Combination of anti-PD-1 and anti-EGFR antibodies and their use in the treatment of head and neck squamous cell carcinoma

Abstract

The present invention provides a combination of an anti-PD-1 antibody and an anti-EGFR antibody and its use in treating head and neck squamous cell carcinoma. Specifically, the present invention provides a drug combination comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-EGFR antibody or an antigen-binding fragment thereof. The drug combination has a relatively good therapeutic effect on the treatment of head and neck squamous cell carcinoma.

Description

[Technical field]

[0001] The present invention relates to the technical field of pharmaceutical use, in particular to a combination of an anti-PD-1 antibody or an antigen-binding fragment thereof with an anti-EGFR antibody or an antigen-binding fragment thereof, and its use in the manufacture of a medicament for treating head and neck squamous cell carcinoma. [Background technology]

[0002] Head and neck tumors are tumors that occur in the mouth, nose, pharynx, larynx, etc., and more than 90% are squamous cell carcinoma or its variants, collectively known as head and neck squamous cell carcinoma (HNSCC).

[0003] HNSCC is the sixth most common cancer worldwide, with 890,000 new confirmed cases and 450,000 new deaths in 2018. HNSCC incidence continues to rise, projected to increase by 30% in 2030. Higher incidence of HNSCC in regions such as Southeast Asia and Australia is associated with consumption of certain carcinogen-containing products, while increased rates of oropharyngeal HPV infection lead to higher incidence of HNSCC in the United States and Western Europe. In general, men are two to four times more likely to develop HNSCC than women. The median age of diagnosis for non-virus-related HNSCC is 66 years, whereas the median ages of diagnosis for HPV-related oropharyngeal cancer and EBV-related nasopharyngeal cancer are 53 and 50 years, respectively.

[0004] More than 65% of head and neck squamous cell carcinomas are recurrent or metastatic at the time of diagnosis. Meanwhile, 15-40% of patients with locally advanced disease still experience recurrence or metastasis after treatment, with a 5-year survival rate of less than 50%. Recurrent or metastatic head and neck squamous cell carcinomas have poor prognosis and short survival times. Their anatomical location is often in vital organs, and they can damage the patient's appearance, basic physiological functions, sensory functions, and language functions, thus affecting the patient's quality of life.

[0005] For first-line treatment of head and neck squamous cell carcinoma (excluding nasopharyngeal carcinoma), platinum-based regimens (platins or taxanes combined with fluorouracils ± cetuximab) are the standard treatments recommended by current national guidelines. For recurrent or metastatic head and neck squamous cell carcinoma that has failed treatment with first-line platinum-containing regimens, there is currently no standard treatment. If PD-L1 is ≥ 1%, nivolumab can be used for treatment. However, for those who have not undergone biomarker screening, treatment is currently mainly with single-agent chemotherapy such as methotrexate and docetaxel, with a response rate of less than 10% and an overall survival of 6-7 months, with very limited therapeutic effects.

[0006] Currently, immunotherapy for recurrent or metastatic head and neck squamous cell carcinoma that has failed treatment with first-line platinum-containing regimens mainly includes immunomodulators, immune checkpoint blockade (PD-1 / PD-L1, CTLA-4 blockade, etc.), tumor vaccines, cellular immunotherapy (cytokine-induced killer cells, i.e., CIK), etc. Here, programmed death receptor-1 (PD-1) is an inhibitory receptor of the immunoglobulin family on the surface of activated T lymphocytes, and its ligands are the B7 homologous proteins programmed death ligand-1 (PD-L1) (also known as B7-H1) and programmed death ligand-2 (PD-L2) (also known as B7-DC). Meanwhile, PD-1 / PD-L1 binding plays an important role in downregulating T cell activation and maintaining peripheral immune tolerance, so tumor cells express PD-L1 and interact with PD-1 to suppress T cell activation, thereby avoiding immune cell killing. Blockade of such immune checkpoints can enhance the proliferation, survival, and killing activity of T cells to achieve tumor immunotherapy effects.

[0007] Epidermal growth factor receptor (EGFR) belongs to the tyrosine kinase receptor family, and aberrant activation of EGFR in cancer cells is induced by various mechanisms, including gene amplification, point mutation, deletion, and autocrine ligand receptor stimulation, and promotes tumor initiation and progression by establishing a non-inflammatory tumor microenvironment, reducing the activity of CD8+ T cells, and enhancing the immunosuppressive function of Treg cells. Monoclonal antibodies targeting EGFR can block the binding of EGF and other ligands to EGFR and prevent EGFR dimerization, thus inhibiting the ligand-induced activation of such receptor tyrosine kinases. This results in the inhibition of cell growth, induction of cell apoptosis, and a decrease in matrix metalloproteinase and vascular endothelial growth factor synthesis. Monoclonal antibodies targeting EGFR also prevent interaction with its ligand by deleting the receptor on the cell surface, stimulating the internalization and eventual degradation of EGFR. In addition, monoclonal antibodies targeting EGFR can mediate antibody-dependent, cell-mediated cytotoxicity, a process that depends not only on the affinity of the monoclonal antibody for the extracellular domain of EGFR, but also on the expression level of cellular EGFR.

[0008] In the process of HNSCC treatment, the therapeutic effect of single administration has certain limitations. Therefore, exploring more effective therapeutic methods to further extend the survival and improve the quality of life of patients with recurrent or metastatic head and neck squamous cell carcinoma is one of the clinical needs that needs to be urgently resolved. Summary of the Invention

[0009] A first aspect of the invention provides a drug combination comprising an anti-PD-1 antibody, or an antigen-binding fragment thereof, and an anti-EGFR antibody, or an antigen-binding fragment thereof.

[0010] In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in the invention comprises an LCDR1 having the amino acid sequence shown in SEQ ID NO:1 or an amino acid sequence that has one, two or three amino acid differences compared to SEQ ID NO:1; an LCDR2 having the amino acid sequence shown in SEQ ID NO:2 or an amino acid sequence that has one, two or three amino acid differences compared to SEQ ID NO:2; an LCDR3 having the amino acid sequence shown in SEQ ID NO:3 or an amino acid sequence that has one, two or three amino acid differences compared to SEQ ID NO:3; an HCDR1 having the amino acid sequence shown in SEQ ID NO:4 or an amino acid sequence that has one, two or three amino acid differences compared to SEQ ID NO:4; an HCDR2 having the amino acid sequence shown in SEQ ID NO:5 or an amino acid sequence that has one, two or three amino acid differences compared to SEQ ID NO:5; and an HCDR3 having the amino acid sequence shown in SEQ ID NO:6 or an amino acid sequence that has one, two or three amino acid differences compared to SEQ ID NO:6.

[0011] In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in the invention comprises a light chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a heavy chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0012] In one or more embodiments, the anti-PD-1 antibody, or antigen-binding fragment thereof, described in the invention comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:7, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8.

[0013] In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in the invention comprises a light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:9, and a heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:10.

[0014] In one or more embodiments, the anti-PD-1 antibody described in the invention comprises a light chain having the amino acid sequence set forth in SEQ ID NO:9, and a heavy chain having the amino acid sequence set forth in SEQ ID NO:10.

[0015] The anti-PD-1 antibody in the drug combination of the invention may be any antibody that is capable of specifically binding to PD-1 and blocking or inhibiting the binding of PD-1 to its receptor PD-L1.

[0016] In one or more embodiments, the anti-PD-1 antibody described in the present invention is one or more selected from Nivolumab or a biosimilar thereof, Pembrolizumab or a biosimilar thereof, Toripalimab or a biosimilar thereof, Sintilimab or a biosimilar thereof, Camrelizumab or a biosimilar thereof, Tislelizumab or a biosimilar thereof, Cemiplimab or a biosimilar thereof, Zimberelimab or a biosimilar thereof, Penpulimab or a biosimilar thereof, and Serplulimab or a biosimilar thereof, preferably Toripalimab or a biosimilar thereof.

[0017] In one or more embodiments, the anti-EGFR antibody or antigen-binding fragment thereof according to the present invention comprises an LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 11 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO: 11, an LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 12 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO: 12, an LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 13 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO: 13, an HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 14 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO: 14, an HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 15 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO: 15, and an HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 16 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO: 16.

[0018] In one or more embodiments, the anti-EGFR antibody or antigen-binding fragment thereof described in the present invention comprises a light chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18.

[0019] In one or more embodiments, the anti-EGFR antibody or antigen-binding fragment thereof described in the present invention comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 18.

[0020] In one or more embodiments, the anti-EGFR antibody or antigen-binding fragment thereof described in the present invention comprises a light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 19, and a heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:20.

[0021] In one or more embodiments, the anti-EGFR antibody according to the invention comprises a light chain having the amino acid sequence shown in SEQ ID NO:19 and a heavy chain having the amino acid sequence shown in SEQ ID NO:20.

[0022] The anti-EGFR antibody in the drug combination of the present invention may be any antibody that is capable of specifically binding to EGFR and blocking or inhibiting the binding of EGF to its receptor EGFR.

[0023] In one or more embodiments, the anti-EGFR antibody described in the present invention is one or more selected from Necitumumab or a biosimilar thereof, Nimotuzumab or a biosimilar thereof, Panitumumab or a biosimilar thereof, and Cetuximab or a biosimilar thereof, preferably Cetuximab or a biosimilar thereof.

[0024] In one or more embodiments, the drug combination described herein includes Toripalimab or a biosimilar thereof and Cetuximab or a biosimilar thereof.

[0025] In one or more embodiments, the drug combination described herein includes Toripalimab and Cetuximab.

[0026] In one or more embodiments, the drug combination comprises one dose of the anti-PD-1 antibody or antigen-binding fragment thereof (preferably Toripalimab) and three doses of the anti-EGFR antibody or antigen-binding fragment thereof (preferably Cetuximab), wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are provided in the form of separate formulations or in a collectively packaged form, respectively. Preferably, the one dose of the formulation of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 240 mg of the anti-PD-1 antibody or antigen-binding fragment thereof, and in the three doses of the formulation of the anti-EGFR antibody or antigen-binding fragment thereof, the anti-EGFR antibody or antigen-binding fragment thereof contained in the one dose of the formulation is 400 mg / m 2 daily dose of 250 mg / m 2 or the anti-EGFR antibody or antigen-binding fragment thereof contained in each of the three doses of the formulation satisfies daily administration of 250 mg / m 2 Preferably, the anti-PD-1 antibody is Toripalimab and the anti-EGFR antibody is Cetuximab.

[0027] A second aspect of the present invention provides the use of the drug combination in the manufacture of a medicament for preventing or treating head and neck squamous cell carcinoma (HNSCC) in a patient, comprising administering to the subject a therapeutically effective amount of the drug combination as described in any one of the above. In one or more embodiments, the head and neck squamous cell carcinoma in the above use is a recurrent or metastatic head and neck squamous cell carcinoma, preferably a recurrent or metastatic head and neck squamous cell carcinoma that has previously failed chemotherapy with a first-line platinum-containing regimen. In one or more embodiments, the patient has PD-L1 expression ≧1 (i.e., PD-L1 CPS ≧1) detected by immunohistochemistry. In one or more embodiments, the head and neck squamous cell carcinoma in the above use has ≧1 measurable lesion according to RECIST v1.1 criteria.

[0028] A third aspect of the invention provides the use of an anti-PD-1 antibody, or an antigen-binding fragment thereof, in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC) in a patient, or the use of a combination of an anti-PD-1 antibody, or an antigen-binding fragment thereof, and an anti-EGFR antibody, or an antigen-binding fragment thereof, in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC) in a patient.

[0029] A fourth aspect of the invention provides a method of preventing or treating head and neck squamous cell carcinoma in a patient, the method comprising administering to an individual in need thereof a therapeutically effective amount of an anti-PD-1 antibody, or antigen-binding fragment thereof, or a combination of an anti-PD-1 antibody, or antigen-binding fragment thereof, and an anti-EGFR antibody, or antigen-binding fragment thereof.

[0030] A fifth aspect of the invention provides an anti-PD-1 antibody, or antigen-binding fragment thereof, or a combination of an anti-PD-1 antibody, or antigen-binding fragment thereof, and an anti-EGFR antibody, or antigen-binding fragment thereof, for preventing or treating head and neck squamous cell carcinoma in a patient.

[0031] In one or more embodiments, the head and neck squamous cell carcinoma according to the present invention is recurrent or metastatic head and neck squamous cell carcinoma, preferably recurrent or metastatic head and neck squamous cell carcinoma that has previously failed chemotherapy with a first-line platinum-containing regimen.

[0032] In one or more embodiments, the patient has a PD-L1 CPS of >=1.

[0033] In one or more embodiments, the head and neck squamous cell carcinoma according to the present invention has ≧1 measurable lesion according to RECIST v1.1 criteria.

[0034] In one or more embodiments, in the second, third, fourth, and fifth aspects of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is an anti-PD-1 antibody or antigen-binding fragment thereof as provided in any one of the embodiments herein.

[0035] In one or more embodiments, in the second, third, fourth and fifth aspects of the present invention, the anti-EGFR antibody or antigen-binding fragment thereof is an anti-EGFR antibody or antigen-binding fragment thereof as set forth in any one of the embodiments herein.

[0036] In one or more embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described herein are administered alone.

[0037] In one or more embodiments, a single dose of an anti-PD-1 antibody or antigen-binding fragment thereof described in the present invention is from about 0.1 mg / kg to about 10.0 mg / kg of an individual's body weight, preferably from about 1.0 mg / kg to about 10.0 mg / kg of an individual's body weight, for example, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, or about 10 mg / kg of an individual's body weight, or a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, for example, a fixed dose of about 120 mg, about 240 mg, about 360 mg, or about 480 mg.

[0038] In one or more embodiments, the administration frequency of the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present invention is about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per two weeks or once per three weeks.

[0039] In one or more embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described herein are administered at a dosage of about 1 mg / kg of an individual's body weight, about 3 mg / kg of an individual's body weight, about 5 mg / kg of an individual's body weight, about 10 mg / kg of an individual's body weight, a fixed dose of about 240 mg, a fixed dose of about 360 mg, or a fixed dose of about 480 mg, once every two or three weeks.

[0040] In one or more embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present invention are administered in liquid dosage forms, such as injections, via parenteral routes, such as intravenous infusion.

[0041] In one or more embodiments, the dosing cycle of the anti-PD-1 antibodies or antigen-binding fragments thereof described in the invention is for a period of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, half a year, 1 year, 2 years or more, optionally, the duration of each dosing cycle is the same or different, and the intervals between each dosing cycle are the same or different.

[0042] In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in the present invention is administered in combination with an anti-EGFR antibody or antigen-binding fragment thereof.

[0043] In one or more embodiments, a single dose of an anti-PD-1 antibody or antigen-binding fragment thereof described in the present invention is about 0.1 mg / kg to about 10.0 mg / kg of an individual's body weight, preferably about 1.0 mg / kg to about 10.0 mg / kg of an individual's body weight, for example, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, or about 10 mg / kg of an individual's body weight, or a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, for example, a fixed dose of about 120 mg, about 240 mg, about 360 mg, or about 480 mg, preferably a fixed dose of about 240 mg.

[0044] In one or more embodiments, a single dose of the anti-EGFR antibody or antigen-binding fragment thereof described in the present invention is about 100 mg / m 2 ~about 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~about 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 of anti-EGFR antibody or antigen-binding fragment thereof, preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 or about 400 mg / m 2 of an individual's body surface area of ​​an anti-EGFR antibody or antigen-binding fragment thereof.

[0045] In one or more embodiments, the administration frequency of the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present invention is about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per three weeks.

[0046] In one or more embodiments, the administration frequency of the anti-EGFR antibody or antigen-binding fragment thereof described in the present invention is about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per week.

[0047] In one or more embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a fixed dose of about 240 mg once every three weeks, and the anti-EGFR antibody or antigen-binding fragment thereof is administered at a fixed dose of about 400 mg / m2 in the first cycle. 2of individual body surface area, and approximately 200 mg / m2 at the time of administration of each subsequent dosing cycle. 2 or 250 mg / m 2 of individual body surface area and is administered once a week.

[0048] In one or more embodiments, the administration cycle of the anti-PD-1 antibody or antigen-binding fragment thereof, or the anti-EGFR antibody or antigen-binding fragment thereof may be for 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, half a year, 1 year, 2 years or more, and optionally, the duration of each administration cycle may be the same or different, and the interval between each administration cycle may be the same or different.

[0049] In one or more embodiments, in the second, third, fourth and fifth aspects of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are administered in a liquid dosage form, such as an injection, via a parenteral route, such as intravenous infusion.

[0050] A sixth aspect of the present invention is Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is as described in any one of the embodiments herein, and more preferably, the anti-PD-1 antibody is Toripalimab or a biosimilar thereof. Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is as described in any one of the embodiments herein, preferably, the anti-EGFR antibody or antigen-binding fragment thereof is as described in any one of the embodiments herein, more preferably, the anti-PD-1 antibody is Toripalimab or a biosimilar thereof, and the anti-EGFR antibody is Cetuximab or a biosimilar thereof. A kit is provided comprising one or more single pharmaceutical dosage units of an anti-PD-1 antibody or antigen-binding fragment thereof and one or more single pharmaceutical dosage units of an anti-EGFR antibody or antigen-binding fragment thereof.

[0051] In one or more embodiments, the kit comprises: (I) one or more of the above single-pharmaceutical dosage units of an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in the single-pharmaceutical dosage unit is a fixed dose of about 120 mg to about 480 mg, e.g., a fixed dose of about 120 mg, a fixed dose of about 240 mg, a fixed dose of about 360 mg, or a fixed dose of about 480 mg, or the amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in the single-pharmaceutical dosage unit is sufficient to be administered to a patient in a single dose of about 1.0 mg / kg to about 10.0 mg / kg of individual body weight, about 1 mg / kg of individual body weight, about 3 mg / kg of individual body weight, about 5 mg / kg of individual body weight, or about 10 mg / kg of individual body weight; (II) The amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in a single-drug dosage unit is a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, for example, about 120 mg, about 240 mg, about 360 mg, or about 480 mg, preferably about 240 mg. The amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in one or more of the above single-drug dosage units, and the amount of the anti-EGFR antibody or antigen-binding fragment thereof contained in a single-drug dosage unit is about 100 mg / m 2 ~about 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~about 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 of anti-EGFR antibody or antigen-binding fragment thereof, preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2or about 400 mg / m 2 The present invention further comprises one or more of said single pharmaceutical dosage units of an anti-EGFR antibody or antigen-binding fragment thereof, sufficient to be administered to a patient in a single dosage amount of about 100 mg / kg of an individual's body surface area.

[0052] In one or more embodiments, the kit according to the invention further comprises instructions for how to use the drug.

[0053] In one or more embodiments, the kit comprises a drug combination described in any one of the embodiments herein. [Brief description of the drawings]

[0054] [Figure 1] Results show change in tumor burden from baseline and treatment efficacy in patients assessed according to RECIST v1.1 (n=45). [Diagram 2] Change in tumor burden versus baseline in patients assessed according to RECIST v1.1 (n=45). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] The present invention relates to a method for treating a malignant tumor, the method comprising administering an anti-PD-1 antibody or an antigen-binding fragment thereof or a combination thereof and an anti-EGFR antibody or an antigen-binding fragment thereof or a combination thereof to a patient in need thereof. The malignant tumor according to the present invention is head and neck squamous cell carcinoma.

[0056] term In order to make the present invention easier to understand, some technical terms are specifically defined below. Unless expressly explained elsewhere in this specification, all technical terms used herein have the meanings commonly understood by those of ordinary skill in the art.

[0057] As used in the specification and appended claims, the singular forms "a," "an," and "the" include plural referents unless expressly stated otherwise. Thus, for example, reference to "a polypeptide" includes a combination of two or more polypeptides, and the like.

[0058] "Administration," "giving," and "treating" refer to the introduction of a composition containing a therapeutic agent into a subject by any one of a variety of methods or delivery systems known to those of skill in the art. Routes of administration of anti-PD-1 antibodies include intravenous, intramuscular, subcutaneous, peritoneal, spinal, or other parenteral routes of administration, such as injection and infusion. "Parenteral administration" refers to a method of administration other than enteral or 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, intradural, and intrasternal injection and infusion, and in vivo electroporation.

[0059] An "adverse event" (AE), as described herein, is any untoward, and generally unintended or undesirable, sign, symptom, or disease associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system or amplification of immune system cells in response to the treatment. A medical treatment may have one or more associated AEs, each of which may have the same or different levels of severity.

[0060] "Tumor burden" is the total amount of tumor material distributed throughout the body. Tumor burden is the total number of cancer cells or the total size of a tumor throughout the body. Tumor burden can be measured by a variety of methods known in the art, such as measuring the size of a tumor after it is removed from a subject with calipers, or when in the body, by imaging techniques (e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scan).

[0061] The term "tumor size" refers to the total size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be measured by a variety of methods known in the art, such as by calipers after the tumor is removed from a subject, or by imaging techniques (e.g., bone scans, ultrasound, CT and MRI scans) to measure the size of the tumor when it is in vivo.

[0062] The terms "subject," "individual," and "subject" include any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit, etc.), and most preferably a human. The terms "subject" and "patient" may be used interchangeably herein.

[0063] An "antibody" as described herein is any form of antibody capable of achieving a desired biological activity or binding activity. It is therefore used in the broadest sense, but is not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies, humanized full-length human antibodies, chimeric antibodies, and single domain antibodies derived from camelids. An "antibody" specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region, which comprises three constant domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (VL) and a light chain constant region, which comprises one constant domain, CL. The VH and VL regions may be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), which are more conserved and distributed in regions called framework regions (FRs). Generally, from N-terminus to C-terminus, both light and heavy chain variable domains include FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Amino acids are generally assigned to each domain according to the definitions in Sequences of Proteins of Immunological Interest, Kabat et al., National Institutes of Health, Bethesda, Md., 5th edition, NIH Press No. 91-3242 (1991): Kabat (1978) Adv. Prot. Chem. 32:1-75, Kabat et al., (1977) J. Biol. Chem. 252:6609-6616, Chothia et al., (1987) J Mol. Biol. 196:901-917 or Chothia et al., (1989) Nature 341:878-883.

[0064] The carboxy-terminal portion of the heavy chain may define a constant region that is primarily responsible for effector functions. Human light chains are usually classified as kappa and lambda chains. Human heavy chains are usually classified as μ, δ, γ, α, or ε, and the antibody isotype is defined as IgM, IgD, IgG, IgA, and IgE, respectively. IgG subclasses are well known to those skilled in the art and include, but are not limited to, IgG1, IgG2, IgG3, and IgG4.

[0065] The term "antibody" includes naturally occurring and non-naturally occurring Abs, monoclonal and polyclonal Abs, chimeric and humanized Abs, human or non-human Abs, fully synthetic Abs, and single chain Abs. Non-human Abs can be humanized by recombinant methods to reduce their immunogenicity in humans.

[0066] Unless otherwise specified, an "antibody fragment" or "antigen-binding fragment" as used herein refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability of the full-length antibody to specifically bind to an antigen, e.g., a fragment that retains one or more CDR regions. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, double-chain antibodies, linear antibodies, single-chain antibody molecules, nanobodies and multispecific antibodies consisting of antibody fragments.

[0067] "Chimeric antibodies" are antibodies and fragments thereof in which a portion of the heavy and / or light chain is similar to or homologous to corresponding sequences in antibodies derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain is similar to or homologous to corresponding sequences in antibodies derived from another species (e.g., mouse) or belonging to another antibody class or subclass, and which exhibit a desired biological activity.

[0068] A "human antibody" is an antibody that contains only human immunoglobulin sequences. A human antibody may contain murine carbohydrate chains if produced in a mouse, a mouse cell, or a hybridoma derived from a mouse cell. Similarly, a "mouse antibody" or a "rat antibody" is an antibody that contains only mouse or rat immunoglobulin sequences, respectively.

[0069] A "humanized antibody" is an antibody format that contains sequences derived from a non-human (e.g., murine) antibody and a human antibody. Such antibodies contain minimal sequence derived from a non-human immunoglobulin. Typically, a humanized antibody will contain substantially all of at least one, and usually two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin. The humanized antibody optionally further comprises at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region.

[0070] As used herein, the term "cancer" or "malignant tumor" refers to a wide variety of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth leads to the formation of malignant tumors, which can invade nearby tissues and spread to distant parts of the body via the lymphatic system or bloodstream. Examples of cancers suitable for treatment or prevention with the methods, drugs and reagent kits of the present invention include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma and sarcoma. Further specific examples of cancer include squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (ductal) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, renal cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, nasopharyngeal cancer, cervical cancer, brain cancer, gastric cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, and head and neck cancer.

[0071] As used herein, the term "tumor mutation burden (TMB)" refers to the cumulative total somatic genetic coding errors, base substitutions, genetic insertions or deletions detected in bases per million. In some embodiments of the present invention, tumor mutation burden (TMB) is estimated by analyzing somatic mutations, including coding base substitutions and megabase insertions of the panel sequences studied.

[0072] The term "head and neck squamous cell carcinoma (HNSCC)" has its usual meaning in the art, and refers to tumors occurring in the mouth, nose, pharynx, larynx, etc. In general, head and neck squamous cell carcinoma refers to head and neck squamous cell cancer. HNSCC can be caused by various factors, including smoking history, alcohol drinking history, contact with carcinogens (e.g., betel nut, air pollutants, etc.), and viral infections (e.g., human papilloma virus (HPV) or Epstein-Barr virus (EBV)). In some embodiments, the HNSCC is early stage HNSCC, non-metastatic HNSCC, primary HNSCC, advanced HNSCC, locally advanced HNSCC, metastatic HNSCC, response stage HNSCC, or recurrent HNSCC.

[0073] The term "immunotherapy" refers to treating a subject suffering from or infected with a disease, or at risk for disease recurrence, by methods that involve inducing, enhancing, suppressing, or otherwise modifying the immune response. "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, with the goal of reversing, mitigating, ameliorating, delaying, or preventing the onset, progression, severity, or recurrence of symptoms, complications, or disease, or biochemical indicators associated with a disease.

[0074] The term "programmed death receptor-1 (PD-1)" refers to an immunosuppressive receptor that belongs to the CD28 family. PD-1 is expressed primarily on preactivated T cells in the body and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isotypes and species homologs of hPD-1, and analogs that share at least one common epitope with hPD-1.

[0075] The term "EGFR" (epidermal growth factor receptor, also called ERBB1 or HER1) is a receptor for signal transduction such as cell proliferation by epidermal growth factor (EGF), and belongs to the ERBB family (also called the HER family), which is a receptor tyrosine kinase (RTK). EGFR is located on the surface of the cell membrane and is activated by binding to ligands including EGF and TGFα (transforming growth factor α). After activation, EGFR is converted from a monomer to a dimer and activates kinase pathways in the cell, including MAPK, Akt, and JNK, to induce cell proliferation.

[0076] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent refers to any amount of the drug, when used alone or in combination with other therapeutic agents, that protects a subject from the onset of a disease or promotes resolution of the disease, as evidenced by a reduction in the severity of symptoms, an increase in the frequency and duration of symptom-free periods of the disease, or a prevention of damage or disability due to pain from the disease. The ability of a therapeutic agent to promote resolution of a disease can be assessed in a variety of ways known to those of skill in the art, for example, by measuring the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0077] A therapeutically effective amount of a drug includes a "prophylactically effective amount," i.e., any amount of a drug that inhibits the progression or recurrence of cancer when administered alone or in combination with an anti-tumor agent to a subject at risk of cancer progression or who has had cancer recurrence.

[0078] A "biological therapeutic agent" is a biological molecule, e.g., an antibody or a fusion protein, that blocks ligand / receptor signaling in any biological pathway that supports tumor maintenance and / or growth or suppresses an anti-tumor immune response.

[0079] Unless otherwise specified, "CDR" as used herein refers to the complementarity determining regions of an immunoglobulin variable region as defined by the Kabat numbering system.

[0080] A "therapeutic anti-PD-1 monoclonal antibody" is an antibody in its mature form that specifically binds to a particular PD-1 expressed on the cell surface of some mammalian organism. Mature PD-1 lacks the pre-secretory leader sequence, also called leader peptide. The terms "PD-1" and "mature PD-1" may be used interchangeably herein and should be understood to refer to the same molecule unless otherwise clearly defined or clearly indicated by the context.

[0081] As described herein, therapeutic anti-human PD-1 antibodies, or anti-PD-1 antibodies, are monoclonal antibodies that specifically bind to mature human PD-1.

[0082] As described herein, therapeutic anti-human EGFR antibodies or anti-EGFR antibodies are monoclonal antibodies that specifically bind to EGFR.

[0083] As used herein, a "framework region" or "FR" is an immunoglobulin variable region without the CDR regions.

[0084] An "isolated antibody or antigen-binding fragment thereof" refers to a molecule that is in a purified state, and is substantially free of other biological molecules, such as nucleic acids, proteins, lipids, carbohydrates and other materials (e.g., cellular debris and growth medium), as the designated molecule in this case.

[0085] "Patient," "patient" or "subject" refers to any single subject in need of a medical procedure or participating in a clinical trial, epidemiological study, or used as a control, and is generally a mammal, including humans and other mammals such as horses, cows, dogs and cats.

[0086] The "RECIST 1.1 therapeutic response criteria" described herein refers to the definition described in Eisenhauver, EA et al., Eur.J Cancer 45:228-247 (2009) for target damage or non-target damage based on the context of the response measured. Before immunotherapy, it is the most commonly used criteria for evaluating the therapeutic effect on solid tumors. However, with the advent of the immune era, many challenges that have never been encountered before in tumor evaluation have emerged, and based on the newly emerged phenomenon brought about by immunotherapy itself, in 2016, the RECIST working group proposed a new criterion after amending the existing "RECIST v.1.1", namely, the "irRECIST criteria" described herein, so that the therapeutic effect of immunotherapy agents can be better evaluated.

[0087] The term "ECOG" score is an index that measures a patient's general health and tolerance to treatment based on their physical fitness. The ECOG physical fitness score can be scored on a scale of 0, 1, 2, 3, 4, or 5. A score of 0 means that the ability to function is completely normal and there is no difference in ability to function compared to before the onset of the disease. A score of 1 means that the patient can walk freely and perform light physical activities, including general housework and office work, but is unable to perform relatively heavy physical activities.

[0088] A "durable response" is a sustained therapeutic effect after a therapeutic agent or combination therapy described herein is stopped. In some embodiments, the sustained response has a duration at least as long as the duration of treatment, or at least 1.5, 2.0, 2.5, or 3 times the duration of treatment.

[0089] A "tissue section" is a single portion or slice of a tissue sample, for example a tissue slice cut from a normal tissue or tumor sample.

[0090] "Treatment" of cancer as described herein refers to the use of a treatment regimen as described herein (e.g., administration of an anti-PD-1 antibody) in a subject suffering from or diagnosed with cancer, so as to achieve at least one positive therapeutic effect (e.g., reduction in the number of cancer cells, reduction in tumor volume, slowing the rate of cancer cell invasion into surrounding organs, or slowing the rate of tumor metastasis or tumor growth). A positive therapeutic effect in cancer can be measured in various ways (see WA Weber, J. Nucl. Med., 50:1S-10S (2009)). For example, for tumor growth inhibition, according to the NCI criteria, T / C≦42% is the minimum level of antitumor activity. T / C(%)=median tumor volume treated / median tumor volume control×100 is considered. In some embodiments, the therapeutic effect achieved by the combination of the present invention is any one of PR, CR, OR, PFS, DFS, and OS. PFS (also called "progression-free survival") is the duration of time during and after treatment without the progression of cancer, and includes the amount of time the patient experiences CR or PR and the amount of time the patient experiences SD. DFS is the duration of time the patient remains disease-free during and after treatment. OS is the extension of life expectancy for an initial or untreated individual or patient. In some embodiments, the response to the combination of the present invention is any one of PR, CR, PFS, DFS, OR, or OS, as assessed by the RECIST 1.1 response criteria. The treatment plan of the combination of the present invention that effectively treats cancer patients can vary depending on various factors, such as the patient's disease state, age, weight, and the ability of the therapy to induce an anti-cancer response in the subject. An embodiment of the present invention may not achieve an effective positive treatment effect in each subject, but should achieve an effective positive treatment effect in a statistically significant number of subjects.

[0091] The terms "method of administration" and "dosage regimen" may be used interchangeably and refer to the dosage and timing of each therapeutic agent in the combination of the present invention.

[0092] The term "immunohistochemistry (IHC)" refers to a method that utilizes the principle of specific binding between antigens and antibodies to detect antigens (polypeptides and proteins) in tissue cells by chemically reacting with a coloring agent (fluorescein, enzyme, metal ion, isotope) labeled with an antibody to develop color, and then perform localization, qualitative, and relative quantitative studies. In some embodiments of the present invention, PD-L1 detection is performed on the tumor tissue sample of the subject before treatment with an anti-PD-1 antibody, and the detection is performed by staining experiments with Roche's anti-human PD-L1 antibody SP142 (Cat No: M4422). In some embodiments, PD-L1 positivity is defined as a membrane staining intensity of ≥ 1% of tumor cells.

[0093] The term "biosimilar," also known as a "generic biologic" or "follow-on biologic" or "subsequent entry biologic," refers to a biological product that is a substantially identical copy of a product approved by a regulatory authority.

[0094] Each aspect of the invention is described in further detail in the following paragraphs.

[0095] Anti-PD-1 antibody As used herein, an "anti-PD-1 antibody" refers to any chemical compound or biological molecule that binds to PD-1 and blocks the binding between PD-L1 expressed on cancer cells and PD-1 expressed on immune cells (T, B, NK cells), and preferably also blocks the binding between PD-L2 expressed on cancer cells and PD-1 expressed on immune cells. Synonyms or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1, PDCD1L1, PDL1, B7-H1, B7H1, B7-4, CD274, and B7-H for PD-L1, and PDCD1L2, PDL2, B7-DC, and CD273 for PD-L2. In any of the therapeutic methods, medicaments and uses of the invention for treating a human individual, the PD-1 antibody blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD1. The human PD-1 amino acid sequence can be found at NCBI Locus No. NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI Locus No. NP_054862 and NP_079515, respectively.

[0096] As used herein, when referring to an "anti-PD-1 antibody," unless otherwise explained or indicated, the term includes antigen-binding fragments thereof.

[0097] The anti-PD-1 antibody applied in any of the uses, therapies, drugs, and reagent kits described in the present invention binds to PD-1 with high specificity and high affinity, blocks the binding of PD-L1 / 2 to PD-1, and inhibits PD-1 signal transduction, thereby achieving an immunosuppressive effect. In any of the uses, therapies, drugs, and reagent kits disclosed herein, the anti-PD-1 antibody includes the full-length antibody itself and an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of the full Ab in inhibiting ligand binding and upregulating the immune system. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is an anti-PD-1 antibody or antigen-binding fragment thereof that cross-competes with toripalimab to bind to human PD-1. In other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is a chimeric, humanized, or human Ab or antigen-binding fragment thereof. In some embodiments for treating a human individual, the Ab is a humanized Ab.

[0098] In some embodiments, the anti-PD-1 antibody used in any of the uses, therapies, medicaments, and reagent kits described in the present invention comprises a monoclonal antibody (mAb) or an antigen-binding fragment thereof, which specifically binds to PD-1, and preferably specifically binds to human PD-1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may comprise a human constant region. In some embodiments, the constant region is selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4 constant regions, and preferably, the anti-PD-1 antibody or antigen-binding fragment thereof applied in any of the uses, therapies, medicaments, and reagent kits described in the present invention comprises a heavy chain constant region of a human IgG1 or IgG4 isotype, more preferably a human IgG4 constant region. In some embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises a S228P mutation replacing a serine residue in the hinge region with a proline residue normally present at the corresponding position in IgG1 isotype antibodies, and the light chain constant region is selected from the light chain constant region of a lambda light chain or a kappa light chain.

[0099] Preferably, in any one embodiment of the uses, therapies, medicaments, and reagent kits described in the present invention, the PD-1 antibody is a monoclonal antibody or an antigen-binding fragment thereof, whose light chain CDRs are the amino acids set forth in SEQ ID NOs: 1, 2, and 3, and whose heavy chain CDRs are the amino acids set forth in SEQ ID NOs: 4, 5, and 6.

[0100] More preferably, in any one of the embodiments of the uses, therapies, medicaments, and reagent kits described in the present invention, the PD-1 antibody is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a light chain variable region as set forth in SEQ ID NO:7, and (b) a heavy chain variable region as set forth in SEQ ID NO:8.

[0101] More preferably, in any one of the embodiments of the uses, therapies, medicaments, and reagent kits described in the present invention, the PD-1 antibody is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a light chain as set forth in SEQ ID NO:9, and (b) a heavy chain as set forth in SEQ ID NO:10.

[0102] Table A below provides the amino acid sequence numbers of the light chain CDRs and heavy chain CDRs of exemplary anti-PD-1 antibody mAbs for use in the uses, therapies, medicaments and reagent kits described in the present invention.

[0103] [Table 1]

[0104] SEQ ID NO:7 DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIK

[0105] SEQ ID NO:8 QGQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAREGITTVATTYYWYFDVWGQGTTVTVSS

[0106] SEQ ID NO:9 DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0107] SEQ ID NO:10 QGQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAREGITTVATTYYWYFD VWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0108] Examples of anti-PD-1 antibodies that bind to human PD-1 and can be used in the uses, therapies, medicaments and reagent kits described in the present invention are described in WO2014206107. In the uses, therapies, the drugs, and the reagent kits described in the present invention, the human PD-1 mAb usable as the anti-PD-1 antibody includes any one of the anti-PD-1 antibodies described in WO2014206107, which includes Toripalimab, a humanized IgG4 mAb having a structure described in (WHO Drug Information (Vol. 32, Phase 2, pp. 372-373 (2018)) and comprising the light chain and heavy chain amino acid sequences shown in SEQ ID NOs: 9 and 10. In a preferred embodiment, the anti-PD-1 antibody usable in any one of the uses, therapies, the drugs, and the reagent kits described in the present invention is selected from humanized antibodies 38, 39, 41, and 48 described in WO2014206107. In a particularly preferred embodiment, the anti-PD-1 antibody usable in any one of the uses, therapies, the drugs, and the reagent kits described in the present invention is Toripalimab.

[0109] Anti-PD-1 antibodies that can be used in any one of the uses, therapies, drugs and reagent kits described in the present invention further include Nivolumab and Pembrolizumab, which are approved by the FDA.

[0110] In some embodiments, the anti-PD-1 antibodies that may be used in any one of the uses, therapies, drugs and reagent kits described in the present invention also include anti-PD-L1 monoclonal antibodies that specifically bind to PD-L1 and block the binding of PD-L1 to PD-1, such as Nivolumab or its biosimilar, Pembrolizumab or its biosimilar, Toripalimab or its biosimilar, Sintilimab or its biosimilar, Camrelizumab or its biosimilar, Tislelizumab or its biosimilar, Cemiplimab or its biosimilar, Zimberelimab or its biosimilar, Penpulimab or its biosimilar, Serplulimab or its biosimilar.

[0111] "PD-L1" expression or "PD-L2" expression as used herein refers to any detectable expression level of a specific PD-L protein on the cell surface or a specific PD-L mRNA within a cell or tissue. PD-L protein expression can be detected in IHC analysis of tumor tissue sections using diagnostic PD-L antibodies or by flow cytometry. Alternatively, PD-L protein expression in tumor cells can be detected by PET imaging with binding agents that specifically bind to the desired PD-L target (e.g., PD-L1 or PD-L2).

[0112] Methods used to quantify PD-L1 protein expression in IHC analysis of tumor tissue sections include, but are not limited to, Thompson, RH et al., PNAS 101(49):17174-17179 (2004); Taube, JM et al., Sci Transl Med 4, 127ra37 (2012); and Toplian, SL et al., New Eng. J. Med. 366(26):2443-2454 (2012).

[0113] One approach employs a simple binary endpoint of positive or negative PD-L1 expression, where a positive result is defined as the percentage of tumor cells that show histological evidence of cell surface membrane staining.Tumor tissue sections in which at least 1% of total tumor cells are counted are defined as positive for PD-L1 expression.

[0114] Another method quantifies PD-L1 expression in tumor tissue sections on tumor cells and on infiltrating immune cells. The percentage of tumor cells and infiltrating immune cells that show membrane staining is quantified separately as <1%, 1%-50%, and then 50%-100%. For tumor cells, a score of <1% counts PD-L1 expression as negative, and a score of ≥1% counts as positive.

[0115] In some embodiments, the level of PD-L1 expression by malignant cells and / or infiltrating immune cells within a tumor is determined to be "overexpressed" or "elevated" based on comparison with the level of PD-L1 expression by an appropriate control. For example, the control PD-L1 protein or mRNA expression level may be the level quantified in non-malignant cells of the same type, or in sections from matched normal tissue.

[0116] Anti-EGFR antibody As used herein, an "anti-EGFR antibody" refers to any chemical compound or biological molecule that binds to EGFR and inhibits the binding of EGF to EGFR. EGFR is also known as ERBB1 or HER1, and has a Gene ID number of 1956, and corresponding protein numbers include NP_001333826.1, NP_001333827.1, NP_001333828.1, NP_001333829.1, NP_001333870.1, NP_005219.2, NP_958439.1, NP_958440.1, and NP_958441.1.

[0117] As used herein, when referring to an "anti-EGFR antibody," unless otherwise explained or indicated, the term includes antigen-binding fragments thereof.

[0118] The anti-EGFR antibody applied to any of the uses, therapies, drugs, and reagent kits described in the present invention binds to EGFR with high specificity and high affinity, blocks the binding of EGFR to EGF, and then inhibits the biological actions of EGFR, including influencing vascular permeability, proliferation, and endothelial cell migration and survival, thereby achieving the effect of inhibiting tumor vascular angiogenesis, growth, and metastasis. In any of the uses, therapies, drugs, and reagent kits disclosed herein, the anti-EGFR antibody includes a full-length antibody itself and an antigen-binding portion or fragment that binds to the EGFR receptor and exhibits functional properties similar to those of a complete Ab in inhibiting ligand binding and inhibiting vascular endothelial cell proliferation and activation. In some embodiments, the anti-EGFR antibody or antigen-binding fragment thereof is an anti-EGFR antibody or antigen-binding fragment thereof that cross-competes with cetuximab and binds to human EGFR. In other embodiments, the anti-EGFR antibody or antigen-binding fragment thereof is a chimeric, humanized, or human Ab or antigen-binding fragment thereof. In some embodiments for treating a human individual, the Ab is a humanized Ab.

[0119] In some embodiments, the anti-EGFR antibody used in any of the uses, therapies, drugs and reagent kits described in the present invention comprises a monoclonal antibody (mAb) or an antigen-binding fragment thereof, specifically binds to EGFR, and preferably specifically binds to human EGFR. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may comprise a human constant region. In some embodiments, the heavy chain constant region is selected from the group consisting of human IgG1, IgG2, IgG3 and IgG4 heavy chain constant regions, and preferably, the anti-EGFR antibody or an antigen-binding fragment thereof applied in any of the uses, therapies, drugs and reagent kits described in the present invention comprises a heavy chain constant region of a human IgG1 or IgG4 isotype, more preferably a human IgG1 heavy chain constant region, and the light chain constant region is selected from a light chain constant region of a λ light chain or a κ light chain, preferably a κ light chain.

[0120] Preferably, in any one of the embodiments of the uses, therapies, drugs and reagent kits described in the present invention, the EGFR antibody is a monoclonal antibody or an antigen-binding fragment thereof, whose light chain CDRs are the amino acids set forth in SEQ ID NOs: 11, 12 and 13 and whose heavy chain CDRs are the amino acids set forth in SEQ ID NOs: 14, 15 and 16.

[0121] More preferably, in any one of the embodiments of the uses, therapies, drugs and reagent kits described in the present invention, the EGFR antibody is a monoclonal antibody that specifically binds to human EGFR and comprises (a) a light chain variable region as shown in SEQ ID NO: 17 and (b) a heavy chain variable region as shown in SEQ ID NO: 18.

[0122] More preferably, in any one of the embodiments of the uses, therapies, drugs and reagent kits described in the present invention, the EGFR antibody is a monoclonal antibody that specifically binds to human EGFR and comprises (a) a light chain as shown in SEQ ID NO: 19 and (b) a heavy chain as shown in SEQ ID NO: 20.

[0123] Table B below provides the amino acid sequence numbers of the light and heavy chain CDRs of exemplary anti-EGFR antibody mAbs for use in the uses, therapies, medicaments and reagent kits described in the present invention.

[0124] [Table 2]

[0125] SEQ ID NO:17 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK

[0126] SEQ ID NO:18 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA

[0127] SEQ ID NO:19 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0128] SEQ ID NO:20 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQG TLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0129] In the uses, therapies, drugs, and reagent kits described in the present invention, the human EGFR mAb usable as an anti-EGFR antibody includes Cetuximab, a humanized IgG1 mAb comprising the amino acid sequences of light and heavy chains shown in SEQ ID NOs: 19 and 20. In a preferred embodiment, the anti-EGFR antibody usable in any one of the uses, therapies, drugs, and reagent kits described in the present invention is one or more selected from Necitumumab or a biosimilar thereof, Nimotuzumab or a biosimilar thereof, Panitumumab or a biosimilar thereof, and Cetuximab or a biosimilar thereof. In a particularly preferred embodiment, the anti-EGFR antibody usable in any one of the uses, therapies, drugs, and reagent kits described in the present invention is Cetuximab.

[0130] Anti-EGFR antibodies that can be used in any one of the uses, therapies, drugs and reagent kits described in the present invention further include Necitumumab or a biosimilar thereof, Nimotuzumab or a biosimilar thereof, Panitumumab or a biosimilar thereof, Cetuximab or a biosimilar thereof.

[0131] Drug Combinations The present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof. In the pharmaceutical combination, the anti-PD-1 antibody and the anti-EGFR antibody are provided in the form of a mixture of the two (i.e., in the form of a pharmaceutical composition) or in the form of separate formulations. In some embodiments, each pharmaceutical combination comprises one dose of an anti-PD-1 antibody or antigen-binding fragment thereof described herein and three doses of an anti-EGFR antibody or antigen-binding fragment thereof described herein, and the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are provided in the form of separate formulations.

[0132] In some embodiments, the anti-PD-1 antibody of the present invention may be as described in any one of the embodiments herein, more preferably an antibody whose light chain CDRs are the amino acids set forth in SEQ ID NOs: 1, 2, and 3, and whose heavy chain CDRs are the amino acids set forth in SEQ ID NOs: 4, 5, and 6, more preferably a monoclonal antibody comprising a light chain variable region set forth in SEQ ID NO: 7 and a heavy chain variable region set forth in SEQ ID NO: 8, even more preferably a monoclonal antibody comprising a light chain set forth in SEQ ID NO: 9 and a heavy chain set forth in SEQ ID NO: 10, even more preferably humanized antibodies 38, 39, 41, and 48 described in WO2014206107, and most preferably toripalimab or a biosimilar thereof.

[0133] In some embodiments, the anti-EGFR antibody according to the present invention may be as described in any one of the embodiments herein, more preferably an antibody having a light chain CDR of the amino acids set forth in SEQ ID NOs: 11, 12 and 13 and a heavy chain CDR of the amino acids set forth in SEQ ID NOs: 14, 15 and 16, more preferably a monoclonal antibody comprising a light chain variable region set forth in SEQ ID NO: 17 and a heavy chain variable region set forth in SEQ ID NO: 18, even more preferably a monoclonal antibody comprising a light chain set forth in SEQ ID NO: 19 and a heavy chain set forth in SEQ ID NO: 20, and most preferably cetuximab or a biosimilar thereof.

[0134] As described in the present invention, a "pharmaceutical acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Preferably, the carrier applied to the composition comprising an anti-PD-1 antibody or an anti-EGFR antibody is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration. The pharmaceutical composition of the present invention may include one or more pharmaceutical acceptable salts, antioxidants, water, non-aqueous carriers, and / or adjuvants such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents.

[0135] The content of the anti-cancer active ingredients (anti-PD-1 antibody and anti-EGFR antibody described herein) in each dose of the drug of the present invention is usually the amount of each of these anti-cancer active ingredients in a single administration. For example, for a fixed dose of 240 mg of the anti-PD-1 antibody described herein each time, each dose of the drug may contain 240 mg of the anti-PD-1 antibody. Of course, for example, in the case of oral tablets, 240 mg of the anti-PD-1 antibody can be divided into two or more tablets, as long as all of these tablets are taken to reach a dose of 240 mg when taken. About 250 mg / m 2 For an anti-EGFR antibody administered at a dose of 250 mg / m2, the content of the anti-EGFR antibody in each dose of the drug is 250 mg / m2. 2 The dosage should be sufficient to allow administration to a body surface area of ​​about 100 mg / kg of the subject's body.

[0136] The amounts of the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof contained in the drug combinations herein satisfy the administration in the treatment or prevention methods described herein. Specifically, the amounts of the anti-PD-1 antibody or antigen-binding fragment thereof contained in the drug combinations described herein satisfy an administration frequency of about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per three weeks, and the amounts of the anti-EGFR antibody or antigen-binding fragment thereof satisfy an administration frequency of about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per week. Preferably, in the drug combinations described herein, the amount of the anti-PD-1 antibody or antigen-binding fragment thereof satisfies a single dose of about 0.1 mg / kg to about 10.0 mg / kg of individual body weight, preferably about 1.0 mg / kg to about 10.0 mg / kg of individual body weight, for example about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg or about 10 mg / kg of individual body weight, or a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, for example a fixed dose of about 120 mg, about 240 mg, about 360 mg or about 480 mg, preferably a fixed dose of about 240 mg; and the amount of the anti-EGFR antibody or antigen-binding fragment thereof satisfies a single dose of about 100 mg / m 2 ~about 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~about 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 , preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m2 , about 350mg / m 2 or about 400 mg / m 2 of individual body surface area for a single dose.

[0137] In some embodiments, the drug combination comprises one dose of an anti-PD-1 antibody or antigen-binding fragment thereof described herein and three doses of an anti-EGFR antibody or antigen-binding fragment thereof described herein, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are provided in the form of separate formulations, wherein the one dose of the anti-PD-1 antibody or antigen-binding fragment thereof formulation comprises 240 mg of the anti-PD-1 antibody or antigen-binding fragment thereof, and in the three doses of the anti-EGFR antibody or antigen-binding fragment thereof formulation, the anti-EGFR antibody or antigen-binding fragment thereof in one dose of the formulation comprises 400 mg / m 2 of individual body surface area per day, and two more doses of 250 mg / m 2 In some other embodiments, each of the three doses of the anti-EGFR antibody or antigen-binding fragment thereof formulation contains an anti-EGFR antibody or antigen-binding fragment thereof at a daily dose of at least 250 mg / m 2 of individual body surface area. Preferably, the anti-PD-1 antibody is Toripalimab and the anti-EGFR antibody is Cetuximab.

[0138] Dosage and Administration Regimens The choice of dosing schedule (also referred to herein as dosing schedule) of the drug combination of the present invention depends on several factors, including the serum or tissue turnover rate of the individual being treated, the symptom level, the overall immunogenicity and the accessibility of the target cells, tissues or organs. Preferably, the dosing schedule maximizes the amount of each therapeutic agent delivered to the patient and is consistent with an acceptable level of side effects. Thus, the dose and frequency of administration of each biological and chemical therapeutic agent depends in part on the specific therapeutic agent, the severity of the cancer being treated and the characteristics of the patient. Guidance is available for selecting the appropriate dose of antibodies, cytokines and small molecules. For example, Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK, Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY, Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY, Baert et al. (2003) New Engl. J. Med.348:601-608, Milgrom et al. (1999) New Engl. J. Med.341:1966-1973, Slamon et al. (2001) New Engl. J. Med.344:783-792, Beniaminovitz et al. (2000) New See Engl. J. Med. 342:613-619, Ghosh et al. (2003) New Engl. J. Med. 348:24-32, Lipsky et al. (2000) New Engl. J. Med. 343:1594-1602, Physicians' Desk Reference 2003 (Physicians' Desk Reference, 57th Ed), Medical Economics Company, ISBN: 1563634457, 57th edition (November 2002).The determination of an appropriate dosing regimen can be made by the clinician, for example, by reference to parameters or factors known or suspected in the art to affect or be expected to affect treatment, and will depend, for example, on the patient's clinical history (e.g., previous treatments), the type and stage of the cancer being treated, and biomarkers responsive to one or more therapeutic agents in the combination therapy.

[0139] Each therapeutic agent of the drug combination of the invention may be administered simultaneously (i.e., in the same pharmaceutical composition), concurrently (i.e., administered one after the other in any order as a single drug formulation), or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the drug combination are administered in different dosage forms (one drug is a tablet or capsule and the other drug is a sterile liquid formulation) and / or on different administration schedules (e.g., the chemotherapeutic agent is administered at least daily and the biological therapeutic agent is administered relatively infrequently (e.g., once a week, once every two weeks, or once every three weeks)).

[0140] In some embodiments, at least one therapeutic agent in the drug combination is administered using the same dosing regimen (therapeutic dose, frequency and duration) as would normally be used if the agent were used as a monotherapy to treat the same tumor. In other embodiments, the patient receives a lower total amount, e.g., a lower dose, a less frequent dose and / or a shorter duration of treatment, of at least one therapeutic agent in the combination therapy than if the agent were used as a monotherapy.

[0141] Each therapeutic agent in the drug combination of the present invention can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical and transdermal routes.

[0142] The anti-PD-1 antibodies of the present invention can be administered by continuous infusion or at interval doses, with the single dose ranging from about 0.01 to about 20.0 mg / kg of individual body weight, about 0.1 to about 10.0 mg / kg of individual body weight, about 1.0 to about 10.0 mg / kg of individual body weight, or a fixed dose of about 120 mg to about 480 mg, or a fixed dose of about 120 mg to about 360 mg. For example, the dose can be about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, or about 10 mg / kg of individual body weight, or a fixed dose of about 120 mg, about 240 mg, about 360 mg, or about 480 mg. Typically, the dosing regimen is designed to achieve an exposure that results in sustained receptor occupancy (RO) based on the typical pharmacokinetic properties of the Ab. Exemplary dosing regimens may be administration about once per week, about once every two weeks, about once every three weeks, about once every four weeks, about once per month, or more frequently. In some embodiments, the anti-PD-1 antibody is administered to an individual about once every three weeks.

[0143] In some embodiments, the anti-PD-1 antibody of the present invention is toripalimab, the single dose of which is selected from about 1.0 to about 10.0 mg / kg of individual body weight, a fixed dose of about 120 mg to about 480 mg, or a fixed dose of about 120 mg to about 360 mg. In some embodiments, the single dose of toripalimab is selected from doses of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, and about 5 mg / kg of individual body weight, or a fixed dose of about 120 mg, about 240 mg, and about 360 mg, administered intravenously. In some preferred embodiments, toripalimab is administered as a liquid drug, infused intravenously at the selected dose of drug, with the administration time being at least 30 minutes, e.g., about 60 minutes. In some embodiments, toripalimab is infused intravenously once every three weeks (Q3W) at a dose of about 3 mg / kg individual body weight or a fixed dose of about 240 mg, with an administration time of at least 30 minutes, e.g., about 60 minutes.

[0144] The anti-EGFR antibodies of the invention can be administered by continuous infusion or in interval doses, with single doses ranging from about 100 mg / m 2~about 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~about 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 , preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 or about 400 mg / m 2 of an individual's body surface area. Typically, the dosing regimen is designed to achieve an exposure that results in sustained receptor occupancy (RO) based on the typical pharmacokinetic properties of the Ab. Exemplary dosing regimens may be administration about once per week, about once per two weeks, about once per three weeks, about once per four weeks, about once per month, or more. In some embodiments, the anti-EGFR antibody is administered to the individual about once per week. In some embodiments, the initial dose of anti-EGFR antibody administered is 300 mg / m 2 of individual body surface area or more, and the dose administered thereafter is 250 mg / m 2 The individual body surface area is equal to or greater than that of the individual.

[0145] In some embodiments, the anti-EGFR antibody of the invention is cetuximab, and the single dose is about 100 mg / m 2 ~about 500mg / m 2 of individual body surface area, or approximately 200 mg / m 2 ~about 500mg / m 2 In some embodiments, a single dose of cetuximab is about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 The dose is selected from a range of doses per unit body surface area and administered intravenously. In some preferred embodiments, cetuximab is administered as a liquid drug and infused intravenously at the selected dose of drug over a period of at least 15 minutes, e.g., about 30 minutes. In some embodiments, cetuximab is administered at a dose of about 250 mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 The dose is administered intravenously once a week (QW) at a dose of 300 mg / m2 of individual body surface area over a period of at least 15 minutes, e.g., about 30 minutes. In some embodiments, the first dose of cetuximab administered is 300 mg / m2. 2 of individual body surface area (e.g., initial dose of 400 mg / m 2 of individual body surface area), and each subsequent dose was 250 mg / m 2 of individual body surface area or more (e.g., subsequent doses are 250 mg / m 2 of individual body surface area or 200 mg / m 2 (The individual body surface area of ​​the animal.)

[0146] In some embodiments, toripalimab is administered alone.

[0147] In some embodiments, in each dosing cycle, toripalimab is administered first, followed by cetuximab, either on the same day or within 3 days of each other.

[0148] In some embodiments, toripalimab is administered at a fixed dose of about 240 mg Q3W and cetuximab is administered at a fixed dose of about 250 mg / m 2 or about 400 mg / m 2The dose is administered QW per individual body surface area.

[0149] The dosing cycles of the anti-PD-1 antibody and anti-EGFR antibody of the present invention may be the same or different, and may be 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, half a year, 1 year, 2 years or more, and optionally the duration of each dosing cycle may be the same or different, and the interval between each dosing cycle may be the same or different. For example, in some embodiments, toripalimab is administered at a fixed dose of about 240 mg once every 3 weeks, and cetuximab is administered at a fixed dose of about 250 mg / m 2 or about 400 mg / m 2 The dose is administered once a week at a dose of 100 mg / kg / day for an individual body surface area.

[0150] In some embodiments, toripalimab is administered at a fixed dose of about 240 mg every three weeks and cetuximab is administered at an initial dose of about 400 mg / m 2 of individual body surface area, and each dose is approximately 250 mg / m 2 of individual body surface area once weekly, preferably with cetuximab administered at least about 60 minutes after toripalimab is administered.

[0151] Treatment Methods and Uses The present invention relates to the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC), or the use of a combination of an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-EGFR antibody or an antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma. Preferably, said combination is a combination of drugs as described in any one of the embodiments herein.

[0152] The present invention also relates to a method for preventing or treating head and neck squamous cell carcinoma, comprising administering to an individual in need thereof an effective amount of an anti-PD-1 antibody, or antigen-binding fragment thereof, or a combination of an anti-PD-1 antibody, or antigen-binding fragment thereof, and an anti-EGFR antibody, or antigen-binding fragment thereof. Preferably, the anti-PD-1 antibody, or antigen-binding fragment thereof, and the anti-EGFR antibody, or antigen-binding fragment thereof, are administered at the doses and dosing schedules described in any one of the embodiments herein.

[0153] The present invention also relates to an anti-PD-1 antibody or antigen-binding fragment thereof, or a combination of an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof for preventing or treating head and neck squamous cell carcinoma, preferably the combination being a drug combination as described in any one of the embodiments herein.

[0154] The head and neck squamous cell carcinoma may be as described in any one of the above embodiments, and preferably, the head and neck squamous cell carcinoma is a recurrent or metastatic head and neck squamous cell carcinoma, preferably a recurrent or metastatic head and neck squamous cell carcinoma that has previously failed a first-line platinum-containing chemotherapy regimen.Furthermore, the head and neck squamous cell carcinoma has ≧1 measurable lesion according to RECIST v1.1 criteria.

[0155] A preferred anti-PD-1 antibody for use in head and neck squamous cell carcinoma may be as described in any one of the embodiments herein, more preferably an antibody whose light chain CDRs are the amino acids set forth in SEQ ID NOs: 1, 2, and 3, and whose heavy chain CDRs are the amino acids set forth in SEQ ID NOs: 4, 5, and 6, more preferably a monoclonal antibody comprising a light chain variable region set forth in SEQ ID NO: 7 and a heavy chain variable region set forth in SEQ ID NO: 8, even more preferably a monoclonal antibody comprising a light chain set forth in SEQ ID NO: 9 and a heavy chain set forth in SEQ ID NO: 10, even more preferably humanized antibodies 38, 39, 41, and 48 described in WO2014206107, and most preferably toripalimab or a biosimilar thereof.

[0156] A preferred anti-EGFR antibody for use in head and neck squamous cell carcinoma may be as described in any one of the embodiments herein, more preferably an antibody having a light chain CDR with amino acids set forth in SEQ ID NOs: 11, 12 and 13 and a heavy chain CDR with amino acids set forth in SEQ ID NOs: 14, 15 and 16, more preferably a monoclonal antibody comprising a light chain variable region set forth in SEQ ID NO: 17 and a heavy chain variable region set forth in SEQ ID NO: 18, even more preferably a monoclonal antibody comprising a light chain set forth in SEQ ID NO: 19 and a heavy chain set forth in SEQ ID NO: 20, preferably cetuximab or a biosimilar thereof.

[0157] The preferred anti-PD-1 antibody for use in head and neck squamous cell carcinoma is Toripalimab or a biosimilar thereof, and the preferred anti-EGFR antibody is Cetuximab or a biosimilar thereof.

[0158] More preferably, the anti-PD-1 antibody is Toripalimab and the anti-EGFR antibody is Cetuximab for use in head and neck squamous cell carcinoma.

[0159] kit The present invention further provides a kit comprising one or more single pharmaceutical dosage units of an anti-PD-1 antibody or antigen-binding fragment thereof, preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is as described in any one of the embodiments herein, more preferably, the anti-PD-1 antibody is Toripalimab or a biosimilar kit thereof.

[0160] In some embodiments, the kits of the invention comprise one or more single pharmaceutical dosage units of an anti-PD-1 antibody or antigen-binding fragment thereof and one or more single pharmaceutical dosage units of an anti-EGFR antibody or antigen-binding fragment thereof, preferably wherein the anti-PD-1 antibody or antigen-binding fragment thereof is as described in any one of the embodiments herein, and preferably wherein the anti-EGFR antibody or antigen-binding fragment thereof is as described in any one of the embodiments herein.

[0161] In some embodiments, the kit of the invention comprises Toripalimab or a biosimilar thereof and Cetuximab or a biosimilar thereof as the anti-cancer active agents in the kit.

[0162] The anti-cancer active ingredients in the kit can be provided independently. For example, the kit may include one or more single-dose units of an anti-PD-1 antibody or an antigen-binding fragment thereof (preferably Toripalimab) and an anti-EGFR antibody or an antigen-binding fragment thereof (preferably Cetuximab). Preferably, the amount of the anti-PD-1 antibody or an antigen-binding fragment thereof contained in the single-dose unit is a fixed dose of about 120 mg to about 480 mg, for example, about 120 mg, about 240 mg, about 360 mg or about 480 mg, preferably about 240 mg, and the amount of the anti-EGFR antibody or an antigen-binding fragment thereof contained in the single-dose unit is about 100 mg / m 2 ~about 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~about 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2of individual body surface area, preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 or about 400 mg / m 2 A single dose of about 100 mg / kg of solid body surface area is sufficient to be administered to the patient.

[0163] In some embodiments, the kit of the invention comprises one drug combination described in any one of the embodiments herein, wherein the drug combination comprises one dose of an anti-PD-1 antibody (preferably Toripalimab) or antigen-binding fragment thereof and three doses of an anti-EGFR antibody (preferably Cetuximab) or antigen-binding fragment thereof, wherein the one dose of the formulation of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 240 mg of the anti-PD-1 antibody or antigen-binding fragment thereof, and in the three doses of the formulation of the anti-EGFR antibody or antigen-binding fragment thereof, the one dose of the formulation comprises 400 mg / m 2 of individual body surface area per day, and two more doses of 250 mg / m 2 or the anti-EGFR antibody or antigen-binding fragment thereof contained in each of the three doses of the formulation satisfies daily administration of 250 mg / m 2 of individual body surface area per day.

[0164] In some embodiments, the drug combination comprises two or more drug combinations described in any one of the embodiments herein, wherein each drug combination comprises one dose of an anti-PD-1 antibody or antigen-binding fragment thereof described herein (preferably Toripalimab) or antigen-binding fragment thereof and three doses of an anti-EGFR antibody or antigen-binding fragment thereof described herein (preferably Cetuximab) or antigen-binding fragment thereof, and wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are provided in the form of separate formulations, wherein in one combination, the one dose of the anti-PD-1 antibody or antigen-binding fragment thereof formulation comprises 240 mg of the anti-PD-1 antibody or antigen-binding fragment thereof and in the three doses of the anti-EGFR antibody or antigen-binding fragment thereof formulation, the one dose of the anti-EGFR antibody or antigen-binding fragment thereof comprises 400 mg / m 2 of individual body surface area per day, and two more doses of 250 mg / m 2 and each of the three doses of the anti-EGFR antibody or antigen-binding fragment thereof in the other combinations satisfies daily administration of 250 mg / m of individual body surface area. 2 of individual body surface area per day.

[0165] Abbreviation The following abbreviations are used in the present specification and examples:

[0166] CDR Complementarity Determining Region DFS disease-free survival DOR Duration of response ECOG Eastern Cooperative Oncology Group FR Framework Area IgG Immunoglobulin G IHC immunohistochemistry OR Overall Response ORR Objective Response Rate OS overall survival mOS mean overall survival PD Disease Progression PFS Progression-free survival mPFS Mean progression-free survival PR Partial Response CR Complete Response SD Stable disease DLT dose-limiting toxicity MTD maximum capacity AE Adverse Event QW Once a week dose Q3W: once every 3 weeks QD once daily dose IRC Independent Review Committee TRAE Treatment-Related Adverse Events irAE immune-related adverse events SAE Serious Adverse Event RO Receptor Occupancy HNSCC Head and neck squamous cell carcinoma RECIST: Evaluation of Treatment Response in Solid Tumors iRECIST: Improved Response Evaluation Criteria for Immune-Related Solid Tumors irRECIST Response Evaluation Criteria for Immune-Related Solid Tumors mRECIST: Improved Response Evaluation Criteria for Solid Tumors imRECIST immune-modified response evaluation criteria in solid tumors DOR Duration of response MSI Microsatellite Instability CI Confidence Interval DCR Disease control rate TTP Time to disease progression HNSCC Head and neck squamous cell carcinoma CPS Binding Positive Score

[0167] The present invention is further illustrated by the following examples, which should not be construed as limiting the invention. The contents of all references cited throughout this specification are expressly incorporated herein by reference.

[0168] Working Example Example 1: Treatment of recurrent or metastatic HNSCC after failure of first-line platinum-containing chemotherapy with a combination of anti-PD-1 and anti-EGFR antibodies 1.1 Research design This study was an open-label, multicenter clinical phase Ib / II study, where the phase Ib study phase was mainly used to evaluate the safety of the combination of toripalimab and cetuximab in the treatment of recurrent or metastatic HNSCC that has failed chemotherapy with a first-line platinum-containing regimen and to determine the phase II recommended dose (RP2D), and the phase II study phase was divided into two cohorts, i.e., cohort A was mainly used to evaluate the efficacy and safety of the combination regimen in the treatment of recurrent or metastatic HNSCC that has failed chemotherapy with a first-line platinum-containing regimen, and cohort B was mainly used to evaluate the efficacy and safety of the combination regimen in the treatment of PD-L1-positive HNSCC that has not previously received systemic treatment for recurrent or metastatic disease. The cohort of the phase II study of the present invention was cohort A.

[0169] The test drugs were the anti-PD-1 antibody toripalimab injection (supplied by Suzhou Zhonghe Biopharmaceutical Technology Co., Ltd., specification 240 mg / 6 ml / bottle) and cetuximab injection (supplied by Merck, Germany, specification 100 mg / 20 ml / bottle).

[0170] The study included a screening period, a treatment period, and a follow-up period. The screening period did not exceed 28 days, and after completing the tests and evaluations of the screening period, eligible subjects entered the study treatment period. Subjects should receive the study treatment according to the protocol until the occurrence of radiologically documented disease progression as determined by the investigator according to RECIST 1.1 criteria, intolerable toxic reactions, the subject voluntarily requesting to discontinue study treatment or withdrawing informed consent, or the investigator determines that discontinuation of treatment is necessary, or until the maximum treatment time of 2 years of toripalimab has been reached (whichever occurs first).

[0171] Safety data were collected continuously throughout the study. Safety and tolerability were assessed according to the NCI-CTCAE v5.0 criteria to determine the incidence and severity of adverse events. Laboratory tests, vital signs, ECOG scores, physical examinations, ECGs, and adverse events were continuously evaluated throughout the study.

[0172] Subjects were assessed for tumor assessment at screening (as baseline), once every 6 weeks (± 7 days) from first dose during the first 12 months, and once every 9 weeks (± 7 days) thereafter until radiologically documented disease progression (PD), iCPD (initial radiological evidence of disease progression but subjects able to continue treatment at the investigator's discretion) as determined by the investigator according to iRECIST, withdrawal of informed consent, loss to follow-up, initiation of new antitumor treatment, or study termination. If subjects were withdrawn from the group for reasons other than disease progression (including withdrawal from the group due to AEs or exceeding the treatment interval) and disease progression had not occurred at the time of withdrawal from the group, radiological assessments were required to continue until disease progression, death, loss to follow-up, or initiation of new antitumor treatment. Subjects were managed for treatment based on the results of the investigator's tumor assessment.

[0173] Phase Ib study design In the Ib study, enrolled subjects received 240 mg of toripalimab intravenously every 3 weeks. Subjects were also required to receive cetuximab intravenously every week, with the first dose of 400 mg / m 2 and the remainder of the first cycle and subsequent cycles are 250 mg / m 2 (Alternative dose is 200 mg / m 2 ) One treatment cycle was given every 3 weeks, and on the first day of each cycle, toripalimab treatment was given first, followed by cetuximab treatment after about 60 minutes of observation. The specific dosage is shown in the table below.

[0174] [Table 3]

[0175] Initially, 6 subjects were enrolled and received the initial dose with the first treatment cycle (21 days) as a tolerance observation period. If <2 subjects showed DLT, 6 more subjects were enrolled (total 12 subjects) to collect sufficient combination therapy safety and PK data. The Safety Management Committee (SMC) decided whether to recommend the dose for Phase II based on the safety, PK, and other data of the 12 subjects.

[0176] If ≥2 subjects in the first 6 subjects showed DLT, the dose was adjusted to the alternative dose, and further enrollment and observation were performed according to the enrollment plan.If ≥2 subjects in the first 6 subjects in the alternative dose group showed DLT, SMC decided to study another dose level / administration cycle according to the safety, PK, etc. data obtained.

[0177] Phase II research design Participants in the Phase II study phase were treated with the combination of toripalimab and cetuximab at the RP2D determined in the Phase Ib phase until radiologically documented disease progression as determined by the investigator using RECIST 1.1 criteria, intolerable toxicities, the patient spontaneously requested to discontinue study treatment or withdraw informed consent, or the investigator deemed necessary to discontinue treatment, or the maximum 2-year treatment time for toripalimab was reached (whichever occurred first). The number of participants planned to be enrolled in this phase included 12 subjects at the same dose in the Phase Ib phase.

[0178] 1.2 Registration Standards and Conditions Registration Standard: 1. The patient voluntarily participated in this study after receiving full informed consent and signed the informed consent form.

[0179] 2. Age ≥ 18 and ≤ 75 years at the time of signing the informed consent form.

[0180] 3. Histologically or cytologically confirmed recurrent or metastatic head and neck squamous cell carcinoma arising in the oral cavity, oropharynx, hypopharynx, larynx, or paranasal sinuses that is not amenable to local treatment such as surgery or radiation therapy.

[0181] 4. Phase Ib and Phase II Cohort A: Previously received first-line chemotherapy with a platinum-containing regimen for recurrent metastatic disease and progresses during or after completion of treatment, or received a platinum-containing regimen as neoadjuvant or adjuvant chemotherapy (or radiochemotherapy) and recurrence or metastasis occurs within 6 months of completing treatment.

[0182] 5. Phase II Cohort B: 1) No prior systemic treatment for recurrent or metastatic disease. Previous systemic treatment as part of local treatment and recurrence or metastasis occurring 6 months after completion of treatment.

[0183] 2) Eligible tumor tissue samples must be provided and have positive PD-L1 expression (positive defined as a Combined Positive Score (CPS) ≥ 1) detected by a central laboratory.

[0184] 6. All acute toxic reactions from previous antitumor treatments, surgery, or radiation therapy, etc., are reduced to grade 0-1 (according to NCI-CTCAE 5.0 version) or to the level specified by the inclusion / exclusion criteria. Alopecia, pigmentation, or other toxicities that the investigator believes do not pose a safety risk to the subject and do not affect treatment compliance are excluded.

[0185] 7. Able to provide a previous tumor specimen or a fresh tumor tissue biopsy sample.

[0186] 8. For oropharyngeal cancer test subjects, a report of a previous HPV16 detection or a qualifying tumor tissue sample may be provided to detect HPV status.

[0187] 9. Have at least one measurable lesion per RECIST 1.1 criteria.

[0188] 10.Expected survival is ≥ 12 weeks.

[0189] 11. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0190] 12. Organ function indicators are good.

[0191] [Table 4]

[0192] 13. Females of childbearing age must have a negative serum pregnancy test within 72 hours prior to the first dose and agree to use effective contraception while using study drug and for 60 days after the last dose. For the purposes of this protocol, females of childbearing age are defined as sexually mature females.

[0193] 1) Have not undergone a hysterectomy or bilateral oophorectomy; 2) natural cessation of menstruation has not continued for 24 consecutive months (menopause after cancer treatment does not preclude fertility) (i.e., menstruation has occurred any time within the past 24 consecutive months).

[0194] Male patients whose sexual partners are females of childbearing age must agree to use effective contraception while using study drug and for 60 days after the final dose.

[0195] Registration Status: A total of 45 patients were enrolled in the phase II cohort A study, including 35 male (77.8%) and 10 female (22.2%) patients. The age range of patients was 32-74 years, with a median age of 59 years. Eighteen patients (40%) presented with distant metastasis, and 31 patients (68.9%) had PD-L1 CPS ≥ 1.

[0196] [Table 5]

[0197] 1.3 Research content and results 1.3.1 Safety research Research method: Safety analysis was performed in the safety analysis set.

[0198] The extent of exposure to each study drug was described based on the number of cycles (number and percentage of patients) treated, duration of administration (days), cumulative total dose (mg) received by each patient, dose intensity, and a summary of relative dose intensity.

[0199] Adverse events were coded using MedDRA 25.1. The number and incidence of treatment-related adverse events (TRAEs) occurring during the treatment period were tabulated according to preferred terminology and system organ class. In addition, serious adverse events, grade 3 and above adverse events, adverse events related to the study drug, and adverse events leading to interruption or discontinuation of the study drug were correspondingly summarized. If the same event occurred multiple times, it was counted as one occurrence at the maximum severity. The table shows each type of adverse event mentioned above.

[0200] Deaths reported during the study treatment period and during the follow-up period after the end of treatment will be summarized.

[0201] Descriptive statistics were used to summarize baseline and final treatment visit measurements and relative baseline changes, including laboratory tests, physical examinations, vital signs, weight, ECOG performance status, and ECG, as well as the number and percentage of patients with abnormal changes after baseline. Measurements at each visit were tabulated.

[0202] Research results: In the Phase Ib study, no DLTs were observed, so the initial dose in the Ib study can be the recommended dose for Phase II trials. By March 15, 2023, the median follow-up time for patients in Cohort A was 9.6 months. Forty-five (100%) patients experienced TEAEs. Forty-one (91.1%) patients experienced TRAEs, the most common of which were rash (35.6%), hypomagnesemia (17.8%), hypothyroidism (17.8%), dermatitis acneiform (15.6%), and paronychia (15.6%). Ten (22.2%) patients experienced grade 3 or higher TRAEs, including oral mucositis, hypomagnesemia, decreased white blood cell count, hypokalemia, lacunar cerebral infarction, soft tissue infection, infusion-related reaction, and gastric perforation. Eleven patients (24.4%) experienced irAEs, including immune-related skin adverse reactions, hypothyroidism, dysthyroidism, duodenitis, peripheral edema, and immune-mediated arthritis. No irAEs of grade 3 or higher occurred. One patient experienced a grade 3 infusion reaction that led to permanent discontinuation of cetuximab, and one patient experienced a grade 5 gastric perforation that led to permanent discontinuation of toripalimab and cetuximab. Seven patients (15.6%) experienced AEs that led to death, including one gastric perforation assessed by the investigator as related to study treatment and the remaining, all of which were assessed by the investigator as not related to study treatment, including hemorrhagic shock, pulmonary embolism, tumor hemorrhage (2 cases), and myocardial infarction. Seven (15.6%) patients had infusion reactions, including two (4.4%) patients with toripalimab-related infusion reactions and five (11.1%) with cetuximab-related infusion reactions. One (2.2%) patient had a grade 3 infusion reaction and no grade 4 or 5 infusion reactions related to cetuximab.

[0203] [Table 6]

[0204] 1.3.2 Antitumor activity studies Research method: The primary endpoint of this study was ORR, and efficacy data were analyzed based on the overall analysis set and efficacy-evaluable analysis set. Objective response rates were analyzed, and the 95% confidence intervals of ORR were calculated using the Clopper-Pearson method.

[0205] The Kaplan-Meier method was used to calculate median DoR, PFS, and OS, and their 95% CIs were estimated using the Brookmeyer-Crowley method, which achieves normal approximation with log-log function transformation. The Kaplan-Meier method was used to estimate 1-year OS rates, and their 95% CIs were estimated using the Greenwood formula.

[0206] Research results: By March 15, 2023, according to investigator assessment, 22 of them achieved PR or CR (ORR 48.9%), and 13 achieved SD (DCR 77.8%) (shown in Figures 1 and 2). Among them, both the ORR (51.6% vs. 40%) and median DOR (546 days vs. 127 days) of patients with PD-L1 CPS ≥ 1 were superior to those with PD-L1 CPS < 1.

[0207] [Table 7]

[0208] [Table 8]

[0209] 1.3.3 Research conclusion The combination of toripalimab and cetuximab was well tolerated and initially demonstrated good clinical efficacy in treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after failure of first-line platinum-containing regimens, according to study results.

Claims

1. comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-EGFR antibody or an antigen-binding fragment thereof; Drug combinations.

2. The anti-PD-1 antibody or antigen-binding fragment thereof comprises an LCDR1 having an amino acid sequence set forth in SEQ ID NO:1 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:1, an LCDR2 having an amino acid sequence set forth in SEQ ID NO:2 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:2, an LCDR3 having an amino acid sequence set forth in SEQ ID NO:3 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:3, an HCDR1 having an amino acid sequence set forth in SEQ ID NO:4 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:4, an HCDR2 having an amino acid sequence set forth in SEQ ID NO:5 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:5, and an HCDR3 having an amino acid sequence set forth in SEQ ID NO:6 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:

6. Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a heavy chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8, More preferably, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:7, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:

8.

2. The drug combination of claim 1.

3. The anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:9, and a heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:10, Preferably, the anti-PD-1 antibody comprises a light chain having the amino acid sequence set forth in SEQ ID NO:9 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:

10.

3. The drug combination of claim 2.

4. The anti-PD-1 antibody is one or more selected from Nivolumab or a biosimilar thereof, Pembrolizumab or a biosimilar thereof, Toripalimab or a biosimilar thereof, Sintilimab or a biosimilar thereof, Camrelizumab or a biosimilar thereof, Tislerizumab or a biosimilar thereof, Cemiplimab or a biosimilar thereof, Zimberelimab or a biosimilar thereof, Penpulimab or a biosimilar thereof, and Serpululimab or a biosimilar thereof, and is preferably Toripalimab or a biosimilar thereof; 2. The drug combination of claim 1.

5. The anti-EGFR antibodies or antigen-binding fragments thereof include an LCDR1 having an amino acid sequence set forth in SEQ ID NO:11 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:11, an LCDR2 having an amino acid sequence set forth in SEQ ID NO:12 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:12, an LCDR3 having an amino acid sequence set forth in SEQ ID NO:13 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:13, an HCDR1 having an amino acid sequence set forth in SEQ ID NO:14 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:14, an HCDR2 having an amino acid sequence set forth in SEQ ID NO:15 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:15, and an HCDR3 having an amino acid sequence set forth in SEQ ID NO:16 or an amino acid sequence having one, two or three amino acid differences compared to SEQ ID NO:

16. A drug combination according to any one of claims 1 to 4.

6. The anti-EGFR antibody or antigen-binding fragment thereof comprises a light chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain variable region having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18, Preferably, the anti-EGFR antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:

18.

6. The drug combination of claim 5.

7. The anti-EGFR antibody or antigen-binding fragment thereof comprises a light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 19, and a heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 20, Preferably, the anti-EGFR antibody comprises a light chain having the amino acid sequence set forth in SEQ ID NO: 19 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 20; 7. The drug combination of claim 6.

8. The anti-EGFR antibody is one or more selected from Necitumumab or a biosimilar thereof, Nimotuzumab or a biosimilar thereof, Panitumumab or a biosimilar thereof, and Cetuximab or a biosimilar thereof, and is preferably Cetuximab or a biosimilar thereof; A drug combination according to any one of claims 1 to 4.

9. the amount of the anti-PD-1 antibody or antigen-binding fragment thereof in the drug combination satisfies an administration frequency of about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per three weeks; and the amount of the anti-EGFR antibody or antigen-binding fragment thereof satisfies an administration frequency of about once per week, once per two weeks, once per three weeks, once per four weeks, or once per month, preferably once per week; Preferably, in the drug combination, the amount of the anti-PD-1 antibody or antigen-binding fragment thereof satisfies a single dose of about 0.1 mg / kg to about 10.0 mg / kg of an individual's body weight, preferably about 1.0 mg / kg to about 10.0 mg / kg of an individual's body weight, such as about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg or about 10 mg / kg of an individual's body weight, or a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, such as a fixed dose of about 120 mg, about 240 mg, about 360 mg or about 480 mg, preferably a fixed dose of about 240 mg, and the amount of the anti-EGFR antibody or antigen-binding fragment thereof satisfies a single dose of about 100 mg / m 2 ~Approx. 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~Approx. 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 , preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 or about 400 mg / m 2 of individual body surface area for a single dose, Preferably, the drug combination comprises one dose of the anti-PD-1 antibody or antigen-binding fragment thereof and three doses of the anti-EGFR antibody or antigen-binding fragment thereof, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are each provided in the form of an independent formulation; Preferably, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof formulation contains 240 mg of the anti-PD-1 antibody or antigen-binding fragment thereof, and in the three doses of the anti-EGFR antibody or antigen-binding fragment thereof formulation, the dose of the formulation contains 400 mg / m of the anti-EGFR antibody or antigen-binding fragment thereof. 2 and two other doses of 250 mg / m 2 or each of the three doses of the anti-EGFR antibody or antigen-binding fragment thereof formulations meets the daily dose requirement of 250 mg / m 2 and Preferably, the anti-PD-1 antibody is Toripalimab or an antigen-binding fragment thereof, and the anti-EGFR antibody is Cetuximab or an antigen-binding fragment thereof. A drug combination according to any one of claims 1 to 8.

10. 10. Use of a combination of drugs according to any one of claims 1 to 9 in the manufacture of a medicament for preventing or treating head and neck squamous cell carcinoma (HNSCC) in a patient.

11. The head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma, preferably recurrent or metastatic head and neck squamous cell carcinoma that has previously failed chemotherapy with a first-line platinum-containing regimen, and preferably the patient has a PD-L1 CPS of ≧1. The use according to claim 10.

12. According to RECIST v1.1 criteria, the head and neck squamous cell carcinoma has > 1 measurable lesion.

12. Use according to claim 10 or 11.

13. 1. Use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC) in a patient, or use of a combination of an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma in a patient, comprising Preferably, said anti-PD-1 antibody or antigen-binding fragment thereof is as described in any one of claims 2 to 4, and preferably, said anti-EGFR antibody or antigen-binding fragment thereof is as described in any one of claims 5 to 8.

14. The head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma, preferably recurrent or metastatic head and neck squamous cell carcinoma that has previously failed chemotherapy with a first-line platinum-containing regimen, and preferably the patient has a PD-L1 CPS of ≧1.

14. The use according to claim 13.

15. According to RECIST v1.1 criteria, the head and neck squamous cell carcinoma has > 1 measurable lesion.

15. The use according to claim 13 or 14.

16. Use of the anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC), wherein the single dose of the anti-PD-1 antibody or antigen-binding fragment thereof is about 0.1 mg / kg to about 10.0 mg / kg of an individual's body weight, preferably about 1.0 mg / kg to about 10.0 mg / kg of an individual's body weight, such as about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg or about 10 mg / kg of an individual's body weight, or a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, such as a fixed dose of about 120 mg, about 240 mg, about 360 mg or about 480 mg; In the use of the combination of the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma, the single dose of the anti-PD-1 antibody or antigen-binding fragment thereof is about 0.1 mg / kg to about 10.0 mg / kg of individual body weight, preferably about 1.0 mg / kg to about 10.0 mg / kg of individual body weight, for example about 0.1 mg / kg, about 0 3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg or about 10 mg / kg of an individual's body weight, or a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, for example a fixed dose of about 120 mg, about 240 mg, about 360 mg or about 480 mg, preferably a fixed dose of about 240 mg, and a single dose of the anti-EGFR antibody or antigen-binding fragment thereof is about 100 mg / m 2 ~Approx. 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~Approx. 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 of anti-EGFR antibody or antigen-binding fragment thereof, preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 or about 400 mg / m 2 an anti-EGFR antibody or antigen-binding fragment thereof of an individual body surface area of Use according to any one of claims 13 to 15.

17. in the use of the anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC), the administration frequency of the anti-PD-1 antibody or antigen-binding fragment thereof is about once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once every two weeks or once every three weeks; In the use of a combination of the anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma, the administration frequency of the anti-PD-1 antibody or antigen-binding fragment thereof is about once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once every three weeks, and the administration frequency of the anti-EGFR antibody or antigen-binding fragment thereof is about once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once a week. Use according to any one of claims 13 to 16.

18. Use of the anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC), wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every two or three weeks at a dosage of about 1 mg / kg of individual body weight, about 3 mg / kg of individual body weight, about 5 mg / kg of individual body weight, about 10 mg / kg of individual body weight, a fixed dose of about 240 mg, a fixed dose of about 360 mg, or a fixed dose of about 480 mg; In the use of a combination of an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every three weeks at a fixed dose of about 240 mg, and the anti-EGFR antibody or antigen-binding fragment thereof is administered at a fixed dose of about 400 mg / m2 in the first cycle. 2 of individual body surface area, and about 250 mg / m upon administration of each subsequent dosing cycle. 2 of individual body surface area and administered once a week; Use according to any one of claims 13 to 16.

19. In the use of the anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC), the administration cycle of the anti-PD-1 antibody or antigen-binding fragment thereof may be for a period of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, half a year, 1 year, 2 years or more, optionally, the duration of each administration cycle is the same or different, and the interval between each administration cycle is the same or different, or In the use of a combination of the anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma, the administration cycle of the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof may be for a period of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, half a year, 1 year, 2 years or more, optionally, the duration of each administration cycle is the same or different, and the interval between each administration cycle is the same or different. Use according to any one of claims 10 to 18.

20. Use of the anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma (HNSCC), wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered via a parenteral route in a liquid dosage form, such as an injection; In the use of a combination of the anti-PD-1 antibody or antigen-binding fragment thereof and an anti-EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for preventing or treating head and neck squamous cell carcinoma, the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-EGFR antibody or antigen-binding fragment thereof are administered via a parenteral route in a liquid dosage form such as an injection. Use according to any one of claims 10 to 19.

21. A kit comprising: One or more single pharmaceutical dosage units of an anti-PD-1 antibody or antigen-binding fragment thereof, preferably the anti-PD-1 antibody or antigen-binding fragment thereof is as defined in any one of claims 2 to 4; or one or more single pharmaceutical dosage units of an anti-PD-1 antibody or antigen-binding fragment thereof, preferably as defined in any one of claims 2 to 4, and one or more single pharmaceutical dosage units of an anti-EGFR antibody or antigen-binding fragment thereof, preferably as defined in any one of claims 5 to 8, kit.

22. (I) an anti-PD-1 antibody or antigen-binding fragment thereof in one or more single-pharmaceutical dosage units, wherein the amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in the single-pharmaceutical dosage unit is sufficient to be administered to a patient in a single dose of about 120 mg to about 480 mg, e.g., about a 120 mg fixed dose, about a 240 mg fixed dose, about a 360 mg fixed dose, about a 480 mg fixed dose, or the amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in the single-pharmaceutical dosage unit is sufficient to be administered to a patient in a single dose of about 1.0 mg / kg to about 10.0 mg / kg of an individual's body weight, e.g., about 1 mg / kg of an individual's body weight, about 3 mg / kg of an individual's body weight, about 5 mg / kg of an individual's body weight, or about 10 mg / kg of an individual's body weight; or (II) The amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in a single-drug dosage unit is a fixed dose of about 120 mg to about 480 mg, preferably a fixed dose of about 120 mg to about 360 mg, for example, about 120 mg, about 240 mg, about 360 mg, or about 480 mg, preferably about 240 mg, and the amount of the anti-PD-1 antibody or antigen-binding fragment thereof contained in a single-drug dosage unit is about 100 mg / m 2 ~Approx. 500mg / m 2 of individual body surface area, preferably 200 mg / m 2 ~Approx. 500mg / m 2 of individual body surface area, e.g., about 100 mg / m 2 , about 150mg / m 2 , about 200mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 , about 400mg / m 2 , about 450mg / m 2 or about 500 mg / m 2 , preferably about 200 mg / m 2 , about 250mg / m 2 , about 300mg / m 2 , about 350mg / m 2 or about 400 mg / m 2 one or more of said single pharmaceutical dosage units of an anti-EGFR antibody or antigen-binding fragment thereof, sufficient to be administered to a patient in a single dosage of about 100 mg / kg of an individual body surface area; The kit of claim 18.

23. The kit comprises one or more drug combinations according to any one of claims 1 to 9. The kit of claim 18.

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