug concentration, and even if the dose is increased, the cerebrospinal fluid concentration is still limited. For patients with meningeal metastasis progression during NTRK / ROS1-TKIs treatment, the patients with clear drug resistance mechanism are recommended to receive intrathecal chemotherapy combined with individualized treatment, and the patients with unknown drug resistance mechanism are recommended to receive intrathecal chemotherapy combined with other systemic treatment or enter clinical research.

[0006] That is, in the prior art, the drugs for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutations mainly include injection chemotherapy drugs and oral targeted drugs NTRK / ROS1-TKIs, but these drugs and their combinations cannot achieve good therapeutic effect. Therefore, there is a need in the art for a new drug for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutations. SUMMARY

[0007] The present application first provides a drug for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutations, which is a lyophilized powder preparation or injection solution for subarachnoid injection of NTRK / ROS1-TKIs, NTRK is neurotrophic factor receptor tyrosine kinase, ROS1 is c-ros sarcoma oncogene-receptor tyrosine kinase, NTRK / ROS1-TKIs includes NTRK and ROS1-TKIs, NTRK-TKIs, ROS1-TKIs, NTRK and ROS1-TKIs are neurotrophic factor receptor tyrosine kinase and c-ros sarcoma oncogene-receptor tyrosine kinase inhibitors, NTRK-TKIs are neurotrophic factor receptor tyrosine kinase inhibitors, and ROS1-TKIs are c-ros sarcoma oncogene-receptor tyrosine kinase inhibitors. The amount of NTRK / ROS1-TKIs per person is 0.1-5 mg; the subarachnoid injection method of the drug includes any one or more of Ommaya sac injection, lumbar puncture and pre-bridge pool indwelling catheter injection.

[0008] In a specific embodiment, the NTRK / ROS1-TKIs is one or more selected from entrectinib, repotrectinib, larotrectinib, and dolutrectinib; the drug further comprises hydroxypropyl beta cyclodextrin and citric acid or citrate, or the drug further comprises hydroxypropyl beta cyclodextrin, mannitol, and citric acid or citrate; and the amount of NTRK / ROS1-TKIs in the drug is 0.2-1.2 mg per person per time.

[0009] The application also provides use of NTRK / ROS1-TKIs in preparation of a drug for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutations, wherein the drug is a lyophilized powder preparation or an injection solution of NTRK / ROS1-TKIs for subarachnoid injection as described above, and the amount of NTRK / ROS1-TKIs in the drug is 0.1-5 mg per person per time.

[0010] In a specific embodiment, the NTRK / ROS1-TKIs is one or more selected from entrectinib, repotrectinib, larotrectinib, and dolutrectinib; the drug further comprises hydroxypropyl beta cyclodextrin and citric acid or citrate, or the drug further comprises hydroxypropyl beta cyclodextrin, mannitol, and citric acid or citrate; and the amount of NTRK / ROS1-TKIs in the drug is 0.2-2 mg per person per time.

[0011] In a specific embodiment, the amount of NTRK / ROS1-TKIs in the drug is 0.2-1.2 mg per person per time.

[0012] In a specific embodiment, the amount of NTRK / ROS1-TKIs in the drug is 0.2-0.8 mg per person per time, the injection method of the drug specifically comprises any one or more of Ommaya reservoir injection, lumbar puncture, and cisterna magna indwelling catheter injection, and the drug is used in combination with an oral NTRK / ROS1-TKIs preparation.

[0013] In a specific embodiment, the drug is used to increase the ratio of the concentration of entrectinib in the cerebrospinal fluid of a patient with meningeal metastasis of a malignant tumor with NTRK and / or ROS1 mutations to the concentration of entrectinib in the plasma.

[0014] In a specific embodiment, the malignant tumor is non-small cell lung cancer.

[0015] The application also provides a preparation method of a drug, wherein the drug is a lyophilized powder preparation of NTRK / ROS1-TKIs for subarachnoid injection as described above; and the preparation method comprises the following steps:

[0016] Step A, dissolving NTRK / ROS1-TKIs and mannitol in water for injection in a light-proof environment, using hydroxypropyl beta cyclodextrin to help NTRK / ROS1-TKIs dissolve, adjusting pH value with citric acid or citrate buffer, and adding water for injection to constant volume; Step B, filtering out impurities and sterilizing with a filter membrane; Step C, rapidly filling the filtrate into multiple brown vials with a full-automatic filling machine; Step D, semi-tamping the brown vials with a full-automatic tamping machine; Step E, nitrogen filling after freezing and drying the drug in a freeze-drying box; Step F, full-tamping under a full-automatic tamping machine in the freeze-drying box, tamping the semi-tamped rubber stopper into the vial to completely seal the drug; Step G, tightly tamping the aluminum plastic cover on the vial with a cover tamping machine, to obtain the injection freeze-dried powder preparation; the content of NTRK / ROS1-TKIs in the injection solution obtained after dissolving the injection freeze-dried powder preparation with water for injection is 0.001-0.5%.

[0017] In a specific embodiment, the content of NTRK / ROS1-TKIs in the injection solution obtained after dissolving the injection freeze-dried powder preparation with water for injection is 0.002-0.3%, preferably 0.01-0.05%, the content of mannitol is 4-6%, the content of hydroxypropyl beta cyclodextrin is 0.1-3%, and the pH value of the injection solution is 5-7.

[0018] In the embodiment of the present application, the content of NTRK / ROS1-TKIs in the injection solution obtained after dissolving the injection freeze-dried powder preparation with water for injection is 0.015%-0.03%.

[0019] The present application has at least the following beneficial effects: the NTRK / ROS1-TKIs injection prepared by the present application can be directly injected into the subarachnoid space of a patient, greatly improving the drug concentration in the cerebrospinal fluid of the patient, and the cerebrospinal fluid / plasma concentration ratio can reach 20 times or even more, the present application can completely solve the problem of insufficient dose caused by the blood-brain barrier after oral administration of targeted drugs, and the drug has a fast onset and can significantly improve the treatment effect of malignant tumor meningeal metastasis. BRIEF DESCRIPTION OF DRAWINGS

[0020] The accompanying drawings, which form a part of this application, are included to provide a further understanding of the application and are incorporated in and constitute a part of this application. The embodiments of the present application illustrated in the drawings and their descriptions are used to explain the present application and are not intended to limit the present application.

[0021] Figure 1 is the Ommaya reservoir catheter schematic diagram in the present application.

[0022] Figure 2 is the head CT film of a patient before Ommaya reservoir catheterization in Embodiment 2 of the present application (September 22, 2025).

[0023] Figure 3 is the head CT film of the patient in Example 2 of the application after Ommaya reservoir placement (September 23, 2025).

[0024] Figure 4 is the head CT film of the patient in Example 2 of the application after Ommaya reservoir placement and NTRK / ROS1-TKIs treatment (December 11, 2025).

[0025] In the figure: 1, Ommaya reservoir body; 2, Ommaya reservoir catheter end; 3, Ommaya reservoir catheter; 4, scalp; 5, skull; 6, lateral ventricle. DETAILED DESCRIPTION

[0026] The embodiments of the application are described in detail below, and the specific embodiments described herein are only used to explain the application and not to limit the application.

[0027] The injection method of the application includes Ommaya reservoir injection, lumbar puncture (i.e. sheath injection) and pre-bridge pool indwelling catheter injection. Ommaya reservoir is a liquid storage device implanted under the scalp and connected to the lateral ventricle, mainly used for intrathecal drug injection or cerebrospinal fluid drainage, containing a puncturable liquid storage bag and a catheter, the liquid storage bag is located under the scalp and has a soft touch, and the doctor can directly inject the drug into the liquid storage bag through puncture, which can avoid repeated lumbar puncture or ventricular puncture, reduce the risk of trauma and infection, and is suitable for patients who need long-term intrathecal treatment; The drug injected by Ommaya reservoir enters the ventricle first and then circulates to the entire subarachnoid space naturally. Sheath injection is a short form of intrathecal injection, which refers to a medical method of directly injecting drugs into the cerebrospinal fluid in the subarachnoid space through lumbar puncture, so as to bypass the blood-brain barrier and efficiently treat central nervous system diseases. The pre-bridge pool indwelling catheter injection technology is to place the catheter into the subarachnoid space through lumbar puncture, with the tip reaching the pre-bridge pool, and the end connected to the infusion port buried in the abdominal subcutaneous tissue, which facilitates repeated puncture for sheath injection through subcutaneous infusion port. The Ommaya reservoir injection, lumbar puncture and pre-bridge pool indwelling catheter injection in the application are collectively referred to as subarachnoid injection.

[0028] The drug for subarachnoid injection provided by the application is completely different from the drug for muscle injection, intravenous injection, arterial injection, subcutaneous injection, intradermal injection, intra-articular injection, intraosseous injection, intravitreal injection, intracardiac injection, etc.

[0029] Entrectinib is a selective NTRK / ROS1 inhibitor, and the clinical use specification of its finished drug is 600mg capsules per day orally. The inventors know through searching that there is no entrectinib injection for lung cancer meningeal metastasis in the prior art. The NTRK / ROS1-TKIs injection designed and configured by the present application can be directly injected into the subarachnoid space, rapidly increase the drug concentration in the cerebrospinal fluid, and see effect quickly. The cerebrospinal fluid / plasma concentration ratio is much greater than 1, which can reach more than 10 times, solving the problem of insufficient NTRK / ROS1-TKIs dose in cerebrospinal fluid caused by blood-brain barrier, greatly improving the treatment effect of lung cancer meningeal metastasis.

[0030] Embodiment 1

[0031] 1. Pharmaceutical formulation and preparation method

[0032] The formulation type of the present application is NTRK / ROS1-TKIs freeze-dried powder injection. The core active ingredient is NTRK / ROS1-TKI entrectinib, with a purity of ≥99%. The excipients in this embodiment include: 1, mannitol, content 4-5%, mainly as stabilizer and osmotic pressure regulator; 2, hydroxypropyl beta cyclodextrin, content 2%, mainly as a solubilizer, and also regulates the osmotic pressure together with mannitol; 3, citric acid solution, mainly as an acid-base regulator for the drug; 4, water for injection, mainly as a solvent.

[0033] The production process of the lyophilized powder injection of entrectinib is as follows: first step, treatment of raw materials and packaging materials: 1. In a light-proof environment, weigh 2.0 g of entrectinib raw material and place it in a sealed light-proof container for standby; 2. Weigh 500 g of mannitol for injection and place it in a sealed container for standby; 3. Freshly prepared water for injection is placed in a container for standby; 4. Wash 5 ml brown vials, siliconize (used to protect the surface of the vial, make the bottle wall smooth, and facilitate drug extraction), dry heat sterilization in a tunnel oven at 300℃ for 5 min for standby; 5. Bromobutyl rubber stopper cleaning, siliconization, 121℃ for 30 min wet heat sterilization, drying standby; 6. Clean the aluminum cap. Second step, preparation and filling of the liquid medicine: 1. Take about 9000 ml of freshly prepared water for injection, add 200 g of hydroxypropyl beta cyclodextrin to it, stir evenly to make a clear solution, add 2.0 g of entrectinib, stir at room temperature until completely dissolved, the stirring speed is 1000 rpm; 2. Add about 500 g of mannitol and stir thoroughly to completely dissolve; 3. Adjust the pH value to 5.0-7.0 with citric acid solution; 4. Add water for injection to 10000 ml; 5. Filter through a 0.45 μm filter membrane to remove larger particles; 6. Filter through a 0.22 μm filter membrane to remove bacteria; 7. In a class A environment, use a fully automatic filling machine to quickly fill the filtrate into brown vials, each vial contains 2.1 ml, 8. Half-press the plug, use a fully automatic plug pressing machine to half-press the plug. The above steps are completed in a light-proof environment. Third step, freeze-drying: 1. Pre-freezing, slowly reduce the product from room temperature to -45 to -50℃ at a rate of 1℃ / min, and keep it at this temperature for 2 hours to ensure that all products are in a frozen state. 2. Primary drying, start the vacuum pump to make the vacuum degree in the freeze-drying box reach 50-100 mTorr, slowly raise the temperature to -20℃, and keep it at this temperature for 24 hours. 3. Secondary drying, under the condition of maintaining high vacuum, raise the plate temperature to 25℃ at a rate of 0.1-0.2℃, and keep it at this temperature for 6 hours. Fourth step, full plug, cap: 1. Nitrogen filling, before the end of secondary drying, slowly fill sterile high-purity nitrogen into the freeze-drying box to destroy the vacuum environment and fill the high-purity nitrogen in the vial. 2. Full plug, use the full-automatic plug pressing machine in the freeze-drying box to press the half-pressed plug into the vial to completely seal the product. 3. Cap, use the cap pressing machine to tightly press the aluminum plastic cap on the vial. 4. Product processing, 100% manual or full-automatic light inspection to ensure that the product appearance is normal and the sealing is good. 5. Packaging and storage, the qualified products are packaged with opaque material outer packaging box.

[0034] The key quality control parameters include: the specification of entrectinib is 0.4 mg / bottle. In this embodiment, the concentration of entrectinib is 0.02% (2.0 g of entrectinib is made up to 10000 ml, i.e. 10000 g, so the concentration is 0.02%), and the filling amount of the drug solution after dispensing is 2.1 ml, and then it is prepared into a lyophilized powder. Before the drug in the vial is injected into the patient's body, the lyophilized powder is first dissolved using 2 ml of water for injection, 2 g of the drug solution is 2000 mg, and the concentration of entrectinib is 0.02%, i.e. the amount of entrectinib per bottle is 0.4 mg. The mannitol content in the drug of the vial is 5%.

[0035] The acidity of the reconstituted drug is 5.0-7.0, the osmotic pressure is 280-320 mOsm / L; the sterile test meets the requirements of the sterile test method in the Chinese Pharmacopoeia 2025 edition; the bacterial endotoxin content is ≤0.20 EU / mg. Storage condition: store in a cool and dark place.

[0036] 2. Clinical administration method

[0037] The administration route of this embodiment is Ommaya sac injection. The specific operation steps of Ommaya sac injection are as follows: first step, the patient takes a sitting / supine position, and a 10 ml syringe tube + 0.6 x 25 TW LB type needle is used to puncture into the subcutaneous reservoir and fixed; second step, 5-10 ml of cerebrospinal fluid is withdrawn, and it is confirmed that it is unobstructed; third step, 1-4 ml of the preparation of the application is slowly injected at a speed of 2 ml / min; fourth step, after injection is completed, 2.5-5 mg of dexamethasone + 2 ml of normal saline is used to seal the tube, and the vital signs of the patient are observed for 5 minutes.

[0038] The dose and course are set as follows: the single administration dose is 0.2 mg-0.8 mg / time; the administration frequency is 5 times per week; the course is set as continuous administration for 2 weeks as a course, which can be repeatedly performed until the patient's condition progresses or cannot be tolerated.

[0039] The adverse reaction treatment plan includes: the common adverse reactions are mild dizziness and headache, and the corresponding treatment measures are to give non-steroidal anti-inflammatory analgesic drugs such as celecoxib for symptomatic treatment when headache occurs.

[0040] Example 2

[0041] This embodiment is a clinical application example of the drug prepared in Example 1.

[0042] The basic information of the case includes patient name: Fan Xmin; gender: male; age: 59 years old; admission (Xiangya Second Hospital of Central South University) date: September 20, 2025; chief complaint: dizziness and imbalance for 2 days after falling; past history: lung cancer history for 1.8 years, admitted to hospital for 2 days of hemoptysis in November 2023, diagnosed as right lung adenocarcinoma with extensive bone metastasis T4aN1M1 IV stage, gene detection showed TP53-NTRK1 fusion, has been taking oral encorafenib 600mg Qd targeted therapy, efficacy evaluation: partial remission PR. Intermittent postural syncope and loss of consciousness since December 2024. Admitted to hospital due to needle-like pain in the back and lower extremities in June 2025, lumbar puncture was performed on June 11, cerebrospinal fluid pressure was 210 mmH2O, Glu 2.24 mmol / L, protein quantification 874.0 ng / ml, keratin 53.56 ng / ml, gastrin releasing precursor 91.29 ng / ml, cerebrospinal fluid gene detection: TP53-NTRK fusion (52.18%), meningeal metastasis was determined, and the disease progressed PD. In June 2025, the patient was treated with ripretinib capsules 160mg Bid orally, but the effect was not obvious, and later the patient had dizziness, headache, vomiting, limb weakness, and loss of mobility. On September 22, 2025, the patient underwent Ommaya reservoir implantation, and the cerebrospinal fluid was drained regularly to reduce intracranial pressure. Later, the patient received four intraventricular injections of pemetrexed through the Ommaya reservoir (20mg of pemetrexed on September 29, 2025, 20mg of pemetrexed on October 2, 2025, 50mg of pemetrexed on October 9, 2025, and 20mg of pemetrexed on October 21, 2025), while taking oral ripretinib treatment, and the symptoms did not improve significantly, and the patient gradually lost consciousness.

[0043] The treatment regimen using encorafenib injection in this example includes Ommaya reservoir administration in the lateral ventricle using the preparation of the present application. The treatment began on October 27, 2025, and the first course of treatment was a single dose of 0.2mg (1ml). The administration frequency was 5 times a week (once a day) of injection administration, with 2 days of rest (while returning to oral encorafenib 600mg per day). The treatment cycle was from October 27, 2025 to November 9, 2025, for 2 weeks of continuous treatment.

[0044] The treatment process record of the first course in this example includes the following aspects. First administration: October 27, 2025, the injection process was smooth, and there was no immediate adverse reaction. TDM blood concentration monitoring: before treatment, high performance liquid chromatography (HPLC) was used for detection, the cerebrospinal fluid encorafenib concentration was <5 ng / ml, the plasma concentration was 46.4 ng / ml, and the cerebrospinal fluid / plasma concentration ratio of encorafenib was <0.11. First administration evaluation: the next day, the patient's consciousness was clearer than before. Adverse reactions: no obvious adverse reactions. The NGS detection results of the cerebrospinal fluid collected on November 7, 2025 at the end of the first course showed that the TP53-NTRK1 fusion mutation abundance decreased from 52.18% in June 2025 to 28.7%, but a new drug-resistant mutation NTRK1 p.G667C was detected, with an abundance of 5.1%.

[0045] Considering the previous disease progression and the emergence of drug-resistant mutations, on November 17, 2025, encorafenib capsules were increased to 800 mg / day orally, and on November 20, 2025, an attempt was made to increase the dose of encorafenib injection from 0.2 mg (1 ml) in the first course to 0.8 mg (4 ml) Ommaya capsule single administration, and the changes in cerebrospinal fluid drug concentration and plasma drug concentration were monitored. The injection process was smooth, and there was no immediate adverse reaction. TDM (therapeutic drug monitoring) results: before administration, high performance liquid chromatography (HPLC) detected that the cerebrospinal fluid encorafenib concentration was <5 ng / ml, the plasma concentration was 50.5 ng / ml, and the cerebrospinal fluid / plasma concentration ratio of encorafenib was <0.10. 15 minutes after administration, the cerebrospinal fluid concentration was 1972 ng / ml, 2 hours later the cerebrospinal fluid concentration decreased to 42 ng / ml, 4 hours later the cerebrospinal fluid concentration decreased to 26.4 ng / ml, and the cerebrospinal fluid / plasma concentration ratio of encorafenib increased to 39:1. Adverse reactions: no obvious adverse reactions. Literature shows that when children take oral encorafenib, the cerebrospinal fluid concentration is about 12.5 ng / ml.

[0046] The patient has been taking entrectinib capsules 800 mg orally every day, but due to post-drug observation and combined lung infection, the patient stopped taking entrectinib Ommaya capsule injection for more than 2 weeks (from November 10, 2025 to November 26, 2025, excluding the single attempt injection on November 20, 2025), and the patient gradually became unconscious. From November 27, 2025 to December 10, 2025, the second course of treatment was started, with a single dose of entrectinib 0.8 mg (4 ml), injected 5 times a week (once a day), with 2 days of rest, and continuous treatment for 2 weeks. Before administration, high performance liquid chromatography (HPLC) detected that the concentration of entrectinib in the plasma was 58.6 ng / ml, the concentration of entrectinib in the cerebrospinal fluid was <5 ng / ml, the ratio of entrectinib in the cerebrospinal fluid to the plasma was <0.10, and 15 minutes after administration, the concentration of entrectinib in the cerebrospinal fluid was 1268 ng / ml, 2 hours later it decreased to 123.2 ng / ml, 4 hours later it decreased to 85.2 ng / ml, 8 hours later it decreased to 57.2 ng / ml, 12 hours later it decreased to 21.12 ng / ml, and 24 hours later it was 7.92 ng / ml. At this time, the concentration of entrectinib in the plasma was 47.6 ng / ml, and the ratio of entrectinib in the cerebrospinal fluid to the plasma was as high as 21.6:1. Two days after administration, the patient's consciousness was clear and accurate, and the general condition improved significantly without obvious adverse reactions. The NGS test results of the cerebrospinal fluid collected on December 4, 2025 showed that the abundance of TP53-NTRK1 fusion mutation decreased from 28.7% to 1.6%, and the abundance of drug-resistant mutation NTRK1 p.G667C decreased from 5.1% to 0.4%. On December 11, 2025, the cerebrospinal fluid biochemistry and routine examination showed no obvious abnormalities, and the re-examination of head CT showed no obvious changes in intracranial changes compared with the changes before and after Ommaya capsule implantation on September 22, 2025 ( Figure 2 ), September 23, 2025 ( Figure 3 ), and no imaging progression was found. Figure 4 ). Figure 2 ). Figure 3 ).

[0047] The patient's diagnosis was based on the following aspects. Imaging examination: MR on August 21, 2025 showed softening lesions in the left parieto-occipital lobe and right parietal lobe, and the left parietal lobe lesion was combined with laminar necrosis. Laboratory examination: cerebrospinal fluid cytology found that the cerebrospinal fluid white blood cell count was elevated, and the cytology was mixed cell reaction type, suggesting central nervous system tumor or metastatic tumor. Cerebrospinal fluid gene detection: TP53-NTRK fusion. Final diagnosis: right lung adenocarcinoma IV stage, bone metastasis, meningeal metastasis.

[0048] The disease assessment before the treatment according to the scheme of the present application includes the following aspects. The disease assessment before the treatment: clinical symptoms: unconsciousness, unable to answer, persistent headache, occasional nausea, vomiting, frequent minor seizures. TDM blood concentration monitoring: the concentration of encorafenib in the cerebrospinal fluid is lower than the lower limit of detection, <5 ng / ml. Cerebrospinal fluid cytology found that the white blood cell count in the cerebrospinal fluid was elevated, and the cytology was mixed cell reaction type, considering central nervous system tumor or metastatic tumor. Physical status score: KPS score 20 points, the KPS score is a tool for quantitatively evaluating the physical status of cancer patients proposed in 1949.

[0049] The efficacy evaluation results of the present embodiment include the following aspects. Clinical symptom improvement: consciousness is clearer than before, can answer accurately, headache, nausea, vomiting are completely relieved, KPS score is improved to 50 points. Laboratory index change: cerebrospinal fluid pressure is reduced to normal, and no obvious abnormalities are found in cerebrospinal fluid biochemistry. After the end of the second course, the abundance of TP53-NTRK1 fusion mutation in the cerebrospinal fluid decreased from 52.18% before treatment to 28.7%, and finally to 1.6%. The drug resistance mutation NTRK1p.G667C detected at the end of the first course decreased from 5.1% to 0.4% at the end of the second course. The review of head CT at the end of the second course showed that there was no significant change in intracranial changes before and after the Ommaya reservoir was implanted, and no imaging progression was found.

[0050] The conclusion of the present application is that after the patient is treated with the preparation of the present application, TDM monitoring confirms that the concentration of encorafenib in the cerebrospinal fluid is significantly improved after the Ommaya reservoir is administered, the clinical symptoms and laboratory indexes are obviously improved, and the tolerance is good.

[0051] The prior art has a way of using chemotherapy drugs such as pemetrexed, methotrexate, thiotepa and cytarabine by lumbar puncture to directly inject the drugs into the cerebrospinal fluid in the subarachnoid space, but the prior art has never used NTRK and / or ROS1 tyrosine kinase inhibitors such as entrectinib for lumbar puncture. The inventors speculate that the main reasons are: 1. At present, there are fewer patients diagnosed with NTRK and / or ROS1 mutant malignant tumor meningeal metastasis in clinical practice; 2. The solubility of the targeted drug NTRK / ROS1-TKIs is extremely poor, and the existing targeted drug entrectinib is only an oral drug, and the patient's dosage is 600 mg per day or more, that is, the technical personnel in the field have a technical bias: the dosage of the injection of the targeted drug NTRK / ROS1-TKIs also needs a large dose to take effect, so the technical bias in the field believes that it is impossible to develop a subarachnoid injection drug of entrectinib and other NTRK / ROS1-TKIs. However, in fact, the cerebrospinal fluid capacity is only 150-200 ml, and a large amount of solubility of the targeted drug is not needed to significantly increase the concentration of the targeted drug in the cerebrospinal fluid. Clinical findings show that 5 mg or less of entrectinib and other NTRK / ROS1-TKIs is enough to treat lung cancer meningeal metastasis in patients, and even when the daily dosage of entrectinib for subarachnoid injection is as low as 0.2 mg, the treatment effect has already appeared, and when the daily dosage of entrectinib is increased to 0.8 mg, the treatment effect is very obvious.

[0052] The present application first develops a lyophilized powder preparation or injection solution for subarachnoid injection of NTRK / ROS1-TKIs, and applies it to the treatment of NTRK / ROS1 mutant non-small cell lung cancer meningeal metastasis patients, and achieves remarkable treatment effect.

[0053] In addition, the inventors believe that in the prior art, non-NTRK / ROS1-TKIs drugs prepared into subarachnoid injection solutions for treating NTRK / ROS1 mutant malignant tumor meningeal metastasis have limited efficacy, for example, Example 2 of the present application shows that multiple treatments of the chemotherapy drug pemetrexed injection have no effect on the treatment of meningeal metastasis of malignant tumors.

[0054] If the drug in the present application is an injection solution of NTRK / ROS1-TKIs, NTRK / ROS1-TKIs and citrate as an auxiliary material are needed, and hydroxypropyl beta cyclodextrin is also needed for solubilization. If the drug in the present application is a lyophilized powder preparation for injection, NTRK / ROS1-TKIs, citrate as an auxiliary material, hydroxypropyl beta cyclodextrin and mannitol are needed.

[0055] The above merely provides the preferred embodiments of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the principles and technical scope of the present application shall fall into the scope of the present application.

Claims

1. A medicament for treating meningeal metastasis of a malignant tumor in which NTRK and / or ROS1 mutation is present, characterized by, The drug is a lyophilized powder preparation or an injection solution for subarachnoid injection of NTRK / ROS1-TKIs, wherein NTRK is neurotrophic tyrosine kinase, ROS1 is c-ros oncogene sarcoma viral oncogene homolog, and the NTRK / ROS1-TKIs include NTRK and ROS1-TKIs, NTRK-TKIs, and ROS1-TKIs, wherein NTRK and ROS1-TKIs are neurotrophic tyrosine kinase and c-ros oncogene sarcoma viral oncogene homolog inhibitors, NTRK-TKIs are neurotrophic tyrosine kinase inhibitors, and ROS1-TKIs are c-ros oncogene sarcoma viral oncogene homolog inhibitors, and the amount of NTRK / ROS1-TKIs in the drug is 0.1-5 mg per person per time; and the subarachnoid injection method of the drug includes any one or more of Ommaya reservoir injection, lumbar puncture, and pre-bridge pool indwelling catheter injection.

2. The medicament according to claim 1, characterized in that, The NTRK / ROS1-TKIs are one or more selected from the group consisting of entrectinib, repotrectinib, larotrectinib, and dorectinib; the drug further comprises hydroxypropyl beta cyclodextrin and citric acid or a citrate salt, or the drug further comprises hydroxypropyl beta cyclodextrin, mannitol, and citric acid or a citrate salt; and the amount of NTRK / ROS1-TKIs in the drug is 0.2-1.2 mg per person per time.

3. Use of NTRK / ROS1-TKIs in the preparation of a medicament for treating meningeal metastasis of malignant tumors with NTRK and / or ROS1 mutations, characterized in that, The drug is a lyophilized powder preparation or an injection solution for subarachnoid injection of NTRK / ROS1-TKIs as described in claim 1 or 2, and the amount of NTRK / ROS1-TKIs in the drug is 0.1-5 mg per person per time.

4. Use according to claim 3, characterized in that, The NTRK / ROS1-TKIs are one or more selected from the group consisting of entrectinib, repotrectinib, larotrectinib, and dorectinib; the drug further comprises hydroxypropyl beta cyclodextrin and citric acid or a citrate salt, or the drug further comprises hydroxypropyl beta cyclodextrin, mannitol, and citric acid or a citrate salt; and the amount of NTRK / ROS1-TKIs in the drug is 0.2-2 mg per person per time.

5. Use according to claim 4, characterized in that, The amount of NTRK / ROS1-TKIs in the drug is 0.2-1.2 mg per person per time.

6. Use according to claim 5, characterized in that, The amount of NTRK / ROS1-TKIs in the drug is 0.2-0.8 mg per person per time, the injection method of the drug specifically includes any one or more of Ommaya reservoir injection, lumbar puncture, and pre-bridge pool indwelling catheter injection, and the drug is used in combination with an oral NTRK / ROS1-TKIs preparation.

7. Use according to claim 3, characterized in that, The drug is used to increase the ratio of the concentration of entrectinib in cerebrospinal fluid to the concentration of entrectinib in plasma in a patient with NTRK and / or ROS1 mutant malignant tumor meningeal metastasis.

8. Use according to claim 3, characterized in that, The malignant tumor is non-small cell lung cancer.

9. A method of preparing a medicament, comprising admixing a compound of any one of claims 1-8 and a pharmaceutically acceptable carrier. The drug is a lyophilized powder preparation for subarachnoid injection of NTRK / ROS1-TKIs as described in claim 1 or 2; and the preparation method of the drug includes the following steps: Step A, dissolve NTRK / ROS1-TKIs and mannitol in water for injection under light protection, use hydroxypropyl β-cyclodextrin to help NTRK / ROS1-TKIs dissolve, adjust pH value with citric acid or citrate buffer, and add water for injection to constant volume; Step B, filter impurities and sterilize using a filter membrane; Step C, use a full-automatic filling machine to quickly fill the filtrate into multiple brown vials; Step D, use a full-automatic capping machine to semi-cap the vials; Step E, freeze dry the drug in a freeze dryer, and then fill nitrogen; Step F, full-cap under a full-automatic capping machine in the freeze dryer, press the semi-cap rubber plug into the vial to completely seal the drug; Step G, use a capping machine to tightly cap an aluminum plastic cover on the vial, and the injection lyophilized powder preparation is obtained; the content of NTRK / ROS1-TKIs in the injection solution obtained by dissolving the injection lyophilized powder preparation in water for injection is 0.001-0.5%.

10. The method for preparing the drug according to claim 9, characterized in that, The content of NTRK / ROS1-TKIs in the injection solution obtained by dissolving the injection lyophilized powder preparation in water for injection is 0.002-0.3%, preferably 0.01-0.05%, the content of mannitol is 4-6%, the content of hydroxypropyl β-cyclodextrin is 0.1-3%, and the pH value of the injection solution is 5-7.

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