Medicaments and methods for treating brain metastases of brain cancer or other cancers or preventing brain metastases of other cancers

Abstract

The present application relates to a kind of drug and method for treating brain cancer or other cancer brain metastasis, or preventing brain metastasis in subject with other cancer, the drug includes unit dose of sesquiterpene lactone compound and its stereoisomer, isotopic marker, solvate, polymorph or its pharmaceutically acceptable salt.The other cancer is selected from small cell lung cancer (SCLC) brain metastasis and non-small cell lung cancer (NSCLC) brain metastasis.The drug of the present application can significantly enhance lung cancer brain metastasis radiotherapy effect, reduce the toxic side reaction of whole brain radiotherapy, activate antitumor immune response and enhance the effect of radiotherapy, thereby the potential of whole body antitumor activity is improved;Taking the drug of the present application can significantly improve the compliance of cancer patients.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to drugs and methods for treating brain metastases of brain cancer or other cancers or for preventing brain metastases of other cancers. Background Technology

[0002] Lung cancer has various histological subtypes, mainly including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). One of the most common sites of distant metastasis for SCLC is the brain; therefore, SCLC patients are highly susceptible to brain metastases, and the rate of brain metastases is very high among patients who survive for more than two years. Although chemotherapy combined with immunotherapy for SCLC has been approved in recent years, which can improve overall survival (OS) to more than one year, once brain metastases occur, the natural average survival time is only 1-2 months. Even after chemotherapy and whole-brain radiotherapy (WBRT), the median survival of SCLC patients with brain metastases is only about 6 months, and the median central nervous system progression-free survival (CNS PFS) is 3.8 months, severely impacting patients' quality of life and survival time. The prognosis of non-small cell lung cancer without targeted gene mutations is also similarly poor.

[0003] When small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) metastasize to the brain, the patient's clinical symptoms deteriorate rapidly, including headache, nausea and vomiting, intense fatigue, apathy, slowed reaction time, decreased vision or even blindness, severe memory loss, epilepsy, weakness in the limbs, hemiplegia, sensory disturbances on one side of the body, and changes in personality traits. Even loss of smell, olfactory hallucinations, visual hallucinations, and auditory hallucinations may occur. SCLC is characterized by rapid metastasis, occurring earlier than other cancers, severely impacting the patient's will to live and quality of life, even affecting subsequent treatment and ultimately impacting survival. It is a life-threatening disease.

[0004] For SCLC and NSCLC patients with brain metastases who have undergone first-line treatment or whose brain metastases have progressed due to new lesions or existing metastases, there are currently no effective chemotherapy drugs. Whole-brain radiotherapy is currently the only recommended treatment for SCLC and NSCLC brain metastases, but it cannot coordinate or enhance the effects on extracranial lesions and the overall anti-tumor immune response. Therefore, there is an urgent need for drugs and methods that can effectively treat brain metastases of small cell lung cancer and non-small cell lung cancer in clinical practice. Summary of the Invention

[0005] To address the aforementioned problems in the prior art, the present invention provides the following technical solution.

[0006] Firstly, this disclosure provides a technical solution I:

[0007] A method for treating brain metastases from brain cancer or other cancers, or for preventing brain metastases in a subject with other cancers, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof, an isotope label, a solvate, a polymorph, a pharmaceutical composition thereof, or a pharmaceutically acceptable salt thereof.

[0008]

[0009] In one embodiment of the technical solution I of this disclosure, the pharmaceutically acceptable salt of the compound with the structure of formula (I) is selected from fumarate.

[0010] In one embodiment of the technical solution I disclosed herein, the brain metastases of the other cancers are selected from lung cancer brain metastases.

[0011] In one embodiment of the technical solution I disclosed herein, the lung cancer brain metastasis is selected from small cell lung cancer (SCLC) brain metastasis and non-small cell lung cancer (NSCLC) brain metastasis.

[0012] In one embodiment of the technical solution I disclosed herein, the method further includes combined radiotherapy or optional surgical resection of the tumor.

[0013] In one embodiment of the technical solution I disclosed herein, at least the following steps are included, which can be performed in any order during treatment:

[0014] Step (a) administering a daily dose to the subject of a compound of formula (I) and its stereoisomers, isotope labels, solvates, polymorphs, pharmaceutical compositions or pharmaceutically acceptable salts thereof;

[0015]

[0016] Step (b) Treat the patient with radiotherapy;

[0017] And the tumor can be removed optionally.

[0018] In one embodiment of the technical solution I disclosed herein, the radiotherapy is selected from whole-brain radiotherapy or local enhanced radiotherapy as needed clinically.

[0019] In one embodiment of the technical solution I disclosed herein, the lung cancer brain metastasis includes lung cancer brain metastasis that occurs after first-line treatment or during first-line treatment and the original brain metastasis progresses; the lung cancer brain metastasis is selected from small cell lung cancer (SCLC) brain metastasis and non-small cell lung cancer (NSCLC) brain metastasis.

[0020] On the other hand, this disclosure provides a technical solution II:

[0021] Use of a compound of formula (I) or its stereoisomers, isotopic labels, solvates, polymorphs, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing such compounds (optionally as defined in Technical Solution III below), in the preparation of a drug for treating brain metastases of brain cancer or other cancers.

[0022]

[0023] In one embodiment of the technical solution II of this disclosure, the pharmaceutically acceptable salt of the compound with the structure of formula (I) is selected from fumarate.

[0024] In one embodiment of technical solution II of this disclosure, the brain metastases of the other cancers are selected from lung cancer brain metastases.

[0025] In one embodiment of technical solution II of this disclosure, the lung cancer brain metastasis is selected from small cell lung cancer (SCLC) brain metastasis and non-small cell lung cancer (NSCLC) brain metastasis.

[0026] In addition, this disclosure provides a technical solution III:

[0027] A pharmaceutical composition for treating brain metastases from brain cancer or other cancers, or for preventing brain metastases in a subject with other cancers, wherein the pharmaceutical composition comprises a compound of formula (I) or a stereoisomer thereof, an isotope label, a solvate, a polymorph thereof, or a pharmaceutically acceptable salt thereof:

[0028] A pharmaceutical composition for treating brain metastases of brain cancer or other cancers, or for preventing brain metastases in a subject with other cancers, wherein the pharmaceutical composition comprises a unit dose of a compound of formula (I) or a stereoisomer thereof, an isotope label, a solvate, a polymorph thereof, or a pharmaceutically acceptable salt thereof:

[0029]

[0030] In one embodiment of the technical solution III of this disclosure, the pharmaceutically acceptable salt of the compound with the structure of formula (I) is selected from fumarate.

[0031] In one embodiment of technical solution III of this disclosure, the brain metastases of the other cancers are selected from lung cancer brain metastases.

[0032] In one embodiment of technical solution III of this disclosure, the lung cancer brain metastasis is selected from small cell lung cancer (SCLC) brain metastasis and non-small cell lung cancer (NSCLC) brain metastasis.

[0033] According to embodiments of the present invention, the pharmaceutically acceptable salt comprises an acid addition salt formed by the sesquiterpene lactone compound and an inorganic acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate; or an acid addition salt formed by the following organic acids: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy -2-Naphthoic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, tervaline, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid or thiocyanate.

[0034] According to an embodiment of the present invention, the pharmaceutically acceptable salt of the sesquiterpene lactone compound is selected from the following structures:

[0035]

[0036] According to an embodiment of the present invention, the pharmaceutically acceptable salt of the sesquiterpene lactone compound is (3R,3aS,9R,9aS,9bS)-3-((dimethylamino)methyl)-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazolo[4,5-b]furan-2(9bH)-one fumarate monohydrate.

[0037] In some embodiments, the fumarate monohydrate is selected from crystal form D, and the hydrate is subjected to Cu-Kα radiation, X-ray powder diffraction in 2θ angles at 7.8±0.2°, 10.5±0.2°, 11.1±0.2°, 11.4±0.2°, 11.7±0.2°, 12.0±0.2°, 12.6±0.2°, 12.9±0.2°, 14.4±0.2°, 15.3±0.2°, 15.6±0.2°, 15.9±0.2°, 16.2±0.2°, 17.0±0.2°, 18 Characteristic peaks are observed at one or more of the following locations: 0.7±0.2°, 19.7±0.2°, 20.6±0.2°, 21.0±0.2°, 21.3±0.2°, 22.1±0.2°, 22.5±0.2°, 23.0±0.2°, 23.7±0.2°, 24.3±0.2°, 25.5±0.2°, 26.2±0.2°, 26.4±0.2°, 27.2±0.2°, 28.2±0.2°, 28.6±0.2°, 29.3±0.2°, 30.4±0.2°, and 31.1±0.2°. The crystal form D is orthorhombic, with space group P212121 and cell parameters of [missing information]. α = 90°, β = 90°, γ = 90°, cell volume is

[0038] According to this disclosure, a “certain dose” means administering 1 to 10 units (selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) to the patient daily. In some embodiments, the administration frequency is 1, 2, 3, or 4 times daily, with each administration consisting of 1, 2, or 3 units.

[0039] According to this disclosure, the unit dose is 20 mg to 1000 mg, for example, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg; in some embodiments, the unit dose is 50-250 mg, or 350-450 mg, or 550-650 mg, or 850-950 mg.

[0040] According to embodiments of the present invention, the pharmaceutical composition is selected from liquid, gaseous, solid, or semi-solid dosage forms. In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the pharmaceutical composition is a capsule.

[0041] According to an embodiment of the present invention, the pharmaceutical composition includes at least one pharmaceutically acceptable excipient.

[0042] In some embodiments, when the pharmaceutical composition is in the form of a capsule, no other excipients are added besides the active pharmaceutical ingredient.

[0043] According to an embodiment of the present invention, the radiotherapy is selected from whole-brain radiotherapy (WBRT) or local enhanced radiotherapy as needed clinically.

[0044] According to embodiments of the present invention (e.g., embodiments of any one of the first to fourth aspects), the lung cancer brain metastasis includes lung cancer brain metastasis that occurs after first-line treatment or during first-line treatment when new lesions appear in the brain or the original brain metastasis progresses.

[0045] According to an embodiment of the present invention (e.g., according to any one of the first to fourth aspects), the lung cancer brain metastasis is selected from small cell lung cancer (SCLC) brain metastasis and non-small cell lung cancer (NSCLC) brain metastasis.

[0046] According to embodiments of the present invention (e.g., embodiments of any one of the first to fourth aspects), the sesquiterpene lactone compounds and their stereoisomers, isotope labels, solvates, polymorphs or pharmaceutically acceptable salts thereof can activate antitumor immune responses and thereby enhance the effects of radiotherapy.

[0047] According to embodiments of the present invention, the sesquiterpene lactone compound and its stereoisomers, isotope labels, solvates, polymorphs, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the first aspect, can be administered via a variety of routes, including but not limited to: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local administration, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal administration. In some embodiments, the route is oral administration.

[0048] In some embodiments, the sesquiterpene lactone compound and its stereoisomers, isotope-labeled forms, solvates, polymorphs, or pharmaceutically acceptable salts thereof are administered to the patient as the sole active ingredient. In other embodiments, the sesquiterpene lactone compound and its stereoisomers, isotope-labeled forms, solvates, polymorphs, or pharmaceutically acceptable salts thereof may be administered to the patient simultaneously or sequentially with other active ingredients. Other active ingredients may be selected from conventional antitumor drugs, such as drugs for treating lung cancer.

[0049] Those skilled in the art will understand that the term "isotope label" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl)-labeled compounds of the present invention. Isotope-labeled compounds of the present invention can be used for the determination of the tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such determinations include 3 H and 14 C. Furthermore, in some cases, substitution with a heavier isotope (e.g., deuterium (2H or D)) can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0050] In some embodiments, the isotope label includes a deuterated form of the sesquiterpene lactone compound.

[0051] Those skilled in the art will understand that the dosages described herein (e.g., a certain dosage, unit dosage, or daily dosage, etc.) are all calculated based on the anhydrous form of the active ingredient.

[0052] Those skilled in the art will understand that the term "therapeutic effective dose" as used herein includes application options such as "a certain dose" and "unit dose".

[0053] Beneficial effects

[0054] The drug of the present invention can significantly enhance the efficacy of radiotherapy for lung cancer brain metastases, reduce the toxic side effects of whole-brain radiotherapy, activate anti-tumor immune response to enhance the radiotherapy effect, thereby improving the potential of systemic anti-tumor activity; taking the drug of the present invention can also significantly improve cancer patient compliance. Attached Figure Description

[0055] Figure 1 Kaplan-Meier survival curve analysis of compound 1 in Phase IIb clinical trial. Detailed Implementation

[0056] The present invention will now be described in detail with reference to the accompanying drawings. This description is merely illustrative and explanatory, and should not be construed as limiting the scope of protection of the present invention. Furthermore, those skilled in the art can combine the features in the embodiments described herein and in different embodiments accordingly based on the description in this document.

[0057] The active pharmaceutical ingredient used in the efficacy examples of this invention is (3R,3aS,9R,9aS,9bS)-3-((dimethylamino)methyl)-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazolo[4,5-b]furan-2(9bH)-ketofumarate (referred to as compound 1). Specifically, it is used in its monohydrate crystal form D, which can be prepared according to CN 111303100B. The dosage form is capsules (prepared according to Example 15 of CN 111303100B).

[0058] The structure of compound 1 is as follows:

[0059] The pharmacodynamics example is a randomized, blinded, placebo-controlled phase IIb / III clinical trial evaluating the efficacy of compound 1 in enhancing radiotherapy for brain metastases in lung cancer and reducing the toxic side effects of whole-brain radiotherapy. Phase IIb is stage 1, and phase III is stage 2. Participants in phase IIb were not included in the final analysis of the phase III study. According to the trial design, interim analyses were conducted in phase IIb at two points: when 60 small cell lung cancer patients were enrolled and followed up for 3 months after completing radiotherapy, and when at least 80 non-small cell lung cancer patients were enrolled and evaluable for efficacy were available. The order of the two interim analyses corresponded to the order of the aforementioned events; however, no termination was initiated based on efficacy or ineffectiveness. Adaptive modifications were made to the phase III trial based on the results of the interim analyses and a pre-defined modification plan. The trial design details and key clinical findings are as follows:

[0060] 1.1 Enrolled patients:

[0061] Patients aged 18-75 years with histologically or cytologically confirmed lung cancer (small cell lung cancer and non-small cell lung cancer), who have received second-line or higher treatment and have developed brain metastases, are eligible for enrollment. Patients who develop new brain metastases or whose existing brain metastases progress during or after first-line treatment may be admitted.

[0062] 1.2 Main efficacy evaluation:

[0063] To evaluate the efficacy of compound 1 in combination with whole-brain radiotherapy for intracranial tumors in patients with lung cancer brain metastases; the primary endpoint was the 3-month objective response rate (ORR) for intracranial tumors [based on the results of assessment by the Independent Imaging Committee (IRC) according to the Evaluation Criteria for the Treatment of Solid Tumors (RECIST) v1.1].

[0064] 1.3 Evaluation of secondary therapeutic effects:

[0065] (1) The efficacy of compound 1 in combination with whole brain radiotherapy for intracranial and extracranial tumors in patients with lung cancer brain metastases was evaluated using other efficacy endpoints; secondary endpoints were: overall survival (OS), time to disease progression (TTP) [based on IRC assessment according to RECIST v1.1 criteria]; and depth of response (DPR) [based on IRC assessment according to RECIST v1.1 criteria].

[0066] (2) Evaluation of the effect of compound 1 in reducing the adverse reactions of whole brain radiotherapy: including the incidence of SAE within 3 months after radiotherapy; the percentage of subjects who completed the 12-week follow-up visit after radiotherapy; the incidence of grade ≥2 WBRT-related AEs; and the incidence of late neurological impairment events caused by WBRT.

[0067] (3) Assessment of the effect of compound 1 on the quality of life of patients with lung cancer brain metastases: changes in QLQ-C30 scores (overall health status Q29+Q30, cognitive function Q20+Q25).

[0068] (4) Evaluation of the pharmacokinetic (PK) characteristics of compound 1 in the test population: Single-dose PK parameters: peak concentration (Cmax), time to peak concentration (Tmax), area under the curve of drug-time over the dosing interval (AUC0-tau), area under the curve of drug-time from 0 time after dosing to the last measurable concentration time point (AUC0-last); if data permits, also calculate the area under the curve of drug-time from 0 time to infinity (AUC0-inf), apparent clearance (CL / F), apparent volume of distribution (VZ / F), and elimination half-life (t1 / 2), etc.; Multiple-dose PK parameters: Cmax, Tmax, trough concentration (Cmin), AUC0-tau, accumulation ratio (Rac_Cmax and Rac_AUC0-tau), etc.

[0069] 1.4 Phase IIb Clinical Trial Results - Baseline Balanced Comparability Among Groups

[0070] The trial (ending July 31, 2024) screened a total of 165 patients with SCLC and NSCLC, and randomly assigned 110 patients to each group. Of these, 60 were SCLC patients, 41 were in the compound 1 group, and 19 were in the placebo group. 60 patients were included in the FAS group, 50 in the PPS group, and 50 in the IN-REAS group. The distribution and baseline characteristics of the participants were balanced across groups, and drug exposure and adherence were similar across groups, making the trial results reliable and comparable, as detailed below:

[0071] The demographic data of the subjects in the SCLC compound 1 group and the placebo group were comparable: the mean age of the enrolled patients was 60.9 ± 7.46 years, and the proportion of males was 91.7%; GPA scores, KPS scores, and radiotherapy regimens were comparable between the SCLC compound 1 group and the placebo group. 83.3% of patients had a baseline GPA score of 1-4; 78.3% of patients received WBRT plus local boost; 63.3% of patients had a baseline KPS score of 90-100; the radiotherapy duration and dose intensity were similar between the SCLC compound 1 group and the placebo group: the mean radiotherapy duration was approximately 16-18 days, and the actual dose intensity was approximately 13.65; the mean exposure days in the SCLC compound 1 group were 138.0 ± 84.43 days, the median exposure time was 118 days, and 87.9% of patients... The exposure duration was >8 weeks, with 7.3% of patients exposed for <4 weeks, and 97.6% of patients had good adherence. The proportion of patients receiving concurrent treatment in the SCLC compound 1 group and the placebo group was comparable: a total of 51 subjects (85%) received other anti-tumor drugs, including taxanes (38.3%), PD-1 / PD-L1 inhibitors (30.0%), and platinum compounds (30.3%). The distribution of last-line treatments among SCLC subjects within the compound 1 group and the placebo group was relatively balanced and consistent. The total population also showed a uniform distribution of prior first-line (46.7%) and second-line (46.7%) treatments.

[0072] 1.5 Phase IIb Clinical Trial Results - Efficacy Data

[0073] (1) Based on the investigator's assessment results, in both the FAS, IN-REAS, and PPS sets, the intracranial ORR of compound 1 within 3 months after secondary confirmation reached over 50%, and all 3 cases of CR after secondary confirmation were in compound 1. In the FAS set, the intracranial ORR of compound 1 within 3 months was 53.7% vs. 31.6% in the placebo group (p=0.0765); in the IN-REAS set, it was 62.9% vs. 40.0% in the compound 1 group (p=0.1291); and in the PPS set, it was 62.9% vs. 33.3% in the compound 1 group (p=0.0339). The trends in the three datasets were consistent, indicating robust and outstanding efficacy. Based on the IRC assessment results, in both the FAS, IN-REAS, and PPS sets, the intracranial ORR of compound 1 within 3 months after secondary confirmation reached over 58%. In the FAS dataset, the intracranial ORR within 3 months was 58.5% in compound 1 versus 31.6% in the placebo group (p = 0.04305); in the IN-REAS dataset, the ORR was 68.6% in compound 1 versus 40.0% in the placebo group (p = 0.0653); and in the PPS dataset, the ORR was 68.6% in compound 1 versus 33.3% in the placebo group (p = 0.0184). The trends in the three datasets were consistent, indicating robust and outstanding efficacy.

[0074] (2) Based on investigator assessment, subgroup sensitivity analysis, except for the subgroup with ≥3 lines of treatment, showed a preference for intracranial ORR benefit in the compound 1 group. Based on IRC assessment, subgroup sensitivity analysis, except for the subgroup with ≥3 lines of treatment, showed a preference for intracranial ORR benefit in the compound 1 group.

[0075] (3) Based on the FAS set, as of July 31, 2024, the number of patients who died in the compound 1 group was 22 (53.7%) vs. 14 (73.7%) in the placebo group, and the number of patients still enrolled in the compound 1 group was 17 (41.5%) vs. 3 (15.8%) in the placebo group. The median OS (95% CI) was 9.5 vs. 6.2 months in the compound 1 group and 0.5 (95% CI) in the placebo group, indicating a significant benefit. Compound 1 significantly improved adherence in SCLC patients, with a significantly higher proportion of enrolled patients compared to the placebo group. Furthermore, based on the proportion of enrolled patients, the future benefit trend was significantly higher in the compound 1 group than in the placebo group. The ORR trend was consistent with the OS benefit trend, indicating remission of intracranial lesions and significantly prolonging patient survival (see [link to study]). Figure 1 and table 1) below.

[0076] Table 1. Median OS and HR of subjects in the FAS group

[0077]

[0078]

[0079] (4) From the perspective of objective complete remission rate over time (investigator imaging assessment), 8 patients with the best remission in SCLC achieved CR (complete remission, 19.5%), all in the compound 1 group, while 0 patients were in the placebo group, demonstrating the superior efficacy of compound 1. The overall survival (OS) of the 8 CR patients was relatively long (updated to December 31, 2024), with a current average of more than 356 days, and this is continuing to increase.

[0080] (5) When the last line of treatment was first-line, the ORR within 3 months after secondary confirmation was 55.6% vs. 30% in the compound 1 group versus placebo group, with a rate difference of 25.56; the median OS was 9.5 vs. 6.1 months in the compound 1 group versus placebo group, with a HR (95% CI) of 0.5 (0.19, 1.18). When the last line of treatment was second-line, the ORR within 3 months after secondary confirmation was 50.0% vs. 25.0% in the compound 1 group versus placebo group, with a rate difference of 25.0; the median OS was 11.6 vs. 6.0 months in the compound 1 group versus placebo group, with a HR (95% CI) of 0.5 (0.17, 1.38). Regardless of whether the last line of treatment before enrollment was first-line or second-line, the ORR and OS benefit trends in the compound 1 group versus placebo were consistent, with the compound 1 group showing a significant benefit.

[0081] (6) Based on the FAS set, for patients who had received chemotherapy combined with immunotherapy before enrollment, the ORR within 3 months after secondary confirmation was 64.7% vs. 30% in the compound 1 group versus placebo group, with a rate difference of 34.71. The median OS was 9.6 vs. 8.4 months in the compound 1 group versus placebo group, with a HR (95% CI) of 0.5 (0.15, 1.37). Based on the FAS set, for patients who had not received chemotherapy combined with immunotherapy before enrollment, the ORR within 3 months after secondary confirmation was 45.8% vs. 33.3% in the compound 1 group versus placebo group, with a rate difference of 12.5. The median OS was 8.7 vs. 6.0 months in the compound 1 group versus placebo group, with a HR (95% CI) of 0.5 (0.21, 1.19). These results show that, based on the FAS set, regardless of whether chemotherapy combined with immunotherapy was received before enrollment, the ORR and OS benefit trends of the compound 1 group versus placebo group were consistent, with compound 1 showing a significant benefit.

[0082] (7) Based on the IN-REAS set, for patients who had received chemotherapy combined with immunotherapy prior to enrollment, the ORR within 3 months after secondary confirmation was 68.8% in the compound 1 group vs. 37.5% in the placebo group, with a rate difference of 31.25, and the median OS was 9.6 months in the compound 1 group vs. 9.5 months in the placebo group, with a HR (95% CI) of 0.5 (0.15, 1.98). Based on the IN-REAS set, for patients who had not received chemotherapy combined with immunotherapy prior to enrollment, the ORR within 3 months after secondary confirmation was 57.9% in the compound 1 group vs. 42.9% in the placebo group, with a rate difference of 15.04, and the median OS was 8.7 months in the compound 1 group vs. 6.0 months in the placebo group, with a HR (95% CI) of 0.5 (0.19, 1.44). The results above show that, based on the IN-REAS set, regardless of whether chemotherapy combined with immunotherapy was used before enrollment, the ORR and OS benefits of compound 1 group versus placebo were consistent, with compound 1 showing a significant benefit.

[0083] 1.6 Phase IIb Clinical Trial Results - Safety Data

[0084] Compound 1-CN-051 enrolled 110 patients with lung cancer brain metastases. The SCLC cohort included 60 patients in the safety set, with 41 in the compound 1 group and 19 in the placebo group. In terms of the incidence of serious adverse events (SAEs) related to the study drug, adverse events of particular concern (AESIs), and grade 3 or higher AEs, the experimental group and the placebo group were essentially comparable. All AEs leading to death were unrelated to the study drug, indicating good safety (Table 2).

[0085] Table 2. Safety data analysis of small cell lung cancer subjects in the IIb trial.

[0086]

[0087]

[0088] Based on subgroup analysis data up to March 10, 2025, among the 20 small cell lung cancer subjects who received checkpoint antibodies after enrollment, the median overall survival (OS) of the 12 patients in the compound 1 treatment group was significantly higher than that of the 8 patients in the placebo group (Table 3).

[0089] Table 3. Overall survival (OS) analysis of the checkpoint antibody subgroup.

[0090]

[0091] During the trial of compound 1-CN-051, some SCLC subjects were found to have new tumor lesions but stable disease. After being discharged according to disease progression, these patients continued to survive for up to six months. Two SCLC subjects developed new lesions and were discharged according to disease progression, but they continued to survive for nine and four months respectively. This data also suggests that compound 1 may prolong overall survival (OS) through tumor immunity.

[0092] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for treating brain metastases from brain cancer or other cancers, or for preventing brain metastases in a subject with other cancers, wherein, This includes administering a therapeutically effective amount of a compound of formula (I) or its stereoisomers, isotopic labels, solvates, polymorphs, pharmaceutical compositions, or pharmaceutically acceptable salts thereof to subjects in need.

2. The method according to claim 1, wherein, Pharmaceutically acceptable salts of compounds with the structure of formula (I) are selected from fumarate salts.

3. The method according to claim 1 or 2, wherein, The brain metastases of the other cancers mentioned were selected from lung cancer brain metastases.

4. The method according to claim 3, wherein, The lung cancer brain metastases mentioned are selected from small cell lung cancer (SCLC) brain metastases and non-small cell lung cancer (NSCLC) brain metastases.

5. The method according to any one of claims 1-4, wherein, The method further includes combined radiotherapy or, optionally, surgical resection of the tumor.

6. The method according to any one of claims 1-5, comprising at least the following steps, which may be performed in any order during treatment: Step (a) administering a daily dose to the subject of a compound of formula (I) and its stereoisomers, isotope labels, solvates, polymorphs, pharmaceutical compositions or pharmaceutically acceptable salts thereof; Step (b) Treat the patient with radiotherapy; And the tumor can be removed optionally.

7. The method according to claim 5 or 6, wherein, The radiotherapy is selected from whole-brain radiotherapy or local enhanced radiotherapy as needed clinically.

8. The method according to claim 6 or 7, wherein, The lung cancer brain metastases include lung cancer brain metastases that occur after first-line treatment or during first-line treatment, or that have progressed from the original brain metastases. The lung cancer brain metastases mentioned are selected from small cell lung cancer (SCLC) brain metastases and non-small cell lung cancer (NSCLC) brain metastases.

9. Use of a compound of formula (I) or its stereoisomers, isotope labels, solvates, polymorphs, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing thereof, in the preparation of a medicament for the treatment of brain metastases of brain cancer or other cancers.

10. The use according to claim 9, wherein, The pharmaceutically acceptable salts of compounds with the structure of formula (I) are selected from fumarates.

11. The use according to claim 10 or 11, wherein, The brain metastases of the other cancers mentioned were selected from lung cancer brain metastases.

12. The method according to claim 11, wherein, The lung cancer brain metastases mentioned are selected from small cell lung cancer (SCLC) brain metastases and non-small cell lung cancer (NSCLC) brain metastases.

13. A pharmaceutical composition for treating brain metastases from brain cancer or other cancers, or for preventing brain metastases in subjects with other cancers, wherein, The pharmaceutical composition comprises a compound of formula (I) or a stereoisomer thereof, an isotope label, a solvate, a polymorph thereof, or a pharmaceutically acceptable salt thereof:

14. The pharmaceutical composition according to claim 13, wherein, Pharmaceutically acceptable salts of compounds with the structure of formula (I) are selected from fumarate salts.

15. The pharmaceutical composition according to claim 13 or 14, wherein, The brain metastases of the other cancers mentioned were selected from lung cancer brain metastases.

16. The pharmaceutical composition according to any one of claims 13-15, wherein, The lung cancer brain metastases mentioned are selected from small cell lung cancer (SCLC) brain metastases and non-small cell lung cancer (NSCLC) brain metastases.

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