Use of compound for treating non-small cell lung cancer

Abstract

The invention discloses an application of a compound for treating non-small cell lung cancer. Specifically, the invention discloses application of a compound I or pharmaceutically acceptable salts thereof in preparation of drugs for treating non-small cell lung cancer. # imgabs0 #

Description

[0001] This application claims the priority of PCT patent application PCT / CN2023 / 108205 with a filing date of 2023 / 07 / 19 and Chinese patent application 2023116708230 with a filing date of 2023 / 12 / 07. This application cites the entire text of the above patent application. Technical Field

[0002] The invention belongs to the field of medicine, and specifically relates to use of a compound for treating non-small cell lung cancer. Background Art

[0003] Non-small cell lung cancer accounts for about 84% of all lung cancers. It is usually diagnosed in the late stage and is accompanied by poor prognosis and low survival rate. Current treatments for non-small cell lung cancer include surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, etc.

[0004] Sequencing results for non-small cell lung cancer have shown that there are gene mutations including EGFR, KRAS, ROS1, BRAF, NTRK, ALK, etc. at the molecular level, which is one of the main causes of non-small cell lung cancer and is also called a driver gene. Among them, the incidence of ROS1 rearrangement is about 1% to 2%. ROS1 gene rearrangement is more common in young patients who do not smoke or smoke lightly, and rarely overlaps with other lung cancer gene mutations such as EGFR, KRAS and ALK rearrangements. The proto-oncogene ROS1 encodes a receptor tyrosine kinase with unknown physiological effects in humans. However, after ROS1 rearrangement and activation, phosphorylation occurs at tyrosine residues 2274 and 2334 of the kinase domain, and the activity of downstream substrate proteins is enhanced, thereby promoting the survival, growth, proliferation, migration and invasion of tumor cells. So far, 23 different ROS1 fusion mutations have been identified. In non-small cell lung cancer, CD74-ROS1 is the most common, with an incidence of up to 50%. The exact mechanism of ROS1 kinase activation in fusion proteins has not yet been determined, but it is known that most fusion partners lack the basic kinase activation domain (Remon J, Pignataro D, Novello S, Passiglia F. Current treatment and future challenges in ROS1-and ALK-rearranged advanced non-small cell lung cancer. Cancer Treat Rev. 2021Apr; 95: 102178; Drilon A, Jenkins C, Iyer S, Schoenfeld A, Keddy C, Davare MA. ROS1-dependent cancers-biology, diagnostics and therapeutics. Nat Rev Clin Oncol. 2021Jan; 18(1): 35-55).

[0005] ROS1 fusion is a classic "diamond mutation" in non-small cell lung cancer. Since its discovery, new targeted drugs have been continuously introduced. Currently, the ROS1 inhibitors approved for marketing in China include crizotinib and entrectinib.

[0006] Drug resistance is a common problem in the treatment of non-small cell lung cancer. Due to the development of drug resistance, patients may experience rapid disease progression during treatment or shortly after treatment. Therefore, there is still a need for new therapies that can effectively treat non-small cell lung cancer. Summary of the invention

[0007] The present invention aims to provide a compound for use in treating non-small cell lung cancer.

[0008] The present invention provides a use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer;

[0009]

[0010] In some embodiments, the non-small cell lung cancer is ROS1-positive non-small cell lung cancer.

[0011] In some embodiments, the non-small cell lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, large cell carcinoma, or sarcomatoid carcinoma. In some embodiments, the non-small cell lung cancer is lung adenocarcinoma.

[0012] In some embodiments, the non-small cell lung cancer is resistant to at least one anticancer agent, wherein the at least one anticancer agent does not include Compound I.

[0013] In some embodiments, the at least one anticancer agent is at least one of the following anticancer agents: a chemotherapeutic drug, an immune checkpoint inhibitor, an anti-angiogenesis inhibitor, a tyrosine kinase inhibitor; wherein the tyrosine kinase inhibitor does not include Compound I.

[0014] In some embodiments, the non-small cell lung cancer is resistant to at least one chemotherapeutic drug. In some embodiments, the at least one chemotherapeutic drug is at least one of the following chemotherapeutic drugs: dihydrofolate reductase inhibitors (e.g., pemetrexed, docetaxel), thymidylate synthase inhibitors (e.g., gemcitabine, vinorelbine), platinum complexes (e.g., cisplatin, carboplatin, nedaplatin), taxanes (e.g., paclitaxel, albumin paclitaxel), topoisomerase inhibitors (e.g., etoposide).

[0015] In some embodiments, the non-small cell lung cancer is resistant to at least one dihydrofolate reductase inhibitor. In some embodiments, the at least one dihydrofolate reductase inhibitor is at least one of the following dihydrofolate reductase inhibitors: pemetrexed, docetaxel.

[0016] In some embodiments, the non-small cell lung cancer is resistant to at least one thymidylate synthase inhibitor. In some embodiments, the at least one thymidylate synthase inhibitor is at least one of the following thymidylate synthase inhibitors: gemcitabine, vinorelbine.

[0017] In some embodiments, the non-small cell lung cancer is resistant to at least one platinum complex. In some embodiments, the at least one platinum complex is at least one of the following platinum complexes: cisplatin, carboplatin, nedaplatin.

[0018] In some embodiments, the non-small cell lung cancer is resistant to at least one taxane. In some embodiments, the at least one taxane is at least one of the following taxanes: paclitaxel, nab-paclitaxel.

[0019] In some embodiments, the non-small cell lung cancer is resistant to at least one topoisomerase inhibitor. In some embodiments, the at least one topoisomerase inhibitor is etoposide.

[0020] In some embodiments, the non-small cell lung cancer is resistant to the combination of platinum complexes and taxanes. In the combination, examples of platinum complexes and taxanes can be as described above; specific examples of the combination include, but are not limited to, a combination of albumin paclitaxel and carboplatin, a combination of albumin paclitaxel and cisplatin, a combination of albumin paclitaxel and nedaplatin, a combination of paclitaxel and cisplatin, a combination of paclitaxel and carboplatin, and a combination of paclitaxel and nedaplatin.

[0021] In some embodiments, the non-small cell lung cancer is resistant to the combination of a platinum complex and a dihydrofolate reductase inhibitor. In the combination, examples of platinum complexes and dihydrofolate reductase inhibitors can be as described above; specific examples of the combination include, but are not limited to, a combination of pemetrexed and carboplatin, a combination of pemetrexed and cisplatin, a combination of pemetrexed and nedaplatin, a combination of docetaxel and carboplatin, a combination of docetaxel and cisplatin, and a combination of docetaxel and nedaplatin.

[0022] In some embodiments, the non-small cell lung cancer is resistant to the combination of a platinum complex and a thymidylate synthase inhibitor. In the combination, examples of platinum complexes and thymidylate synthase inhibitors can be as described above; examples of the combination include, but are not limited to, a combination of gemcitabine and carboplatin, a combination of gemcitabine and cisplatin, a combination of gemcitabine and nedaplatin, a combination of vinorelbine and carboplatin, a combination of vinorelbine and cisplatin, and a combination of vinorelbine and nedaplatin.

[0023] In some embodiments, the non-small cell lung cancer is resistant to a combination of a platinum complex and a topoisomerase inhibitor. In the combination, examples of platinum complexes and topoisomerase inhibitors can be as described above; specific examples of the combination include, but are not limited to, a combination of etoposide and carboplatin, a combination of etoposide and cisplatin, and a combination of etoposide and nedaplatin.

[0024] In some embodiments, the non-small cell lung cancer is resistant to at least one immune checkpoint inhibitor. In some embodiments, the at least one immune checkpoint inhibitor is at least one of the following immune checkpoint inhibitors: anti-PD-1 / PD-L1 antibody, anti-LAG3 antibody.

[0025] In some embodiments, the non-small cell lung cancer is resistant to at least one anti-PD-1 / PD-L1 antibody. In some embodiments, the at least one anti-PD-1 / PD-L1 antibody is at least one of the following anti-PD-1 / PD-L1 antibodies: tislelizumab, nivolumab, pembrolizumab, atezolizumab, carrelizumab, sintilimab, slulizumab, sugemalimab, penampalimumab, durvalumab, toripalimumab, AK112 (ivonescimab). In some embodiments, the non-small cell lung cancer is resistant to tislelizumab. In some embodiments, the non-small cell lung cancer is resistant to AK112.

[0026] In some embodiments, the non-small cell lung cancer is resistant to at least one anti-LAG3 antibody. In some embodiments, the at least one anti-LAG3 antibody is SHR-1802.

[0027] In some embodiments, the non-small cell lung cancer is resistant to at least one anti-angiogenesis inhibitor. In some embodiments, the at least one anti-angiogenesis inhibitor is at least one of the following anti-angiogenesis inhibitors: bevacizumab, recombinant human endostatin (eg, endostatin).

[0028] In some embodiments, the non-small cell lung cancer is resistant to at least one tyrosine kinase inhibitor, wherein the at least one tyrosine kinase inhibitor does not include Compound I. In some embodiments, the at least one tyrosine kinase inhibitor is at least one of the following tyrosine kinase inhibitors: crizotinib, entrectinib, icotinib, succinate frutinib, ensartinib, APG-2449, anlotinib, ceritinib, osimertinib, ametinib, vometinib, afatinib, dacomitinib, gefitinib, erlotinib, mobosetinib, alectinib, brigatinib, lorlatinib, capmatinib, tepotinib, pralsetinib, sepretinib, dabrafenib, trametinib, larotrectinib, savotinib, pyrotinib, lorlatinib, LZ001, AB-106 (Taletrectinib), TQ-B3139 (Envonalkib), TPX-0005 (Repotrectinib), TL139. In some embodiments, the non-small cell lung cancer is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is resistant to entrectinib. In some embodiments, the non-small cell lung cancer is resistant to ensartinib. In some embodiments, the non-small cell lung cancer is resistant to APG-2449. In some embodiments, the non-small cell lung cancer is resistant to AB-106. In some embodiments, the non-small cell lung cancer is resistant to TPX-0005.

[0029] In some embodiments, the resistance is primary resistance.

[0030] In some embodiments, the resistance is acquired resistance.

[0031] Compound I and its pharmaceutically acceptable salts can be administered in any suitable manner, including oral administration, injection, etc. In some embodiments, Compound I and its pharmaceutically acceptable salts can be formulated for oral administration. The effective amount of Compound I and its pharmaceutically acceptable salts can vary according to the compound, the disease and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0032] Depending on the administration method, Compound I and its pharmaceutically acceptable salts can be formulated into various suitable dosage forms, including tablets and the like.

[0033] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0034] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0035] The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.

[0036] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0037] The term "patient" refers to any animal that is about to or has been administered, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0038] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0039] The reagents and raw materials used in the present invention are commercially available. DETAILED DESCRIPTION

[0040] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0041] The compound I in the following examples refers to

[0042] Example 1: Clinical trial evaluating the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of Compound I in patients with ROS1-positive non-small cell lung cancer

[0043] Screen eligible subjects for clinical trials.

[0044] Effectiveness Assessment:

[0045] (1) The tumor response to treatment was measured according to RECIST 1.1 criteria.

[0046] Disease progression (PD) is the increase of the sum of the maximum diameters of target lesions by at least 20%, or the appearance of new lesions.

[0047] Stable disease (SD): The sum of the maximum diameters of target lesions does not decrease to PR or increase to PD.

[0048] Partial response (PR): The sum of the maximum diameters of target lesions decreases by ≥30% and lasts for at least 4 weeks.

[0049] Complete response (CR): All target lesions disappear, no new lesions appear, and tumor markers are normal, which lasts for at least 4 weeks.

[0050] (2) Evaluate overall survival, median survival, progression-free survival, objective response rate, disease control rate, and duration of response.

[0051] Safety assessment: Evaluate adverse reactions and their incidence associated with the investigational drug.

[0052] Subject 1

[0053] A patient with lung adenocarcinoma was diagnosed with pathology, and NGS test confirmed ROS1 gene fusion mutation. The patient had previously resisted multiple lines of treatment, such as first-line icotinib, second-line crizotinib, third-line pemetrexed combined with carboplatin, and fourth-line succinate frutinib, of which crizotinib and succinate frutinib are tyrosine kinase inhibitors targeting ROS1; icotinib is a tyrosine kinase inhibitor targeting EGFR; pemetrexed and carboplatin are chemotherapy drugs. The subject participated in the clinical trial after multiple lines of treatment resistance. Vital signs, physical examination, ECOG physical score, infectious disease markers, blood routine, urine routine, coagulation function, liver function, kidney function, electrolytes, fasting blood sugar, blood lipids, 12-lead electrocardiogram and other examinations were performed at baseline to meet the inclusion criteria. Imaging studies before enrollment determined the location and size of the target lesions to be (1) right upper lung, 15 mm in diameter, (2) left upper lung, 15.5 mm in diameter, (3) lymph node (right neck), 25.4 mm in diameter, (4) lymph node (in front of the superior vena cava), 28.5 mm in diameter, and (5) brain (left frontal lobe), 13.6 mm, for a total diameter of 97.8 mm.

[0054] After the subject received Compound I monotherapy on 2023-01-02, the specific administration method was as follows: Compound I tablets, taken orally on an empty stomach, once a day, 300 mg each time, for continuous administration. Vital signs, physical examination, blood routine examination, urine routine examination, liver function, kidney function, electrolytes, fasting blood sugar, blood lipids, 12-lead electrocardiogram and other examinations were performed weekly (within the first month after taking the medicine) or every two weeks (after the first month after taking the medicine). No serious side effects occurred during the medication period; after Compound I monotherapy, the first imaging tumor assessment on 2023-01-29 showed that (1) the right upper lung had a diameter of 8.5 mm, (2) the left upper lung had a diameter of 10.5 mm; (3) the lymph node (right neck) had a diameter of 19.9 mm, (4) the lymph node (in front of the superior vena cava) had a diameter of 26.5 mm, (5) the brain (left frontal lobe) had a diameter of 8.7 mm, and the total diameter was 74.1 mm. Compared with baseline, the overall diameter of the tumor decreased by 24.2%, and the overall diameter of brain tumor metastases decreased by 36%; the swelling rating continued to be SD on 2023-03-22 and 2023-05-18, and there were no serious adverse reactions related to the medication during the medication.

[0055] Subject 2

[0056] Female, 33 years old, was first diagnosed with stage IV lung adenocarcinoma on 2022-01-06, and genetic testing indicated positive ROS1 rearrangement. The disease progressed after first-line crizotinib and second-line ensartinib, both of which are tyrosine kinase inhibitors targeting ROS1. The subject was enrolled in the clinical trial on 2022-10-24 and took compound I for the first time at a dose of 250 mg once a day. The subject's baseline target lesion sum was 74mm, and the first tumor assessment on 2022-11-25 was 43mm. The overall assessment was PR, and the tumor was 41.9% smaller than the baseline; and PR was continuously evaluated on 2023-01-20, 2023-03-17, and 2023-05-12. The subject's disease progression-free survival after medication was close to 8 months, and there were no serious adverse reactions related to medication during the medication period.

[0057] Subject 3

[0058] Male, 47 years old, first diagnosed with stage IIIa lung adenocarcinoma on 2018-12-12, metastasized during subsequent drug treatment and diagnosed with stage IV lung adenocarcinoma. Genetic testing of the subject indicated positive ROS1 rearrangement. He was resistant to multiple lines of drugs such as crizotinib, docetaxel combined with pemetrexed, anlotinib, ensartinib and gemcitabine, and albumin paclitaxel. Among them, crizotinib and ensartinib are tyrosine kinase inhibitors targeting ROS1; anlotinib is a multi-target tyrosine kinase inhibitor; docetaxel, gemcitabine, and albumin paclitaxel are chemotherapy drugs. The subject was enrolled in the clinical trial on 2022-08-03 and took compound I for the first time at a dose of 100 mg once a day. The subject's baseline target lesion sum was 71mm, and the first tumor assessment on 2022-08-29 was 51.1mm. The overall assessment was SD, and the tumor was 28% smaller than the baseline; and it was continuously assessed as SD of tumor shrinkage on 2022-12-20 and 2023-02-13. The subject's disease progression-free survival after medication was 8 months, and there were no serious adverse reactions related to medication during the medication period.

[0059] Subject 4

[0060] Male, 54 years old, first diagnosed with stage IV lung adenocarcinoma on November 12, 2017. Genetic testing of the subject indicated that he was positive for ROS1 rearrangement. He was resistant to multiple lines of treatment including cisplatin combined with pemetrexed, tislelizumab, docetaxel, crizotinib, gemcitabine combined with cisplatin, albumin paclitaxel combined with carboplatin, ceritinib, and SHR-1802. Among them, crizotinib and ceritinib are targeted ROS1 tyrosine kinase inhibitors; tislelizumab and SHR-1802 are immune checkpoint inhibitors; docetaxel, gemcitabine, cisplatin, and albumin paclitaxel are chemotherapy drugs; the subject was enrolled in the clinical trial on October 31, 2022, and took compound I for the first time, at a dose of 250 mg once a day. The subject's baseline target lesion sum was 69mm, and the first tumor assessment on November 28, 2022 showed a sum of 60.2mm. The overall assessment was SD, and the tumor was shrunk by 12.8% compared with the baseline; and the SD of shrinkage was continuously assessed on 2023-01-06, 2023-03-15, 2023-05-09, 2023-07-04, 2023-08-30, 2023-10-24, 2024-01-16, and 2024-04-15. The subject had no disease progression for more than 20 months. The subject had no serious adverse reactions related to medication during the medication.

[0061] Subject 5

[0062] Male, 55 years old, first diagnosed with stage IV lung adenocarcinoma in March 2022, genetic testing of the subject indicated positive ROS1 rearrangement. The subject was resistant to the entrectinib regimen, which is a targeted ROS1 tyrosine kinase inhibitor. The subject was enrolled in the clinical trial on August 8, 2023, and took compound I for the first time, at a dose of 100 mg once a day. The subject's baseline target lesion sum was 87mm, and the first tumor assessment on September 4, 2023 was 56mm. The overall assessment was PR, and the tumor was 35.6% smaller than the baseline. The baseline target lesion sum was 45mm again on October 30, 2023, and PR was confirmed. The tumor was 48.3% smaller than the baseline, and continued to be PR on December 28, 2023 and February 19, 2024. The subject had no serious adverse reactions related to medication during the medication.

[0063] Subject 6

[0064] Female, 53 years old, was first diagnosed with stage IV lung adenocarcinoma on 2023-01-06. Genetic testing of the subject indicated that she was positive for ROS1 rearrangement. She was resistant to multiple lines of therapy, including crizotinib and yew capsules. Crizotinib is a targeted ROS1 tyrosine kinase inhibitor, and yew capsules are Chinese patent medicines. The subject was enrolled in the clinical trial on 2023-08-07 and took compound I for the first time at a dose of 100 mg once daily. The subject's baseline target lesion sum was 10.2 mm, and the first tumor assessment on 2023-09-04 was 5.1 mm. The overall assessment was PR, and the tumor was 50% smaller than the baseline; the target lesion sum was 5.1 mm again on 2023-11-01, and PR was confirmed; the tumor was continuously assessed as PR on 2023-12-26, 2024-2-21, and 2024-04-15. No serious adverse reactions related to the medication were observed during the treatment period.

[0065] Subject 7

[0066] Female, 48 years old, was first diagnosed with stage IV lung adenocarcinoma on 2020-06-21. Genetic testing of the subject indicated that she was positive for ROS1 rearrangement. She was resistant to multiple lines of treatment, including AK112 combined with pemetrexed plus carboplatin, and APG-2449. APG-2449 is a targeted ROS1 tyrosine kinase inhibitor; AK112 is an immune checkpoint inhibitor; pemetrexed and carboplatin are chemotherapy drugs; the subject was enrolled in the clinical trial on 2023-09-15 and took compound I for the first time, at a dose of 100 mg twice a day. The subject's baseline target lesion sum was 18mm, and the first tumor assessment on 2022-10-11 was 13mm. The overall assessment was SD, and the tumor was reduced by 27.8% compared with the baseline; and the tumor was continuously assessed as PR on 2024-12-04, 2024-02-01, and 2024-3-24, and the subject had no disease progression for more than 9 months. No serious adverse reactions related to the medication were observed during the treatment period.

[0067] Subject 8

[0068] Female, 44 years old, first diagnosed with stage IV lung adenocarcinoma on 2023-01-27, genetic testing of the subject indicated positive ROS1 rearrangement. Docetaxel, nedaplatin combined with ametinib, pemetrexed combined with nedaplatin and other multi-line regimens were used successively and resistant. Among them, ametinib is a targeted EGFR tyrosine kinase inhibitor; docetaxel, nedaplatin, and pemetrexed are chemotherapy drugs; the subject was enrolled in the clinical trial on 2023-09-14 and took compound I for the first time, with a dose of 100 mg twice a day. The subject's baseline target lesion sum was 127.82mm, and the first tumor assessment on 2023-10-10 was 84.4mm. The overall assessment was PR, the tumor was reduced by 33.3% compared with the baseline, and the tumor was continuously assessed as PR on 2023-12-6 and 2024-02-01. The subject had no serious adverse reactions related to medication during the medication.

[0069] Subject 9

[0070] Female, 60 years old, first diagnosed with stage IIIa lung adenocarcinoma on September 2, 2014. Genetic testing of the subject indicated positive ROS1 rearrangement. Relapsed after surgical treatment, and multiple lines of treatment such as crizotinib, ceritinib, lorlatinib, and LZ001 were used successively, showing resistance. All drugs used were targeted ROS1 tyrosine kinase inhibitors. The subject was enrolled in the clinical trial on July 13, 2023, and took compound I for the first time, with a dose of 100 mg once a day. The subject's baseline target lesion sum was 19 mm, and the first tumor assessment on August 14, 2023 showed a total of 18 mm target lesions. The overall assessment was SD, and the tumor was continuously assessed as SD on October 8, 2023, December 3, 2023, January 28, 2024, and March 26, 2024. The subject has no disease progression for more than 12 months. The subject had no serious adverse reactions related to medication during the medication period.

[0071] Subject 10

[0072] Female, 52 years old, first diagnosed with lung adenocarcinoma in September 2020, genetic testing of the subject indicated positive ROS1 rearrangement. She was resistant to multiple lines of therapy including ceritinib, APG-2449, bevacizumab combined with pemetrexed plus carboplatin. Ceritinib and APG-2449 are targeted ROS1 tyrosine kinase inhibitors; bevacizumab is an angiogenesis inhibitor; pemetrexed and carboplatin are chemotherapy drugs. The subject was enrolled in the clinical trial on September 14, 2023, and took compound I for the first time, at a dose of 200 mg once a day. The subject's baseline target lesion sum was 98mm, and the first tumor assessment on 2023-10-12 was 71mm. The overall assessment was SD, and the tumor was reduced by 27.6% compared with the baseline. The tumor was continuously assessed as PR on 2023-12-07, 2024-02-04, 2024-04-01, and 2024-05-27. The subject has no disease progression for more than 10 months. The subject had no serious adverse reactions related to medication during the medication.

[0073] Subject 11

[0074] Female, 43 years old, diagnosed with lung adenocarcinoma on 2022-08-19, genetic testing of the subject indicated positive ROS1 rearrangement. She was resistant to multiple lines of therapy, including crizotinib and bevacizumab. Crizotinib is a targeted ROS1 tyrosine kinase inhibitor; bevacizumab is an angiogenesis inhibitor. The subject was enrolled in the clinical trial on 2023-09-18 and took compound I for the first time at a dose of 200 mg once daily. The subject's baseline target lesion sum was 11.04 mm, and the first tumor assessment on 2023-10-18 was 11.12 mm. The overall assessment was SD, and the tumor was continuously assessed as SD on 2023-12-14, 2024-02-07, 2024-04-04, and 2024-05-30. The subject has no disease progression for more than 8.4 months. The subject had no serious adverse reactions related to medication during the medication.

[0075] Subject 12

[0076] Female, 54 years old, diagnosed with lung adenocarcinoma on 2022-08-26, genetic testing of the subject indicated positive ROS1 rearrangement. She was resistant to multiple lines of therapy such as APG-2449 and crizotinib. All drugs used were targeted ROS1 tyrosine kinase inhibitors. The subject was enrolled in the clinical trial on 2023-10-19 and took compound I for the first time at a dose of 150 mg twice daily. The subject's baseline target lesions were 36.38 mm, and the total target lesions were 17.11 mm for the first tumor assessment on 2023-11-14. The overall assessment was PR, and the tumor was 53.0% smaller than the baseline. The tumor was continuously assessed as PR on 2024-01-10, 2024-03-05, and 2024-04-30. The subject has no disease progression for more than 8 months. The subject had no serious adverse reactions related to medication during the medication.

[0077] Subject 13

[0078] Male, 49 years old, diagnosed with left lung adenocarcinoma on 2020-05-05, genetic testing of the subject indicated positive ROS1 rearrangement. He was resistant to multiple lines of therapy, including crizotinib, AB-106, bevacizumab combined with pemetrexed and nedaplatin. Among them, crizotinib and AB-106 are targeted ROS1 tyrosine kinase inhibitors; bevacizumab is an angiogenesis inhibitor; pemetrexed and nedaplatin are chemotherapy drugs. The subject was enrolled in the clinical trial on 2024-02-01 and took compound I for the first time, at a dose of 150 mg twice a day. The subject's baseline target lesion sum was 67.7 mm, and the first tumor assessment on 2024-02-26 was 52.21 mm. The overall assessment was SD, and the tumor was reduced by 22.9% compared with the baseline. It was evaluated as sustained PR on 2024-04-22 and 2024-06-21, and the subject has no disease progression for more than 6 months. No serious adverse reactions related to the medication were observed during the treatment period.

[0079] Subject 14

[0080] Male, 51 years old, diagnosed with right lung adenocarcinoma on 2016-08-17, genetic testing of the subject indicated positive ROS1 rearrangement. After surgery, carboplatin + pemetrexed was used for adjuvant treatment, and after recurrence, TQ-B3139 treatment was resistant. Carboplatin and pemetrexed are chemotherapy drugs, and TQ-B3139 is a targeted drug. The subject was enrolled in the clinical trial on 2023-11-02 and took compound I for the first time, with a dose of 100 mg twice a day. The subject's baseline target lesions were 17mm, and the total target lesions were 13mm for the first tumor assessment on 2023-1-27. The overall assessment was SD, and the tumor was 23.5% smaller than the baseline. On 2024-05-13 and 2024-07-07, the tumor was continuously assessed as PR. The subject has no disease progression for more than 9 months. The subject had no serious adverse reactions related to medication during the medication.

[0081] Subject 15

[0082] Male, 51 years old, diagnosed with lung adenocarcinoma on 2022-01-08, genetic testing of the subject indicated positive ROS1 rearrangement. He was resistant to multiple lines of therapy, including crizotinib, pemetrexed combined with carboplatin and bevacizumab, and lorlatinib. Among them, crizotinib and lorlatinib are targeted ROS1 tyrosine kinase inhibitors; bevacizumab is an angiogenesis inhibitor; pemetrexed and carboplatin are chemotherapy drugs. The subject was enrolled in the clinical trial on 2024-01-25 and took compound I for the first time, at a dose of 150 mg twice a day. The subject's baseline target lesion sum was 70.41 mm, and the first tumor assessment on 2024-02-26 was 48.9 mm. The overall assessment was PR, the tumor was 30.6% smaller than the baseline, and the tumor was continuously assessed as PR on 2024-04-16. The subject has no disease progression for more than 6 months. The subject had no serious adverse reactions related to medication during the medication.

[0083] Subject 16

[0084] Female, 53 years old, diagnosed with lung adenocarcinoma on 2022-06-14, genetic testing of the subject indicated positive ROS1 rearrangement. Resistant after treatment with TPX-0005. TPX-0005 is a tyrosine kinase inhibitor targeting ROS1. The subject was enrolled in the clinical trial on 2024-01-30 and took compound I for the first time at a dose of 150 mg twice daily. The subject's baseline target lesions were 11.07 mm, and the total target lesions were 12.18 mm for the first tumor assessment on 2024-02-26. The overall assessment was SD, and the tumors were continuously assessed as SD on 2024-04-22 and 2024-06-17. The subject has no disease progression for more than 6 months. The subject had no serious adverse reactions related to medication during the medication.

[0085] This study showed that for patients with lung adenocarcinoma with ROS1 fusion mutations, treatment with compound I had significant clinical benefits (showing effectiveness and high safety).

Claims

1. Use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer; 2. The use according to claim 1, characterized in that The non-small cell lung cancer is ROS1-positive non-small cell lung cancer; and / or, The non-small cell lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, large cell carcinoma or sarcomatoid carcinoma, such as lung adenocarcinoma.

3. The use according to claim 1 or 2, characterized in that: The non-small cell lung cancer is resistant to at least one anticancer agent, wherein the at least one anticancer agent does not include Compound I.

4. The use according to claim 3, characterized in that The at least one anticancer agent is at least one of the following anticancer agents: a chemotherapeutic drug, an immune checkpoint inhibitor, an anti-angiogenesis inhibitor, a tyrosine kinase inhibitor; wherein the tyrosine kinase inhibitor does not include Compound I.

5. The use according to any one of claims 1 to 4, characterized in that: The non-small cell lung cancer is resistant to at least one of the following tyrosine kinase inhibitors: crizotinib, entrectinib, icotinib, frumetinib succinate, ensartinib, APG-2449, anlotinib, ceritinib, osimertinib, ametinib, vometinib, afatinib, dacomitinib, gefitinib, erlotinib, mobocinib, alectinib, brigatinib, lorlatinib, capmatinib, tepotinib, pralsetinib, sepretinib, dabrafenib, trametinib, larotrectinib, sirotinib, pyrotinib, lorlatinib, LZ001, AB-106, TQ-B3139, TPX-0005, TL139; and / or, The non-small cell lung cancer is resistant to at least one of the following chemotherapy drugs: dihydrofolate reductase inhibitors, thymidylate synthase inhibitors, platinum complexes, taxanes, topoisomerase inhibitors; or, the non-small cell lung cancer is resistant to a combination of a platinum complex and a dihydrofolate reductase inhibitor, a combination of a platinum complex and a thymidylate synthase inhibitor, a combination of a platinum complex and a taxane, or a combination of a platinum complex and a topoisomerase inhibitor; and / or, The non-small cell lung cancer is resistant to at least one of the following immune checkpoint inhibitors: anti-PD-1 / PD-L1 antibody, anti-LAG3 antibody; and / or, The non-small cell lung cancer is resistant to at least one of the following anti-angiogenesis inhibitors: bevacizumab and recombinant human endostatin.

6. The use according to claim 5, characterized in that The platinum complex is selected from cisplatin, carboplatin and nedaplatin; and / or, The dihydrofolate reductase inhibitor is selected from pemetrexed and docetaxel; and / or, The thymidylate synthase inhibitor is selected from gemcitabine and vinorelbine; and / or, The taxanes are selected from paclitaxel and nab-paclitaxel; and / or, The topoisomerase inhibitor is etoposide; and / or, The anti-PD-1 / PD-L1 antibody is at least one of the following anti-PD-1 / PD-L1 antibodies: tislelizumab, nivolumab, pembrolizumab, atezolizumab, carrelizumab, sintilimab, slulizumab, sugemalimab, penampalimumab, durvalumab, toripalimumab, AK112; and / or, The anti-LAG3 antibody is SHR-1802.

7. The use according to any one of claims 1 to 6, characterized in that The non-small cell lung cancer is resistant to crizotinib.

8. The use according to any one of claims 1 to 7, characterized in that The non-small cell lung cancer is resistant to entrectinib.

9. The use according to any one of claims 1 to 8, characterized in that The non-small cell lung cancer is resistant to TPX-0005.

10. The use according to any one of claims 3 to 9, characterized in that: The drug resistance is primary drug resistance or acquired drug resistance.

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