WO2024022282A1 - 吡啶胺化合物在特定ros1基因融合的非小细胞肺癌中的应用 - Google Patents

吡啶胺化合物在特定ros1基因融合的非小细胞肺癌中的应用 Download PDF

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WO2024022282A1
WO2024022282A1 PCT/CN2023/108855 CN2023108855W WO2024022282A1 WO 2024022282 A1 WO2024022282 A1 WO 2024022282A1 CN 2023108855 W CN2023108855 W CN 2023108855W WO 2024022282 A1 WO2024022282 A1 WO 2024022282A1
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Prior art keywords
gene fusion
ros1 gene
carboplatin
alternatively
compound
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PCT/CN2023/108855
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English (en)
French (fr)
Inventor
苏楠
汪荣亮
贾佼佼
马雷雷
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN202380056169.6A priority Critical patent/CN119584964A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • 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.
  • 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.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • 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.
  • 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
  • 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,
  • 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.
  • 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.
  • 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.
  • 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
  • the pharmaceutically acceptable salt of the compound of Formula (I) is the fumarate salt of the compound of Formula (I).
  • the pharmaceutically acceptable salt of the compound of Formula (I) is a compound of Formula (II),
  • 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.
  • 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.
  • 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.
  • the ROS1 gene fused non-small cell lung cancer is ROS1 gene fused locally advanced or metastatic non-small cell lung cancer.
  • the ROS1 gene fused non-small cell lung cancer is ROS1 gene fused brain metastatic non-small cell lung cancer.
  • the ROS1 gene fused non-small cell lung cancer is a ROS1 gene fused non-small cell lung cancer non-squamous cell carcinoma.
  • the ROS1 gene fusion non-small cell lung cancer is a ROS1 gene fusion lung adenocarcinoma.
  • the ROS1 gene fused non-small cell lung cancer is a ROS1 gene fused locally advanced or metastatic lung adenocarcinoma.
  • the clinical stage of the ROS1 gene fusion non-small cell lung cancer is stage III or stage IV.
  • the patient with non-small cell lung cancer with the ROS1 gene fusion is treatment-na ⁇ ve.
  • the patient with non-small cell lung cancer with the ROS1 gene fusion has not received ROS1 inhibitor treatment.
  • 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.
  • the prior treatment regimen includes radical cancer treatment, radiation therapy, or anti-tumor drug therapy.
  • the patient with non-small cell lung cancer with the ROS1 gene fusion has been previously treated with anti-tumor drugs.
  • the patient with non-small cell lung cancer having the ROS1 gene fusion is an EGFR negative patient.
  • the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion non-small cell lung cancer.
  • the ROS1 gene fusion non-small cell lung cancer is CD74-ROS1 gene fusion locally advanced or metastatic non-small cell lung cancer.
  • the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion brain metastatic non-small cell lung cancer.
  • the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion non-small cell lung cancer, non-squamous cell carcinoma.
  • the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion lung adenocarcinoma.
  • the ROS1 gene fusion non-small cell lung cancer is a CD74-ROS1 gene fusion locally advanced or metastatic lung adenocarcinoma.
  • the clinical stage of the CD74-ROS1 gene fusion non-small cell lung cancer is stage III or stage IV.
  • the patient with non-small cell lung cancer having the CD74-ROS1 gene fusion is treatment-na ⁇ ve.
  • the patient with non-small cell lung cancer having the CD74-ROS1 gene fusion has not received ROS1 inhibitor treatment.
  • 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.
  • the prior treatment regimen includes radical cancer treatment, radiation therapy, or anti-tumor drug therapy.
  • the patient with non-small cell lung cancer suffering from the CD74-ROS1 gene fusion has been previously treated with anti-tumor drugs.
  • the anti-tumor drug treatment is selected from single-agent chemotherapy or double-agent chemotherapy, optionally in combination with bevacizumab.
  • the double-drug chemotherapy drug includes platinum-based drugs (eg, cisplatin, carboplatin, nedaplatin).
  • platinum-based drugs eg, cisplatin, carboplatin, nedaplatin.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • chemotherapy regimens AC regimen, EP regimen, NP regimen, PC regimen, PP regimen, nab-PP regimen, LP regimen, GP regimen, DP regimen, or AP regimen.
  • 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).
  • the anti-tumor drug treatment is selected from the following chemotherapy regimens: AC regimen, AP regimen, EP regimen, PC regimen or DP regimen.
  • chemotherapy regimens AC regimen, AP regimen, EP regimen, PC regimen or DP regimen.
  • 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.
  • chemotherapy regimens please refer to the CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer (2022 Edition).
  • the anti-tumor drug treatment is selected from the following chemotherapy regimens: docetaxel or pemetrexed.
  • 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, atez
  • 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.
  • the dosage or mass of the pharmaceutically acceptable salt of the compound of formula (I) is calculated based on the compound of formula (I).
  • 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.
  • 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.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered for a period of 28 days.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily for 28 consecutive days.
  • a compound of Formula (I) of the present application is used as the single active agent.
  • 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.
  • the pharmaceutical composition is a unit dose pharmaceutical composition.
  • the unit dose pharmaceutical composition contains 10 mg to 300 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the unit dose pharmaceutical composition contains 25 mg to 200 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the unit dose pharmaceutical composition contains 50 mg to 150 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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).
  • RT-PCR real-time quantitative reverse transcription-polymerase chain reaction
  • FISH fluorogen hybridization
  • IHC immunohistochemistry
  • NGS next-generation sequencing
  • RT-PCR reverse transcription-polymerase chain reaction
  • the "/" in the gene fusion type represents the relationship of "and”.
  • "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 anti-tumor drug treatment means combination, and “/” means “or” relationship.
  • “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.
  • 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.
  • 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.
  • terapéuticaally 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
  • 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.
  • the terms "subject” or “patient” or “individual” are used interchangeably.
  • the subject or patient is a mammal.
  • the subject or patient is a mouse.
  • the subject or patient is human.
  • 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.
  • 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.
  • 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. .
  • 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.
  • the daily dosage of administering the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 50 mg to 1000 mg.
  • 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.
  • CR complete response
  • 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.
  • 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.
  • intracranial response was assessed using RANO-BM criteria.
  • 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.
  • Test drug capsule of compound of formula (II).
  • test drug capsule of compound of formula (II).
  • WO2020233710A1 Example 1 (Prescription 1).
  • 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.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • Dosing regimen 250 mg, bid, p.o.;
  • Second dose reduction Dosing regimen: 200 mg, bid, p.o.;
  • At least one evaluable target lesion other than brain lesions has been confirmed by imaging (evaluated with reference to RECIST1.1 standards).
  • 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).
  • DOR duration of response
  • PFS progression-free survival
  • DCR disease control rate
  • OS overall survival
  • C-ORR intracranial response rate
  • C-DOR intracranial duration of response
  • C-TTP time to intracranial disease progression
  • 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.
  • 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 median PFS was calculated using the Kaplan-Meier method.

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Abstract

本申请提供了一种吡啶胺化合物在特定ROS1基因融合的非小细胞肺癌中的应用。具体而言，本申请涉及式(I)化合物或其药学上可接受的盐在制备治疗特定ROS1基因融合非小细胞肺癌的药物中的用途。

Description

吡啶胺化合物在特定ROS1基因融合的非小细胞肺癌中的应用
相关申请的引用
本申请要求于2022年07月25日向中华人民共和国国家知识产权局提交的第202210875942.9号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请属于医药领域，涉及一种吡啶胺化合物在特定ROS1基因融合的非小细胞肺癌中的应用。
背景技术
肺癌是起源于支气管上皮细胞的肺恶性肿瘤，依病理形态可分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)。其中，非小细胞肺癌约占85％，是肺癌的主要病理类型。随着癌症分子机制研究的逐渐深入，NSCLC的治疗模式开始侧重于针对驱动基因的个体化治疗。
ROS1是NSCLC重要的驱动基因，ROS1基因发生融合后，激活胞内酪氨酸激酶结构域，使得下游JAK/STAT、PI3K/AKT、RAS/MAPK等多条信号通路活化，进而引起肿瘤的发生。
WO2020233710A1公开了式(I)所示的一种吡啶胺化合物及其药物组合物在ROS1阳性非小细胞肺癌中的应用，
发明概述
本申请提供了式(I)化合物或其药学上可接受的盐在制备治疗ROS1基因融合非小细胞肺癌的药物中的用途，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、CCDC6-ROS1基因融合、KDELR2-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种，
发明内容
本申请提供了式(I)化合物或其药学上可接受的盐在制备治疗ROS1基因融合的非小细胞肺癌的药物中的用途，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、CCDC6-ROS1基因融合、KDELR2-ROS1基因融合、TGFBR1-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种，
另一方面，本申请提供了一种治疗ROS1基因融合的非小细胞肺癌的方法，包括对需要该治疗的受试者，给予治疗有效量的式(I)化合物或其药学上可接受的盐，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、CCDC6-ROS1基因融合、KDELR2-ROS1基因融合、TGFBR1-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种。
另一方面，本申请提供式(I)化合物或其药学上可接受的盐在治疗ROS1基因融合的非小细胞肺癌中的用途，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、CCDC6-ROS1基因融合、KDELR2-ROS1基因融合、TGFBR1-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种。
另一方面，本申请提供用于治疗ROS1基因融合的非小细胞肺癌的式(I)化合物或其药学上可接受的盐，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、CCDC6-ROS1基因融合、KDELR2-ROS1基因融合、TGFBR1-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种。
式(I)化合物或其药学上可接受的盐
在一些实施方案中，所述式(I)化合物药学上可接受的盐为式(I)化合物的富马酸盐。
在一些实施方案中，所述式(I)化合物药学上可接受的盐为式(II)化合物，
ROS1基因融合的非小细胞肺癌
在一些实施方案中，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、TGFBR1-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种。
在一些实施方案中，所述ROS1基因融合选自CD74-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、EZR-ROS1基因融合、TPM3-ROS1基因融合、EZR/TGFBR1-ROS1基因融合、EZR/SLC34A2-ROS1基因融合或TPM3/LRIG3/GOPC-ROS1基因融合。
在一些实施方案中，所述ROS1基因融合选自CD74-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、EZR-ROS1基因融合、TPM3-ROS1基因融合中的一种或几种。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的局部晚期或转移性非小细胞肺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的脑转移性非小细胞肺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的非小细胞肺癌非鳞癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的肺腺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的局部晚期或转移性肺腺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌的临床分期为III期或IV期。
在一些实施方案中，患有所述ROS1基因融合的非小细胞肺癌的患者未接受过治疗。
在一些实施方案中，患有所述ROS1基因融合的非小细胞肺癌的患者未接受过ROS1抑制剂治疗。
在一些实施方案中，患有所述ROS1基因融合的非小细胞肺癌的患者已接受过一种或两种以上在先治疗方案的治疗。在一些实施方案中，患有所述ROS1基因融合的非小细胞肺癌的患者未接受或已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在一些实施方案中，所述在先治疗方案包括癌症根治术治疗、放射治疗或抗肿瘤药物治疗。
在一些实施方案中，患有所述ROS1基因融合的非小细胞肺癌的患者既往接受过抗肿瘤药物治疗。
在一些实施方案中，患有所述ROS1基因融合的非小细胞肺癌的患者为EGFR阴性患者。
CD74-ROS1基因融合的非小细胞肺癌
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是CD74-ROS1基因融合的非小细胞肺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是CD74-ROS1基因融合的局部晚期或转移性非小细胞肺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是CD74-ROS1基因融合的脑转移性非小细胞肺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是CD74-ROS1基因融合的非小细胞肺癌非鳞癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是CD74-ROS1基因融合的肺腺癌。
在一些实施方案中，所述ROS1基因融合的非小细胞肺癌是CD74-ROS1基因融合的局部晚期或转移性肺腺癌。
在一些实施方案中，所述CD74-ROS1基因融合的非小细胞肺癌的临床分期为III期或IV期。
在一些实施方案中，患有所述CD74-ROS1基因融合的非小细胞肺癌的患者未接受过治疗。
在一些实施方案中，患有所述CD74-ROS1基因融合的非小细胞肺癌的患者未接受过ROS1抑制剂治疗。
在一些实施方案中，患有所述CD74-ROS1基因融合的非小细胞肺癌的患者已接受过一种或两种以上在先治疗方案的治疗。在一些实施方案中，患有所述CD74-ROS1基因融合的非小细胞肺癌的患者未接受或已接受过一种、两种、三种、四种、或五种在先治疗方案的治疗。
在一些实施方案中，所述在先治疗方案包括癌症根治术治疗、放射治疗或抗肿瘤药物治疗。
在一些实施方案中，患有所述CD74-ROS1基因融合的非小细胞肺癌的患者既往接受过抗肿瘤药物治疗。
抗肿瘤药物治疗
在一些实施方案中，所述抗肿瘤药物治疗选自单药化疗或双药化疗，任选地与贝伐珠单抗联合治疗。
在一些实施方案中，所述双药化疗的药物包含铂类药物(例如顺铂、卡铂、奈达铂)。
在一些实施方案中，所述单药化疗或双药化疗的药物选自顺铂、卡铂、奈达铂、长春瑞滨、紫杉醇、白蛋白紫杉醇、紫杉醇脂质体、吉西他滨、多西他赛、培美曲赛或依托泊苷。
在一些实施方案中，所述抗肿瘤药物选自顺铂、卡铂、奈达铂、长春瑞滨、紫杉醇、白蛋白紫杉醇、紫杉醇脂质体、吉西他滨、多西他赛、培美曲赛、依托泊苷、阿替利珠单抗、度伐利尤单抗、纳武利尤单抗、舒格利单抗、贝伐珠单抗、信迪利单抗、Amivantamab、帕博利珠单抗、卡瑞利珠单抗、替雷利珠单抗、特瑞普利单抗、伊匹木单抗、奥希替尼、埃克替尼、吉非替尼、厄洛替尼、阿法替尼、达可替尼、阿美替尼、阿帕替尼、伏美替尼、安罗替尼、Mobocertinib、阿来替尼、恩沙替尼、达拉非尼、曲美替尼、Larotrectinib、Capmatinmib、Tepotinib、Selpercatinib、赛沃替尼、普拉替尼、Sotorasib、吡咯替尼、血管内皮抑制素中的一种或几种的联合。
在一些实施方案中，所述抗肿瘤药物治疗选自如下化疗方案：依托泊苷+顺铂/卡铂、长春瑞滨+顺铂、紫杉醇+顺铂/卡铂、白蛋白紫杉醇+顺铂/卡铂、紫杉醇脂质体+顺铂/卡铂、吉西他滨+顺铂/卡铂、多西他赛+顺铂/卡铂、培美曲塞+顺铂/卡铂、多西他赛或培美曲塞。
在一些实施方案中，所述抗肿瘤药物治疗选自如下化疗方案：长春瑞滨+顺铂、紫杉醇+顺铂/卡铂、 白蛋白紫杉醇+顺铂/卡铂、紫杉醇脂质体+顺铂/卡铂、吉西他滨+顺铂/卡铂、多西他赛+顺铂/卡铂、培美曲塞+顺铂/卡铂、多西他赛或培美曲塞。
在一些实施方案中，所述抗肿瘤药物治疗选自如下化疗方案：AC方案、EP方案、NP方案、PC方案、PP方案、nab-PP方案、LP方案、GP方案、DP方案或AP方案。上述化疗方案的具体方案参见CSCO非小细胞肺癌诊疗指南(2022年版)。
在一些实施方案中，所述抗肿瘤药物治疗选自如下化疗方案：AC方案、AP方案、EP方案、PC方案或DP方案。上述化疗方案的具体方案参见CSCO非小细胞肺癌诊疗指南(2022年版)。
在一些实施方案中，所述抗肿瘤药物治疗选自如下化疗方案：NP方案、PP方案、nab-PP方案、LP方案、GP方案、DP方案或AP方案。上述化疗方案的具体方案参见CSCO非小细胞肺癌诊疗指南(2022年版)。
在一些实施方案中，所述抗肿瘤药物治疗选自如下化疗方案：多西他赛或培美曲塞。
在一些实施方案中，所述抗肿瘤药物治疗选自以下免疫治疗用药方案：纳武利尤单抗、帕博利珠单抗、阿替利珠单抗、替雷利珠单抗、信迪利单抗、帕博利珠单抗+卡铂+培美曲塞、帕博利珠单抗+卡铂+紫杉醇/白蛋白紫杉醇、卡瑞利珠单抗+卡铂+培美曲塞、卡瑞利珠单抗+卡铂+紫杉醇、信迪利单抗+顺铂/卡铂+培美曲塞、信迪利单抗+顺铂/卡铂+吉他西滨、替雷利珠单抗+顺铂/卡铂+培美曲塞、替雷利珠单抗+卡铂+紫杉醇/白蛋白紫杉醇、阿替利珠单抗+贝伐珠单抗+卡铂+紫杉醇、阿替利珠单抗+顺铂/卡铂+培美曲塞、舒格利单抗+卡铂+培美曲塞或舒格利单抗+卡铂+紫杉醇。上述免疫治疗用药方案的具体方案参见CSCO非小细胞肺癌诊疗指南(2022年版)。
在一些实施方案中，所述抗肿瘤药物治疗选自以下靶向药物治疗：奥希替尼、埃克替尼、吉非替尼、厄洛替尼、阿法替尼、达可替尼、阿美替尼、阿帕替尼、伏美替尼、安罗替尼、Mobocertinib、阿来替尼、恩沙替尼、达拉非尼、曲美替尼、Larotrectinib、Capmatinmib、Tepotinib、Selpercatinib、赛沃替尼、普拉替尼、Sotorasib或吡咯替尼。
施用方式
本申请中，式(I)化合物药学上可接受的盐的剂量或质量以式(I)化合物计。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为50mg～1000mg/天。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为200～800mg/天。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为500mg/天。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为每次250mg，每日两次。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为600mg/天。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为每次300mg，每日两次。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为400mg/天。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的剂量为每次200mg，每日两次。
在一些实施方案中，式(I)化合物或其药学上可接受的盐可以每日给药一次或多次。在一些实施方案中，式(I)化合物或其药学上可接受的盐每日给药两次。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的给药周期为28天。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐每日给药两次，连续给药28天。
在一些实施方案中，本申请式(I)化合物或其药学上可接受的盐是作为单一活性剂使用。
在一些实施方案中，本申请式(I)化合物或其药学上可接受的盐可以是包含治疗有效量的式(I)化合物或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述药物组合物为单位剂量药物组合物。在一些实施方案中，所述单位剂量药物组合物包含10mg～300mg的式(I)化合物或其药学上可接受的盐。在一些实施方案中，所述单位剂量药物组合物包含25mg～200mg的式(I)化合物或其药学上可接受的盐。在一些实施方案中，所述单位剂量药物组合物包含50mg～150mg的式(I)化合物或其药学上可接受的盐。在一些实施方案中，所述单位剂量药物组合物包含50mg、100mg、125mg、或150mg的式(I)化合物或其药学上可接受的盐。
技术效果
本申请的式(I)化合物或其药学上可接受的盐在ROS1阳性非小细胞肺癌患者的临床治疗中表现出良好的安全性和有效性，在ORR、PFS、DCR、DOR方面体现出优异的治疗效果，同时，眼科不良反应发生率较低，还可产生持久的颅内响应。
本申请的式(I)化合物或其药学上可接受的盐对于CD74-ROS1基因融合的非小细胞肺癌患者的疗效明显优于其对于非CD74-ROS1基因融合的非小细胞肺癌患者的疗效，CD74-ROS1基因融合患者亚组的ORR更高，中位PFS更长。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本申请中，所述ROS1基因融合可通过FDA或NMPA批准的检测方法或是非小细胞肺癌诊疗指南推荐的检测方法确定，如实时定量逆转录-聚合酶链式反应(RT-PCR)、荧光原位杂交(FISH)、免疫组织化学(IHC)和二代测序(NGS)。
本申请中，所述逆转录-聚合酶链式反应(RT-PCR)可采用FDA或NMPA批准的ROS1RT-PCR检验试剂盒。
本申请中，除非特别规定，所述临床分期是根据国际抗癌联盟的TNM分期标准(第八版)划分的。
本申请中，基因融合类型中的“/”表示“和”的关系。例如，“TPM3/LRIG3/GOPC-ROS1基因融合”表示患者同时具有TPM3-ROS1基因融合、LRIG3-ROS1基因融合和GOPC-ROS1基因融合。
本申请中，抗肿瘤药物治疗中的“+”表示联用，“/”表示“或”的关系。例如，“信迪利单抗+顺铂/卡铂+培美曲塞”表示以下两种用药方案：信迪利单抗、顺铂与培美曲塞三药联用，或者信迪利单抗、卡铂与培美曲塞三药联用。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
本申请中，术语“受试者”或“患者”或“个体”可互换使用。在一些实施方案中，所述受试者或患者是哺乳动物。在部分实施方案中，所述受试者或患者是小鼠。在部分实施方案中，所述受试者或患者是人。
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
术语“单位剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单位剂量；或者每瓶注射液为单位剂量。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
本申请的式(I)化合物或其药学上可接受的盐可通过多种途径给药，包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药，优选为口服给药。
本申请的式(I)化合物或其药学上可接受的盐的给药剂量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予式(I)化合物或其药学上可接受的盐的日剂量可为50mg～1000mg，在一些实施方案中，给予式(I)化合物或其药学上可接受的盐的日剂量可为100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg或1000mg。式(I)化合物或其药学上可接受的盐可以每日施用一次、两次或更多次。
本申请的式(I)化合物或其药学上可接受的盐的给药方案可根据药物活性、副作用和患者耐受性等综合确定，可以是连续给药，也可以是间歇给药，例如，其中在若干天的期间内，个体接受每日剂量的式(I)化合物或其药学上可接受的盐，接着在若干天或更多天的期间，患者不接受每日剂量的式(I)化合物或其药学上可接受的盐。
本申请中，靶病灶疗效采用RECIST 1.1标准进行评价。其中，“CR”表示完全缓解，具体是指除结节性疾病外，所有目标病灶完全消失。所有目标结节须缩小至正常大小(短轴＜10mm)。所有目标病灶均须评价。“PR”表示部分缓解，具体是指所有可测量目标病灶的直径总和低于基线≥30％。目标结节总和使用短径，而所有其它目标病灶的总和使用最长直径。所有目标病灶均须评价。“PD"表示疾病进展，具体是指以整个实验研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm(出现 一个或多个新病灶也视为疾病进展)。“SD"表示疾病稳定，具体是指靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。术语“NE”表示不确定，具体是指未记录进展，且：1)1个或以上可测量的目标病灶未评价；2)或所用评价方法与基线不一致；3)或1个或以上目标病灶不能准确测量(如：看不清除，除非由于太小而不能测量)；4)或1个或以上目标病灶被切除或辐射，且未复发或增大。
本申请中，颅内响应采用RANO-BM标准进行评估。
本申请中，式(I)化合物可以根据WO2016169030A1实施例1制备，式(II)化合物可以根据WO2016169030A1实施例2制备。
具体实施方式
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。
实施例1临床II期试验-式(II)化合物对ROS1阳性非小细胞肺癌的安全性和有效性研究
1、试验药物和给药方案
1)试验药物：式(II)化合物胶囊，具体处方及制备方法参见WO2020233710A1实施例1(处方1)。
2)服药方法：
300mg，bid，p.o.，分别于早上、傍晚空腹服用，建议用药前后一小时内不要进食。连续服用28天为1个周期，直至受试者出现疾病进展或经处理后无法耐受的不良事件。
3)剂量调整：
如果受试者出现美国立癌症研究所不良事件通用术语标准(NCI CTCAE，第5.0版)规定的严重程度为3级及以上不良事件，可按以下方法进行剂量调整：
第一次减少剂量：给药方案：250mg，bid，p.o.；
第二次减少剂量：给药方案：200mg，bid，p.o.；
如200mg bid剂量水平下仍无法耐受，则受试者需终止研究。
2、主要入组标准
1)年龄≥18岁；
2)ECOG体力状况：0～1分；预计生存期超过3个月；
3)主要器官功能正常；
4)通过组织学或细胞学证明诊断为局部晚期或转移性NSCLC(依据第八版TNM分期标准)；
5)经RT-PCR检验确认为ROS1阳性；
6)既往接受过不超过2个化疗方案，如使用超过2个化疗方案，则筛选期需再次进行活检，检测结果需确认为ROS1阳性(NMPA批准的ROS1RT-PCR检验试剂盒)；
7)距离首次研究用药前28天内，经影像学证实，至少有一处脑部病灶除外的可评价的靶病灶(参照RECIST1.1标准进行评价)。
3、评价标准
有效性评价标准：采用RECIST 1.1标准进行评价，另对脑转移灶采用RANO-BM标准进行评估；
◆主要疗效评价指标：客观缓解率(ORR)，即(CR+PR例数)/总例数，包含完全缓解(CR)和部分缓解(PR)；
◆次要疗效评价指标：缓解持续时间(DOR)、无进展生存期(PFS)、疾病控制率(DCR)、总生存期(OS)；对脑转移病灶，颅内缓解率(C-ORR)、颅内缓解持续时间(C-DOR)、颅内疾病进展时间(C-TTP)。
安全性评价标准：采用NCI-CTC AE5.0标准评价药物的不良反应。
4、试验结果
1)入组患者
表1.患者人口统计学信息

2)整体有效性
表2.有效性评价指标

注：CI表示置信区间；有效性评价指标采用RECIST 1.1标准进行评价；95％CI采用Clopper-Pearson法计算；PFS采用Kaplan-Meier法计算。
其中，27例CD74-ROS1重排患者表现出显著的治疗效果，1例CR,23例PR,ORR为88.9％。
3)CD74-ROS1基因融合患者与非CD74-ROS1基因融合患者
非CD74-ROS1基因融合患者包括以下基因融合类型的患者：SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、EZR-ROS1基因融合、TPM3-ROS1基因融合、EZR/TGFBR1-ROS1基因融合、EZR/SLC34A2-ROS1基因融合和TPM3/LRIG3/GOPC-ROS1基因融合。
CD74-ROS1基因融合患者与非CD74-ROS1基因融合患者的疗效对比结果如下：
表3.疗效对比结果
其中，中位PFS采用Kaplan-Meier法计算。

Claims (15)

  1. 式(I)化合物或其药学上可接受的盐在制备治疗ROS1基因融合非小细胞肺癌的药物中的用途，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、CCDC6-ROS1基因融合、KDELR2-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种，
  2. 如权利要求1所述的用途，其中，所述式(I)化合物药学上可接受的盐为式(I)化合物的富马酸盐；或者，所述式(I)化合物药学上可接受的盐为式(II)化合物，
  3. 如权利要求1或2所述的用途，其中，所述ROS1基因融合选自CD74-ROS1基因融合、EZR-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、TPM3-ROS1基因融合、GOPC-ROS1基因融合、FIG-ROS1基因融合、TGFBR1-ROS1基因融合、LRIG3-ROS1基因融合中的一种或几种；
    或者，所述ROS1基因融合选自CD74-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、EZR-ROS1基因融合、TPM3-ROS1基因融合、EZR/TGFBR1-ROS1基因融合、EZR/SLC34A2-ROS1基因融合或TPM3/LRIG3/GOPC-ROS1基因融合；
    或者，所述ROS1基因融合选自CD74-ROS1基因融合、SDC4-ROS1基因融合、SLC34A2-ROS1基因融合、EZR-ROS1基因融合、TPM3-ROS1基因融合中的一种或几种；
    或者，所述ROS1基因融合选自CD74-ROS1基因融合。
  4. 如权利要求1-3任一项所述的用途，其中，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的局部晚期或转移性非小细胞肺癌；
    或者，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的脑转移性非小细胞肺癌；
    或者，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的非小细胞肺癌非鳞癌；
    或者，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的肺腺癌；
    或者，所述ROS1基因融合的非小细胞肺癌是ROS1基因融合的局部晚期或转移性肺腺癌。
  5. 如权利要求1-4任一项所述的用途，其中，所述ROS1基因融合的非小细胞肺癌的临床分期为III期或IV期。
  6. 如权利要求1-5任一项所述的用途，其中，患有所述ROS1基因融合的非小细胞肺癌的患者未接受过治疗；
    或者，患有所述ROS1基因融合的非小细胞肺癌的患者未接受过ROS1抑制剂治疗；
    或者，患有所述ROS1基因融合的非小细胞肺癌的患者已接受过一种或两种以上在先治疗方案的 治疗。
  7. 如权利要求6所述的用途，其中，所述在先治疗方案包括癌症根治术治疗、放射治疗或抗肿瘤药物治疗。
  8. 如权利要求6所述的用途，其中，患有所述ROS1基因融合的非小细胞肺癌的患者既往接受过抗肿瘤药物治疗。
  9. 如权利要求7或8所述的用途，其中，所述抗肿瘤药物选自顺铂、卡铂、奈达铂、长春瑞滨、紫杉醇、白蛋白紫杉醇、紫杉醇脂质体、吉西他滨、多西他赛、培美曲赛、依托泊苷、阿替利珠单抗、度伐利尤单抗、纳武利尤单抗、舒格利单抗、贝伐珠单抗、信迪利单抗、Amivantamab、帕博利珠单抗、卡瑞利珠单抗、替雷利珠单抗、特瑞普利单抗、伊匹木单抗、奥希替尼、埃克替尼、吉非替尼、厄洛替尼、阿法替尼、达可替尼、阿美替尼、阿帕替尼、伏美替尼、安罗替尼、Mobocertinib、阿来替尼、恩沙替尼、达拉非尼、曲美替尼、Larotrectinib、Capmatinmib、Tepotinib、Selpercatinib、赛沃替尼、普拉替尼、Sotorasib、吡咯替尼、血管内皮抑制素中的一种或几种的联合；
    或者，所述抗肿瘤药物治疗选自如下化疗方案：依托泊苷+顺铂/卡铂、长春瑞滨+顺铂、紫杉醇+顺铂/卡铂、白蛋白紫杉醇+顺铂/卡铂、紫杉醇脂质体+顺铂/卡铂、吉西他滨+顺铂/卡铂、多西他赛+顺铂/卡铂、培美曲塞+顺铂/卡铂、多西他赛或培美曲塞；
    或者，所述抗肿瘤药物治疗选自如下化疗方案：长春瑞滨+顺铂、紫杉醇+顺铂/卡铂、白蛋白紫杉醇+顺铂/卡铂、紫杉醇脂质体+顺铂/卡铂、吉西他滨+顺铂/卡铂、多西他赛+顺铂/卡铂、培美曲塞+顺铂/卡铂、多西他赛或培美曲塞；
    或者，所述抗肿瘤药物治疗选自如下化疗方案：AC方案、EP方案、NP方案、PC方案、PP方案、nab-PP方案、LP方案、GP方案、DP方案或AP方案；
    或者，所述抗肿瘤药物治疗选自如下化疗方案：NP方案、PP方案、nab-PP方案、LP方案、GP方案、DP方案或AP方案；
    或者，所述抗肿瘤药物治疗选自如下化疗方案：多西他赛或培美曲塞；
    或者，所述抗肿瘤药物治疗选自以下免疫治疗用药方案：纳武利尤单抗、帕博利珠单抗、阿替利珠单抗、替雷利珠单抗、信迪利单抗、帕博利珠单抗+卡铂+培美曲塞、帕博利珠单抗+卡铂+紫杉醇/白蛋白紫杉醇、卡瑞利珠单抗+卡铂+培美曲塞、卡瑞利珠单抗+卡铂+紫杉醇、信迪利单抗+顺铂/卡铂+培美曲塞、信迪利单抗+顺铂/卡铂+吉他西滨、替雷利珠单抗+顺铂/卡铂+培美曲塞、替雷利珠单抗+卡铂+紫杉醇/白蛋白紫杉醇、阿替利珠单抗+贝伐珠单抗+卡铂+紫杉醇、阿替利珠单抗+顺铂/卡铂+培美曲塞、舒格利单抗+卡铂+培美曲塞或舒格利单抗+卡铂+紫杉醇；
    或者，所述抗肿瘤药物治疗选自以下靶向药物治疗：奥希替尼、埃克替尼、吉非替尼、厄洛替尼、阿法替尼、达可替尼、阿美替尼、阿帕替尼、伏美替尼、安罗替尼、Mobocertinib、阿来替尼、恩沙替尼、达拉非尼、曲美替尼、Larotrectinib、Capmatinmib、Tepotinib、Selpercatinib、赛沃替尼、普拉替尼、Sotorasib或吡咯替尼；
    或者，所述抗肿瘤药物治疗选自单药化疗或双药化疗，任选地与贝伐珠单抗联合治疗；
    或者，所述抗肿瘤药物选自单药化疗或双药化疗，所述双药化疗的药物包含铂类药物；
    或者，所述抗肿瘤药物选自单药化疗或双药化疗，所述单药化疗或双药化疗的药物选自顺铂、卡铂、奈达铂、长春瑞滨、紫杉醇、白蛋白紫杉醇、紫杉醇脂质体、吉西他滨、多西他赛、培美曲赛或依托泊苷。
  10. 如权利要求1-9任一项所述的用途，其中，所述式(I)化合物或其药学上可接受的盐的剂量为50mg～1000mg/天；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为200～800mg/天；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为500mg/天；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为每次250mg，每日两次；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为600mg/天；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为每次300mg，每日两次；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为400mg/天；
    或者，所述式(I)化合物或其药学上可接受的盐的剂量为每次200mg，每日两次。
  11. 如权利要求1-10任一项所述的用途，其中，所述式(I)化合物或其药学上可接受的盐的给药周期为28天。
  12. 如权利要求1-11任一项所述的用途，其中，所述式(I)化合物或其药学上可接受的盐是作为单一活性剂使用。
  13. 如权利要求1-12任一项所述的用途，其中，所述式(I)化合物或其药学上可接受的盐可以是包含治疗有效量的式(I)化合物或其药学上可接受的盐的药物组合物。
  14. 如权利要求13所述的用途，其中，所述药物组合物为单位剂量药物组合物。
  15. 如权利要求14所述的用途，其中，所述单位剂量药物组合物包含10mg～300mg的式(I)化合物或其药学上可接受的盐；
    或者，所述单位剂量药物组合物包含25mg～200mg的式(I)化合物或其药学上可接受的盐；
    或者，所述单位剂量药物组合物包含50mg～150mg的式(I)化合物或其药学上可接受的盐；
    或者，所述单位剂量药物组合物包含50mg、100mg、125mg、或150mg的式(I)化合物或其药学上可接受的盐。
PCT/CN2023/108855 2022-07-25 2023-07-24 吡啶胺化合物在特定ros1基因融合的非小细胞肺癌中的应用 Ceased WO2024022282A1 (zh)

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CN103263416A (zh) * 2013-04-28 2013-08-28 杭州鸿运华宁生物医药工程有限公司 一种吡啶胺化合物在制备适于口服给药的治疗肺癌的药物中的应用
CN104557870A (zh) * 2013-10-25 2015-04-29 正大天晴药业集团股份有限公司 一种吡啶胺化合物的富马酸盐
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