Therapeutic agent combinations for the prevention or treatment of tumor diseases
阅读说明：本技术 用于预防或治疗肿瘤疾病的治疗剂组合 (Therapeutic agent combinations for the prevention or treatment of tumor diseases ) 是由 周远锋 张晓婷 于 2021-06-16 设计创作，主要内容包括：本发明提供了用于预防或治疗肿瘤疾病的治疗剂组合,即EGFR抑制剂与化疗药物联合在制备治疗肿瘤疾病的药物中的用途。具体而言,本发明提供一种式(I)化合物、其立体异构体、复合物或其可药用盐与培美曲塞和/或顺铂联合在制备预防或治疗肿瘤疾病的药物中的用途。(The invention provides a therapeutic agent combination for preventing or treating tumor diseases, namely an application of an EGFR inhibitor and a chemotherapeutic medicament in preparing a medicament for treating tumor diseases. Specifically, the invention provides an application of a compound shown as a formula (I), a stereoisomer, a compound or a pharmaceutically acceptable salt thereof in preparation of a medicament for preventing or treating tumor diseases by combining pemetrexed and/or cisplatin.)
Use of an EGFR inhibitor in combination with a chemotherapeutic agent for the manufacture of a medicament for the prevention or treatment of a neoplastic disease, wherein said EGFR inhibitor is a compound of formula (I), a stereoisomer, a complex or a pharmaceutically acceptable salt thereof,
wherein:
the pharmaceutically acceptable salt of the compound represented by the formula (I) is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillite, mandelate, succinate, gluconate, lactobionate or laurylsulfonate; preferably a mesylate salt;
the compound shown in the formula (I) is preferably Almonetinib as a pharmaceutically acceptable salt.
2. Use according to claim 1, characterized in that the tumor disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gall bladder cancer, bile duct cancer or chorioepithelial cancer; preferably non-small cell lung cancer; non-small cell lung cancer is selected from squamous cell carcinoma or non-squamous cell carcinoma; non-squamous cell carcinomas are preferred.
3. The use according to claim 1, wherein the tumor disease is an EGFR-mutated tumor disease; EGFR-mutated neoplastic disease is non-small cell lung cancer; preferably, the EGFR mutant comprises a common or rare EGFR mutation or a combination thereof, wherein the common mutation is an EGFR 19 exon deletion, 858 site mutation; a rare mutation is at position 719, 861, 768, 289, 598, 709, 865, 790, or any combination thereof; more preferably EGFR 19 exon deletion, EGFR L858R/T790M or EGFR Del 19/T790M.
4. Use according to any one of claims 1 to 3, characterized in that the chemotherapeutic agent is selected from alkylating agents, antineoplastic antimetabolites, antineoplastic antibiotics, antineoplastic animal or plant components, antineoplastic hormones and/or platinum compounds;
preferably an antineoplastic antimetabolite and/or a platinum-based compound;
more preferably a folic acid antagonist and/or a platinum compound;
further preferred are pemetrexed, cisplatin, carboplatin, oxaliplatin and/or combinations thereof;
most preferred is pemetrexed and/or cisplatin.
5. The use of claim 1, wherein the single administration dose range of the EGFR inhibitor is selected from the group consisting of 1-1000 mg; preferably 20-300 mg; more preferably 50-300 mg;
alternatively, the EGFR inhibitor is administered once a day, twice a day, three times a day;
preferably, the EGFR inhibitor is administered once daily at a dose selected from 55mg, 110mg, 220mg or 260 mg.
6. The use of claim 1, wherein the single administration dose of the chemotherapeutic agent is selected from the range of 1-1000mg/m2Preferably 50 to 800mg/m2More preferably 50 to 600mg/m2(ii) a Further preferably, the single administration dose of the chemotherapeutic drug pemetrexed is 500mg/m2(ii) a The single administration dose of the chemotherapeutic drug cisplatin is 75mg/m2；
Alternatively, the frequency of administration of the chemotherapeutic agent may be once a week, twice a week, once every two weeks, once every three weeks;
preferably, the chemotherapy drug pemetrexed is administered once every three weeks at a dose of 500mg/m2，
The administration frequency of the chemotherapy medicament cisplatin is once in three weeks, and the administration dosage is 75mg/m2。
7. The use of claim 1, wherein the dose ratio of EGFR inhibitor to chemotherapeutic agent is 1:100 to 10: 1; preferably 1:10 to 1: 1; more preferably, the dose ratio of almonetinib to pemetrexed is 1:1-1: 10; further preferably 1: 8; the dose ratio of Almonertinib to cisplatin is 1:2-2: 1; preferably 1: 1; the combination dose ratio of Almonertib to pemetrexed and cisplatin is 1:1-1: 10; preferably 1: 9.
8. The use according to claim 1, wherein the EGFR inhibitor is for simultaneous, concurrent, separate or sequential use with the chemotherapeutic agent.
9. A combination formulation comprising:
(a) one or more EGFR inhibitors;
(b) one or more chemotherapeutic drugs;
the method is characterized in that:
the EGFR inhibitor is Almonertinib;
the chemotherapeutic drug is selected from pemetrexed, cisplatin, carboplatin, oxaliplatin and/or combinations thereof; pemetrexed and/or cisplatin are preferred.
10. The combined preparation according to claim 9, for use in a medicament for the prophylaxis or treatment of a tumor disease selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, or chorioepithelial cancer;
preferably, the neoplastic disease is lung cancer, more preferably non-small cell lung cancer.
Technical Field
The invention belongs to the field of medicines, and relates to application of a human Epidermal Growth Factor Receptor Inhibitor (EGFRI) and a chemotherapeutic drug in preparation of a drug for preventing or treating non-small cell lung cancer (NSCLC).
Background
Worldwide, lung cancer has become the leading cause of cancer death, both morbidity and mortality are on the rise, with about 180 new lung cancer cases worldwide in 2012, and 210 thousands of lung cancer diagnosis cases worldwide by 2018. In China, from the aspect of morbidity, the statistical data of the Chinese cancer center shows that lung cancer is the first to occur nationwide, the lung cancer occurs about 78.1 ten thousand every year, and the lung cancer accounts for 20.55 percent of the weight of various types of cancers; from the aspect of mortality, lung cancer, liver cancer, stomach cancer and esophageal cancer are the main causes of death of tumors. Despite the recent generations of cytotoxic drugs and targeted therapies that have been introduced over the last 20 years, patients with advanced lung cancer, particularly those who do not have known driver mutations or develop resistance after treatment with EGFR inhibitors, have poor treatment options and prognosis of survival, and advanced or metastatic lung cancer remains a fatal disease with an unmet medical need.
Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, with about 75% of NSCLC patients found in the middle-to late stage with a very low 5-year survival rate. There is still a great clinical need to select an appropriate systemic treatment for patients with advanced or metastatic NSCLC. NSCLC can be further classified as squamous cell carcinoma and non-squamous cell carcinoma. Non-squamous cell carcinomas include adenocarcinomas, large cell carcinomas and other subtypes of cell carcinoma. Non-squamous cell carcinoma patients are further classified according to the presence or absence of the driver mutant gene (EGFR mutation, ROS1 mutation, or ALK gene rearrangement).
Egfr (epidemal Growth Factor receptor) is a member of the erbB receptor family of transmembrane protein tyrosine kinases. EGFR can form homodimers on cell membranes by binding to its ligand, e.g., Epidermal Growth Factor (EGF), or heterodimers with other receptors in the family, such as erbB2, erbB3, or erbB 4. The formation of these dimers can lead to phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cells. These intracellular signaling pathways play important roles in cell proliferation, survival, and resistance to apoptosis. Dysregulation of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can promote cellular transformation to malignancy, and play an important role in proliferation, invasion, metastasis and angiogenesis of tumor cells. Overexpression of EGFR has been reported in a number of human malignancies, including bladder, brain, head and neck, pancreatic, lung, breast, ovarian, colon, prostate, and kidney cancers. In many cases, overexpression of EGFR is associated with poor prognosis in patients.
At present, four main basic treatment methods for lung cancer are available, namely surgery, radiotherapy, chemotherapy and targeted treatment. The optimal treatment means is different for different stages of lung cancer with different pathological types. With the gradual and deep understanding of disease biology, pathogenesis and the functions of proto-oncogene mutation in the process of generating and developing tumors, the targeted EGFR inhibitor represented by Gefitinib brings unprecedented survival benefit to non-small cell lung cancer patients containing EGFR mutation. The method has the advantages of remarkably improving the objective response rate, the disease-free development survival time, the toxic and side effects of the medicine and the like compared with the prior chemotherapy. However, both first-generation EGFR inhibitors, represented by Gefitnib, second-generation EGFR inhibitors, represented by Afatinib, and third-generation EGFR inhibitors, represented by osimertinib (AZD9291), develop drug resistance in non-small cell lung cancer patients after long-term clinical use. Currently, there is no good clinical treatment for the above patients who develop resistance. Therefore, the improvement of the clinical curative effect of the existing treatment scheme or the delay of the clinical drug resistance of the EGFR inhibitor is particularly important for improving the survival period and the prognosis of the non-small cell lung cancer patients.
Disclosure of Invention
The invention provides an application of an EGFR inhibitor and a chemotherapeutic medicament in preparation of medicaments for preventing or treating tumor diseases. The novel EGFR inhibitor and chemotherapy drug provided by the invention show good effects in treating non-small cell lung cancer.
The tumor disease according to the present invention is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer or chorioepithelial cancer, preferably non-small cell lung cancer.
In a preferred embodiment of the invention, the non-small cell lung cancer is selected from the group consisting of squamous cell carcinoma and non-squamous cell carcinoma, preferably non-squamous cell carcinoma, wherein the non-squamous cell carcinoma may be adenocarcinoma, large cell carcinoma and other sub-types of cell carcinoma.
The EGFR inhibitor and chemotherapeutic drug provided by the invention are used for preparing drugs for preventing or treating tumor diseases, wherein the tumor diseases are EGFR mutant tumor diseases.
In a preferred embodiment of the invention, the EGFR mutated tumor disease is preferably non-small cell lung cancer, preferably the EGFR mutant is a mutant comprising a common or rare EGFR mutation or a combination thereof, wherein the common mutations are EGFR 19 exon deletion (EGFR Del19), 858 site mutation (L858R); rare mutations are at position 289 (G289V), site 598 (G598V), site 709 (E709X), site 865 (E865K), etc., preferably at position 719 (G719X), site 861 (L861Q), site 768 (S768I), or any combination thereof, preferably EGFR L858R/T790M or EGFR Del 19/T790M.
In certain embodiments of the invention, the EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, vandetanib, brigitinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, thelitatinib, epitinib succinate, S-222611, porzitinib, AST-2818, GNS-1480, maveltinib, AP-32788, AZD-3759, naztinib, Sym-013, tesivatinib, dyssyllate, tareotinib SCTP, ziprofibrib, kyphotinib, SYNC-101-1118, SKIN-84, SKL-150, BCG-121, BCG-200, BCB-H-200, BCB-2, BCB, The compound or the pharmaceutically acceptable salt thereof, preferably olmutinib, affinib, osiertinib, CK-101, erlotinib, icotinib, gefitinib or the compound of formula (I) or the stereoisomer, the compound or the pharmaceutically acceptable salt thereof, most preferably the compound of formula (I) or the stereoisomer, the compound or the pharmaceutically acceptable salt thereof,
in a preferred embodiment of the invention, the pharmaceutically acceptable salt of the drug may be a hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate. Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salts, and the like.
In a more preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is a mesylate salt.
In a most preferred embodiment of the present invention, the compound of formula (I), a stereoisomer, a complex or a pharmaceutically acceptable salt thereof is almonetinib, wherein almonetinib has the following structure:
the present invention further relates to a method of administering an EGFR inhibitor in the preparation of a medicament for the prevention or treatment of tumor diseases, wherein the EGFR inhibitor may be administered once a day, twice a day, three times a day; the frequency of administration of the chemotherapeutic agent may be once a week, twice a week, once every two weeks, once every three weeks.
In a preferred embodiment of the invention, the single administration dose of the EGFR inhibitor is selected from the range of 1 to 1000mg, and the administration frequency may be once a day, twice a day, or three times a day. Exemplary doses are selected from 1mg, 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 950mg, 1000 mg.
In a preferred embodiment of the invention, the EGFR inhibitor is administered once daily at a dose selected from the group consisting of 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175 mg; the EGFR inhibitor is administered once daily at a dose selected from 55mg, 110mg, 220mg, 260 mg.
In a preferred embodiment of the invention, the EGFR inhibitor is a compound of formula (I) or a stereoisomer, complex or pharmaceutically acceptable salt thereof, administered once daily at a dose selected from 55mg, 110mg, 220mg, 260 mg.
In a more preferred embodiment of the invention, the EGFR inhibitor is Almonertib administered once daily at a dose selected from the group consisting of 55mg, 110mg, 220mg, 260 mg.
In certain embodiments of the invention, the chemotherapeutic agent is selected from alkylating agents, antineoplastic antimetabolites, antineoplastic antibiotics, antineoplastic animal or plant components, antineoplastic hormones, and/or platinum compounds.
Such alkylating agents include, without limitation, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel) or Temozolomide (TEMODAR). Cyclophosphamide can be used, for example, in the form as it is marketed.
The antineoplastic antimetabolites include, without limitation, 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating agents such as 5-azacytidine and decitabine, methotrexate, edatrexate, and folic acid antagonists such as, but not limited to, pemetrexed.
The anti-tumor antibiotics include, but are not limited to, anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin.
The antitumor animal and plant component medicine includes vincristine, etoposide, teniposide, taxol and docetaxel without limitation.
The anti-tumor hormones include, without limitation, antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, renoxiphenol, droloxifene, and idoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vilazone, and exemestane), and 5 α reductase inhibitors (e.g., finasteride).
The platinum compounds include, but are not limited to, carboplatin, cisplatin (cissplatin), cisplatin (cissplatinum), oxaliplatin, satraplatin, and platinum agents. Carboplatin, for example, can be in its commercially available form.
In a preferred embodiment of the invention, the chemotherapeutic agent is selected from the group consisting of antineoplastic antimetabolites and/or platinum compounds.
In a preferred embodiment of the invention, the chemotherapeutic agent is selected from a folate antagonist and/or a platinum compound.
In a more preferred embodiment of the invention, the chemotherapeutic agent is selected from pemetrexed, cisplatin, carboplatin, oxaliplatin and/or combinations thereof.
In a most preferred embodiment of the invention, the chemotherapeutic agent is selected from pemetrexed and/or cisplatin.
In preferred embodiments of the invention, the frequency of administration of the chemotherapeutic agent may be once a week, twice a week, once every two weeks or once every three weeks.
In a preferred embodiment of the invention, the single administration dose of the chemotherapeutic agent is selected from 15mg/m2、20mg/m2、30mg/m2、40mg/m2、50mg/m2、60mg/m2、70mg/m2、75mg/m2、、80mg/m2、85mg/m2、90mg/m2、100mg/m2、125mg/m2、150mg/m2、175mg/m2、200mg/m2、250mg/m2、300mg/m2、350mg/m2、400mg/m2、450mg/m2、500mg/m2，600mg/m2、700mg/m2、750mg/m2、800mg/m2、900mg/m2、1000mg/m2。
In a preferred embodiment of the invention, the chemotherapeutic agent is administered once in three weeks at a dose selected from 25mg/m2、50mg/m2、75mg/m2、100mg/m2、125mg/m2、150mg/m2、175mg/m2、200mg/m2、250mg/m2、300mg/m2、350mg/m2、400mg/m2、450mg/m2、500mg/m2；
In a preferred embodiment of the invention, the chemotherapeutic agent is preferably pemetrexed and/or cisplatin, administered once in three weeks at a dose selected from 25mg/m2、50mg/m2、75mg/m2、100mg/m2、125mg/m2、500mg/m2。
In preferred embodiments of the invention, the dose ratio of the EGFR inhibitor to the chemotherapeutic agent is 1:100 to 10: 1; preferably 1:10 to 1:1. Specific choices are 10:1, 8:1, 6:1, 5:1, 3.18:1, 2.72:1, 2.27:1, 2:1, 1.81:1, 1.59:1, 1.36:1, 1.14:1, 1:1.1, 1:1.5, 1:1.26, 1:1.47, 1:1.49, 1:1.73, 1:1.76, 1:2, 1:2.08, 1:2.2, 1:2.6, 1:2.93, 1:3.47, 1:3.5, 1:4.4, 1:5, 1:5.2, 1:7.5, 1:8.8, 1:10, 1:10.4, 1:12.5, 1:15, 1:20, 1:25, 1:30, 1:50, 1:75, 1: 100.
In a preferred embodiment of the invention, the dose ratio of EGFR inhibitor to pemetrexed is 1; 1-1; 10, preferably 1:8.
In a preferred embodiment of the invention, the dose ratio of EGFR inhibitor to cisplatin is from 1:2 to 2:1, preferably 1:1.
In a preferred embodiment of the invention, the combined dose ratio of the EGFR inhibitor to pemetrexed and cisplatin is from 1:1 to 1:10, preferably 1: 9.
In a more preferred embodiment of the present invention, the dose ratio of the compound of formula (I), its stereoisomer, complex or a pharmaceutically acceptable salt thereof to pemetrexed is 1; 1-1; 10, preferably 1:8.
In a more preferred embodiment of the present invention, the dose ratio of the compound of formula (I), its stereoisomer, complex or a pharmaceutically acceptable salt thereof to cisplatin is from 1:2 to 2:1, preferably 1:1.
In a more preferred embodiment of the present invention, the compound of formula (I), a stereoisomer, a complex thereof or a pharmaceutically acceptable salt thereof, is present in a combined dose ratio of pemetrexed and cisplatin of from 1:1 to 1:10, preferably 1: 9.
In a more preferred embodiment of the invention, the dose ratio of almonetinib to pemetrexed is 1; 1-1; 10, preferably 1:8.
In a more preferred embodiment of the invention, the dose ratio of Almonetinib to cisplatin is from 1:2 to 2:1, preferably 1:1.
In a more preferred embodiment of the invention, the combined dose ratio of Almonertib to pemetrexed, cisplatin is from 1:1 to 1:10, preferably 1: 9.
In a preferred embodiment of the invention, Almonertinib is administered once daily at a dose selected from 55mg, 110mg, 220mg or 260mg, the chemotherapeutic drug pemetrexed is administered once every three weeks at a dose of 500mg/m2The administration frequency of the chemotherapeutic cisplatin is once in three weeks, and the administration dosage is 75mg/m2。
The combined administration route of the invention is selected from oral administration, parenteral administration and transdermal administration, wherein the parenteral administration includes but is not limited to intravenous injection, intravenous drip, subcutaneous injection and intramuscular injection, and the oral administration is preferred.
In the embodiment of the invention, the combination optionally further comprises other components, and the other components include but are not limited to the application of other medicines for treating tumor diseases.
The invention also provides a method in a medicament for treating a neoplastic disease comprising administering to a patient an effective amount of an EGFR inhibitor as described above.
In certain embodiments of the present invention, there is also provided a method in a medicament for treating a neoplastic disease comprising administering to a patient a combination comprising administering an effective dose of:
(a) an EGFR inhibitor;
(b) one or more chemotherapeutic drugs;
the EGFR inhibitor is applied simultaneously, concurrently, separately or sequentially with the chemotherapeutic agent.
In a preferred embodiment of the invention, the EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, vandetanib, brigitinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, thelitatinib, epitinib succinate, S-222611, pozitinib, AST-2818, GNS-1480, maveltinib, AP-32788, AZD-3759, nazurtinib, Sym-013, tesevatinib, allotinib tosynate, tarloxtinib bromide, pozitinib, CK-101, QL-1203, JNJ-61186372, SKLB-1028, TAS-121, Hemay-020, Hemay-022, NRC-2694-A, simotinib hydrochloride, vandetanib, SPH-1188-11, GR-1401, 004-221, ABBV-221, MP-0274, GC-1118, BPI-15000, DBPR-112, Pirotinib, PB-357, lifirafenib, SCT-200, QLNC-120, agrafenib hydrochloride, or Almonetinib.
In a more preferred embodiment of the invention, there is also provided a method in a medicament for treating a neoplastic disease comprising administering to a patient a combination comprising administering an effective dose of:
(a)Almonertinib；
(b) one or more chemotherapeutic agents.
In a preferred embodiment of the invention, the chemotherapeutic agent is selected from alkylating agents, antineoplastic antimetabolites, platinum compounds and/or topoisomerase II inhibitors;
preferably an antineoplastic antimetabolite and or a platinum compound;
more preferably a folate antagonist and/or a platinum compound;
further preferred are pemetrexed, cisplatin, carboplatin, oxaliplatin and/or combinations thereof;
most preferred is pemetrexed and/or cisplatin.
The invention also relates to a pharmaceutical composition of the EGFR inhibitor and one or more medicinal carriers, excipients and diluents. The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, it can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
The pharmaceutical compositions containing an EGFR inhibitor of the present invention can be administered alone or in combination with one or more therapeutic agents.
The present invention also provides a combined preparation comprising:
(a) one or more EGFR inhibitors;
(b) one or more chemotherapeutic agents.
In a preferred embodiment of the invention, the combined preparation comprises:
(a)Almonertinib；
(b) one or more chemotherapeutic agents.
In a preferred embodiment of the invention, the combined preparation is used for the treatment of a tumor disease.
The invention also provides a pharmaceutical kit for use in a medicament for treating a neoplastic disease, wherein a pharmaceutical composition of an EGFR inhibitor according to the invention is packaged.
The present invention provides for the administration of EGFR inhibitors in combination with chemotherapeutic agents, thereby enhancing the utility in the treatment of neoplastic diseases and improving the therapeutic efficacy.
Herein, unless otherwise indicated, the dosages and ranges provided herein are based on the molecular weight calculation of the free base form of compound I.
The term "combination" as used herein is intended to mean a mode of administration in which at least one dose of a chemotherapeutic agent and at least one dose of an EGFR inhibitor are administered over a period of time, wherein both substances exhibit pharmacological effects. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. The chemotherapeutic agent and the EGFR inhibitor may be administered simultaneously or sequentially. Such terms include treatments wherein the chemotherapeutic agent and the EGFR inhibitor are administered by the same route of administration or different routes of administration.
The term "effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably prevent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and/or to alleviate one or more symptoms associated with the condition to some extent. Depending on the extent to which the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. For cancer treatment, in vivo efficacy can be measured by assessing survival duration, Progression Free Survival (PFS) duration, Response Rate (RR), response duration, and/or quality of life.
Drawings
FIG. 1: the growth inhibition effect of Almonertib 3mg/kg combined pemetrexed on PC-9 subcutaneous transplantation tumor;
FIG. 2: the effect of Almonertinib 3mg/kg combined pemetrexed on the body weight of a PC-9 transplanted tumor bearing mouse;
FIG. 3: the growth inhibition effect of Almonertib 10mg/kg combined pemetrexed/cisplatin on PC-9 subcutaneous transplantation tumor;
FIG. 4: the effect of Almonertinib 10mg/kg combined pemetrexed/cisplatin on the body weight of a PC-9 transplanted tumor bearing mouse;
FIG. 5: the growth inhibition effect of Almonertib combined with pemetrexed/cisplatin on HCC827 subcutaneous transplanted tumors;
FIG. 6: effect of almonetini in combination with pemetrexed/cisplatin on body weight in HCC827 transplantable tumor bearing mice.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Example 1 evaluation of the Experimental therapeutic Effect of Almonertib in combination with chemotherapeutic drugs (Pemetrexed and cisplatin) on human Lung cancer PC-9 nude mouse transplantable tumors
1. Experimental Material
Almonertinib was prepared according to the method disclosed in WO2016054987 using a pH4.18 acetate buffer for pharmaceutical formulations.
Pemetrexed and cisplatin, supplied by Jiangsu Haisen pharmaceutical industry group, Inc.
PC-9 cells (containing an EGFR Del19 deletion) were purchased from Biotech, Inc., Ginie, Guangzhou. 150cm2Culturing in adherent culture bottle under the conditions of RPMI1640 medium supplemented with 10% fetal calf serum and 1% streptomycin/penicillin at 37 deg.C and 5% CO2Air incubator. Carrying out 1-2 passages in one week, when the cells are in exponential growth phase, carrying out pancreatin digestion, collecting the cells, counting and inoculating.
Nude mice, female; at 6-8 weeks, 80 inoculates, 54 practical uses, and the unit is Shanghai Sphere-BiKai laboratory animals Co., Ltd
2. Experimental methods
Will be 5X 106Injecting human lung cancer cell PC-9 into the subcutaneous part of the right upper back of the nude mouse until the tumor grows to the average volume of 150-3Thereafter, the animals were grouped according to tumor volume (D0). Gavage (p.o) mice, 1 time daily (QD), or intraperitoneal injection (i.p), 1 time weekly (QW); the administration volume is 10 mL/kg; solvent group administration phaseThe same volume of "solvent" (pH 4.18 acetate buffer); the specific dosage and administration schedule are shown in table 1 and table 2. Tumor volume was measured, mouse body weight was weighed and data was recorded.
The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
The tumor diameter is measured by a vernier caliper, and the tumor volume (V) is calculated by the formula:
V＝1/2×a×b2wherein a and b represent length and width, respectively.
T/C(％)＝(T-T0)/(C-C0) X 100 wherein: t, C is the tumor volume at the end of the experiment, T0、C0Tumor volume at the beginning of the experiment.
Tumor inhibition rate (TGI) (%) 100-T/C (%).
When tumors regress, tumor inhibition rate (TGI) (%) 100- (T-T)0)/T0×100
If the tumor is reduced from the initial volume, i.e. T<T0Or C<C0When, it is defined as partial tumor regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR).
The experiment is finished, the experimental end point is reached, or the tumor volume reaches 2000mm3，CO2The sacrifice was anesthetized.
The experimental data were analyzed and plotted using GraphPad Prism 6.0. Two groups of tumor volumes were compared using a two-tailed T-test. Three or more groups were compared using one-way ANOVArepeated measures, and if there were significant differences in F-values, multiple comparisons should be made using Dunnett's after ANOVA analysis. P <0.05 was defined as statistically significant.
TABLE 1 mouse dosing regimen of Almonertib 3mg/kg in combination with pemetrexed in PC-9 model
Note:
the administration of Almonertinib was started on the same day as pemetrexed.
TABLE 2 mouse dosing regimen of Almonertib 10mg/kg in combination with pemetrexed/cisplatin in PC-9 model
Note:
the administration of Almonertinib, pemetrexed and cisplatin was started on the same day.
3. Results of the experiment
TABLE 3 growth inhibition of Almonertib 3mg/kg in combination with pemetrexed on PC-9 transplantable tumors
Note:
d0, day before first administration;
p value D28 is the value obtained compared to the solvent set;
p <0.001, compared to pemetrexed;
# P <0.05, compared to Almonertib (3 mg/kg);
TABLE 4 growth inhibition of Almonertib 10mg/kg combination pemetrexed/cisplatin on PC-9 transplantable tumors
Note:
"-" denotes no particular numerical value
P-value D80 is a number compared to solvent set (D28);
p <0.01, values compared to chemotherapeutic drugs (pemetrexed + cisplatin D28).
The curative effects of Almonertinib, pemetrexed and cisplatin on single or combined use on human lung cancer PC-9 nude mouse subcutaneous transplantation tumor are shown in figure 1 and figure 2.
The effect of Almonertinib, pemetrexed and cisplatin alone or in combination on the body weight of PC-9 tumor-bearing mice is shown in figure 3 and figure 4.
The single-drug tumor inhibition rate of Almonertib (3mg/kg) is 83 percent; the tumor inhibition rate of the combination of Almonertib (3mg/kg) and the chemotherapeutic drug pemetrexed is 97%, and compared with the respective single drug groups, the combination has significant differences (P is less than 0.05 compared with Almonertib, and P is less than 0.001 compared with pemetrexed), 1/6 tumors have partial regression.
The tumor inhibition rate of the single-drug treatment group of Almonertib (10mg/kg) is 188%, and the tumor inhibition rate of the combined chemotherapy drug (pemetrexed + cisplatin) treatment group is increased to 191%.
Observation period data show: the tumor growth trend of the animals in the combination group is obviously slower than that of the animals in the single-drug treatment group, and the experimental end (D80) is that the animals in the Almonertib group TV is 1355mm3The almonetinib combination chemotherapy drug (pemetrexed + cisplatin) group TV is 615mm 3; the combination of Almonertib and chemotherapeutic drug group (D80) and the solvent group (D28) and the chemotherapeutic drug (pemetrexed + cisplatin) group (D28) are significantly different (P compared with the solvent group)<0.05, P compared to the chemotherapeutic drug group<0.01), and 1/6 tumors in the combination completely regressed.
The tumor-bearing mice can well tolerate the above dosage in the whole experimental process, and no obvious weight loss symptom occurs.
And (4) conclusion: the single-drug treatment group and the combined treatment group of the Almonettinib have obvious tumor inhibition effect, and the single-drug treatment of the Almonettinib is in a dose-dependent relationship; the combined chemotherapeutic drug can synergistically enhance the tumor inhibition effect of low-dose Almonertinib and delay the drug resistance process of high-dose Almonertinib.
Example 2 evaluation of the therapeutic Effect of Almonertib in combination with chemotherapeutic drugs (Pemetrexed and cisplatin) on human Lung cancer HCC827 nude mouse transplantable tumors
1. Experimental Material
Almonertinib was prepared according to the method disclosed in WO2016054987 using a pH4.18 acetate buffer for pharmaceutical formulations.
Pemetrexed and cisplatin, supplied by Jiangsu Haisen pharmaceutical industry group, Inc.
HCC827 cells were purchased from tokyo baibo biotechnology limited. 150cm2Culturing in adherent culture bottle under the conditions of RPMI1640 medium supplemented with 10% fetal calf serum and 1% streptomycin/penicillin at 37 deg.C and 5% CO2Air incubator. Carrying out 1-2 passages in one week, when the cells are in exponential growth phase, carrying out pancreatin digestion, collecting the cells, counting and inoculating.
Nude mice, female; in 6-8 weeks, 54 inoculations, in practice 20, were provided in Shanghai Sphere-BiKa laboratory animals Co.
2. Experimental methods
Will be 1 × 107HCC827 cells (containing EGFR Del19 deletion) of human lung cancer cells are injected into the subcutaneous tissue of the right upper back of the nude mice, and the tumors are grown to the average volume of 150-200mm3Thereafter, the animals were grouped according to tumor volume (D0). Gavage (p.o) mice, 1 time daily (QD), or intraperitoneal injection (i.p), 1 time weekly (QW); the administration volume is 10 mL/kg; solvent group the same volume of "solvent" (pH 4.18 acetate buffer) was administered; specific dosages and schedules are shown in table 5. Tumor volume was measured, mouse body weight was weighed and data was recorded.
The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
The tumor diameter is measured by a vernier caliper, and the tumor volume (V) is calculated by the formula:
V＝1/2×a×b2wherein a and b represent length and width, respectively.
T/C(％)＝(T-T0)/(C-C0) X 100 where T, C is the tumor volume at the end of the experiment, T0、C0Tumor volume at the beginning of the experiment.
Tumor inhibition rate (TGI) (%) 100-T/C (%).
When tumors regress, tumor inhibition rate (TGI) (%) 100- (T-T)0)/T0×100
If the tumor is reduced from the initial volume, i.e. T<T0Or C<C0When, it is defined as partial tumor regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR).
The experiment is finished, the experimental end point is reached, or the tumor volume reaches 2000mm3，CO2The sacrifice was anesthetized, and the tumor was dissected and photographed.
The experimental data were analyzed and plotted using GraphPad Prism 6.0. Two groups of tumor volumes were compared using a two-tailed T-test. Three or more groups were compared using one-way ANOVA reproduced measures, and if there were significant differences in F-values, multiple comparisons should be made using Dunnett's after ANOVA analysis. P <0.05 was defined as statistically significant.
TABLE 5 mouse dosing regimen of Almonertib in combination with pemetrexed/cisplatin in HCC827 model
Note:
the administration of Almonertinib, pemetrexed and cisplatin was started on the same day.
The single and combined doses of Almonertib from Day1 to Day12 were 10mg/kg, modified from Day13 to Day16 to 5 mg/kg.
3. Results of the experiment
TABLE 6 growth inhibition of HCC827 by Almonetinib and cisplatin/pemetrexed in HCC827 model
Note:
the administration of Almonertinib, pemetrexed and cisplatin was started on the same day.
D0: the day prior to the first dose;
p valueaIs the value obtained in comparison with the solvent set;
p valuebThe values obtained are compared with Almonertib.
The curative effect of the Simonetinib, pemetrexed and cisplatin on single use or combined use on human lung cancer HCC827 nude mouse subcutaneous transplantation tumor is shown in figure 5.
The effects of Almonertib, pemetrexed and cisplatin alone or in combination on HCC827 tumor-bearing mouse body weight are shown in figure 6.
The tumor inhibition rate of Almonertib (10mg/kg,5mg/kg) on HCC827 is 89%, the tumor inhibition rate of the combination of Almonertib and pemetrexed (200mg/kg) is 98%, the tumor inhibition rate of the combination of Almonertib and pemetrexed (200mg/kg) and cisplatin (3mg/kg) is improved to 134%, the curative effect is obviously better than that of single medicine (p is less than 0.01, compared with single medicine), and the combination of Almonertib and pemetrexed has 5/5 tumor partial regression. The tumor-bearing mice can well tolerate the above dosage, and no obvious weight loss symptom occurs. The results show that the double or triple combination of Almonertib, pemetrexed and cisplatin has synergistic effect on subcutaneous transplantation tumor of nude mice with human lung cancer HCC 827.
And (4) conclusion: almonertinib (10mg/kg,5mg/kg) can inhibit the growth of human HCC827 lung cancer, and can synergistically enhance the tumor inhibition effect when being combined with chemotherapeutic drugs pemetrexed and cisplatin. The tumor-bearing mice can well tolerate the dosage of single drug or combined drug.
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