WO2021180027A1

WO2021180027A1 - Pharmaceutical combination of anti-pd-1 antibody and multi-receptor tyrosine kinase inhibitor and method for using same

Info

Publication number: WO2021180027A1
Application number: PCT/CN2021/079522
Authority: WO
Inventors: 苏慰国; 谭攀峰; 刘辉; 冯辉; 姚盛
Original assignee: 和记黄埔医药（上海）有限公司; 上海君实生物医药科技股份有限公司
Priority date: 2020-03-09
Filing date: 2021-03-08
Publication date: 2021-09-16
Also published as: TW202143969A; CN115052605A

Abstract

Disclosed are a pharmaceutical combination of an anti-PD-1 antibody and a multi-receptor tyrosine kinase inhibitor and a method for using same. In particular, the present invention relates to a pharmaceutical combination of an anti-PD-1 antibody and a multi-receptor tyrosine kinase inhibitor, and the use thereof in the preparation of drugs for preventing or treating cancers, and a method for using same.

Description

Drug combination of anti-PD-1 antibody and multi-receptor tyrosine kinase inhibitor and use method thereof

Technical field

The present invention relates to a combination comprising an anti-PD-1 antibody or an antigen-binding fragment thereof targeting programmed cell death receptor 1 (Programmed Cell Death 1, PD-1) and a multi-receptor tyrosine kinase (multi-RTK) inhibitor A drug combination product, which is used to prevent or treat cancer. The present invention also relates to the use and method of using the combination product to prevent or treat cancer.

Background technique

Programmed Cell Death 1 (PD-1) is a cell surface signal transduction receptor that plays a key role in the regulation of T cell activation and tolerance (Annu Rev Immunol 2008; 26: 677 -704.). In the tumor tissue microenvironment, PD-1 is highly expressed on tumor-infiltrating lymphocytes, and its ligands PD-L1 and PD-L2 are upregulated on the cell surface of many different tumors (Nat Med. 2002 Aug; 8( 8): 793-800.), the binding of PD-1 and ligand leads to immune evasion. At present, a number of drugs that inhibit the interaction of PD-1/PD-L1 have been approved for marketing, including Nivolumab, Pembrolizumab, and Toripalimab, all of which have a wide range of anti-tumor activities. However, the effective rate of PD-1 inhibitor alone in most unselected solid tumors is low, about 10%-30%. It has been proposed that if combined with other cancer therapies, such as radiotherapy, surgery, chemotherapeutics, and targeted drugs that inhibit other signaling pathways that are dysregulated in tumors, it has the potential to enhance the efficacy of anti-PD-1 antibodies.

Target a variety of tumor growth regulators at the same time, such as VEGFR (vascular endothelial growth factor receptor), FGFRs (fibroblast growth factor receptor), CSF1R (colony stimulating factor 1 receptor) and platelet-derived growth factor receptor ( PDGFR) kinase inhibitors are a new type of targeted drugs. Studies have proven that the signaling pathways mediated by VEGFRs and FGFRs play a key role in tumor angiogenesis and angiogenesis. A large number of highly selective inhibitors of VEGFR or FGFR have been approved for tumor treatment. In addition, recent studies have also found that proteins such as VEGFRs, FGFRs and CSF1R also play a role in tumor immune escape. VEGF released by tumor cells can activate the VEGFR signaling pathway on T cells, leading to overexpression of PD-1 receptors on T cells. Then reduce the anti-tumor activity of T cells and cause tumor immune tolerance; CSF1R and FGFRs-mediated signals are also involved in the proliferation, survival and differentiation of monocyte/macrophage cell lines (J Exp Med. 2015 February 9; 212(2) ): 139-48; Int J Mol Med. 2016 Jul; 38(1): 3-15). Therefore, targeted therapies that simultaneously inhibit the pathways mediated by VEGFRs, FGFRs, and CSF1R may be able to more effectively inhibit tumor angiogenesis and tumor immune escape, which represents an attractive therapeutic strategy for cancer treatment. Surufatinib is a potent small molecule tyrosine kinase inhibitor that simultaneously targets VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R.

Anti-PD-1 antibody is combined with multi-receptor (such as VEGFR/FGFR1/CSF1R) tyrosine kinase inhibitor to enhance the anti-angiogenesis or immune activation function of a single agent, improve the tumor microenvironment, and improve clinical benefit and safety , Will be a potential treatment plan.

Summary of the invention

Overview

The present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and a multi-receptor tyrosine kinase (multi-RTK) inhibitor and its use and method for preventing or treating cancer.

Specifically, the present invention provides the following embodiments:

1. A pharmaceutical combination product comprising (i) an anti-PD-1 antibody or an antigen-binding fragment thereof, and (ii) a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof, wherein the anti-PD The -1 antibody or its antigen-binding fragment includes the light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, and SEQ ID NO: 1 respectively , SEQ ID NO: 2 and SEQ ID NO: 3 show the heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3.

2. The pharmaceutical combination product of embodiment 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the same as SEQ ID NO: 7 has the same sequence or an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity with it, and The light chain variable region has the same sequence as SEQ ID NO: 8 or at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or A sequence of amino acids with higher identity.

3. The pharmaceutical combination product according to embodiment 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the same sequence as SEQ ID NO: 9 or at least 90%, 91%, 92%, 93% of the sequence. %, 94%, 95%, 96%, 97%, 98%, 99% or higher identity of the heavy chain amino acid sequence, and the sequence of SEQ ID NO: 10 is the same or has at least 90%, 91%, A light chain amino acid sequence of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity.

4. The pharmaceutical combination product according to any one of embodiments 1-3, wherein the multi-receptor tyrosine kinase inhibitor inhibits at least the tyrosine kinase activity of two or more of the following receptors:( 1) One, two, or three of VEGFR1, VEGFR2, and VEGFR3, (2) one, two, three, or four of FGFR1, FGFR2, FGFR3, and FGFR4; and (3) CSF1R.

5. The pharmaceutical combination product according to embodiment 4, wherein the multi-receptor tyrosine kinase inhibitor can simultaneously inhibit the tyrosine kinase activity of the receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R.

6. The pharmaceutical combination product of embodiment 5, wherein the multi-receptor tyrosine kinase inhibitor is sofatinib.

7. The pharmaceutical combination product according to any one of the preceding embodiments, wherein

(i) The single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from about 1 mg/kg to about 5 mg/kg of the individual's body weight, such as 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg /kg individual body weight, or a fixed dose selected from about 120mg to about 480mg, preferably 120mg, 240mg, 360mg or 480mg; and/or

(ii) The single administration dose of a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is selected from a fixed dose of about 150 to about 350 mg, such as 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg.

8. The pharmaceutical combination product according to any one of the preceding embodiments, wherein

(i) The frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof is once a week, once every two weeks, once every three weeks, once every four weeks, or once every five weeks, preferably once every three weeks; and/ or

(ii) The frequency of administration of a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is twice a day, once a day, once every two days, or once every three days, preferably once a day.

9. The pharmaceutical combination product according to any one of the preceding embodiments, wherein

(i) The single administration dose of anti-PD-1 antibody or its antigen-binding fragment is 1 mg/kg body weight, 2 mg/kg body weight, 3 mg/kg body weight, or 240 mg fixed dose, preferably 240 mg fixed dose, once every three weeks (Q3W) apply; if/or

(ii) The single administration dose of a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is 200 mg, 250 mg or 300 mg, preferably 250 mg, and is continuously administered once a day (QD).

10. The pharmaceutical combination product according to any one of the preceding embodiments, wherein

(i) The anti-PD-1 antibody or antigen-binding fragment thereof is administered in a liquid dosage form, such as an injection, via a parenteral route, such as intravenous infusion; and/or

(ii) The multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof can be administered via an intragastric route or a parenteral route, for example, in a solid dosage form, such as a capsule or a tablet, for oral administration.

11. The pharmaceutical combination product according to any one of the preceding embodiments, wherein (i) and (ii) are administered separately, simultaneously or sequentially; preferably wherein the multi-receptor tyrosine kinase inhibitor is 1 hour after breakfast Orally.

12. The pharmaceutical combination product according to any one of the preceding embodiments, wherein the administration cycle of the pharmaceutical combination product can be one week, two weeks, three weeks, one month, two months, three months, four months, Five months, half a year or longer, optionally, the time of each dosing cycle can be the same or different, and the interval between each dosing cycle can be the same or different.

13. The pharmaceutical combination product according to any one of the preceding embodiments, which is used for the prevention or treatment of cancer in an individual in need, wherein the cancer is a solid tumor selected from neuroendocrine tumors (e.g., neuroendocrine tumors and neuroendocrine tumors). Endocrine carcinoma; pancreatic neuroendocrine tumor (pNET); non-pancreatic neuroendocrine tumors, such as lung carcinoid tumors, gastric carcinoid tumors, duodenal carcinoid tumors, jejunal carcinoid tumors, ileal carcinoid tumors, colon carcinoid tumors And rectal carcinoid tumors), biliary tract cancer, gastric cancer (e.g. gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, lung cancer (e.g. non-small cell lung cancer, lung squamous cell carcinoma and small cell lung cancer), soft tissue sarcoma, uterus Endometrial cancer, colorectal cancer, breast cancer, bladder cancer, renal clear cell carcinoma, head/neck squamous cell carcinoma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer, and esophageal cancer (e.g., esophageal squamous cell carcinoma) Or the cancer is a hematological malignancy, selected from leukemia or lymphoma.

14. A method of preventing or treating cancer, the method comprising administering to an individual in need an effective amount of a pharmaceutical combination product as defined in any one of the preceding embodiments, wherein the cancer is a solid tumor selected from neuroendocrine tumors (For example: neuroendocrine tumors and neuroendocrine carcinomas; pancreatic neuroendocrine tumors (pNET); non-pancreatic neuroendocrine tumors, such as lung carcinoid tumors, gastric carcinoid tumors, duodenal carcinoid tumors, jejunal carcinoid tumors, ileum Carcinoid tumors, colon carcinoid tumors and rectal carcinoid tumors), biliary tract cancer, gastric cancer (e.g. gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, lung cancer (e.g. non-small cell lung cancer, lung squamous cell carcinoma and small Cell lung cancer), soft tissue sarcoma, endometrial cancer, colorectal cancer, breast cancer, bladder cancer, renal clear cell carcinoma, head/neck squamous cell carcinoma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer and Esophageal cancer (such as esophageal squamous cell carcinoma); or the cancer is a hematological malignancy, selected from leukemia or lymphoma.

15. The method of embodiment 14, wherein:

(ii) The single administration dose of the multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is selected from a fixed dose of about 150 to about 350 mg, such as 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg.

16. The method according to embodiment 14 or 15, wherein

17. The method according to any one of embodiments 14-16, wherein

18. The method according to any one of embodiments 14-17, wherein the administration period of (i) and/or (ii) in the pharmaceutical combination product can be one week, two weeks, three weeks, or one month , Two months, three months, four months, five months, six months or longer, optionally, the time of each dosing cycle can be the same or different, and the interval between each dosing cycle can be Same or different.

19. The use of the pharmaceutical combination product according to any one of the embodiments 1-13 for the prevention or treatment of cancer in individuals suffering from cancer or at risk of cancer, or in preparation for use in patients suffering from cancer or suffering from cancer. The use of drugs to prevent or treat cancer in individuals at risk of cancer.

20. The use according to embodiment 19, wherein the cancer is selected from the cancer of claim 13.

21. The use according to embodiment 20, wherein the cancer is refractory to monotherapy with anti-PD-1 antibodies, and/or the cancer is difficult to treat with a multi-receptor tyrosine kinase inhibitor In terms of refractory cancer.

22. A kit comprising a drug combination product as defined in any one of the preceding embodiments, preferably the kit includes one or more single drug dosage units.

23. The kit of embodiment 22, comprising:

(1) One or more single drug dosage units containing about 120 mg to about 480 mg, such as 120 mg, 240 mg, 360 mg or 480 mg, preferably 240 mg, of the anti-PD-1 antibody or antigen-binding fragment thereof ;and / or

(2) One or more single drug dosage units containing about 150 mg to about 350 mg, such as 150 mg, 200 mg, 250 mg, 300 mg or 350 mg, preferably 250 mg dose of multi-receptor tyrosine kinase inhibitor Agent or a pharmaceutically acceptable salt thereof.

24. The kit according to embodiment 22 or 23, further comprising instructions for instructing the method of use of the pharmaceutical combination product.

In each of the above embodiments, the individual is a mammal, such as a human. In some preferred embodiments, the individual is an individual who has cancer or is at risk of cancer, such as a cancer patient.

In some more preferred embodiments, the individual includes individuals with a lower expected response rate to treatment with anti-PD-1 antibody alone, for example, cancers with a lower expected response rate to treatment with anti-PD-1 antibody alone. patient.

The cancer that is refractory to a monotherapy using an anti-PD-1 antibody refers to a cancer that is expected to have a low response rate to a treatment administered with an anti-PD-1 antibody alone.

In other more preferred embodiments, the individual includes individuals who are expected to have a lower response rate to treatment with a multi-receptor tyrosine kinase inhibitor administered alone, for example, those who are administered a multi-receptor tyrosine kinase inhibitor alone. Treat cancer patients whose expected response rate is low.

The cancer that is refractory to a single treatment using a multi-receptor tyrosine kinase inhibitor refers to a cancer for which the response rate is expected to be low to the treatment of the single-administered multi-receptor tyrosine kinase inhibitor.

Surprisingly, the pharmaceutical combination product or treatment method of the present invention has significantly better anti-cancer effects than the single administration of anti-PD-1 antibody or its antigen-binding fragment or the single administration of a multi-receptor tyrosine kinase inhibitor. Efficacy, similar clinical safety and/or side effects.

Description of the drawings

Figure 1 shows the inhibitory effect of drugs on tumor tissue growth in tumor-bearing mice.

Detailed description of the invention

Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be changed. In addition, the terms used herein are only for describing specific embodiments, and are not meant to limit the scope of the present invention in any way.

definition

In order to make it easier to understand the present invention, certain scientific and technological terms are specifically defined as follows. Unless otherwise clearly defined in other parts of this document, the scientific and technological terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

The abbreviation for amino acid residues is the standard 3-letter and/or 1-letter code used in the art to refer to one of the 20 commonly used L-amino acids. The singular form used herein (including the claims) includes its corresponding plural form, unless the context clearly stipulates otherwise.

The term "about" refers to a value or composition within an acceptable error range of a specific value or composition as determined by a person of ordinary skill in the art, which partly depends on how the value or composition is measured or determined, that is, the limitation of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation according to practice in the art. Alternatively, "about" can refer to a range of up to 10% or 20% (ie, ±10% or ±20%). For example, about 240 mg may include any number between 216 mg and 264 mg (relative to 10%), and between 192 mg and 288 mg (relative to 20%). In this article, when a specific value or composition is provided, unless expressly stated otherwise, the meaning of "about" shall be assumed to be within the acceptable error range of the specific value or composition.

All numerical ranges herein should be understood as disclosing every value and a subset of values within the range, regardless of whether it is specifically disclosed otherwise. For example, when referring to any numerical range, it should be regarded as referring to every numerical value in the numerical range, for example, every integer in the numerical range. The present invention relates to all values falling within these ranges, all smaller ranges, and the upper or lower limit of the range of values.

When the term "and/or" is used to connect two or more alternatives, it should be understood to mean any one of the alternatives or any two or more of the alternatives.

As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this document, when the term "comprises" or "includes" is used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps. For example, when referring to an antibody variable region that "comprises" a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.

The term "antibody" refers to any form of antibody having the desired biological activity. Therefore, it is used in the broadest sense, specifically including but not limited to monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), humanized antibodies, fully human antibodies, Chimeric antibodies, camelidized single domain antibodies and antigen-binding fragments of antibodies.

The term "antigen-binding fragment" includes fragments or derivatives of antibodies, usually including at least one fragment of the antigen-binding region or variable region (eg, one or more CDRs) of the parent antibody, which retains at least some of the binding specificity of the parent antibody. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies formed from antibody fragments And multispecific antibodies. When the antigen-binding activity is expressed on a molar concentration basis, the binding fragment or derivative usually retains at least 10% of its antigen-binding activity. Preferably, the binding fragment or derivative retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the antigen binding affinity of the parent antibody. It is also expected that the antigen-binding fragment of an antibody may include conservative or non-conservative amino acid substitutions that do not significantly change its biological activity (referred to as "conservative variants" or "functionally conservative variants" of the antibody).

The term "humanized antibody" refers to an antibody form containing sequences derived from human and non-human (e.g., murine, rat) antibodies. Generally speaking, a humanized antibody contains substantially all of at least one and usually two variable domains, wherein all or substantially all of the hypervariable loops are equivalent to those of non-human immunoglobulins, and all or substantially all of the hypervariable loops are The framework (FR) region is the framework region of human immunoglobulin sequences. The humanized antibody optionally may comprise at least a portion of a human immunoglobulin constant region (Fc). The humanized form of the rodent antibody will generally contain the same CDR sequences of the parent rodent antibody, but may include certain amino acid substitutions to increase affinity, increase the stability of the humanized antibody, or for other reasons.

The terms "whole antibody", "full-length antibody", "full antibody" and "whole antibody" are used interchangeably herein to refer to at least two heavy chains (H) and two Light chain (L) glycoprotein. Each heavy chain is composed of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region. The heavy chain constant region is composed of three structural domains CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region. The light chain constant region consists of a domain CL. The VH and VL regions can be further divided into hypervariable regions (complementarity determining regions (CDR)), with more conservative regions (framework regions (FR)) interposed between them. Each VH and VL consists of three CDRs and four FR composition, arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this article, HCDR1, HCDR2, and HCDR3 denote the three CDRs of the heavy chain variable region, LCDR1, LCDR2 and LCDR3 in turn represent the three CDRs of the variable region of the light chain. The constant region does not directly participate in the binding of antibodies to antigens, but exhibits a variety of effector functions. In a given VH or VL amino acid sequence, the The precise amino acid sequence boundary can be determined using any one or a combination of many well-known schemes, including, for example, the Chothia numbering scheme (Chothia et al., Canonical structures for the hypervariable regions of immunoglobulins). Some hypervariable loops of immunoglobulins are equivalent to non-human Hypervariable loops of immunoglobulins, and all or almost all of the frameworks (involving -917 (1987) that fall into these ranges); Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, USDepartment of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath) and Contact (University College London); North numbering plan (North et al., A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)). The CDRs of the antibodies of the present invention can be defined by those skilled in the art according to any scheme in the art (for example, different assignment systems or combinations).

Although CDRs are different from antibody to antibody, there are only a limited number of amino acid positions within the CDR that directly participate in antigen binding. Using at least two of the Kabat, Chothia, AbM, and Contact methods, the minimum overlap area can be determined, thereby providing the "minimum binding unit" for antigen binding. The minimum binding unit can be a sub-portion of the CDR. As those skilled in the art know, through the structure of the antibody and protein folding, the residues of the rest of the CDR sequence can be determined. Therefore, the present invention also considers any CDR variants given herein. For example, in a CDR variant, the amino acid residues of the smallest binding unit can remain unchanged, while the remaining CDR residues defined by Kabat or Chothia can be replaced by conserved amino acid residues.

"Multi-receptor tyrosine kinase inhibitor" or "tyrosine kinase inhibitor" refers to an agent that inhibits or reduces the tyrosine kinase activity of at least two or more receptors. The activity of tyrosine kinase includes direct and indirect activity. Exemplary direct activities include, but are not limited to, association with a target molecule or phosphorylation of a target substrate (ie, kinase activity). Exemplary indirect activities include, but are not limited to, activation or inhibition of downstream biological events, such as NF-KB-mediated activation of gene transcription.

The terms "cancer" and "cancer" refer to or describe a physiological or pathological condition in mammals that is usually characterized by unregulated cell growth. This definition includes benign and malignant cancers as well as dormant tumors or micrometastasis. Cancers include but are not limited to solid tumors and blood cancers. Examples of various cancers include, but are not limited to, squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myelogenous leukemia (AML) , Multiple myeloma, gastrointestinal (tract) cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, cartilage Sarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, gastric cancer, bladder cancer, hepatocytoma, breast cancer, colon cancer, neuroendocrine tumor and head and neck cancer. The cancer is preferably advanced cancer, recurrent and/or refractory cancer, or cancer resistant to chemotherapy, more preferably advanced solid tumor, such as (confirmed by histology or cytology) that cannot be surgically removed or metastatic Advanced solid tumors.

The term "tumor" when applied to individuals diagnosed with or suspected of having cancer refers to malignant or potentially malignant neoplasms or tissue masses of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain a cyst or fluid area. Different types of solid tumors are named for the cell types that form them. Leukemia (blood cancer) usually does not form solid tumors (National Cancer Institute of Cancer Terms).

The term "patient", "subject" or "patient" refers to any single individual in need of treatment or participation in clinical trials, epidemiological studies or used as a control, including humans and mammals such as cows, horses, dogs and cats .

The "therapeutically effective amount" of a drug or therapeutic agent refers to the amount of an active agent (such as antibodies, soluble receptors, polypeptides, polynucleotides, small organic molecules or other drugs) that is effective to "treat" a disease or disorder in a patient or mammal . For cancer, a therapeutically effective amount of active agent can reduce the number of cancer cells; reduce tumor size; inhibit or stop the infiltration of cancer cells into peripheral organs including, for example, the spread of cancer to soft tissues and bones; inhibit and stop tumor metastasis; inhibit and stop tumors Growth; alleviate one or more symptoms related to cancer to a certain extent; reduce morbidity and mortality; improve quality of life; reduce tumorigenesis, tumor frequency or tumorigenesis ability; reduce cancer stem cells in tumors The number or frequency of tumorigenesis; differentiate tumorigenic cells into a non-tumorigenic state; or a combination of these effects. The extent to which the active agent prevents the growth of existing cancer cells and/or kills existing cancer cells can be referred to as cytostatic and/or cytotoxicity.

The term "dose" is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated in the product packaging, product information sheet, or in the instructions attached to the kit.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is non-toxic, biologically tolerable, or other biologically suitable for the treatment or prevention of diseases. Including but not limited to acid addition salt or base addition salt, for example: hydrochloride, hydrobromide, phosphate, sulfate, sulfite, nitrate, malate, maleate, fumaric acid Salt, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate And with the formula HOOC-(CH2)n-COOH (wherein n is 0-4) alkane dicarboxylic acid formed salt and so on.

The term "inhibition" means that a given molecule (e.g. (i) an anti-PD-1 antibody or antigen-binding fragment thereof and/or (ii) a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof) makes a certain These parameters (such as PD-1 activity and/or VEGFR, FGFR1, CSF1R activity) are reduced. For example, the term includes inhibition of activity of at least 5%, 10%, 20%, 30%, 40% or more. Therefore, the suppression does not have to be 100%.

The term "treatment" refers to 1) therapeutic measures that cure, slow down, alleviate the symptoms of a diagnosed pathological condition or disorder and/or stop the progress of the diagnosed pathological condition or disorder, and 2) preventive or preventive Sexual measures, which prevent and/or slow down the development of individual pathological conditions or disorders. Therefore, those in need of treatment include patients who have suffered from the disease, patients who are prone to suffer from the disease, and patients who want to prevent the disease. In certain embodiments, the individual successfully "treats" cancer by the method of the present invention, wherein the individual exhibits one or more of the following: a decrease or complete disappearance of cancer cells; a decrease in tumor size; inhibition or lack of infiltration of cancer cells to the periphery Organs include, for example, the spread of cancer to soft tissues and bones; inhibition or lack of tumor metastasis; inhibition or lack of tumor growth; alleviation of one or more symptoms related to the specific cancer; reduction of morbidity and mortality; improvement of quality of life; reduction of tumors Occurrence, tumor frequency or tumorigenesis ability; reduce the number or frequency of cancer stem cells in tumors; differentiate tumorigenic cells into a non-tumorigenic state; or a combination of the above effects.

The term "prevention" includes the suppression or delay of the occurrence or frequency of the occurrence or occurrence of a disease or disorder or its symptoms, and it generally refers to the administration of a drug before the occurrence or occurrence of the symptoms or symptoms, especially before the occurrence of the symptoms or symptoms in individuals at risk.

The term "inhibition of tumor growth" refers to any mechanism by which tumor cell growth can be inhibited. In certain embodiments, tumor cell growth is inhibited by delaying tumor cell proliferation. In certain embodiments, tumor cell growth is inhibited by stopping tumor cell proliferation. In certain embodiments, tumor cell growth is inhibited by killing tumor cells. In certain embodiments, tumor cell growth is inhibited by inducing tumor cell apoptosis. In certain embodiments, tumor cell growth is inhibited by inducing tumor cell differentiation. In certain embodiments, tumor cell growth is inhibited by depriving tumor cells of nutrients. In certain embodiments, tumor cell growth is inhibited by preventing tumor cell migration. In certain embodiments, tumor cell growth is inhibited by preventing tumor cell invasion.

The term "administration" refers to the physical introduction of each active ingredient of the pharmaceutical combination of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. The route of administration of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral routes of administration . As used herein, the phrase "parenteral administration" refers to methods of administration other than gastrointestinal and topical administration, usually via intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation. Correspondingly, each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.

The term "continuous administration" refers to daily administration. In the case of continuous administration, the drug may be administered one or more times a day, for example, the drug may be administered at a frequency of once a day, twice a day, or three times a day, preferably at a frequency of once a day.

The terms "drug combination" and "drug combination product" are used interchangeably herein and refer to non-fixed combination products or fixed combination products, including but not limited to kits and pharmaceutical compositions. The term "non-fixed combination" means that the active ingredients (e.g., anti-PD-1 antibodies, multi-RTK inhibitors) are separated entities at the same time, without a specific time limit, or with the same or different The two agents are administered to the patient sequentially at intervals of time, wherein such administration provides a preventive or therapeutically effective level of the two active agents in the patient. In some embodiments, the anti-PD-1 antibodies, multi-receptor tyrosine kinase (multi-RTK) inhibitors used in the drug combination are administered at a level not exceeding their levels when used alone. The term "fixed combination" means that the two active agents are simultaneously administered to the patient in the form of a single entity. Preferably, the dosage and/or time interval of the two active agents are selected, so that the combined use of each part can produce an effect greater than that achieved by using either component alone in the treatment of diseases or conditions. Each component may be in the form of a separate preparation, and the preparation form may be the same or different.

The term "individual" refers to mammals and non-mammals. Mammal refers to any member of the mammalian class, including but not limited to: humans; non-human primates, cows, horses, sheep, pigs, rabbits, dogs, cats, etc. The term "individual" does not limit a specific age or gender. In some embodiments, the individual is a human.

The term "adverse event" (AE) is any unfavorable and often unexpected or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of medical treatment. For example, an adverse event may be related to the activation of the immune system in response to treatment or the expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatments can have one or more related AEs, and each AE can have the same or different levels of severity.

The term "overall survival" or "OS" is the time from the first use of the study drug to death from any cause.

The term "progression-free survival" or "PFS" refers to the time from the first use of the drug under study to the onset of disease progression or death from any cause.

The term "single drug dosage unit" refers to a single drug dosage form containing the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention and/or containing the multi-receptor tyrosine of the present invention for single administration to a patient A single-dose form of kinase inhibitors. The single drug dosage form may be a dosage form for parenteral administration, such as a vial, ampule, prefilled needle or prefilled syringe for injection, a solution or lyophilized powder containing the drug, or a parenteral administration The dosage form of, such as tablets, capsules, lozenges, powders, suspensions, etc. for oral administration.

The term "liquid formulation" or "liquid composition" refers to a formulation in liquid form. The liquid composition may be, for example, a composition comprising: (i) the anti-PD-1 antibody or antigen-binding fragment thereof according to the present invention; (ii) an optional buffer; and (iii) a vehicle. "Buffering agent" refers to a pH buffering agent. For example, the buffer can be selected from buffers known in the art for antibody preparations, such as histidine, glutamate, phosphate, acetate, citrate, or tris.

The technical and scientific terms used herein that are not specifically defined have the meanings commonly understood by those skilled in the art to which the present invention belongs.

Drug combination

In one aspect, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention includes the anti-PD-1 antibody or antigen-binding fragment thereof described in WO2014206107 and other patent applications/patents of the same family. The entire contents of (including definitions of terms) are introduced into this article.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the drug combination of the present invention includes the LCDR1 shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively. , LCDR2, LCDR3, and amino acid sequences such as HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region contains the same as SEQ ID NO: 7 has the same sequence or an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity with it, and the light chain The variable region contains the same sequence as SEQ ID NO: 8 or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity with it The amino acid sequence.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention comprises the sequence identical to SEQ ID NO: 9 or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity of the heavy chain amino acid sequence, and the same as SEQ ID NO: 10 sequence or at least 90%, 91%, 92%, A light chain amino acid sequence with 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity.

In some embodiments, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is teriprizumab (also referred to herein as JS001 or toripalimab), which contains sequences as shown in SEQ ID NOs: 9 and 10, respectively Humanized IgG4mAb based on the amino acid sequence of the light chain and heavy chain.

In some embodiments, the multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention inhibits at least the tyrosine kinase activity of two or more of the following receptors: (1) VEGFR1, VEGFR2, and VEGFR3 One, two, or three; (2) one, two, three, or four of FGFR1, FGFR2, FGFR3, and FGFR4; and (3) CSF1R.

In some embodiments, the multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention can simultaneously inhibit the tyrosine kinase activity of the receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R.

In some embodiments, the multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention is described in WO2018090324A1 and other patent applications/patents of the same family. The entire content of the patent or patent application (including definitions of terms) is This article is included for all purposes.

In some embodiments, the multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention is "Sofantinib", also referred to herein as "HMPL-012", which has a positive effect on the receptors VEGFR1, VEGFR2 (KDR), The tyrosine kinases of VEGFR3, FGFR1 and CSF1R have a strong inhibitory effect. The half inhibitory concentrations are 2, 24, 1, 15 and 4nM, respectively. The inhibition of the kinases of other receptors is relatively weak, and most of the half inhibitory concentrations are greater than 100nM, showing better selectivity. "Sofantinib" is a compound having the structure of formula (I).

Sofatinib and its pharmaceutically acceptable salts herein are described in patent CN102070618, WO2011060746A1 and other patent applications/patents of the same family. In some embodiments, Sofatinib is a crystal, such as the crystal form I or the crystal form II described in CN102070618, WO2011060746A1 and other patent applications/patents of the same family. The above patent applications/patents are incorporated herein by reference for all purposes.

In some embodiments, sofatinib may also refer to a composition comprising a micronized compound of formula (I), and/or a pharmaceutically acceptable compound of at least one micronized compound of formula (I) Accepted salt, and at least one pharmaceutically acceptable excipient, the composition is described in patent WO2016188399A1 and other patent applications/patents of the same family, which are incorporated herein by reference, with For all purposes.

The pharmaceutical combination of the present invention may also include one or more additional therapeutic agents. Additional therapeutic agents may be, for example, chemotherapeutic agents, biotherapeutics, immunogenic agents other than VEGR inhibitors (e.g., attenuated cancer cells, tumor antigens, antigen-presenting cells (such as tumor-derived antigens or nucleic acid pulses) Dendritic cells), immunostimulatory cytokines (for example, IL-2, IFN-tumor, GM-CSF), and cells transfected with genes encoding immunostimulatory cytokines (such as but not limited to GM-CSF).

Dosage and dosing schedule

The choice of the dosing regimen (also referred to herein as the administration regimen) for the drug combination of the present invention depends on several factors, including the individual's solid serum or tissue turnover rate, symptom level, overall immunogenicity, and target. The accessibility of cells, tissues, or organs. Preferably, the dosing regimen maximizes the amount of each therapeutic agent delivered to the patient, consistent with an acceptable level of side effects. Therefore, the dosage and frequency of administration of each biotherapeutic agent and chemotherapeutic agent in the drug combination depends in part on the specific therapeutic agent, the severity of the cancer being treated, and the characteristics of the patient. Guidance on choosing the appropriate dosage of antibodies, cytokines, and small molecules can be obtained. See, 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 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 a suitable dosage regimen can be performed by a clinician, for example, with reference to parameters or factors known or suspected to affect treatment or expected to affect treatment in the art, and it will depend on, for example, the patient's clinical history (e.g., previous treatment). ), the type and stage of cancer being treated, and biomarkers that respond to one or more therapeutic agents in the combination therapy.

Each therapeutic agent of the pharmaceutical combination of the present invention can be administered simultaneously (ie, in the same pharmaceutical composition), concurrently (ie, in separate pharmaceutical formulations, administered one after the other in any order), or sequentially in any order Apply. The therapeutic agents in the drug combination can be in different dosage forms (e.g., one drug is a tablet or capsule and the other drug is a sterile liquid formulation) and/or in a different administration schedule (e.g., the chemotherapeutic agent is administered at least daily And when the biotherapeutics are administered less frequently (e.g., once a week, once every two weeks, or once every three weeks), sequential administration is particularly useful.

In some embodiments, the therapeutic agent in at least one drug combination is administered using the same dosage regimen (therapeutic dose, frequency, and duration) that is commonly used when the agent is used to treat the same tumor as a single treatment. In other embodiments, the patient receives a smaller total amount of at least one therapeutic agent in the combination therapy than when the agent is used as a single treatment, such as a smaller dose, a less frequent dose, and/or a shorter duration of treatment .

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

The anti-PD-1 antibody in the pharmaceutical combination of the present invention can be administered by continuous infusion or by interval doses, and the dose range for a single administration can be about 0.01 to about 20 mg/kg, about 0.1 to about 10 mg/kg of individual body weight, or about 120 mg Up to a fixed dose of about 480mg. For example, the dosage may be about 0.1, about 0.3, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg/kg of the body weight, or about 120 mg, 240mg, 360mg or 480mg fixed dose. Dosing regimens are usually designed to achieve such exposures that result in sustained receptor occupancy (RO) based on the typical pharmacokinetic properties of Ab. A representative dosing regimen may be about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once a month, or more once. In some embodiments, the anti-PD-1 antibody is administered to the individual about once every three weeks.

In some embodiments, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is teriprizumab, and its single administration dose is selected from about 1 to about 5 mg/kg of the individual's body weight. In some embodiments, the single administration dose of teriprizumab is selected from doses of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 3 mg/kg, 4 mg/kg, and 5 mg/kg of the individual’s body weight, or 120 mg, Fixed doses of 240 mg and 480 mg, administered intravenously. In some preferred embodiments, teriprizumab is administered as a liquid drug, and the selected dose of the drug is administered by intravenous infusion over a period of 30 to 60 minutes. In some embodiments, teriprizumab is administered in a fixed dose of about 3 mg/kg or about 240 mg, once every three weeks (Q3W), by intravenous infusion over a period of 30 minutes.

The multi-receptor tyrosine kinase (multi-RTK) inhibitor in the pharmaceutical combination of the present invention is administered at its approved or recommended dose, and the treatment is continued until clinical effects are observed or until unacceptable toxicity or disease progression occurs. In some embodiments, the multi-receptor tyrosine kinase (multi-RTK) inhibitor in the pharmaceutical combination of the present invention is Sofatinib, and its single administration dose is selected from any fixed dose of about 50 mg to about 350 mg. In some embodiments, the single administration dose of Sofatinib is selected from any fixed dose of about 50 mg, 75 mg, 100 mg, 110 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, or 350 mg. A typical dosing regimen may be twice a day, once a day, once every two days, or once every three days. In some embodiments, Sofatinib is administered to the individual once a day. In some embodiments, Sofatinib is administered at a dose selected from about 125 mg, about 150 mg twice daily (BID). In other embodiments, Sofatinib is administered at a dose of about 250 mg once daily.

The most preferred dose of sofatinib in combination can be identified by the dose of one of teriprizumab. In one embodiment, teriprizumab is administered at a fixed dose of about 240 mg Q3W, sofatinib is administered at a starting dose of about 250 mg QD, and if the patient tolerates this dose combination, sofat Increase the dose level of tinib by 50 mg/day, and if the patient does not tolerate the starting dose combination, reduce the dose level of sofatinib by 50 mg/day, and the number of dose reductions for each patient cannot exceed 2 times. The lowest dose level can be Downgrade to 150mg QD.

In some embodiments, teriprizumab is administered at a fixed dose of about 240 mg, Q3W, and sofatinib is administered at a fixed dose of about 300 mg, QD continuously. In some embodiments, teriprizumab is administered at a fixed dose of about 240 mg, Q3W, and sofatinib is administered at a fixed dose of about 250 mg, QD continuously. In some embodiments, teriprizumab is administered at a fixed dose of about 240 mg, Q3W, and sofatinib is administered at a fixed dose of about 200 mg, QD continuously.

In some embodiments, Sofatinib is taken orally within 1 hour after breakfast. On the day of teriprizumab administration, sofatinib may be administered before or after the administration of teriprizumab.

The administration period of the anti-PD-1 antibody and/or multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention can be the same or different, and is one week, two weeks, three weeks, one month, two months, three months. Months, four months, five months, half a year or longer, optionally, the time of each dosing cycle can be the same or different, and the interval between each dosing cycle can be the same or different. For example, in some embodiments, teriprizumab is administered in a fixed dose of about 240 mg, once every three weeks, and sofatinib is administered in a fixed dose of about 250 mg, once a day, for continuous administration. The drug cycle is three weeks.

Treatment method or use

The present invention provides the aforementioned pharmaceutical combination product of the present invention, which is used to prevent and/or treat the severity of at least one symptom or indication of cancer in an individual or inhibit the growth of cancer cells.

The present invention provides a method of preventing or treating cancer, which comprises administering an effective amount of the pharmaceutical combination of the present invention to an individual in need. The effective amount includes a preventive effective amount and a therapeutically effective amount.

The present invention provides the use of the aforementioned pharmaceutical combination of the present invention in the preparation of drugs for the prevention or treatment of cancer. The drug combination of the present invention can be used before or after surgery to remove tumors, and can be used before, during, or after radiotherapy.

In some embodiments, the drug combination of the present invention is administered to a patient who has not been previously treated with a biotherapeutic agent or chemotherapeutic agent, that is, treated for the first time. In other embodiments, the combination therapy is administered to patients who have not achieved a sustained response after previous treatment (ie, undergoing treatment) with a biotherapeutic agent or chemotherapeutic agent.

The drug combination of the present invention can be used to treat tumors discovered by palpation or by imaging techniques known in the prior art, such as MRI, ultrasound or CAT scan.

The drug combination of the present invention is administered to display one or more cancer-related biomarkers [e.g., programmed death ligand 1 (PD-L1), CA125, CA19-9, prostate specific antigen (PSA), lactate Individuals with elevated levels of hydrogenase, KIT, carcinoembryonic antigen, vascular endothelial growth factor (VEGF)]. For example, a prophylactically effective amount or a therapeutically effective amount of the pharmaceutical combination of the present invention is administered to an individual with an elevated PD-L1 level and/or an elevated VEGF level.

The drug combination of the present invention is used to treat cancer, such as neuroendocrine tumors, biliary tract cancer, gastric cancer (such as gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, lung cancer (such as non-small cell lung cancer, lung squamous cell carcinoma and small Cell lung cancer), soft tissue sarcoma, endometrial cancer, colorectal cancer, breast cancer, bladder cancer, renal clear cell carcinoma, head/neck squamous cell carcinoma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer and Esophageal cancer (such as esophageal squamous cell carcinoma); or hematological malignancy, which is selected from leukemia or lymphoma. In some embodiments, wherein the cancer is a neuroendocrine tumor. In some embodiments, wherein the cancer is selected from biliary tract cancer, gastric cancer (such as gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, soft tissue sarcoma, endometrial cancer, or esophageal cancer (such as esophageal squamous cell carcinoma). It should be noted that the biliary tract cancer, gastric cancer, thyroid cancer, soft tissue sarcoma, endometrial cancer, and esophageal cancer described in the present invention do not include the biliary tract, stomach, thyroid, soft tissue, and intrauterine tumors that are pathologically classified as neuroendocrine tumors. Cancer or tumor in the membrane and esophagus. In some embodiments, wherein the cancer is selected from non-small cell lung cancer and small cell lung cancer. . It should be noted that the neuroendocrine tumors described in the present invention do not include non-small cell lung cancer and small cell lung cancer.

Neuroendocrine neoplasm (NEN) is a tumor derived from cells of the endocrine (hormonal) and nervous system. Neuroendocrine tumors include tumors with different types, functions, and behavioral characteristics. Neuroendocrine tumors can be classified according to grade and differentiation. Generally, well-differentiated neuroendocrine tumors are defined as neuroendocrine tumor (NET), and poorly differentiated neuroendocrine tumors are defined as neuroendocrine carcinoma (NEC), refer to 2018 IARC /WHO proposed classification framework for neuroendocrine tumors. In certain embodiments, the neuroendocrine tumor is a neuroendocrine tumor (NET). In certain embodiments, the neuroendocrine tumor is neuroendocrine carcinoma (NEC).

Neuroendocrine tumors are classified according to the source location. In certain embodiments, the neuroendocrine tumor is selected from pancreatic neuroendocrine tumors (pNET), lung carcinoid tumors, gastric carcinoid tumors, duodenal carcinoid tumors, jejunal carcinoid tumors, ileal carcinoid tumors, colon Carcinoid tumors and rectal carcinoid tumors. In other embodiments, the neuroendocrine tumor is a neuroendocrine tumor selected from the group consisting of ovary, thymus, medulla of thyroid, adrenal gland (e.g., pheochromocytoma), and paraganglia (paraganglioma). In certain embodiments, the neuroendocrine tumor is a primary tumor. In certain embodiments, the neuroendocrine tumor is a metastatic tumor. In certain embodiments, the neuroendocrine tumor has not spread beyond the wall of the primary organ. In certain embodiments, the neuroendocrine tumor spreads out of the wall of the primary organ to reach adjacent tissues, such as fat, muscle, or lymph nodes. In certain embodiments, the neuroendocrine tumor has spread to tissues or organs away from the primary organ, such as the liver, bones, or lungs.

In certain embodiments, the neuroendocrine tumor is resistant to treatment. By way of non-limiting example, the tumor may be chemotherapy resistant (ie, resistant to one or more forms of chemotherapy). In certain embodiments, the tumor is resistant to treatment with somatostatin analogs. In certain embodiments, the tumor is resistant to treatment with kinase inhibitors.

Pill box

The anti-PD-1 antibody or antigen-binding fragment thereof described herein and the multi-receptor tyrosine kinase (multi-RTK) inhibitor or a pharmaceutically acceptable salt thereof described herein can be used as a container comprising a first container and a second container. Pill box with container and package insert is provided. The first container contains at least one dose of the preparation containing the anti-PD-1 antibody or antigen-binding fragment thereof, and the second container contains at least one dose of the multi-receptor tyrosine kinase inhibitor described therein or its pharmaceutically acceptable The salt preparation, and the package insert or label contains instructions on using the preparation to treat cancer in patients. The first and second containers may comprise the same or different shapes (e.g. vials, syringes and bottles) and/or materials (e.g. plastic or glass). The kit may further contain other materials that can be used to administer the formulation, such as diluents, filters, IV bags and tubing, needles, and syringes.

In some embodiments, the kit includes:

(1) One or more single drug dosage units containing about 120 mg to about 480 mg, such as 120 mg, 240 mg, 360 mg or 480 mg, preferably 240 mg, of the anti-PD-1 antibody or antigen-binding fragment thereof ;with

In the above embodiment, the single drug dosage unit refers to a single drug dosage form containing the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention for a single administration to a patient and/or a multiple drug dosage form of the present invention. Single-dose dosage form of receptor tyrosine kinase inhibitor. The single drug dosage form may be a dosage form for parenteral administration, such as a vial, ampule, prefilled needle or prefilled syringe for injection, a solution or lyophilized powder containing the drug, or a parenteral administration The dosage form of, such as tablets, capsules, lozenges, powders, suspensions, etc. for oral administration.

These and other aspects of the invention, including the exemplary embodiments listed below, will be apparent from the teachings contained herein.

Detailed ways

Example 1 Anti-tumor synergistic effect of JS001 and Sofatinib in combination with MC38 tumor model

1.1 The purpose of the experiment:

In this experiment, human PD-1 transgenic mice were injected subcutaneously with mouse MC38 colon cancer cells to establish a tumor model. The synergistic effect of JS001 and HMPL-012 on anti-tumor was evaluated by the size of the tumor and the weight of the mouse.

1.2 Source of medicine

JS001 (Treprizumab), batch number 20171208, produced and provided by Suzhou Junmeng Biomedical Technology Co., Ltd. HMPL-012 (Sofatinib), the batch number is C12053128-AF17001M, produced by Hequan Pharmaceutical.

1.3 Test method

MC38 cells (purchased from Shunran Shanghai Biological Technology Co., Ltd.) were harvested on the day of inoculation, and cells resuspended in PBS (5*10 ⁵ cells/0.1ml/cell) were inoculated into transgenic B-hPD-1 C57bl/c cells. Mouse (from Biocytogen Jiangsu Gene Biotechnology Co., Ltd.; female; 7-8W) under the skin of the right axillary, and the tumor grows to about 123mm ³ volume on the 6th day. The mice are randomly divided into 4 groups (control group G1 , Administration group G2, G3 and G4), each group has 12 rats. The administration was started on the day of grouping, and the specific dosing schedule is shown in Table 1.

Table 1 Experimental grouping and dosing plan

Note: a: Configure the administration volume (10μl/g) according to the weight of the mouse;

b: i.p.: refers to administration via intraperitoneal injection; p.o: administration via oral route;

c: BIW: Dosing frequency is twice a week; BID: Dosing frequency is twice a day.

1.4 Observation indicators and statistical analysis of data

The tumor volume was measured twice a week, the animals were weighed once a week, and the data was recorded.

If any mouse in the experiment has one of the following conditions, the mouse will be suspended from the experiment and removed from the data collection: (1) the tumor volume of the mouse exceeds 3000mm ³ ; (2) 3 mice have severe tumors Ulcers, and no scar formation within three days; (3) abnormal movement or paralysis in the mice; (4) the weight loss of the mice exceeded 20% before the start of the experiment.

At the end of the experiment 25 days after the first administration, the mice were euthanized, the isolated tumor tissues were photographed and weighed for measurement, the tumor weight and volume (end tumor volume) of each group of mice were measured, and the relative tumor growth inhibition rate TGI (%) ). The calculation formula for the relative tumor growth inhibition rate is as follows:

Relative tumor growth inhibition rate TGI(%)=100%×(Tvol _control -Tvol _treated )/(Tvol _control -Tvol _predose )

Among them, Tvol _control -Tvol _treated = terminal tumor volume after administration of the control group-terminal tumor volume of the administration group after administration; Tvol _control- Tvol _predose = final tumor volume of the control group after administration-before administration of the control group Tumor volume (Tumor volume before administration on day 7).

The body weight and tumor volume of each group of animals are expressed as mean±standard deviation (Mean±SEM), and the tumor volume is calculated ^{according to (length×width 2 )/2.} T-test was used to determine statistical significance, and a P value of <0.05 was considered statistically significant in all analyses.

1.5 Experimental results

The results of the experiment are shown in Table 2 and Figure 1, which show that the test drug JS001 has a certain inhibitory effect on tumor growth at the level of 0.3 mg/kg; the test drug Sofantinib has a certain inhibitory effect on tumor growth at the dose level of 40 mg/kg. Effect: Compared with JS001 (0.3mg/kg) and Sofatinib (40mg/kg) single drug, JS001 (0.3mg/kg) combined with Sofatinib (40mg/kg) is statistically more significant To inhibit tumor growth.

Table 2 Inhibitory effects of drugs on tumor tissue growth in tumor-bearing mice

Note: a: *P＜0.05

Example 2 An open, single-arm, multi-center phase II clinical study to evaluate the efficacy and safety of sofantinib combined with teriprizumab in the treatment of patients with advanced solid tumors

This study is an open, single-arm, multi-center phase II clinical study evaluating sofatinib combined with teriprizumab in the treatment of patients with advanced solid tumors who have failed standard therapies or have no effective treatments.

2.1 Research purpose

The main purpose of this study is to evaluate the objective response rate (ORR) (RECIST1.1 standard) of sofatinib combined with teriprizumab in the treatment of patients with advanced solid tumors and to evaluate the safety and tolerability of some patients. .

The secondary objectives of this study include: (1) To evaluate the ORR (irRECIST criteria), duration of remission (DoR), and progression-free survival (PFS) in patients with advanced solid tumors treated with sofatinib combined with teriprizumab. Disease control rate (DCR) (RECIST1.1 standard and irRECIST standard) and overall survival (OS); (2) Evaluation of Sofatinib combined with Teriprizumab in the treatment of patients with advanced solid tumors (safety introduction) Except part) safety and tolerability; (3) To evaluate the pharmacokinetics (PK) of sofatinib combined with teriprizumab in patients with advanced solid tumors; (4) to evaluate the combination of sofatinib The immunogenicity of teriprizumab in patients with advanced solid tumors; (5) To detect the expression of PD-L1 in the tumor tissue specimens of the patients, and to perform related efficacy analysis (RECIST1.1 standard and irRECIST standard), in order to determine the advantages The crowd provides reference.

And the exploratory purpose is to study the biomarkers of drug efficacy prediction and the mechanism of drug resistance.

2.2 Research principle

According to the investigator's manual, the recommended dose of teriprizumab in current clinical studies is a fixed dose of 240 mg, administered once every three weeks. The recommended dose of sofatinib as a single agent is 300 mg, QD. In the phase I exploratory study (NCT03879057) of the combination of sofatinib and teriprizumab, teriprizumab is still a fixed dose of 240 mg, once every three weeks; sofantinib explored 200 mg, 250 mg and 300mg, QD, a total of 3 dose groups. Among them, no DLT was observed in 3 patients in the 200mg group and 6 patients in the 250mg group, and 1 DLT was observed in 7 patients in the 300mg group, which was grade 3 hyperthyroidism and recovered after treatment. Moreover, all three dose groups also showed certain anti-tumor efficacy. Although the safety and tolerability of the three dose groups are good, and they are all clinically effective doses, in the same treatment time window, the 250mg group has better efficacy and fewer adverse reactions. Therefore, combined with the results of clinical drug safety, tolerability, and efficacy, the combined dose of this study selected: sofatinib 250mg, QD; teriprizumab, 240mg, intravenously, once every three weeks.

2.3 Research plan

The research plan enrolls about 200 patients with advanced solid tumors (about 30-40 cases of neuroendocrine tumors, about 10-20 cases of biliary tract cancer, about 10-20 cases of gastric adenocarcinoma and gastroesophageal junction adenocarcinoma, and about 10- 20 cases of thyroid cancer). 20 cases, about 10-20 cases of small cell lung cancer, about 10-20 cases of soft tissue sarcoma, about 10-20 cases of endometrial cancer, about 10-20 cases of esophageal squamous cell carcinoma, about 10-20 cases of non-small cell lung cancer, including Introduced into the safety of some 6 patients, all of them will receive the combination therapy of sofatinib and teriprizumab every 3 weeks: sofatinib 250mg, QD, orally after meals + teriprizumab, 240mg, intravenous drip, Q3W.

The safety introduction part plans to enroll 6 patients. The safety of these 6 patients will be evaluated by the Drug Safety Evaluation Committee (SRC) within 28 days after the first administration (DLT observation period). Only when the DLT observation period of 6 patients is completed and the safety is determined by SRC to be tolerable (≤1/6 subjects have DLT) can they continue to be enrolled. If the safety assessment of some patients cannot be tolerated, the Drug Safety Review Committee (SRC) will recommend the use of 200 mg of sofatinib based on the part of the patient’s safety assessment and the phase I study of sofatinib combined with teriprizumab , Once a day (QD), orally after a meal + teriprizumab, 240 mg, intravenous drip, once every 3 weeks (Q3W); or other new combined doses.

DLT definition: According to the NCI CTCAE 5.0 evaluation criteria, within 28 days after the first administration (DLT observation period), the investigator judges that the following toxic reactions related to sofatinib and/or teriprizumab will be Defined as DLT:

1. Non-hematological toxicity:

· Grade 4 non-hematological toxicity;

· Grade 3 non-hematological toxicity, except for the following conditions:

· Nausea, vomiting, diarrhea, constipation, fatigue, and electrolyte imbalance are restored to grade 2 or below within 7 days after supportive treatment;

·Grade 3 endocrine diseases that can be adequately controlled by hormone replacement therapy;

·Laboratory abnormalities related to Level 3 drugs that are not clinically significant;

·Drug treatment can control hypertension with systolic blood pressure ≤140mmHg and diastolic blood pressure ≤90mmHg;

· Whether grade 3 and grade 4 infusion reactions belong to DLT is determined by the investigator and the sponsor through discussion.

2. Blood toxicity:

· Grade 4 simple neutropenia, and the duration is more than 3 days;

· Grade 3 or 4 fever neutropenia;

·Grade 3 thrombocytopenia with bleeding tendency;

·Grade 4 thrombocytopenia;

· Grade 4 anemia.

3. Any life-threatening adverse events.

DLT can evaluate patients who need to meet all of the following conditions:

·The subject received at least one cycle of teriprizumab and 85% or more of the prescribed dose of sofatinib during the DLT observation period; adverse events that occurred during the DLT observation period have not been It is confirmed that no medical intervention is taken before DLT (except for the adverse events that are allowed to be treated in the DLT definition and some of the grade 2 adverse events recommended for treatment in the plan);

· Completed the safety evaluation of the entire DLT observation period or withdrew early due to DLT.

Patients who do not meet the above conditions need to be added to the group of new subjects to ensure that at least 6 patients can be evaluated by DLT in the safety introduction part.

If patients undergoing DLT during the DLT observation period, the investigator can judge whether to receive follow-up study drug treatment, and reduce the dose according to the dose adjustment principle specified in the plan (the dose adjustment of teriprizumab is not allowed) or stop the drug.

All patients will receive treatment with sofatinib combined with teriprizumab until the disease progresses, death, toxicity is intolerable, patients voluntarily request to terminate the study treatment or withdraw their informed consent, start new anti-tumor therapy, pregnancy, severe Violation of the study procedure stipulated in the protocol, the investigator's decision to terminate the study treatment based on the best interests of the patient, and the loss to follow-up, whichever occurs first, but the treatment time of tereprizumab is up to 24 months.

During the study period, the investigator will use RECIST 1.1 and irRECIST standards for tumor evaluation. Tumor imaging evaluation will be performed every 6 weeks (±7 days) from the first medication, and once every 12 weeks (±7 days) after 48 weeks. Tumor imaging evaluation until the disease progresses, death, toxicity is intolerable, or other criteria for terminating the study treatment specified in the protocol are reached, whichever occurs first. When CR or PR appears for the first time, it needs to be confirmed after 4 weeks (±7 days).

Patients who terminate the study treatment for any reason other than disease progression (except withdrawal of informed consent or death) should still go to the research center for tumor evaluation according to the visit plan stipulated in the research plan until the disease progresses, death, and the start of a new anti-tumor Treatment, loss to follow-up, withdrawal of informed consent, and end of the study, whichever occurs first. If the patient has not undergone a tumor evaluation within 28 days before the termination of study treatment/withdrawal from the study, a tumor evaluation should be performed at the time of termination of study treatment/withdrawal from the study.

Since the termination of study treatment (termination of sofatinib or teriprizumab treatment, whichever occurs later) as the starting point, a survival follow-up (telephone follow-up) will be carried out every 12 weeks, and the anti-tumor treatment after the disease progression will be recorded at the same time. Until the patient's death, loss to follow-up, withdrawal of informed consent, and the end of the study, the first event shall prevail.

During the study period, from the signing of the informed consent, to reporting all SAEs (Severity Adverse Event) before using the first dose of study drug; from the first use of study drug until the last administration of study drug (sofantinib) Or the last administration of teriprizumab, whichever occurs later) or before starting new anti-tumor therapy, record all AEs and report SAEs (including special adverse events specified in the protocol); 90 days after the last administration Or start a new anti-tumor treatment until the end of the study, and only report the SAE that the investigator confirms related to the study drug. All AEs will be classified by NCI CTCAE version 5.0. All SAEs will be followed up until the adverse event returns to the baseline state, the investigator judges that it is in a stable state, the patient starts a new anti-tumor treatment, is lost to follow-up, withdraws informed consent, and died, subject to the first event.

The study is divided into 3 periods: the screening period, the treatment period and the follow-up period, as shown in Table 3.

Table 3 Time definition of the three periods during the study period

The patient ended the trial in the following 5 cases:

1) The patient withdrew his informed consent and refused to continue to provide information;

2) Screening failed;

3) Death;

4) The patient was lost to follow-up;

5) The entire clinical study is over.

2.4 Study population

About 16 domestic research centers such as Peking University Cancer Hospital and Fudan University Cancer Hospital.

The target population of the study was confirmed by histology or cytology, failed standard treatment (disease progression after treatment or intolerable side effects of treatment), no standard treatment method or unable to receive standard treatment, and cannot be surgically removed or metastatic advanced entities Tumor patients (mainly neuroendocrine tumors, biliary tract cancer, gastric cancer, thyroid cancer, small cell lung cancer, soft tissue sarcoma, endometrial cancer, esophageal cancer, non-small cell lung cancer and other tumors).

Requirements for previous anti-tumor system therapy:

1) Patients with unresectable or metastatic advanced solid tumors confirmed by histology or cytology (such as neuroendocrine tumors, biliary tract cancer, gastric cancer, thyroid cancer, small cell lung cancer, soft tissue sarcoma, endometrial cancer, esophageal cancer, non- Mainly small cell lung cancer and other tumors);

2) Patients who have failed standard treatment (disease progression after treatment or intolerable side effects of treatment), no standard treatment method or unable to receive standard treatment; non-small cell lung cancer is not previously received systemic anti-tumor treatment;

3) It is clear that there is a measurable lesion that meets the requirements of the solid tumor efficacy evaluation standard (RECIST 1.1 standard); if the lesion that has received local treatment (radiotherapy, ablation, vascular intervention, etc.) is the only lesion, it must have disease progression in the lesion Clarify the basis of imaging;

2.5 Treatment plan

During the study period, on the day of the combination of sofatinib and teriprizumab, it is recommended that sofantinib be taken orally first, followed by intravenous infusion of teriprizumab. All patients will be treated with sofatinib and teriprizumab, a treatment cycle of 3 weeks, until the disease progresses, death, the patient voluntarily requests the termination of the study treatment, the toxicity is intolerable, the start of a new anti-tumor therapy, and pregnancy , Serious violation of the research procedure stipulated in the protocol, the researcher decided to terminate the research treatment based on the best interests of the patient, and the loss to follow-up, whichever occurs first, but the longest treatment time of teriprizumab is 24 months.

Sofatinib: 250mg, orally within 1 hour after breakfast, once a day for continuous administration.

During the research process, every effort should be made to ensure that patients are taking medication according to the research protocol. If the patient misses taking the medicine in the morning, he can take it again at any time before 10 o'clock in the evening of the same day. However, if the patient misses taking the prescribed medication and fails to take it again on the same day, he must take the prescribed medication next time, but the missed medication will not need to be retaken. Missed medications must be reported to the investigator and recorded on the CRF. If the patient vomits after taking the medicine, it is not recommended to take the medicine unless the complete capsule is seen.

Strenuous exercise should be avoided during the trial; patients should avoid drinking high-concentration grapefruit juice and eating grapefruit and beverages containing this ingredient.

Teriprolizumab: 240mg, intravenous drip, Q3W, the first intravenous infusion time is at least 60 minutes. If the first infusion is well tolerated, the time for the second infusion can be shortened to 30 minutes. If the patient also has a good tolerance for the 30-minute infusion, all subsequent infusions can be completed within 30 minutes. Do not use intravenous bolus injection or single rapid intravenous injection.

The dosage forms and specifications of the drugs are shown in Table 4.

Table 4 Dosage Forms and Specifications of Drugs

2.6 Dose adjustment

2.6.1 Sofatinib

When drug toxicity and side effects occur during treatment, the dose can be reduced, but the number of dose reductions for each patient cannot exceed 2 times, and the minimum dose level can be reduced to 150 mg/day. After the dose is reduced, it cannot be returned to the previous dose level.

In order to restore the toxicity, unless otherwise specified, treatment can generally be suspended for up to 28 days. If the toxicity cannot be restored to grade 1 or baseline after stopping the drug for more than 28 days, it is considered intolerant and Sofatinib is permanently discontinued.

Table 5 Reference table for dose adjustment

2.6.2 Teriprolizumab

According to the safety and tolerability of the patient, the researcher may need to suspend the administration or permanently discontinue the drug during the treatment of teriprizumab. It is not recommended to increase or decrease the dose. A maximum of 12 weeks of drug suspension is allowed, calculated from the time of the last administration. If there is a delay during the period of teriprizumab treatment every 3 weeks, all future dosing days will be delayed to ensure that the dosing interval between teriprizumab treatment cycles is 21 ± 3 days . When patients who need to delay dosing meet the criteria for resuming dosing, study dosing can be resumed. Regardless of whether there is a delay in dosing, tumor evaluation for all patients should continue as required by the protocol. If after a 12-week suspension, the patient still does not meet the criteria for re-dosing, the study treatment of teriprizumab needs to be permanently terminated. For patients who meet the criteria for permanent discontinuation of treatment, if the treatment of teriprizumab is restarted, the investigator should discuss with the sponsor and fully consider the patient's benefit and immune-related adverse events have fully recovered.

2.7 Sample size calculation and statistical analysis:

2.7.1 Calculation of sample size:

It is planned to enroll about 200 patients with advanced solid tumors whose tumor efficacy can be evaluated (about 30-40 cases of neuroendocrine tumors, about 10-20 cases of biliary tract cancer, about 10-20 cases of gastric adenocarcinoma and gastroesophageal junction adenocarcinoma, and thyroid cancer. About 10-20 cases, about 10-20 cases of small cell lung cancer, about 10-20 cases of soft tissue sarcoma, about 10-20 cases of endometrial cancer, about 10-20 cases of esophageal squamous cell carcinoma, about 10-20 cases of non-small cell lung cancer Among them, about 20 patients with the above-mentioned tumors who have received immunotherapy in the past). The actual sample size may be adjusted according to the progress of the study of sofantinib combined with teriprizumab.

2.7.2 Statistical analysis methods:

The results of this study mainly use descriptive statistical methods. The measurement data lists the number of people, mean, standard deviation, median, maximum, and minimum. Count data and grade data list frequency and percentage.

2.7.3 Effectiveness analysis:

The analysis of tumor efficacy-related indicators will be mainly based on the evaluable population of tumor efficacy, which is defined as all patients who have used study drugs, have measurable lesions at baseline, and have at least one tumor evaluation after baseline. Based on the tumor efficacy, the population can be evaluated to calculate ORR and DCR, and the Clopper-pearson method is used to calculate the 95% accurate confidence interval (CI). In addition, a supportive analysis of tumor efficacy indicators will be made based on the ITT set. The ITT (Intention-to-Treat) set is defined as all patients who have received at least one study drug treatment. The analysis of PFS and OS will be based on the ITT set. For the time variables of the event, including DoR, PFS and OS, if the data allows, the Kaplan-Meier method will be used to estimate the median value, the quartile and its 95% CI, as well as the probability of PFS and OS at the time of interest. .

Consider that the above analysis will be repeated in different PD-L1 expressing populations.

2.7.4 Security analysis:

The security analysis will be based on the ITT set. Safety evaluation includes adverse events, serious adverse events, changes in laboratory test results, changes in vital signs, electrocardiogram, left ventricular ejection fraction and ECOG score. Adverse events will be classified according to NCI CTCAE5.0. Use the International Dictionary of Medical Terms (MedDRA) to code adverse events. Summarize the number and frequency of adverse events according to the classification of human system organs and corresponding preferred terms. For laboratory test results, vital signs, electrocardiogram, left ventricular ejection fraction and ECOG, changes before and after treatment will be compared. The abnormal values with clinical significance will be displayed in a list.

2.7.5 Pharmacokinetic analysis:

All patients who have used the study drug, have at least one PK sampling and analysis, and have not had an important protocol deviation that affects the PK data will be included in the PK analysis (i.e., PK analysis set). The non-compartmental model will be used to analyze blood drug concentration data through Winnolin software to calculate related PK parameters, including: t _1/2 , T _max , C _max , AUC _0-∞ , AUC _0-t , CL/F, VZ/F etc. The blood drug concentration data and PK parameters will be described using appropriate statistical tables and graphs.

2.7.6 Immunogenicity analysis:

Calculate the positive rates of teriprizumab anti-drug antibody (ADA) and neutralizing antibody (NAb), and use descriptive statistical analysis for summary.

2.7.7 Biomarker analysis:

Descriptive statistical analysis results of possible correlation between biomarkers and disease prognosis will be provided, and the results will be listed in a separate report.

2.8 Research results

2.8.1 Security Summary

In this clinical trial, a total of 3 solid tumor patients have been enrolled in the drug combination of sofatinib and teriprizumab of the present invention, all of whom have passed the DLT observation period and have not DLT is observed. So far, no adverse events of CTCAE level 2 or above have occurred, and no unexpected safety signals (adverse events) have been observed, and it is well tolerated. Some patients (2 cases) achieved partial remission after receiving treatment, showing excellent anti-tumor activity.

2.8.2 Safety analysis results

In this clinical trial, a total of 157 solid tumor subjects were enrolled in the drug combination of sofatinib and teriprizumab of the present invention, with 96.8% of subjects enrolled as of December 31, 2020. At least one adverse event occurred; 42.7% of subjects had an adverse event of grade ≥3 (CTCAE v5.0), and 33.8% of subjects had a treatment-related adverse event of grade ≥3 (CTCAE v5.0); 26.1% Of the subjects experienced serious adverse events, of which the incidence of treatment-related serious adverse events was 15.3%. No unexpected safety signals (adverse events) were observed, and it is well tolerated. The safety analysis results of different tumor types and/or cohorts are shown in Table 6 below.

2.8.3 Results of effectiveness analysis

In the ITT population, as of December 31, 2020, a total of 139 subjects have undergone efficacy evaluation, including 20 neuroendocrine carcinomas, 19 neuroendocrine tumors, 20 esophageal squamous cell carcinomas, 18 biliary tract cancers, and 19 Cases of small cell lung cancer, 8 cases of thyroid cancer, 14 cases of soft tissue sarcoma, 15 cases of gastric adenocarcinoma and gastroesophageal junction adenocarcinoma, 6 cases of endometrial cancer. According to the RECIST 1.1 standard, the best efficacy evaluation evaluated by the investigator is shown in Table 7.

Overall efficacy evaluation:

Among the 139 subjects who received efficacy evaluation, 1 subject achieved complete remission (CR), 27 subjects were partial remission (PR), and 20 subjects were confirmed partial remissions (PR), the best curative effect in 75 subjects was stable disease (SD), and one subject could not be evaluated. The ORR and confirmed ORR were 20.1% (95% CI 13.8%-27.8%) and 15.1% (95% CI 13.8%-27.8%). %CI 13.8%-27.8%), DCR is 74.8% (95%CI 66%-81.2%).

Efficacy evaluation of each subgroup:

Among the 20 neuroendocrine cancer subjects who have undergone efficacy evaluation, 5 subjects achieved partial remission (PR), of which 4 subjects were confirmed partial remission (PR), and 9 subjects were the best The curative effect is stable disease (SD), ORR and confirmed ORR are 25.0% (95% CI 8.7%-49.1%) and 20.0% (95% CI 5.7%-43.7%), and DCR (95% CI) is 70.0% ( 95% CI 45.7%-88.1%).

Among the 19 neuroendocrine tumor subjects who have undergone efficacy evaluation, one subject achieved confirmed partial remission (PR), and the best efficacy for 16 subjects was stable disease (SD), with a confirmed ORR of 5.3% (95%CI 0.1%-26.0%), DCR is 89.5% (95%CI 66.9%-98.7%).

Among the 20 subjects with esophageal squamous cell carcinoma undergoing efficacy evaluation, 1 subject achieved a confirmed complete remission (CR), 5 subjects achieved partial remission (PR), and 4 of them In order to confirm partial remission (PR), the best therapeutic effect for 6 subjects was stable disease (SD), ORR and confirmed ORR were 30.0% (95% CI 11.9%-54.3%) and 25.0% (95% CI 8.7%) -49.1%), the DCR is 60.0% (95% CI 36.1%-80.9%).

Among the 18 subjects with biliary tract cancer who have undergone efficacy evaluation, 3 subjects achieved confirmed partial remission (PR), and the best efficacy in 8 subjects was stable disease (SD), with a confirmed ORR of 16.7% (95 %CI 3.58%-41.4%), DCR is 61.1% (95%CI 35.8%-82.7%).

Among the 19 subjects with small cell lung cancer who have undergone efficacy evaluation, 3 subjects achieved partial remission (PR), of which 2 subjects were confirmed partial remission (PR), and 15 subjects were the best Efficacy is stable disease (SD), ORR and confirmed ORR are 15.8% (95% CI 3.38%-39.6%) and 10.5% (1.3%-33.1%) respectively, DCR is 94.7% (95% CI 74%-99.9%) ).

Among the 8 subjects with thyroid cancer that have undergone efficacy evaluation, 2 subjects achieved confirmed partial remission (PR), and the best efficacy in 5 subjects was stable disease (SD), and the confirmed ORR was 25.0% (95 %CI 3.2%-65.1%), DCR is 87.5% (95%CI 47.4%-99.7%). Among the 14 subjects with soft tissue sarcoma that have undergone efficacy evaluation, one subject achieved confirmed partial remission (PR), and the best efficacy in eight subjects was stable disease (SD), with a confirmed ORR of 7.1% (95 %CI 0.2%-33.9%), DCR is 64.3% (95%CI 35.1%-87.2%).

Among the 15 subjects with gastric adenocarcinoma and gastroesophageal junction adenocarcinoma who have undergone efficacy evaluation, 5 subjects achieved partial remission (PR), of which 2 subjects were confirmed partial remission (PR), 6 The best curative effect for each subject was stable disease (SD), ORR and confirmed ORR were 33.3% (95% CI 11.8%-61.6%) and 13.3% (1.7%-40.5%), and DCR was 73.3% (95%) CI 44.9%-92.2%).

Among the 6 subjects with endometrial cancer that have undergone efficacy evaluation, 2 subjects achieved partial remission (PR), of which 1 subject was confirmed partial remission (PR), and 2 subjects had the most The best curative effect is stable disease (SD), ORR and confirmed ORR are 33.3% (95% CI 4.3%-77.7%) and 16.7% (0.4%-64.1%) respectively, and DCR is 66.7% (95% CI 22.3%-95.7) %).

Claims

A pharmaceutical combination product comprising (i) an anti-PD-1 antibody or an antigen-binding fragment thereof, and (ii) a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof, wherein the anti-PD-1 antibody Or its antigen-binding fragments include the light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, and the amino acid sequence shown in SEQ ID NO: 1. The heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO: 2 and SEQ ID NO: 3.
The pharmaceutical combination product of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region contains the same as SEQ ID NO : 7 has the same sequence or an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity with it, and the light chain The variable region contains the same sequence as SEQ ID NO: 8 or at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the sequence Sexual amino acid sequence.
The pharmaceutical combination product of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the same sequence as SEQ ID NO: 9 or at least 90%, 91%, 92%, 93%, A heavy chain amino acid sequence with 94%, 95%, 96%, 97%, 98%, 99% or higher identity, and the same as SEQ ID NO: 10 or at least 90%, 91%, 92% with the sequence , 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity of the light chain amino acid sequence.
The pharmaceutical combination product according to any one of claims 1 to 3, wherein the multi-receptor tyrosine kinase inhibitor inhibits at least the tyrosine kinase activity of two or more of the following receptors: (1) One, two, or three of VEGFR1, VEGFR2, and VEGFR3, (2) one, two, three, or four of FGFR1, FGFR2, FGFR3, and FGFR4; and (3) CSF1R.
The pharmaceutical combination product of claim 4, wherein the multi-receptor tyrosine kinase inhibitor can simultaneously inhibit the tyrosine kinase activity of the receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R.
The pharmaceutical combination product of claim 5, wherein the multi-receptor tyrosine kinase inhibitor is sofatinib.
A pharmaceutical combination product according to any one of the preceding claims, wherein

(i) The single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from about 1 mg/kg to about 5 mg/kg of the individual's body weight, such as 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg /kg individual body weight, or a fixed dose selected from about 120mg to about 480mg, preferably 120mg, 240mg, 360mg or 480mg; and/or

(ii) The single administration dose of a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is selected from a fixed dose of about 150 to about 350 mg, such as 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg.
A pharmaceutical combination product according to any one of the preceding claims, wherein

(i) The frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof is once a week, once every two weeks, once every three weeks, once every four weeks, or once every five weeks, preferably once every three weeks; and/ or

(ii) The frequency of administration of a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is twice a day, once a day, once every two days, or once every three days, preferably once a day.
A pharmaceutical combination product according to any one of the preceding claims, wherein

(i) The single administration dose of anti-PD-1 antibody or its antigen-binding fragment is 1 mg/kg individual body weight, 2 mg/kg individual body weight, 3 mg/kg individual body weight, or 240 mg fixed dose, preferably 240 mg fixed dose per unit Three-weekly (Q3W) administration; and/or

(ii) The single administration dose of a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is 200 mg, 250 mg or 300 mg, preferably 250 mg, and is continuously administered once a day (QD).
A pharmaceutical combination product according to any one of the preceding claims, wherein

(i) The anti-PD-1 antibody or antigen-binding fragment thereof is administered in a liquid dosage form, such as an injection, via a parenteral route, such as intravenous infusion; and/or

(ii) The multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof can be administered via an intragastric route or a parenteral route, for example, in a solid dosage form, such as a capsule or a tablet, for oral administration.
The pharmaceutical combination product according to any one of the preceding claims, wherein the administration period of (i) and/or (ii) in the pharmaceutical combination product can be one week, two weeks, three weeks, one month, or two months , Three months, four months, five months, six months or longer, optionally, the time of each dosing cycle can be the same or different, and the interval between each dosing cycle can be the same or different.
The pharmaceutical combination product according to any one of the preceding claims, which is used for the prevention or treatment of cancer in an individual in need, wherein the cancer is a solid tumor selected from neuroendocrine tumors (eg: neuroendocrine tumors; neuroendocrine cancers) ; Pancreatic neuroendocrine tumors (pNET); non-pancreatic neuroendocrine tumors, such as lung carcinoid tumors, gastric carcinoid tumors, duodenal carcinoid tumors, jejunal carcinoid tumors, ileal carcinoid tumors, colon carcinoid tumors and rectum Carcinoid tumor), biliary tract cancer, gastric cancer (e.g. gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, lung cancer (e.g. non-small cell lung cancer, lung squamous cell carcinoma and small cell lung cancer), soft tissue sarcoma, endometrial Cancer, colorectal cancer, breast cancer, bladder cancer, renal clear cell carcinoma, head/neck squamous cell carcinoma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer and esophageal cancer (e.g. esophageal squamous cell carcinoma); or The cancer is a hematological malignancy, selected from leukemia or lymphoma.
A method of preventing or treating cancer, the method comprising administering to an individual in need an effective amount of a pharmaceutical combination product as defined in any one of the preceding claims, wherein the cancer is a solid tumor selected from neuroendocrine tumors (e.g., : Neuroendocrine tumors; neuroendocrine carcinomas; pancreatic neuroendocrine tumors (pNET); non-pancreatic neuroendocrine tumors, such as lung carcinoid tumors, gastric carcinoid tumors, duodenal carcinoid tumors, jejunal carcinoid tumors, and ileal carcinoid tumors Tumors, colon carcinoid tumors and rectal carcinoid tumors), biliary tract cancer, gastric cancer (e.g. gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, lung cancer (e.g. non-small cell lung cancer, lung squamous cell carcinoma, and small cell lung cancer) ), soft tissue sarcoma, endometrial cancer, colorectal cancer, breast cancer, bladder cancer, renal clear cell carcinoma, head/neck squamous cell carcinoma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer, and esophageal cancer (Such as esophageal squamous cell carcinoma); or the cancer is a hematological malignancy, selected from leukemia or lymphoma.
A kit comprising a drug combination product as defined in any one of the preceding claims, preferably the kit includes one or more single drug dosage units.
The kit of claim 14, comprising:

(1) One or more single drug dosage units containing about 120 mg to about 480 mg, such as 120 mg, 240 mg, 360 mg or 480 mg, preferably 240 mg, of the anti-PD-1 antibody or antigen-binding fragment thereof ;and / or

(2) One or more single drug dosage units containing about 150 mg to about 350 mg, such as 150 mg, 200 mg, 250 mg, 300 mg or 350 mg, preferably 250 mg dose of multi-receptor tyrosine kinase inhibitor Agent or a pharmaceutically acceptable salt thereof.