CN115779095A - Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody for treating colorectal cancer - Google Patents

Abstract

There is provided a pharmaceutical combination of a quinoline derivative and PD-1 mab for the treatment of colorectal cancer comprising a tyrosine kinase inhibitor and an immune checkpoint inhibitor and a chemotherapeutic agent, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The medicine composition has good anti-colorectal cancer activity.

Description

Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody for treating colorectal cancer

Technical Field

The application belongs to the technical field of medicines and relates to a combined treatment for resisting tumors. In particular, the application relates to the use of a pharmaceutical combination chemotherapy regimen based on quinoline derivatives in combination with PD-1 mab in the treatment of colorectal cancer.

Background

Anlotinib (Anlotinib), the chemical name of which is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, is a quinoline derivative tyrosine kinase inhibitor which plays a role in influencing tumor angiogenesis and proliferation signal transduction as a multi-target Tyrosine Kinase Inhibitor (TKI), and the main targets comprise: receptor tyrosine kinases Vascular Endothelial Growth Factor Receptors (VEGFR) 1 to 3, epidermal Growth Factor Receptors (EGFR), fibroblast Growth Factor Receptors (FGFR) 1 to 4, platelet Derived Growth Factor Receptors (PDGFR) α and β, and Stem Cell Factor Receptors (SCFR) 7, 8, and 9. The chemical structure of the nilotinib is shown as formula I:

PD-1 (programmed death-1, PD-1) is a key immune checkpoint receptor expressed by activated T and B lymphocytes and mediates immunosuppression, and its ligands include at least PD-L1 and PD-L2.PD-L1 (Programmed death-ligand 1), also known as CD274 or B7-H1, is a 40kDa type 1 transmembrane protein encoded by the CD274 gene and is a ligand for PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and both consist of two extracellular Ig domains, an N-terminal V domain and a C-terminal constant domain. The formation of the PD-1/PD-L1 complex transmits inhibitory signals and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al (2011) Nature Immunology 10; induction of depletion or anergy among cognate antigen-specific T cells (Hofmeyer et al (2011) Journal of Biomedicine and Biotechnology 2011; promote differentiation of Th1 cells into Foxp3+ regulatory T cells (Armanath et al (2011) Science TransMed 3; and inducing apoptosis of effector T cells. Disruption of the PD-L1 gene results in an up-regulated T cell response and the production of autoreactive T cells (Latchman et al (2004) PNAS 101, 10691-10696). Antibody blockade of PD-1 or PD-L1 results in increased anti-tumor immunity (Iwai et al (2002) PNAS 99. Chinese patent document CN106977602A discloses a PD-1 monoclonal antibody 14C12H1L1, i.e., a deanopril monoclonal antibody, which can effectively block the binding of PD1 and PDL1 and shows good antitumor activity.

Common chemotherapeutic regimens are: FOLFOX, CAPEOX, FOLFIRI, etc. A CAPEOX treatment regimen or CAPEOX regimen, also known as XELOX regimen, i.e. a chemotherapy regimen in which oxaliplatin and capecitabine are administered in combination to a patient, one cycle of chemotherapy every 21 days, oxaliplatin 130mg/m2, D1 intravenous infusion, capecitabine 1000mg/m2, D1 (1 time in the evening), D2-14, 2 times per day (BID), D15 (1 time in the morning), orally. Similar to the FOLFOX proposal in curative effect and safety, but the 3-4 grade neutropenia has lower incidence (7 percent) and more convenient application, can reduce the occurrence of complications related to central venous catheterization, and has important function on the health and autonomy of patients. And the oral drug is used for replacing 5-FU intravenous administration, so that the occurrence of adverse reactions related to transfusion can be reduced. The CAPEOX regimen also observed high efficacy in older patients, while also providing a novel, positive, better-tolerated first-line chemotherapy regimen for the treatment of metastatic colorectal cancer in combination with novel targeted drugs.

The biggest challenge in the course of tumor immunotherapy in foreigners is poor treatment due to tumor immune tolerance and escape. Therefore, the immune tolerance of the body to the tumor cells established by the body is broken through the combined use of the micromolecule anti-tumor compound and the anti-PD-1/PD-L1 antibody, and the method has important theoretical significance and application value. In addition, based on the strong side effects of the current large-dose multi-drug combination chemotherapy and the lack of more effective therapeutic drugs, it is suggested that it is necessary and urgent to further improve the therapeutic effect.

Disclosure of Invention

The invention aims at providing a drug combination which comprises a tyrosine kinase inhibitor and a human PD-1 antibody, and is used for preparing a drug for treating colorectal cancer by combining a chemotherapeutic drug.

In some embodiments, the human PD-1 antibody comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 consisting of the amino acid sequences set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 consisting of the amino acid sequences set forth in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively.

In some embodiments, the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof, and in some particular embodiments, the tyrosine kinase inhibitor is a hydrochloride salt of a compound of formula I, i.e., angutinib hydrochloride.

In some embodiments, the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8.

In some embodiments, the human PD-1 antibody is 14C12H1L1, i.e., pimazepril.

In some embodiments, the compound of formula I may be present in the form of a pharmaceutically acceptable salt or a pharmaceutically acceptable formulation thereof, preferably in the form of its hydrochloride salt.

In some embodiments, the compound is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, namely, nilotinib hydrochloride.

In some embodiments, the pharmaceutical combination comprises: a compound of formula I or a hydrochloride salt thereof (e.g., dihydrochloride); and 14C12H1L1 monoclonal antibody or an antigen-binding fragment thereof.

In some embodiments, the chemotherapeutic agent:

is one or more of platinum drugs, fluoropyrimidine derivatives, taxanes drugs, camptothecin drugs, anthracyclines, alkylating agents, podophyllum drugs and vinca alkaloids drugs; wherein, the first and the second end of the pipe are connected with each other,

the platinum drug is one or more of oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, leplatin, triplatin tetranitrate, phenanthroline, picoplatin and satraplatin;

the fluoropyrimidine derivative is one or more of gemcitabine, capecitabine, fluorouracil, difurfurol, doxifluridine, tegafur, carmofur, trifluridine and efidine;

the taxane medicine is one or more of paclitaxel, albumin-bound paclitaxel and docetaxel;

the camptothecin medicament is one or more of camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan and topotecan;

the anthracycline compound is one or more of epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, pyrarubicin and liposome adriamycin;

the alkylating agent is one or more of cyclophosphamide, ifosfamide, carmustine and melphalan;

the podophyllum drug is one or more of etoposide, tennixin platinum glycoside and epipodophyllotoxin glucopyranoside;

the vinblastine is one or more of vinorelbine, vinblastine, vincristine, vindesine, vinflunine;

optionally, the first and second liquid crystal films are coated with a binder, the chemotherapy medicine also comprises methotrexate, cytarabine, ancitabine, azacitidine, thioguanine, pemetrexed, mitomycin, bendamustine, temozolomide, actinomycin D, bleomycin, pingyangmycin, amikamide, pellomycin, eribulin, sapacitabine, plinabulin, troosufagin, treosulfan, and a pharmaceutically acceptable salt thereof, ¹⁵³ One or more of Sm-EDTMP, tegafur and encequidar.

In some embodiments, the chemotherapeutic agent is one, two or three of oxaliplatin, calcium folinate, fluorouracil, in particular the mfoflox 6 regimen.

In some embodiments, the chemotherapeutic agent is one, two or three of oxaliplatin, calcium folinate, fluorouracil, in particular the mfoflox 7 regimen.

In some embodiments, the chemotherapeutic agent is one or both of oxaliplatin and capecitabine, in particular a CAPEOX regimen.

In some embodiments, the chemotherapeutic agent is one, two or three of irinotecan, calcium folinate, fluorouracil, in particular the FOLFIRI regimen.

In some embodiments, the chemotherapeutic agent is one, two, three, or four of irinotecan, oxaliplatin, calcium folinate, fluorouracil, specifically the FOLFOXIRI regimen.

In some embodiments, the chemotherapeutic agent is one or both of irinotecan, oxaliplatin, and in particular an IROX regimen.

In some embodiments, the chemotherapeutic agent is one or both of calcium folinate and fluorouracil, particularly in the Roswell-Park protocol.

In some embodiments, the chemotherapeutic agent is one or both of oxaliplatin, irinotecan, and in particular, an OI regimen.

In some embodiments, the chemotherapeutic agent is one, two or three of oxaliplatin, aldehydic acid, fluorouracil, in particular an OLF regimen.

In some embodiments, the chemotherapeutic agent is one or both of fluorouracil, mitomycin, in particular an FM regimen.

In some embodiments, the chemotherapeutic agent is one, two or three of hydroxycamptothecin, aldehydic acid, fluorouracil, in particular a HLF regimen.

In some embodiments, the chemotherapeutic agent is one, two, three or four of hydroxycamptothecin, cisplatin, aldehydic acid, fluorouracil, in particular HDLF regimens.

In some embodiments, the chemotherapeutic agent is one or both of fluorouracil, levamisole, in particular a FL regimen;

in some embodiments, the chemotherapeutic agent is one or both of ulivudine and tetrahydrofolate, specifically a UFTCF regimen.

In some embodiments, the chemotherapeutic agent is one, two or three of methotrexate, fluorouracil, aldehydo-folate, in particular a MEL regimen.

In some embodiments, the chemotherapeutic agent is capecitabine.

In some embodiments, the chemotherapeutic agent is oxaliplatin.

In some embodiments, the chemotherapeutic agent is irinotecan.

In some embodiments, the chemotherapeutic agent is capecitabine and oxaliplatin.

In some embodiments of the present application, colorectal cancer groups are classified by histological type including, but not limited to, adenocarcinoma, adenosquamous carcinoma, spindle cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and the like. In some embodiments, the colorectal cancer is colorectal adenocarcinoma; in some embodiments, the colorectal adenocarcinoma is an ethmoid adenocarcinoma, a medullary carcinoma, a microemulsion head carcinoma, a mucinous adenocarcinoma, a jagged adenocarcinoma, or a signet ring cell carcinoma.

In some embodiments, the colorectal cancer is selected from colon cancer or rectal cancer. In some embodiments, the colorectal cancer is primary colorectal cancer and/or secondary colorectal cancer. In some embodiments, the colorectal cancer, its clinical stage includes, but is not limited to, locally advanced, and/or advanced (e.g., stage IIIB/IV) colorectal cancer. In some embodiments, in some embodiments metastatic colorectal cancer. Wherein metastatic colorectal cancer includes, but is not limited to, distant metastasis, focal single metastasis, disseminated metastasis, diffuse metastasis; the metastatic lesions include, but are not limited to, lung, lymph node, pleura, bone, brain, pericardium, adrenal gland, liver; in some embodiments, the colorectal cancer is lung metastatic colorectal cancer. In some embodiments, the colorectal cancer is brain metastatic colorectal cancer. In some embodiments, the colorectal cancer is a lymph node metastasized colorectal cancer. In some embodiments, the colorectal cancer is a colorectal cancer that is intolerant of chemotherapy.

In some embodiments of the present application, the colorectal cancer is recurrent; in certain embodiments, the colorectal cancer is refractory; in certain embodiments, the colorectal cancer is unresectable. In some embodiments, the colorectal cancer is a colorectal cancer that has failed chemotherapy and/or targeted drug therapy. In some embodiments, the colorectal cancer is colorectal cancer that has received at least two chemotherapy regimens. In some embodiments, the colorectal cancer is a colorectal cancer that has received at least two chemotherapeutic drugs. In some embodiments, the colorectal cancer is a colorectal cancer that has failed second-line and beyond. In one embodiment, the colorectal cancer is refractory relapsed colorectal cancer, wherein the refractory relapsed colorectal cancer refers to colorectal cancer that is not remitted by chemotherapy, and colorectal cancer that is effective by chemotherapy but shows disease progression within 3 months after chemotherapy is completed.

In some embodiments, the colorectal cancer is RAS wild-type colorectal cancer; in some embodiments, the colorectal cancer is a RAS wild-type colorectal cancer that has failed radiotherapy and/or chemotherapy and/or targeted drug therapy. In some embodiments, the colorectal cancer is a BRAF wild-type colorectal cancer; in some embodiments, the colorectal cancer is BRAF wild-type colorectal cancer that has failed radiotherapy and/or chemotherapy and/or targeted drug therapy. In some embodiments, the colorectal cancer is a RAS/BRAF wild-type colorectal cancer.

In some embodiments, the colorectal cancer is a PIK3CA wild-type colorectal cancer; in some embodiments, the colorectal cancer is a wild-type colorectal cancer of PIK3CA that has failed radiotherapy and/or chemotherapy and/or targeted drug therapy.

In some embodiments, the colorectal cancer is a RAS mutant colorectal cancer; in some embodiments, the colorectal cancer is a RAS mutant colorectal cancer that has failed radiotherapy and/or chemotherapy and/or targeted drug therapy. In some embodiments, the colorectal cancer is a BRAF mutant colorectal cancer; in some embodiments, the colorectal cancer is a BRAF mutant colorectal cancer that has failed radiotherapy and/or chemotherapy and/or targeted drug therapy. In some embodiments, the colorectal cancer is a RAS/BRAF mutant colorectal cancer.

In some embodiments, the colorectal cancer is a PIK3CA mutant colorectal cancer; in some embodiments, the colorectal cancer is a colorectal cancer of PIK3CA mutant that has failed radiotherapy and/or chemotherapy and/or targeted drug therapy.

In some embodiments, the colorectal cancer is advanced and/or metastatic colorectal cancer with RAS mutation; in some embodiments, the colorectal cancer is advanced and/or metastatic colorectal cancer with RAS mutations that have failed radiotherapy and/or chemotherapy and/or targeted drug therapy. In some embodiments, the chemotherapy comprises first-line chemotherapy and second-line chemotherapy; including but not limited to camptothecin drugs, platinum drugs, fluoropyrimidine derivatives; in some embodiments, the targeted drug includes, but is not limited to, one or more of EGFR inhibitors. It will be appreciated by those skilled in the art that the patient may also receive radiation therapy either simultaneously with or subsequent to the described chemotherapy.

In some embodiments, the colorectal adenocarcinoma is an advanced and/or metastatic colorectal adenocarcinoma mutated in the RAS; such RAS mutations include, but are not limited to, KRAS and NRAS mutations. In some embodiments, the RAS mutation is a KRAS mutation. In some exemplary embodiments, the KRAS mutation is a mutation at codon 2 of the KRAS gene. In some embodiments, the RAS mutation is an NRAS mutation. In some more typical embodiments, the NRAS mutation is a mutation at position 2 and/or 3 of the NRAS gene codon. In some typical embodiments, the colorectal cancer is advanced and/or metastatic colorectal cancer with KRAS mutation that failed treatment with camptothecin drugs, platinum drugs, fluoropyrimidine derivatives, and/or EGFR inhibitors.

The application specifically provides an application of a drug combination in preparing a drug for treating colorectal cancer, wherein the drug combination comprises aritinib, a 14C12H1L1 antibody, capecitabine and oxaliplatin.

In some embodiments, the colorectal cancer is colorectal adenocarcinoma, preferably, the colorectal adenocarcinoma is an ethmoid adenocarcinoma, a medullary carcinoma, a microemulsion head carcinoma, a mucinous adenocarcinoma, a serrate adenocarcinoma, or a signet ring cell carcinoma.

In some embodiments, the colorectal cancer is a RAS wild-type and/or a BRAF wild-type and/or a PIK3CA wild-type colorectal cancer.

In some embodiments, the colorectal cancer is RAS mutated advanced and/or metastatic colorectal cancer, preferably, KRAS mutated advanced and/or metastatic colorectal cancer.

In some embodiments, the colorectal cancer is unresectable colorectal cancer.

In some embodiments, the colorectal cancer is metastatic colorectal cancer.

In some embodiments, the colorectal cancer is unresectable metastatic colorectal cancer.

In some embodiments, the use of the pharmaceutical combination for the manufacture of a medicament for the first line treatment of colorectal cancer.

The application further specifically provides a use of a pharmaceutical combination comprising aritinib, a 14C12H1L1 antibody, and capecitabine and oxaliplatin for the preparation of a medicament for the first-line treatment of unresectable metastatic colorectal cancer.

In some embodiments of the present application, the 14C12H1L1 antibody and the compound of formula I, chemotherapeutic agent in the pharmaceutical combination are each in the form of a pharmaceutical composition.

In some embodiments of the present application, the pharmaceutical composition comprises a compound of formula I in an amount of 6 to 168 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount selected from 6mg, 8mg, 10mg, 12mg, 15mg, 20mg, 30mg, 50mg, 56mg, 70mg, 84mg, 112mg, 140mg, 168mg, or any range formed by any of the foregoing. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount from 10mg to 12 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount of 10 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount of 12 mg.

In some embodiments, the 14C12H1L1 antibody is administered in one or more uniform doses effective to treat the cancer. In some embodiments, the unitized dose is in the range of about 10mg to about 1000mg of 14C12H1L1 antibody. In some embodiments, the unitary dose is selected from about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or about 1000mg of the 14C12H1L1 antibody. In some embodiments, the unitized dose is selected from about 200mg of 14C12H1L1 antibody.

In some embodiments, the treatment with the 14C12H1L1 antibody is administered intravenously with 2 weeks (14 days) or 3 weeks (21 days) as a cycle, preferably the first day (D1) of each cycle. That is, the 14C12H1L1 antibody is administered at a frequency of once every two weeks (q 2 w) or once every three weeks (q 3 w).

In some embodiments, the oxaliplatin is at 130mg/m ² D1 intravenous infusion; capecitabine 1000mg/m ² D1 (1 in the evening), D2-14 (BID), 2 times daily (BID), D15 (1 in the morning), administered orally.

In some embodiments of the pharmaceutical combination of the present invention, the pharmaceutical administration regimen is: the 14C12H1L1 antibody is 200 mg/time, and D1 is infused in a vein; arotinib 12 mg/dose, D1-14 oral dosing 1 time per day (QD); oxaliplatin 130mg/m ² D1 intravenous infusion; capecitabine 1000mg/m ² D1 (1 in the evening), D2-14 (BID), 2 times daily (BID), D15 (1 in the morning), administered orally. Every 3 weeks (Q3W) is one dosing cycle and oxaliplatin is co-administered for 6 cycles.

In other embodiments of the pharmaceutical combination of the present invention, the drug administration regimen is divided into a treatment period (6 cycles) and a maintenance treatment period. The treatment period administration regimen is: the 14C12H1L1 antibody is 200 mg/time, and D1 is infused intravenously; arotinib 12 mg/dose, D1-14 oral dosing 1 time per day (QD); oxaliplatin 130mg/m ² D1 intravenous infusion; capecitabine 1000mg/m ² D1 (1 time in the evening), D2-14, 2 times a day (BID), D15 (morning)Last 1 time), oral administration. Every 3 weeks (Q3W) is one dosing cycle, oxaliplatin is co-administered for 6 cycles. The maintenance treatment period administration regimen is: the 14C12H1L1 antibody is 200 mg/time, and D1 is infused intravenously; arotinib at 12 mg/dose, D1-14, orally administered 1 time per day (QD); capecitabine 1000mg/m ² D1 (1 in the evening), D2-14 (BID), 2 times daily (BID), D15 (1 in the morning), administered orally. One dosing cycle was every 3 weeks (Q3W).

Arotinib

As used herein, the chemical name of said nilotinib (i.e., the compound of formula I) is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

as used herein, the nilotinib includes its non-salt forms (e.g., free acid or free base), as well as its pharmaceutically acceptable salts, which are all included within the scope of the present application. For example, the pharmaceutically acceptable salt of erlotinib can be the hydrochloride salt or the dihydrochloride salt. The dosage of the nilotinib or salt thereof referred to herein is calculated based on the free base of the nilotinib, unless otherwise indicated.

14C12H1L1

As used herein, 14C12H1L1 or14C12H1L1 monoclonal antibody,is an anti-PD-1 monoclonal antibody, and the sequence and the structure of the monoclonal antibody can be seen in the literature (CN 106977602A). In the 14C12H1L1 monoclonal antibody, LCDR1 comprises the sequence QDINTY (SEQ ID NO: 1), LCDR2 comprises the sequence RAN (SEQ ID NO: 2), LCDR3 comprises the sequence LQYDEFPLT (SEQ ID NO: 3), HCDR1 comprises the sequence GFSSYD (SEQ ID NO: 4), HCDR2 comprises the sequence ISGGGRYT (SEQ ID NO: 5), and HCDR3 comprises the sequence ANRYGEAWFAY (SEQ ID NO: 6).

The amino acid sequence of the light chain variable region is as follows:

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK(SEQ ID NO:7)。

the amino acid sequence of the heavy chain variable region is as follows:

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:8)。

definitions and explanations

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to its corresponding commodity, composition, or active ingredient thereof.

The term "treatment" generally refers to an act of obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of preventing the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Preventing a disease or condition that occurs in a patient susceptible to the disease or condition but has not yet been diagnosed as having the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

As used herein, the term "systemic treatment" refers to treatment in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.

As used herein, the term "systemic chemotherapy" refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as one of the links of multimodal treatment, wherein chemotherapy for locally advanced disease includes induction chemotherapy, concurrent chemotherapy with radiotherapy, and adjuvant chemotherapy.

As used herein, the term "subject" means a mammal, such as a rodent, feline, canine, and primate. Preferably, the subject according to the present application is a human.

By "administering" is meant physically introducing the composition comprising the therapeutic agent to the subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

As used herein, an "adverse event" (AE) is any adverse and often unintended or undesirable sign (including abnormal laboratory findings), symptom or disease associated with the use of medical therapy. For example, an adverse event can be associated with activation of the immune system or expansion of cells of the immune system (e.g., T cells) in response to treatment. The medical treatment may have one or more related AEs, and each AE may have the same or a different severity level. Reference to a method capable of "altering an adverse event" refers to a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.

As used herein, "dosing interval" refers to the amount of time that elapses between multiple doses of a formulation disclosed herein administered to a subject. The dosing interval may thus be indicated as a range.

The term "dosing frequency" as used herein means the frequency of administered doses of a formulation disclosed herein over a given time. The frequency of administration may be indicated as the number of administrations per given time, e.g. 1 or 2 weeks 1 per week.

The use of the term "flat dose" refers to a dose that is administered to a patient without regard to the weight or Body Surface Area (BSA) of the patient. Thus, a uniform dose is defined as the absolute amount of the agent (e.g., anti-PD-1 antibody) rather than the mg/kg dose. For example, a 60kg human and a 100kg human will receive the same dose of antibody (e.g., 240mg anti-PD-1 antibody).

The use of the term "fixed dose" in reference to a composition of the present application means that two or more different antibodies in a single composition are present in the composition in a specific (fixed) ratio to each other. In certain embodiments, the fixed dose is based on the weight of the antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg/ml). In certain embodiments, the ratio of the mg primary antibody to. For example, a 3 ratio of primary antibody to secondary antibody of 1 may mean that the vial may contain about 240mg of primary antibody and 80mg of secondary antibody, or about 3mg/ml of primary antibody and 1mg/ml of secondary antibody.

The term "weight-based dose" as referred to herein refers to a dose administered to a patient that is calculated based on the weight of the patient. For example, when a patient with 60kg body weight requires 3mg/kg of anti-PD-1 antibody and 1mg/kg of anti-CTLA-4 antibody, one can extract appropriate amounts of anti-PD-1 antibody (i.e., 180 mg) and anti-CTLA-4 antibody (i.e., 60 mg) at a time from a 3 ratio fixed dose formulation of anti-PD-1 antibody and anti-CTLA-4 antibody.

"programmed death receptor-1 (PD-1)" means an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to both ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, homologs, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1.

"programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down-regulates T cell activation and cytokine secretion upon binding to PD-1.

"subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject," "subject," and "patient" are used interchangeably herein in certain contexts.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of damage or disability resulting from the affliction of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predicting efficacy for humans, or by determining the activity of the agent in an in vitro assay.

A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the occurrence or recurrence of cancer when administered, alone or in combination with an anti-neoplastic agent, to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of cancer recurrence. In certain embodiments, the prophylactically effective amount completely prevents the occurrence or recurrence of cancer. By "inhibiting" the occurrence or recurrence of cancer is meant reducing the likelihood of occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.

A "recurrent" cancer is one that regenerates at the initial site or a distant site in response to initial treatment (e.g., surgery). A "locally recurrent" cancer is one that occurs at the same location after treatment as a previously treated cancer.

A "non-resectable" cancer is one that cannot be removed by surgery.

"metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the lungs) to another part of the body.

The use of alternatives (e.g., "or") should be understood to refer to either, both, or any combination thereof. The indefinite articles "a" or "an" as used herein shall be understood to mean "one or more" of any enumerated or enumerated component.

The definition of "failure of a systemic standard chemotherapy" is: disease progression during or after the last treatment, or intolerance during treatment due to toxic side effects.

"first line therapy" refers to the drug or treatment regimen that is first used after a clinical symptom has been diagnosed.

The definition of "failure of chemotherapy at or above one line" is: disease progression during or after the last treatment; or can not be tolerated in the treatment process because of toxic and side effects.

The terms "about," about, "or" consisting essentially of mean a value or composition within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about," about, "or" consisting essentially of can mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "consisting essentially of may refer to a range that differs by up to 10% or 20% (i.e., ± 10% or ± 20%) from the parameter or value modified thereby. For example, about 3mg may include any number between 2.7mg and 3.3mg (for 10%) or between 2.4mg and 3.6mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the term may refer to up to an order of magnitude or up to at most 5 times the numerical value. Where a particular value or composition is provided in the application and claims, unless otherwise stated, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

As used herein, the terms "about once per week", "about once per two weeks" or any other similar dosing interval term refer to approximations. "about once per week" can include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "about once every two weeks" may include every 14 days ± 3 days, i.e., every 11 days to every 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that a first dose may be administered on any day of the first week, and then a second dose may be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to administration of a first dose on a particular day of the first week (e.g., monday) and then administration of a second dose on the same day of the sixth or twelfth week (i.e., monday), respectively. Similar principles apply to phrases including, but not limited to, \8230; "about 1 time every 2 weeks," "about 1 time per month," and so on.

As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the recited range, and when appropriate, to include fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated.

Unless otherwise stated, "about" or "approximately" in this application means within ± 5%, preferably within ± 2%, and more preferably within ± 1% of the specified numerical range given. For example, a pH of about 5.5 means a pH of 5.5. + -. 5%, preferably a pH of 5.5. + -. 2%, more preferably a pH of 5.5. + -. 1%.

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

The term "pharmaceutically acceptable salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free acid to the base ion is from about 1.5 to 1, preferably 1.5, 1, 2, 1, 3, 1, 4, 1, 5, 1. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is from about 1.

As used herein, "in combination" or "in combination" means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g., an anti-PD-1 antibody or a compound of formula I) or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application, or a pharmaceutical combination thereof, to a subject.

The term "synergistic effect" refers to a simple addition of two or more components (e.g., an anti-PD-1 antibody or a compound of formula I) that produces an effect (e.g., inhibiting the growth of colon cancer, or ameliorating symptoms of colon cancer) that is greater than the effect of the components when administered alone.

Mode of administration

The following is not intended to limit the mode of administration of the pharmaceutical combinations of the present application.

The components of the pharmaceutical combination of the present application may be formulated separately from each other or some or all of them may be co-formulated. In one embodiment, the pharmaceutical combination of the present application may be formulated as a pharmaceutical composition suitable for single or multiple administration.

The components of the pharmaceutical combination of the present application may each be administered separately, or some or all of them may be co-administered. The components of the pharmaceutical combination of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the pharmaceutical combination of the present application may be administered independently of each other, or some or all of them together in a variety of routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may be administered orally or parenterally, such as intravenously or intraperitoneally, each independently, or together with some or all of them.

The components of the pharmaceutical combination of the present application may each independently, or some or all of them together be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms for sustained release formulations for oral or non-oral administration.

The components of the pharmaceutical combination of the present application may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical combination of the present application may also comprise additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

The application also includes the following scheme:

1. use of a pharmaceutical combination for the manufacture of a medicament for the treatment of colorectal cancer, comprising:

a) The medicine for chemotherapy is a medicine for treating tumor,

b) A human PD-1 antibody that comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 consisting of the amino acid sequences set forth in SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 consisting of the amino acid sequences set forth in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively, and

c) A tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

2. the use according to item 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, preferably the dihydrochloride.

3. The use according to any one of items 1-2, wherein the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8.

4. The use according to any one of claims 1 to 3, wherein the chemotherapeutic drug is selected from one or more of platinum drugs, fluoropyrimidine derivatives, taxanes, camptothecin drugs, anthracyclines, alkylating agents, podophyllum drugs, vinblastine drugs; wherein, the first and the second end of the pipe are connected with each other,

the platinum drug is one or more of oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, leplatin, triplatin tetranitrate, phenanthroline, picoplatin and satraplatin;

the fluoropyrimidine derivative is one or more of gemcitabine, capecitabine, fluorouracil, difurfurol, doxifluridine, tegafur, carmofur, trifluridine and efidine;

the taxane medicine is one or more of paclitaxel, albumin-bound paclitaxel and docetaxel;

the camptothecin medicament is one or more of camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan and topotecan;

the anthracycline compound is one or more of epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, pyrarubicin and liposome adriamycin;

the alkylating agent is one or more of cyclophosphamide, ifosfamide, carmustine and melphalan;

the podophyllum medicine is one or more of etoposide, teniposide and epipodophyllotoxin glucopyranoside;

the vinblastine is one or more of vinorelbine, vinblastine, vincristine, vindesine, vinflunine;

optionally, the step of (a) is carried out, the chemotherapy medicine also comprises methotrexate, cytarabine, ancitabine, azacitidine, thioguanine, pemetrexed, mitomycin, bendamustine, temozolomide, actinomycin D, bleomycin, pingyangmycin, dacarbazine, pellomycin, eribulin, sapacitabine, plinabulin, trooshusu, trovamat, fluazinam, and the like, ¹⁵³ One or more of Sm-EDTMP, tegafur and encequidar.

5. The use according to any one of items 1 to 4 wherein the chemotherapeutic agent is capecitabine and oxaliplatin.

6. The use according to any one of items 1 to 5, wherein the pharmaceutical combination comprises erlotinib, the 14C12H1L1 antibody and capecitabine with oxaliplatin.

7. The use according to any one of items 1-6, wherein the colorectal cancer is colorectal adenocarcinoma, preferably, the colorectal adenocarcinoma is acne-type ethmoid adenocarcinoma, medullary carcinoma, micro-emulsion head carcinoma, mucous adenocarcinoma, serrate adenocarcinoma, or signet ring cell carcinoma.

8. Use according to any one of items 1-7, wherein the colorectal cancer is of RAS wild type and/or BRAF wild type and/or PIK3CA wild type.

9. Use according to any one of claims 1-8, wherein the colorectal cancer is RAS mutated advanced and/or metastatic colorectal cancer, preferably KRAS mutated advanced and/or metastatic colorectal cancer.

10. The use according to any one of items 1-9, wherein the colorectal cancer is unresectable colorectal cancer, or metastatic colorectal cancer, or unresectable metastatic colorectal cancer.

11. Use according to any one of claims 1 to 10, in the manufacture of a medicament for the first line treatment of colorectal cancer.

12. The use according to any one of items 1 to 11, wherein the administration of the aniotinib in the pharmaceutical combination is 1 time daily, 8mg, 10mg or 12mg each time, 2 weeks for continuous oral administration and 1 week off, and the administration of the 14C12H1L1 antibody is 1 time every 3 weeks, 100 mg/time, 150 mg/time or 200 mg/time.

13. The use according to any one of claims 1 to 12, wherein the 14C12H1L1 antibody is administered 1 time every 3 weeks at 200 mg/time; the erlotinib is taken orally for 2 weeks and stops for 1 week, 1 time daily at 12 mg/time; oxaliplatin 130mg/m ² Once every three weeks, intravenous infusion; capecitabine 1000mg/m ² The drug is administered once in the evening on day 1, 2 times per day on days 2-14, and once in the morning on day 15, and is administered orally.

14. The use according to any one of claims 1 to 13, wherein the pharmaceutical combination administration regimen is divided into a treatment period of 6 weeks and a maintenance treatment period, the treatment period administration regimen being: the 14C12H1L1 antibody is administered 1 time every 3 weeks at a dose of 200 mg/time; the erlotinib is taken orally for 2 weeks and stops for 1 week, 1 time daily at 12 mg/time; oxaliplatin 130mg/m ² Once every three weeks, intravenous infusion; capecitabine 1000mg/m ² Evening on day 1Once a dose, 2 times daily on days 2-14, once in the morning on day 15, orally, one dosing cycle every 3 weeks, 6 cycles of oxaliplatin total; the maintenance treatment period administration regimen is: the 14C12H1L1 antibody is administered 1 time every 3 weeks at a dose of 200 mg/time; the erlotinib is taken orally for 2 weeks and stops for 1 week, 1 time daily at 12 mg/time; capecitabine 1000mg/m ² Once daily on day 1 in the evening, 2 times daily on days 2-14, once daily on day 15 in the morning, orally, with a dosing cycle of every 3 weeks.

Detailed Description

The present application is further described below with reference to specific examples, which are, however, only for illustration and do not limit the scope of the present application. Likewise, the present application is not limited to any particular preferred embodiment described herein. It should be understood by those skilled in the art that equivalent substitutions and corresponding modifications of the technical features of the present application still fall within the protective scope of the present application. The reagents used in the following examples are commercially available products, and the solutions can be prepared by techniques conventional in the art, except where otherwise specified.

TABLE 1 abbreviation table

"14C12H1L1 injection" refers to a medical preparation for injection containing the 14C12H1L1 monoclonal antibody, which is usually administered to a patient by intravenous infusion route. In a particular embodiment, the expression "14C12H1L1 injection, 200 mg/time" may be understood in the manner usual in the art as a liquid injectable medical formulation containing 200mg of 14C12H1L1 monoclonal antibody per administration to a patient.

Example a clinical study protocol-study criteria and endpoints

1.1 inclusion exclusion criteria

And (3) inclusion standard: the following candidates can be put into the test

1) The subject voluntarily joins the study, signs an informed consent, and the compliance is good;

2) Age: 18-75 years of age (when signed with an informed consent); ECOG PS score: 0-1 min; the expected life span exceeds 3 months;

3) Histopathologically confirmed non-surgically resectable untreated metastatic colorectal adenocarcinoma patients (UICC/AJCC colorectal cancer TNM staging system (2017, 8 th edition) identified as stage IV);

4) Systemic treatment for colorectal cancer has not been received before, and comprises chemotherapy, targeted therapy, immunotherapy and the like; patients who have had tumor recurrence or metastasis after at least 6 months after the previous adjuvant or neoadjuvant chemotherapy is completed can be enrolled;

5) Can provide a tumor tissue sample stored in the past or perform biopsy to collect tumor focus tissues for detecting PD-L1 expression and KRAS/NRAS mutation conditions;

6) According to RECIST 1.1 criteria, there are at least 1 measurable lesion. Requiring that the selected target lesion has not previously received local treatment, or that the selected target lesion is located in a previous local treatment area but is determined by imaging as PD;

7) Good organ function.

8) Female subjects of reproductive age should agree that contraceptive measures (such as abstinence, intrauterine contraceptive devices, contraceptives or condoms) must be taken during the study and within 6 months after the study is complete; seropregnancy test negative within 7 days prior to study enrollment and must be a non-lactating subject; the male subjects should agree that contraceptive measures must be taken during the study and within 6 months after the study period.

Exclusion criteria: subjects presenting any of the following subjects would not be able to enter the study

1) Disease and history of disease incorporation:

a) Other malignancies appeared or currently co-morbid within 3 years. The following cases can be grouped: cured carcinoma of the cervix in situ, skin carcinoma other than melanoma and superficial bladder tumor [ Ta (non-invasive tumor), tis (carcinoma in situ) and T1 (tumor-infiltrating basement membrane) ];

b) Has various factors (such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.) affecting oral drugs;

c) Digestive tract bleeding or perforation and the like exist or tend to occur within 4 weeks before the group is added;

d) Patients with ulcerative colitis, crohn's disease; patients with active inflammatory bowel disease were present within 4 weeks prior to enrollment;

e) Uncontrollable pleural effusion and ascites which need to be drained repeatedly, and moderate or more pericardial effusion;

f) Unrelieved toxic response above CTC AE grade 1 due to any previous treatment (excluding alopecia);

g) Significant surgical treatment, open biopsy or overt traumatic injury (except for gastrointestinal tissue biopsy) was received within 28 days prior to group entry;

h) Imaging (CT or MRI) shows that the tumor invades the great vessels or is poorly demarcated from the vessels;

i) Patients with symptoms of hematemesis and hematochezia and daily bleeding amount of more than or equal to 2.5mL or any bleeding event of more than or equal to CTCAE3 grade are screened in the first 3 months, or patients with any bleeding signs or medical history which are judged by researchers to be unsuitable to be grouped regardless of the severity;

j) Presence of non-healing wounds, ulcers or fractures;

k) Arterial/venous thrombosis events occur within 6 months, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, pulmonary embolism and the like;

l) those who have a history of substance abuse and are unable to be withdrawn;

m) subjects with any severe and/or uncontrolled disease, including:

uncontrolled hypertension (systolic pressure is more than or equal to 150mmHg or diastolic pressure is more than or equal to 100mmHg after standard antihypertensive treatment);

unstable angina pectoris/≧ 2 cardiogenic chest pain; myocardial infarction occurred within less than or equal to 12 months before randomization; grade 1 or greater heart failure (NYHA classification); restrictive cardiomyopathy; atrioventricular block of grade 2 or more, arrhythmias not stably controllable with drugs [ including QTc of 450ms or more (male) and 470ms or more (female)) and arrhythmias which may potentially affect trial therapy;

active infection (grade ≧ CTC AE 2 infection);

decompensated phase of cirrhosis, active hepatitis;

renal failure requires hemodialysis or peritoneal dialysis;

a history of immunodeficiency, including HIV positive or having other acquired, congenital immunodeficiency disorders, or a history of organ transplantation;

poor control of diabetes (fasting plasma glucose (FBG) >10 mmol/L);

the urine routine prompts that the urine protein is more than or equal to + +, and the quantitative rate of the urine protein is more than 1.0g after 24 hours;

patients with a defined history of neurological or psychiatric disorders, including epilepsy or dementia, and in need of treatment.

2) Tumor-related symptoms and treatments:

a) Surgery (except for past diagnostic biopsy), radiotherapy, chemotherapy or other anti-cancer therapies (counting the elution period from the end of the last treatment) were performed within 4 weeks prior to group entry; note: the patients who have received local radiotherapy before can be grouped if the following conditions are met: the end of radiotherapy is more than 4 weeks from the beginning of study treatment (brain radiotherapy is more than 2 weeks), and the target lesion selected in this study is not in the radiotherapy area; or the target lesion is located within the radiotherapy region, but progression has been confirmed;

b) The composition is administered with Chinese medicinal composition (including compound Mylabris capsule, KANGAI injection, KANGLEITE Capsule/injection, AIDI injection, oleum fructus Bruceae injection/capsule, XIAOAIPING tablet/injection, and HUACHANSU Capsule) with anti-tumor indication in NMPA approved medicine specification within 2 weeks before administration;

c) Those who have previously received anti-PD-1 or anti-PD-L1/PD-L2 therapy or other therapies that act on T cell co-stimulatory targets or checkpoints;

d) Postoperative adjuvant therapy with anti-vascular or anti-EGFR targeting drugs (including but not limited to bevacizumab, cetuximab, panitumumab, aflibercept, regorafenib, etc.);

e) Central nervous system metastases with symptoms or symptom control time of less than 2 months;

3) Study of therapeutic relevance

a) History of live attenuated vaccination within 28 days before enrollment or scheduled live attenuated vaccination during the study period;

b) Those known to be allergic to study drugs or adjuvants, or to similar drugs;

c) Active autoimmune disease that requires systemic treatment (e.g., with disease modifying drugs, corticosteroids, or immunosuppressants) occurred within 2 years prior to group entry. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency, etc.) is not considered systemic treatment;

d) Diagnosed as immunodeficient or receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy (dose >10 mg/day prednisone or other therapeutic hormone), and is still in use for 2 weeks after first administration;

4) Other anti-tumor drugs are participated in clinical trials (the elution period is calculated from the end time of the last treatment) within 4 weeks before group entry;

5) At the discretion of the investigator, there are concomitant disease subjects who seriously compromise the safety of the subject or affect the completion of the study, or subjects considered otherwise unsuited for inclusion into the group.

1.2 Exit Standard

1) Disease progression occurred and the investigator judged that the subject would not benefit from continued treatment;

2) Adverse events occurred, were not tolerated, not alleviated;

3) Subjects who had a severe adverse event and were not eligible to continue the study;

4) Those who deviate or violate the protocol severely and impact the evaluation of drug safety or efficacy;

5) Subject withdraws informed consent;

6) Follow-up cannot be continued on time for various reasons.

1.3 study endpoint

Primary endpoint

Investigator-assessed progression-free survival (PFS);

secondary endpoint

Overall Survival (OS), objective remission rate (ORR = CR + PR), disease control rate (DCR = CR + PR + SD), duration of remission (DOR), hepatic metastatic resection rate, quality of life score;

the incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAEs), and abnormal laboratory test indices.

Example two clinical trial design

Random, open, multi-cohort, multi-center phase II clinical trials were employed.

2.1 sample size

120 subjects were planned in this study.

2.2 image evaluation design

The primary efficacy endpoint of this study was ORR, using results assessed by researchers at each study center. An independent imaging group is additionally arranged in the research to carry out imaging curative effect evaluation and recheck.

2.3 dosing regimen design

Treatment period (6 cycles):

the 14C12H1L1 injection is 200 mg/time, and D1 is used for intravenous drip;

arotinib 12 mg/dose, D1-14 oral dosing 1 time per day (QD);

oxaliplatin 130mg/m ² D1 intravenous infusion;

capecitabine 1000mg/m ² D1 (1 in the evening), D2-14 (BID), 2 times daily (BID), D15 (1 in the morning), administered orally.

Maintaining the treatment period:

the 14C12H1L1 injection is 200 mg/time, and D1 is instilled in a vein;

arotinib 12 mg/dose, D1-14, orally administered 1 time per day (QD);

capecitabine 1000mg/m ² D1 (1 in the evening), D2-14 (BID), 2 times daily (BID), D15 (1 in the morning), administered orally.

Every 3 weeks (Q3W) is one dosing cycle, oxaliplatin is co-administered for 6 cycles, and the 14C12H1L1 injection can be administered for 1 year but at most 2 years. Other cases continued until the scheduled termination event occurred.

2.4 disease progression and efficacy assessment

Evaluation criteria

The study adopts RECIST 1.1 and iRECIST standards to judge the disease state.

Request for image evaluation

The imaging evaluation mode of the tumor can adopt CT or MRI

Confirmation procedure for disease Progression (PD)

The efficacy evaluation criteria of this study were in accordance with RECIST 1.1, while efficacy was confirmed using the irrecist criteria. I.e., subjects judged to be disease Progression (PD) according to RECIST 1.1 criteria, were further confirmed according to irrecist criteria to determine whether to further study medication.

Evaluation index

Progression Free Survival (PFS): time from the start of random grouping to the first appearance of objective progression or recurrence of disease or death from various causes (whichever comes first) according to RECIST 1.1.

Lifetime (OS): refers to the time from the start of the random grouping to death due to various causes.

Objective Remission Rate (ORR): percentage of subjects with Complete (CR) or Partial Remission (PR) as determined by RECIST 1.1.

Disease Control Rate (DCR): percentage of subjects with complete remission, partial remission, or Stable Disease (SD) for 6 weeks or more as determined by RECIST 1.1.

Time to remission (DOR): for subjects with the best remission being Complete Remission (CR) or Partial Remission (PR), it is defined as the time from the date of first recording of tumor remission to the date of first recording of disease progression or death due to any cause (whichever comes first).

Example four evaluation of effectiveness and safety

4.1. Analysis of the main efficacy index

The primary efficacy index analysis is based on the FAS set and the compliance protocol set.

Investigators assessed Progression Free Survival (PFS), three sets of median PFS and their 95% Confidence Intervals (CI) were estimated using the Kaplan-Meier method, and Survival plots were plotted. The log-rank test method will be used to compare the difference in PFS between test 1 and test 3, with only descriptive statistics between test 2 and test 3, and no statistical differences are required. The interclass risk ratio (HR) and its 95% ci were calculated for test groups 1 and 3, and for test groups 2 and 3 using the Cox proportional hazards model.

4.1.1. Analysis of secondary efficacy index

Objective Remission Rate (ORR): the proportion of the objective remission number (PR + CR) to the total number of cases was calculated and 95% CI was calculated. The 95% CI of the ORR was calculated based on the exact binomial method of F distribution. Comparisons of ORRs between groups were made using the chi-square test or Fisher's exact probability method.

Disease Control Rate (DCR): the ratio of the number of disease control cases (CR + PR + SD) to the total number of cases was calculated and 95% CI was calculated. The 95% of DCR CI was calculated based on the exact binomial method of F distribution. Comparison of interclass DCRs was performed using the Chi-Square test or Fisher's exact probability method.

Duration of remission (DOR): three sets of median DOR and 95% CI were estimated using the Kaplan-Meier method and survival plots were plotted. Comparison between groups of DOR was done using the log-rank test, together with the COX proportional hazards model to estimate the between-group HR and its 95% CI.

Overall Survival (OS): three groups of median OS and 95% thereof CI were estimated by Kaplan-Meier method, and survival curves were plotted. Comparisons between OS groups were performed using the log-rank test, while the COX proportional hazards model was used to estimate HR and its 95% CI between groups.

Conversion and excision rate of liver metastasis: the percentage of the total number of cases of the three groups of liver metastasis conversion resection subjects and the 95% CI were calculated. 95% CI was calculated based on the exact two-item method of F distribution. The comparison of hepatic metastasis conversion resection rates between groups was performed by chi-square test or Fisher's exact probability method.

Quality of life scoring: the QLQ-C30 adopts a range-differentiation method to carry out linear transformation, converts the rough score into a standardized score which takes values within 0-100, carries out descriptive statistics on the result, calculates the average, standard deviation, median, minimum and maximum of each visit according to treatment groups, adopts a symbol rank test to carry out group comparison if necessary, and adopts an H test (Kruskal-Wallis method) to carry out group comparison. The EQ-5D health questionnaire was subjected to descriptive analysis, and the mean, standard deviation, median, minimum and maximum values for each visit were calculated by treatment group. If necessary, the symbol rank test is used for comparing in groups, and the H test is used for comparing between groups

4.2. Evaluation of safety

4.2.1. Drug exposure and compliance

The drug exposure is described by mean, standard deviation, maximum, minimum, median.

Summary of subject exposure to study drug treatment, patient cycle count, dose adjustments during treatment, cumulative number of doses adjusted during treatment, etc.

Statistical descriptions of study drug treatment time, study drug total dose and daily average dose and study drug dose compliance over the treatment period are presented.

Study drug dose compliance will be calculated based on the actual daily study drug total dose and the regimen prescribed study drug total dose recorded by the eCRF.

The comparison of the treatment time of each study drug, the total dose and the daily average dose of the study drug and the study drug dose compliance adopts one-factor analysis of variance, and the comparison of the compliance classification adopts chi-square test or Fisher accurate probability method.

4.2.2. Adverse events

Summary adverse events, pre-first-dose adverse events, adverse events during treatment, unexpected adverse events during treatment, significant adverse events during treatment, adverse events of particular interest during treatment, adverse events of grade 3 and above during treatment, severe adverse events during treatment, adverse events related to study drug during treatment, SAEs related to study drug during treatment, instances, number of instances, and incidence of adverse events that led to dose adjustments during treatment, permanent cessation of treatment, termination of trial, patient death were summarized by SOC, PT classification.

Adverse events with incidence rate of more than or equal to 5% during treatment and drug-related adverse events are summarized according to PT classification.

Drug-related adverse events with CTC AEs graded as grade 3 or 4 during treatment were summarized according to PT classification.

Adverse events with incidence rate of more than or equal to 10% during treatment and drug-related adverse events are summarized according to PT classification.

The median first occurrence time of adverse events of particular concern.

4.2.3. Vital signs

The mean ± standard deviation, maximum, minimum, median were used to describe the measurements and changes before and after treatment.

4.2.4. Laboratory test index

Table 2 examination item table

The measured values and the changed values before and after treatment are described by mean values +/-standard deviation, maximum values, minimum values and median values for blood routine, blood biochemistry, thyroid function, blood coagulation function, amylase and lipase, and the paired t test is adopted for group comparison. And describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

The routine of urine: and describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

And (3) conventionally: and describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

Describes the proportion of "abnormal, clinically significant" in subjects with abnormal changes, where the presence or absence of an abnormality is judged by the investigator.

4.2.5. Electrocardiogram

Electrocardiogram: according to the normal and abnormal conditions judged by the researchers, the change conditions of the normal and abnormal conditions before and after treatment are described.

The heart rate, PR interval, QRS interval, QT interval and QTc are described by using average number plus or minus standard deviation, maximum value, minimum value and median before and after taking medicine. The electrocardiogram total evaluation result adopts a cross classification table to describe normal and abnormal change conditions before and after administration. The proportion of "clinically significant" abnormalities in subjects describing abnormal changes, where the clinical significance of the abnormalities is at the discretion of the investigator. The list presents a post-administration exception list.

4.2.6. Physical examination

The changes of normal and abnormal before and after treatment are described.

EXAMPLE five therapeutic effects

1. The patients: liver metastasis of cancer cT3-4N + Mla IVA stage at rectum-sigmoid colon junction

The current medical history is as follows: for men aged 64 years, pain is aggravated during defecation due to persistent attack without obvious anal distending pain, accompanied by hematochezia and black stool 2021.12.08 is caught by "direct B junction tumor", 2021.12.10 puncture pathology: (rectal-sigmoid colon biopsy) invasive carcinoma, predisposition to adenocarcinoma, preliminary diagnosis (cT 3-4N + Mla IVA stage liver metastases), patient CT suggested multiple metastases to the liver, with no surgical indication.

The dosage is as follows: starting at 2021.12.13, 1 time daily, oral administration of 12mg of Arotinib hydrochloride capsule, 3000 mg/day oral administration of capecitabine tablet (1500 mg/bid), 2 weeks for 1 week; the 14C12H1L1 injection is injected at 200 mg/time and is intravenously injected at 130mg/m2, and the injection is injected at 1 time every 3 weeks. Every 3 weeks for 1 treatment cycle, treatment until disease progression or intolerance. The patient is currently on C8 cycle medication and has good overall tolerability during dosing.

And (3) pathological report: 2021.12.10 puncture pathology: invasive carcinoma, adenocarcinoma with poorly differentiated

The gene detection report: KRAS A59T mutant MSS PD-L1 (22 c 3) CPS:1

And (3) evaluating the curative effect:

and (3) screening period:

target lesion: the mass of the S6 liver is 34mm; liver S5 segment nodule 28mm; overall diameter 62mm

Non-target lesions: nodules in the liver; thickening the colon; paracolonic lymph node metastasis

After cycle 2 dosing: target lesion: 34mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 23mm; non-target lesions: non-CR/non-PD

After cycle 6 dosing: target lesion: 17mm; non-target lesions: non-CR/non-PD

After cycle 8 dosing: target lesion: 16mm; non-target lesions: non-CR/non-PD

2. The patients: sigmoid colon carcinoma

The current medical history: female, age 44, with bloody stool appearing in 2022 years in no apparent cause at 1 month, bright red or brown with purple blood clots, without regard, after enteroscopy in the hospital: sigmoid colon space occupying. In 2022.02.17, the pathological manifestations of the root treatment of sigmoid colon cancer in lower reaches of general anesthesia are shown: differentiated adenocarcinomas in the (sigmoid colon) ulcerative form were accompanied by partial mucinous adenocarcinomas (pathological stage: pT4aN2 aMx). After MDT diagnosis, patients have colon cancer operation, liver and lung metastasis frequently occurs, and the focus can not be resected by operation. Addition to the clinical study was considered, 2022.03.20 was included.

The dosage is as follows: beginning at 2022.03.20, treatment period (cycles 6-8): 14C12H1L1 injection, 200 mg/time, D1 intravenous drip; arotinib at 12 mg/dose, D1-14, orally administered 1 time per day (QD); oxaliplatin 130mg/m2, D1 intravenous infusion; capecitabine 1000mg/m2, D1 (1 evening), D2-14, 2 times daily (BID), D15 (1 morning), orally. Maintaining the treatment period: the 14C12H1L1 injection is injected at 200 mg/time, and D1 is injected in an intravenous way; arotinib at 12 mg/dose, D1-14, orally administered 1 time per day (QD); capecitabine 1000mg/m2, D1 (1 evening), D2-14, 2 times daily (BID), D15 (1 morning), orally. Every 3 weeks (Q3W) is one administration cycle, oxaliplatin is co-administered for 6 to 8 cycles, and 14C12H1L1 injection can be administered for 1 year but at most 2 years. Other cases continued until the scheduled termination event occurred. The patient is currently on C5 cycle medication and has good overall tolerability during dosing.

And (3) pathological report: 2022.02.22 histopathology: ( Sigmoid colon) ulcer type with partial mucinous adenocarcinoma (pathological stage: pT4aN2aMx )

The gene detection report: MSS, BRAF wild type, KRAS mutation, NRAS wild type

And (3) evaluating the curative effect:

and (3) screening period:

target lesion: liver right lobe lump 11mm;

non-target lesions: 8.5mm of lower right pulmonary nodule

After cycle 2 dosing: target lesion: 5.3mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 4.91mm; non-target lesions: non-CR/non-PD

3. The patients: postoperative metastasis of rectal cancer

The current medical history is as follows: for men, patients in the age of 58 and in the month of 2020 in 1 month see the diagnosis due to hematochezia, the post-operative pathological review after "rectal cancer radical treatment" of 2021-01-14 general anesthesia is as follows: differentiation of adenocarcinoma in (rectal) bulge pattern, preliminary diagnosis (pT 3N2aM0 IIB stage), post-colorectal cancer metastasis review at 5 months 2021, post-rectal cancer metastasis review at 11 months 5 days 2021 CT review: s8, liver tumor of segment involves caudate lobe and is unclear with inferior vena cava, the inferior cavity is possibly invaded, surgical excision can not be carried out, no standard treatment scheme is provided, and the clinical research is considered to be added, 2021.11.04 is used for group.

The dosage is as follows: starting at 2021.11.13, 1 time daily, arotinib hydrochloride capsule 12mg is orally administered for 2 weeks and 1 week is stopped; the 14C12H1L1 injection is injected by intravenous drip at the dose of 200mg for 1 time every 3 weeks; oxaliplatin injection is 20 mg/time, and is instilled in the vein, 1 time every 3 weeks; capecitabine tablets are taken orally twice a day, 2g for 2 weeks and 1 week for rest. Every 3 weeks for 1 treatment cycle, treatment until disease progression or intolerance. The patient is currently on C8 cycle medication and has good overall tolerance during dosing. And (3) pathological report: 2020.01.23 puncture pathology: (rectal) bulge type of differentiated adenocarcinoma (dMMR)

The gene detection report: KR AS mutation, NRAS, BRAF wild type

And (3) evaluating the curative effect:

and (3) screening period:

target lesion: a second hepatic right collateral lump of 76.52mm;

non-target lesion 1: right pulmonary nodule

Non-target lesion 2: right pulmonary nodule

After cycle 2 dosing: target lesion: 46.01mm;

non-target lesion 1: non-CR/non-PD

Non-target lesion 2: non-CR/non-PD

After cycle 4 dosing: target lesion: 39.01mm;

non-target lesion 1: non-CR/non-PD

Non-target lesion 2: non-CR/non-PD

After cycle 6 dosing: target lesion: 39.47mm;

non-target lesion 1: non-CR/non-PD

Non-target lesion 2: non-CR/non-PD

After cycle 8 dosing: target lesion: 41.99mm;

non-target lesion 1: non-CR/non-PD

Non-target lesion 2: non-CR/non-PD

5. The patients: liver metastasis of colorectal cancer cT2N + M1 IV stage

The current medical history: for men aged 58, stool characteristics changed by 5+ month in hemafecia and were examined in 2021.12.07 hospital for 1 month, 2021.12.11 enteroscopy: the rectum corresponds to high-medium differentiated adenocarcinoma, 2021.12.14 harbors: 2021.12.16 upper abdomen MR shows: the liver is occupied frequently, liver metastasis tumor, hepatoportal area and portal space lymph node swelling are considered, preliminary diagnosis (liver metastasis of differentiated adenocarcinoma in cT2N + M1 IV stage) is carried out, and clinical research is considered and 2021.12.29 group medication is considered because a plurality of lumps and nodules are diffused in the liver of a patient and no surgical indication exists.

The dosage is as follows: starting at 2021.12.29, 1 time a day, orally taking 12mg of an anrotinib hydrochloride capsule, orally taking 3500mg of capecitabine tablets per day (2000 mg in the morning and 1500mg in the evening), and continuously taking for 2 weeks and stopping for 1 week; the 14C12H1L1 injection is administered by intravenous infusion at a dose of 200 mg/time, and the oxaliplatin for injection is administered by intravenous infusion at a dose of 130mg/m2, 1 time every 3 weeks. Every 3 weeks for 1 treatment cycle, treatment until disease progression or intolerance. 2022.2.10 dose of C3 was adjusted on schedule for myelosuppression AE grade 3: the capecitabine dose is 2500 mg/day, the oxaliplatin dose is 100mg/m < 2 >, and the Arotinib dose is 10mg/qd.2022.3.29 Arotinib 10mg/qd was planned to be restored to 12mg/qd according to patient condition C5. 2022.5.12 dose of C7 was adjusted on schedule for the second appearance of myelosuppression AE grade 3: the capecitabine dose is 2000 mg/day, the oxaliplatin dose is 85mg/m < 2 >, and the patient is currently in C9 cycle medication and has good overall tolerance during the medication period.

And (3) pathological report: 2021.12.11 enteroscopy pathological diagnosis: rectal coincidence of high-medium differential adenocarcinoma

And (3) evaluating the curative effect:

and (3) screening period:

target lesion: liver S8 mass 65mm; liver S3 mass 64mm; overall diameter 129mm

Non-target lesions: the lower rectum; multiple metastatic masses of liver

After cycle 2 dosing: target lesion: 81mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 74mm; non-target lesions: non-CR/non-PD

After cycle 6 dosing: target lesion: 57mm; non-target lesions: non-CR/non-PD

After cycle 8 dosing: target lesion: 51mm; non-target lesions: non-CR/non-PD.

Claims (10)

1. Use of a pharmaceutical combination for the manufacture of a medicament for the treatment of colorectal cancer, comprising:

a) The medicine for chemotherapy is a medicine for treating tumor,

b) A human PD-1 antibody that comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, the light chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, the heavy chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, and

c) A tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

2. use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, preferably the dihydrochloride.

3. The use of any one of claims 1-2, wherein the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID No. 7 and a heavy chain variable region as set forth in SEQ ID No. 8.

4. Use according to any one of claims 1 to 3, wherein the chemotherapeutic agent is selected from one or more of platinum group drugs, fluoropyrimidine derivatives, taxanes, camptothecin group drugs, anthracyclines, alkylating agents, podophyllum group drugs, vinblastine group drugs; wherein the content of the first and second substances,

the platinum drug is one or more of oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, leplatin, triplatin tetranitrate, phenanthroline, picoplatin and satraplatin;

the fluoropyrimidine derivative is one or more of gemcitabine, capecitabine, fluorouracil, difurofluorouracil, doxifluridine, tegafur, carmofur, trifluridine and efadine;

the taxane medicine is one or more of paclitaxel, albumin-bound paclitaxel and docetaxel;

the camptothecin medicament is one or more of camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan and topotecan;

the anthracycline compound is one or more of epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, pyrarubicin and liposome adriamycin;

the alkylating agent is one or more of cyclophosphamide, ifosfamide, carmustine and melphalan;

the podophyllum drug is one or more of etoposide, tennixin platinum glycoside and epipodophyllotoxin glucopyranoside;

the vinblastine is one or more of vinorelbine, vinblastine, vincristine, vindesine, and vinflunine;

optionally, the step of (a) is carried out, the chemotherapy medicine also comprises methotrexate, cytarabine, ancitabine, azacitidine, thioguanine, pemetrexed, mitomycin, bendamustine, temozolomide, actinomycin D, bleomycin, pingyangmycin, dacarbazine, pellomycin, eribulin, sapacitabine, plinabulin, trooshusu, trovamat, fluazinam, and the like, ¹⁵³ One or more of Sm-EDTMP, tegafur and encequidar.

5. The use according to any one of claims 1 to 4 wherein the chemotherapeutic agent is capecitabine and oxaliplatin.

6. The use according to any one of claims 1 to 5, wherein the pharmaceutical combination comprises erlotinib, the 14C12H1L1 antibody and capecitabine with oxaliplatin.

7. Use according to any one of claims 1 to 6, said colorectal cancer being a colorectal adenocarcinoma, preferably said colorectal adenocarcinoma is a acne-cribriform adenocarcinoma, a medullary carcinoma, a microemulsion head carcinoma, a mucous adenocarcinoma, a serrate adenocarcinoma or a signet ring cell carcinoma.

8. Use according to any one of claims 1 to 7, in the manufacture of a medicament for the first line treatment of colorectal cancer.

9. The use according to any one of claims 1 to 8, wherein the administration of the Arotinib in the pharmaceutical combination is 1 dose daily, 8mg, 10mg or 12mg each time, 2 weeks for 1 week with continuous oral administration, and the administration of the 14C12H1L1 antibody is 1 dose every 3 weeks, 100 mg/dose, 150 mg/dose or 200 mg/dose.

10. The use according to any one of claims 1 to 9, wherein the 14C12H1L1 antibody is administered 1 time every 3 weeks at 200 mg/time; the erlotinib is taken orally for 2 weeks and stops for 1 week, 1 time daily at 12 mg/time; oxaliplatin 130mg/m ² Once every three weeks, intravenous infusion; capecitabine 1000mg/m ² The drug is administered once in the evening on day 1, 2 times per day on days 2-14, and once in the morning on day 15, and is administered orally.