WO2024022282A1

WO2024022282A1 - Use of pyridylamine compound in specific ros1 gene fusion non-small cell lung cancer

Info

Publication number: WO2024022282A1
Application number: PCT/CN2023/108855
Authority: WO
Inventors: 苏楠; 汪荣亮; 贾佼佼; 马雷雷
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2022-07-25
Filing date: 2023-07-24
Publication date: 2024-02-01

Abstract

The present application provides use of a pyridylamine compound in specific ROS1 gene fusion non-small cell lung cancer. Specifically, the present application relates to use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating specific ROS1 gene fusion non-small cell lung cancer.

Description

Application of pyridinium compounds in non-small cell lung cancer with specific ROS1 gene fusion

References to related applications

This application claims the priority and rights of Chinese patent application No. 202210875942.9 submitted to the State Intellectual Property Office of the People's Republic of China on July 25, 2022, the entire content of which is hereby incorporated into the text by reference.

Technical field

This application belongs to the field of medicine and relates to the application of a pyridine amine compound in non-small cell lung cancer with specific ROS1 gene fusion.

Background technique

Lung cancer is a malignant lung tumor originating from bronchial epithelial cells. It can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) according to pathological morphology. Among them, non-small cell lung cancer accounts for about 85% and is the main pathological type of lung cancer. With the gradual deepening of research on the molecular mechanisms of cancer, the treatment model of NSCLC has begun to focus on personalized treatment targeting driver genes.

ROS1 is an important driver gene for NSCLC. After the ROS1 gene is fused, it activates the intracellular tyrosine kinase domain, activating multiple downstream signaling pathways such as JAK/STAT, PI3K/AKT, and RAS/MAPK, thereby causing tumor occurrence.

WO2020233710A1 discloses the application of a pyridine amine compound represented by formula (I) and its pharmaceutical composition in ROS1-positive non-small cell lung cancer.

Summary of the invention

The present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating non-small cell lung cancer with ROS1 gene fusion selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 gene Fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, GOPC-ROS1 gene fusion, FIG-ROS1 gene fusion, CCDC6-ROS1 gene fusion, KDELR2-ROS1 gene fusion, LRIG3-ROS1 gene fusion in progress one or more types of

Contents of the invention

The present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of non-small cell lung cancer with ROS1 gene fusion selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 Gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, GOPC-ROS1 gene fusion, FIG-ROS1 gene fusion, CCDC6-ROS1 gene fusion, KDELR2-ROS1 gene fusion, TGFBR1-ROS1 gene fusion , one or more of the LRIG3-ROS1 gene fusions,

On the other hand, the present application provides a method for treating non-small cell lung cancer with ROS1 gene fusion, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of the treatment. , the ROS1 gene fusion is selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, GOPC-ROS1 gene fusion, FIG-ROS1 gene fusion, One or more of CCDC6-ROS1 gene fusion, KDELR2-ROS1 gene fusion, TGFBR1-ROS1 gene fusion, and LRIG3-ROS1 gene fusion.

On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of non-small cell lung cancer with ROS1 gene fusion, the ROS1 gene fusion being selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 Gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, GOPC-ROS1 gene fusion, FIG-ROS1 gene fusion, CCDC6-ROS1 gene fusion, KDELR2-ROS1 gene fusion, TGFBR1-ROS1 gene fusion , one or more of the LRIG3-ROS1 gene fusions.

On the other hand, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with ROS1 gene fusion selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 gene Fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, GOPC-ROS1 gene fusion, FIG-ROS1 gene fusion, CCDC6-ROS1 gene fusion, KDELR2-ROS1 gene fusion, TGFBR1-ROS1 gene fusion, One or more of the LRIG3-ROS1 gene fusions.

Compounds of formula (I) or pharmaceutically acceptable salts thereof

In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is the fumarate salt of the compound of Formula (I).

In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is a compound of Formula (II),

ROS1 gene fusion non-small cell lung cancer

In some embodiments, the ROS1 gene fusion is selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, GOPC-ROS1 gene fusion, FIG. -One or more of ROS1 gene fusion, TGFBR1-ROS1 gene fusion, LRIG3-ROS1 gene fusion.

In some embodiments, the ROS1 gene fusion is selected from the group consisting of CD74-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, EZR-ROS1 gene fusion, TPM3-ROS1 gene fusion, and EZR/TGFBR1-ROS1 gene fusion. , EZR/SLC34A2-ROS1 gene fusion or TPM3/LRIG3/GOPC-ROS1 gene fusion.

In some embodiments, the ROS1 gene fusion is selected from one or more of CD74-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, EZR-ROS1 gene fusion, and TPM3-ROS1 gene fusion.

In some embodiments, the ROS1 gene fused non-small cell lung cancer is ROS1 gene fused locally advanced or metastatic non-small cell lung cancer.

In some embodiments, the ROS1 gene fused non-small cell lung cancer is ROS1 gene fused brain metastatic non-small cell lung cancer.

In some embodiments, the ROS1 gene fused non-small cell lung cancer is a ROS1 gene fused non-small cell lung cancer non-squamous cell carcinoma.

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is a ROS1 gene fusion lung adenocarcinoma.

In some embodiments, the ROS1 gene fused non-small cell lung cancer is a ROS1 gene fused locally advanced or metastatic lung adenocarcinoma.

In some embodiments, the clinical stage of the ROS1 gene fusion non-small cell lung cancer is stage III or stage IV.

In some embodiments, the patient with non-small cell lung cancer with the ROS1 gene fusion is treatment-naïve.

In some embodiments, the patient with non-small cell lung cancer with the ROS1 gene fusion has not received ROS1 inhibitor treatment.

In some embodiments, the patient with the ROS1 gene fusion non-small cell lung cancer has been treated with one or more prior treatment regimens. In some embodiments, the patient with the ROS1 gene fusion non-small cell lung cancer has not received or has been treated with one, two, three, four, or five prior treatment regimens.

In some embodiments, the prior treatment regimen includes radical cancer treatment, radiation therapy, or anti-tumor drug therapy.

In some embodiments, the patient with non-small cell lung cancer with the ROS1 gene fusion has been previously treated with anti-tumor drugs.

In some embodiments, the patient with non-small cell lung cancer having the ROS1 gene fusion is an EGFR negative patient.

CD74-ROS1 gene fusion non-small cell lung cancer

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion non-small cell lung cancer.

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is CD74-ROS1 gene fusion locally advanced or metastatic non-small cell lung cancer.

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion brain metastatic non-small cell lung cancer.

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion non-small cell lung cancer, non-squamous cell carcinoma.

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion lung adenocarcinoma.

In some embodiments, the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion locally advanced or metastatic lung adenocarcinoma.

In some embodiments, the clinical stage of the CD74-ROS1 gene fusion non-small cell lung cancer is stage III or stage IV.

In some embodiments, the patient with non-small cell lung cancer having the CD74-ROS1 gene fusion is treatment-naïve.

In some embodiments, the patient with non-small cell lung cancer having the CD74-ROS1 gene fusion has not received ROS1 inhibitor treatment.

In some embodiments, the patient with the CD74-ROS1 gene fusion non-small cell lung cancer has been treated with one or more prior treatment regimens. In some embodiments, the patient with the CD74-ROS1 gene fusion non-small cell lung cancer has not received or has been treated with one, two, three, four, or five prior treatment regimens.

In some embodiments, the patient with non-small cell lung cancer suffering from the CD74-ROS1 gene fusion has been previously treated with anti-tumor drugs.

Anti-tumor drug treatment

In some embodiments, the anti-tumor drug treatment is selected from single-agent chemotherapy or double-agent chemotherapy, optionally in combination with bevacizumab.

In some embodiments, the double-drug chemotherapy drug includes platinum-based drugs (eg, cisplatin, carboplatin, nedaplatin).

In some embodiments, the drug of single-agent chemotherapy or double-agent chemotherapy is selected from cisplatin, carboplatin, nedaplatin, vinorelbine, paclitaxel, albumin-paclitaxel, paclitaxel liposome, gemcitabine, docetaxel , pemetrexed or etoposide.

In some embodiments, the anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, vinorelbine, paclitaxel, albumin-paclitaxel, paclitaxel liposome, gemcitabine, docetaxel, pemetrexed, Etoposide, atezolizumab, durvalumab, nivolumab, sugelimumab, bevacizumab, sintilimab, amivantamab, pembrolizumab, Camrelizumab, tislelizumab, toripalimab, ipilimumab, osimertinib, icotinib, gefitinib, erlotinib, afatinib ni, dacomitinib, ametinib, apatinib, fumetinib, anlotinib, Mobocertinib, aletinib, ensartinib, dabrafenib, trametinib, larotrectinib, One or a combination of capmatinmib, Tepotinib, Selpercatinib, savotinib, platinib, sotorasib, pyrotinib, and endostatin.

In some embodiments, the anti-tumor drug treatment is selected from the following chemotherapy regimens: etoposide + cisplatin/carboplatin, vinorelbine + cisplatin, paclitaxel + cisplatin/carboplatin, albumin paclitaxel + cisplatin/ Carboplatin, paclitaxel liposome + cisplatin/carboplatin, gemcitabine + cisplatin/carboplatin, docetaxel + cisplatin/carboplatin, pemetrexed + cisplatin/carboplatin, docetaxel or pemetrexed Metrexate.

In some embodiments, the anti-tumor drug treatment is selected from the following chemotherapy regimens: vinorelbine + cisplatin, paclitaxel + cisplatin/carboplatin, Album paclitaxel + cisplatin/carboplatin, paclitaxel liposome + cisplatin/carboplatin, gemcitabine + cisplatin/carboplatin, docetaxel + cisplatin/carboplatin, pemetrexed + cisplatin/carboplatin , docetaxel or pemetrexed.

In some embodiments, the anti-tumor drug treatment is selected from the following chemotherapy regimens: AC regimen, EP regimen, NP regimen, PC regimen, PP regimen, nab-PP regimen, LP regimen, GP regimen, DP regimen, or AP regimen. For the specific regimen of the above chemotherapy regimen, please refer to the CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer (2022 Edition).

In some embodiments, the anti-tumor drug treatment is selected from the following chemotherapy regimens: AC regimen, AP regimen, EP regimen, PC regimen or DP regimen. For the specific regimen of the above chemotherapy regimen, please refer to the CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer (2022 Edition).

In some embodiments, the anti-tumor drug treatment is selected from the following chemotherapy regimens: NP regimen, PP regimen, nab-PP regimen, LP regimen, GP regimen, DP regimen, or AP regimen. For the specific regimen of the above chemotherapy regimen, please refer to the CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer (2022 Edition).

In some embodiments, the anti-tumor drug treatment is selected from the following chemotherapy regimens: docetaxel or pemetrexed.

In some embodiments, the anti-tumor drug treatment is selected from the following immunotherapy regimen: nivolumab, pembrolizumab, atezolizumab, tislelizumab, sintilimab Anti-, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel, camrelizumab + carboplatin + pemetrexed, camrelizumab Monoclonal antibody + carboplatin + paclitaxel, sintilimab + cisplatin/carboplatin + pemetrexed, sintilimab + cisplatin/carboplatin + cisplatin, tislelizumab + cisplatin /carboplatin + pemetrexed, tislelizumab + carboplatin + paclitaxel/nab-paclitaxel, atezolizumab + bevacizumab + carboplatin + paclitaxel, atezolizumab + Cisplatin/carboplatin + pemetrexed, sugemalimab + carboplatin + pemetrexed, or sugemalimab + carboplatin + paclitaxel. For specific plans on the above immunotherapy medication regimen, please refer to the CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer (2022 Edition).

In some embodiments, the anti-tumor drug treatment is selected from the following targeted drug treatments: osimertinib, icotinib, gefitinib, erlotinib, afatinib, dacomitinib, Amitinib, apatinib, fumetinib, anlotinib, Mobocertinib, alectinib, ensartinib, dabrafenib, trametinib, larotrectinib, capmatinmib, Tepotinib, Selpercatinib, vortinib, platinib, sotorasib, or pyrotinib.

Mode of administration

In this application, the dosage or mass of the pharmaceutically acceptable salt of the compound of formula (I) is calculated based on the compound of formula (I).

In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg to 1000 mg/day. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 200 to 800 mg/day. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 500 mg/day. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 250 mg twice daily. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 600 mg/day. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 300 mg twice daily. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 400 mg/day. In some embodiments, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is 200 mg twice daily.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one or more times daily. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily.

In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered for a period of 28 days.

In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily for 28 consecutive days.

In some embodiments, a compound of Formula (I) of the present application, or a pharmaceutically acceptable salt thereof, is used as the single active agent.

In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof of the present application may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition is a unit dose pharmaceutical composition. In some embodiments, the unit dose pharmaceutical composition contains 10 mg to 300 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose pharmaceutical composition contains 25 mg to 200 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose pharmaceutical composition contains 50 mg to 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose pharmaceutical composition contains 50 mg, 100 mg, 125 mg, or 150 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Technical effect

The compound of formula (I) of the present application or its pharmaceutically acceptable salt shows good safety and efficacy in the clinical treatment of patients with ROS1-positive non-small cell lung cancer, and exhibits excellent ORR, PFS, DCR, and DOR. The treatment effect is very good. At the same time, the incidence of ophthalmic adverse reactions is low, and it can also produce a durable intracranial response.

The therapeutic effect of the compound of formula (I) of the present application or its pharmaceutically acceptable salt on non-small cell lung cancer patients with CD74-ROS1 gene fusion is significantly better than its therapeutic effect on non-small cell lung cancer patients with non-CD74-ROS1 gene fusion. The ORR and median PFS were higher in the CD74-ROS1 gene fusion patient subgroup.

definition

Unless otherwise stated, the following terms used in this application have the following meanings. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

In this application, the ROS1 gene fusion can be determined by detection methods approved by the FDA or NMPA or detection methods recommended by the non-small cell lung cancer diagnosis and treatment guidelines, such as real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR), fluorogen hybridization (FISH), immunohistochemistry (IHC) and next-generation sequencing (NGS).

In this application, the reverse transcription-polymerase chain reaction (RT-PCR) can use the ROS1 RT-PCR test kit approved by FDA or NMPA.

In this application, unless otherwise specified, the clinical stages are classified according to the TNM staging criteria of the International Union against Cancer (eighth edition).

In this application, the "/" in the gene fusion type represents the relationship of "and". For example, "TPM3/LRIG3/GOPC-ROS1 gene fusion" means that the patient has TPM3-ROS1 gene fusion, LRIG3-ROS1 gene fusion and GOPC-ROS1 gene fusion at the same time.

In this application, "+" in anti-tumor drug treatment means combination, and "/" means "or" relationship. For example, "sintilimab + cisplatin/carboplatin + pemetrexed" means the following two drug regimens: a combination of sintilimab, cisplatin, and pemetrexed, or sintilimab, cisplatin, and pemetrexed, or sintilimab, cisplatin, and pemetrexed A three-drug combination of antibiotics, carboplatin, and pemetrexed.

The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.

The term "therapeutically effective amount" means (i) treating a particular disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) delaying the symptoms described herein An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.

In this application, the terms "subject" or "patient" or "individual" are used interchangeably. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is human.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or a pharmaceutical combination thereof or a salt thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate the administration of a compound of the present application or a pharmaceutical combination thereof to a subject.

The term "unit dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a unit dose; or each bottle of injection is a unit dose.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .

In this document, unless stated otherwise, the terms "comprise, comprises and comprising" or equivalents are open-ended expressions meaning that in addition to the listed elements, components and steps, there may be Covers other unspecified elements, components and steps.

The compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof can be administered through a variety of routes, including but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular , intraperitoneal, intramuscular, subcutaneous, intravenous administration, preferably oral administration.

The dosage of the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, the daily dosage of administering the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 50 mg to 1000 mg. In some embodiments, the daily dosage of administering the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg or 1000mg. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once, twice or more per day.

The dosage regimen of the compound of formula (I) of the present application or its pharmaceutically acceptable salt can be comprehensively determined based on drug activity, side effects, patient tolerance, etc., and can be continuous administration or intermittent administration, for example, wherein the subject receives a daily dose of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, over a period of several days, followed by a period of several or more days in which the patient does not receive a daily dose of Formula (I) compound or a pharmaceutically acceptable salt thereof.

In this application, the efficacy of target lesions was evaluated using the RECIST 1.1 standard. Among them, "CR" means complete response, which specifically refers to the complete disappearance of all target lesions except nodular disease. All target nodules must be reduced to normal size (short axis <10 mm). All target lesions must be evaluated. “PR” indicates partial response, specifically when the sum of the diameters of all measurable target lesions is ≥30% below baseline. The sum of target nodules uses the shortest diameter, while the sum of all other target lesions uses the longest diameter. All target lesions must be evaluated. "PD" means disease progression, specifically referring to the minimum value of the sum of the diameters of all measured target lesions during the entire experimental study as a reference, and the relative increase in diameter by at least 20% (if the baseline measurement value is the smallest, the baseline value is used as the reference) ; In addition, it must be satisfied that the absolute value of the diameter sum increases by at least 5mm (appears One or more new lesions are also considered disease progression). "SD" means the disease is stable, which specifically means that the reduction of the target lesion does not reach the PR level, and the increase does not reach the PD level, but is somewhere in between. The minimum value of the sum of diameters can be used as a reference during research. The term "NE" means indeterminate, specifically when progression is not documented and: 1) 1 or more measurable target lesions are not evaluated; 2) or the evaluation method used is inconsistent with baseline; 3) or 1 or more target lesions are Unable to accurately measure (eg: unable to see clearly, unless too small to measure); 4) or 1 or more target lesions were resected or irradiated and did not recur or grow.

In this application, intracranial response was assessed using RANO-BM criteria.

In this application, the compound of formula (I) can be prepared according to WO2016169030A1 Example 1, and the compound of formula (II) can be prepared according to WO2016169030A1 Example 2.

Detailed ways

For the sake of clarity, examples are further used to illustrate the invention, but the examples do not limit the scope of the application.

Example 1 Clinical Phase II Trial - Study on the Safety and Effectiveness of Compounds of Formula (II) on ROS1 Positive Non-Small Cell Lung Cancer

1. Experimental drugs and dosing regimen

1) Test drug: capsule of compound of formula (II). For specific prescription and preparation method, please refer to WO2020233710A1 Example 1 (Prescription 1).

2) How to take the medicine:

300mg, bid, p.o., take on an empty stomach in the morning and evening. It is recommended not to eat within one hour before and after taking the medicine. One cycle of continuous administration is 28 days, until the subject develops disease progression or adverse events that are intolerable after treatment.

3) Dosage adjustment:

If a subject experiences an adverse event with severity grade 3 or above specified by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0), the dose can be adjusted as follows:

First dose reduction: Dosing regimen: 250 mg, bid, p.o.;

Second dose reduction: Dosing regimen: 200 mg, bid, p.o.;

If the dose level of 200 mg bid is still intolerable, the subject needs to terminate the study.

2. Main entry criteria

1) Age ≥18 years old;

2)ECOG physical status: 0-1 points; expected survival time is more than 3 months;

3)Major organ functions are normal;

4) Diagnosed as locally advanced or metastatic NSCLC through histology or cytology (according to the eighth edition of TNM staging criteria);

5) Confirmed to be ROS1 positive by RT-PCR test;

6) Those who have received no more than 2 chemotherapy regimens in the past. If more than 2 chemotherapy regimens are used, another biopsy will be required during the screening period, and the test result must be confirmed to be ROS1 positive (NMPA-approved ROS1 RT-PCR test kit);

7) Within 28 days before the first study medication, at least one evaluable target lesion other than brain lesions has been confirmed by imaging (evaluated with reference to RECIST1.1 standards).

3. Evaluation criteria

Effectiveness evaluation criteria: RECIST 1.1 criteria are used for evaluation, and brain metastases are evaluated using RANO-BM criteria;

◆Main efficacy evaluation index: objective response rate (ORR), that is, (number of CR+PR cases)/total number of cases, including complete response (CR) and partial response (PR);

◆Secondary efficacy evaluation indicators: duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS); for brain metastases, intracranial response rate (C-ORR) , intracranial duration of response (C-DOR), and time to intracranial disease progression (C-TTP).

Safety evaluation standards: NCI-CTC AE5.0 standards are used to evaluate adverse drug reactions.

4. Test results

1) Enrolled patients

Table 1. Patient Demographic Information

2) Overall effectiveness

Table 2. Effectiveness evaluation indicators

Note: CI represents the confidence interval; effectiveness evaluation indicators are evaluated using the RECIST 1.1 standard; 95% CI is calculated using the Clopper-Pearson method; PFS is calculated using the Kaplan-Meier method.

Among them, 27 patients with CD74-ROS1 rearrangement showed significant therapeutic effects, with 1 CR and 23 PR, with an ORR of 88.9%.

3) CD74-ROS1 gene fusion patients and non-CD74-ROS1 gene fusion patients

Patients with non-CD74-ROS1 gene fusion include patients with the following gene fusion types: SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, EZR-ROS1 gene fusion, TPM3-ROS1 gene fusion, EZR/TGFBR1-ROS1 gene fusion, EZR/SLC34A2 -ROS1 gene fusion and TPM3/LRIG3/GOPC-ROS1 gene fusion.

The comparative results of the efficacy of patients with CD74-ROS1 gene fusion and those without CD74-ROS1 gene fusion are as follows:

Table 3. Efficacy comparison results

Among them, the median PFS was calculated using the Kaplan-Meier method.

Claims

Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating non-small cell lung cancer with ROS1 gene fusion, the ROS1 gene fusion being selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 gene fusion, SDC4- One or several kinds,
The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is the fumarate salt of the compound of formula (I); or, the pharmaceutically acceptable salt of the compound of formula (I) The salt is a compound of formula (II),
The use according to claim 1 or 2, wherein the ROS1 gene fusion is selected from the group consisting of CD74-ROS1 gene fusion, EZR-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, TPM3-ROS1 gene fusion, One or more of GOPC-ROS1 gene fusion, FIG-ROS1 gene fusion, TGFBR1-ROS1 gene fusion, LRIG3-ROS1 gene fusion;

Alternatively, the ROS1 gene fusion is selected from the group consisting of CD74-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, EZR-ROS1 gene fusion, TPM3-ROS1 gene fusion, EZR/TGFBR1-ROS1 gene fusion, and EZR/SLC34A2 -ROS1 gene fusion or TPM3/LRIG3/GOPC-ROS1 gene fusion;

Alternatively, the ROS1 gene fusion is selected from one or more of CD74-ROS1 gene fusion, SDC4-ROS1 gene fusion, SLC34A2-ROS1 gene fusion, EZR-ROS1 gene fusion, and TPM3-ROS1 gene fusion;

Alternatively, the ROS1 gene fusion is selected from CD74-ROS1 gene fusion.
The use according to any one of claims 1 to 3, wherein the non-small cell lung cancer with ROS1 gene fusion is locally advanced or metastatic non-small cell lung cancer with ROS1 gene fusion;

Alternatively, the non-small cell lung cancer with ROS1 gene fusion is brain metastatic non-small cell lung cancer with ROS1 gene fusion;

Alternatively, the non-small cell lung cancer with ROS1 gene fusion is a non-squamous cell lung cancer with ROS1 gene fusion;

Alternatively, the non-small cell lung cancer with ROS1 gene fusion is lung adenocarcinoma with ROS1 gene fusion;

Alternatively, the non-small cell lung cancer with ROS1 gene fusion is locally advanced or metastatic lung adenocarcinoma with ROS1 gene fusion.
The use according to any one of claims 1 to 4, wherein the clinical stage of the ROS1 gene fused non-small cell lung cancer is stage III or stage IV.
The use of any one of claims 1-5, wherein the patient suffering from non-small cell lung cancer with the ROS1 gene fusion has not received treatment;

Alternatively, patients with non-small cell lung cancer suffering from the ROS1 gene fusion have not received ROS1 inhibitor treatment;

Alternatively, patients with non-small cell lung cancer with ROS1 gene fusion have received one or more prior treatment regimens. treat.
The use of claim 6, wherein the prior treatment regimen includes radical cancer treatment, radiation therapy or anti-tumor drug treatment.
The use according to claim 6, wherein the patient suffering from non-small cell lung cancer with ROS1 gene fusion has previously received anti-tumor drug treatment.
The use according to claim 7 or 8, wherein the anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, vinorelbine, paclitaxel, albumin-paclitaxel, paclitaxel liposome, gemcitabine, docetaxel Cemetrexed, pemetrexed, etoposide, atezolizumab, durvalumab, nivolumab, sugalizumab, bevacizumab, sintilimab, amivantamab , pembrolizumab, camrelizumab, tislelizumab, toripalimab, ipilimumab, osimertinib, icotinib, gefitinib, ercotinib Lotinib, afatinib, dacomitinib, ametinib, apatinib, fumetinib, anlotinib, Mobocertinib, alectinib, ensartinib, dabrafenib, One or a combination of trametinib, Larotrectinib, Capmatinmib, Tepotinib, Selpercatinib, Savotinib, Platinib, Sotorasib, Pyrrotinib, and endostatin;

Alternatively, the anti-tumor drug treatment is selected from the following chemotherapy regimens: etoposide + cisplatin/carboplatin, vinorelbine + cisplatin, paclitaxel + cisplatin/carboplatin, albumin paclitaxel + cisplatin/carboplatin, paclitaxel Liposome + cisplatin/carboplatin, gemcitabine + cisplatin/carboplatin, docetaxel + cisplatin/carboplatin, pemetrexed + cisplatin/carboplatin, docetaxel or pemetrexed;

Alternatively, the anti-tumor drug treatment is selected from the following chemotherapy regimens: vinorelbine + cisplatin, paclitaxel + cisplatin/carboplatin, albumin paclitaxel + cisplatin/carboplatin, paclitaxel liposome + cisplatin/carboplatin, Gemcitabine + cisplatin/carboplatin, docetaxel + cisplatin/carboplatin, pemetrexed + cisplatin/carboplatin, docetaxel or pemetrexed;

Alternatively, the anti-tumor drug treatment is selected from the following chemotherapy regimens: AC regimen, EP regimen, NP regimen, PC regimen, PP regimen, nab-PP regimen, LP regimen, GP regimen, DP regimen or AP regimen;

Alternatively, the anti-tumor drug treatment is selected from the following chemotherapy regimens: NP regimen, PP regimen, nab-PP regimen, LP regimen, GP regimen, DP regimen or AP regimen;

Alternatively, the anti-tumor drug treatment is selected from the following chemotherapy regimens: docetaxel or pemetrexed;

Alternatively, the anti-tumor drug treatment is selected from the following immunotherapy regimens: nivolumab, pembrolizumab, atezolizumab, tislelizumab, sintilimab, pembrolizumab Tizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel, camrelizumab + carboplatin + pemetrexed, camrelizumab + paclitaxel Platinum + paclitaxel, sintilimab + cisplatin/carboplatin + pemetrexed, sintilimab + cisplatin/carboplatin + cisplatin, tislelizumab + cisplatin/carboplatin + Pemetrexed, tislelizumab + carboplatin + paclitaxel/nab-paclitaxel, atezolizumab + bevacizumab + carboplatin + paclitaxel, atezolizumab + cisplatin/paclitaxel Platinum + pemetrexed, sugemalimab + carboplatin + pemetrexed or sugemalimab + carboplatin + paclitaxel;

Alternatively, the anti-tumor drug treatment is selected from the following targeted drug treatments: osimertinib, icotinib, gefitinib, erlotinib, afatinib, dacomitinib, ametinib, Apatinib, Fumetinib, Anlotinib, Mobocertinib, Aletinib, Ensartinib, Dabrafenib, Trametinib, Larotrectinib, Capmatinmib, Tepotinib, Selpercatinib, Saivotinib, platinib, sotorasib, or pyrotinib;

Alternatively, the anti-tumor drug treatment is selected from single-agent chemotherapy or double-agent chemotherapy, optionally combined with bevacizumab;

Alternatively, the anti-tumor drug is selected from single-drug chemotherapy or double-drug chemotherapy, and the drugs of the double-drug chemotherapy include platinum-based drugs;

Alternatively, the anti-tumor drug is selected from single-drug chemotherapy or double-drug chemotherapy, and the drug of single-drug chemotherapy or double-drug chemotherapy is selected from the group consisting of cisplatin, carboplatin, nedaplatin, vinorelbine, paclitaxel, albumin-paclitaxel, liposomal paclitaxel, gemcitabine, docetaxel, pemetrexed, or etoposide.
The use according to any one of claims 1 to 9, wherein the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 50 mg to 1000 mg/day;

Alternatively, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 200 to 800 mg/day;

Alternatively, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 500 mg/day;

Alternatively, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 250 mg each time, twice a day;

Alternatively, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 600 mg/day;

Alternatively, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 300 mg each time, twice a day;

Alternatively, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 400 mg/day;

Alternatively, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200 mg twice a day.
The use according to any one of claims 1 to 10, wherein the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 28 days.
The use according to any one of claims 1 to 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used as a single active agent.
The use according to any one of claims 1 to 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof may comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical composition of salt.
The use of claim 13, wherein the pharmaceutical composition is a unit dose pharmaceutical composition.
The use according to claim 14, wherein the unit dose pharmaceutical composition contains 10 mg to 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof;

Alternatively, the unit dose pharmaceutical composition contains 25 mg to 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof;

Alternatively, the unit dose pharmaceutical composition contains 50 mg to 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof;

Alternatively, the unit dose pharmaceutical composition contains 50 mg, 100 mg, 125 mg, or 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.