TW202143969A - Pharmaceutical combinations of anti-pd-1 antibodies and multi-receptor tyrosine kinase inhibitors and methods of use thereof - Google Patents

Abstract

The present invention relates to pharmaceutical combinations of anti-PD-1 antibodies and multi-receptor tyrosine kinase inhibitors and methods of use thereof. In particular, the present invention relates to pharmaceutical combinations of anti-PD-1 antibodies and multi-receptor tyrosine kinase inhibitors, as well as their use in the manufacture of a medicament for the prevention or treatment of cancer and methods of use thereof.

Description

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

The present invention relates to an anti-PD-1 antibody or an antigen-binding fragment thereof targeting programmed cell death 1 (Programmed Cell Death 1, PD-1) and a multi-receptor tyrosine kinase (multi-RTK) inhibitor. Pharmaceutical combination products for the prevention or treatment of cancer. The present invention also relates to uses and methods of using the combination product to prevent or treat cancer.

Programmed Cell Death 1 (PD-1) is a cell surface signaling 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 to ligands leads to immune evasion. A number of drugs that inhibit PD-1/PD-L1 interaction have been approved for marketing, including Nivolumab, Pembrolizumab, and Toripalimab, etc. broad antitumor activity. However, the effective rate of PD-1 inhibitor alone in the vast majority of unselected solid tumors is low, about 10%-30%. It has been proposed that it has the potential to enhance the efficacy of anti-PD-1 antibodies if administered in combination with other cancer therapies, such as radiation therapy, surgery, chemotherapeutic agents, targeted drugs that inhibit other signaling pathways that are dysregulated in tumors.

Simultaneous targeting of multiple tumor growth regulators 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 class of targeted drugs. Studies have shown that the signaling pathways mediated by VEGFRs and FGFRs play a key role in tumor angiogenesis and angiogenesis, and 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, resulting in the overexpression of PD-1 receptors on T cells. In turn, it reduces the anti-tumor activity of T cells and induces tumor immune tolerance; CSF1R and FGFRs-mediated signals are also involved in the proliferation, survival and differentiation of monocyte/macrophage cells (J Exp Med. 2015 Feb 9; 212(2 ): 139-48; Int J Mol Med. 2016 Jul; 38(1): 3-15). Therefore, targeted therapies that simultaneously inhibit pathways mediated by VEGFRs, FGFRs, and CSF1R may be able to more effectively inhibit tumor angiogenesis and tumor immune escape, representing 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 combined with multiple receptor (such as VEGFR/FGFR1/CSF1R) tyrosine kinase inhibitors, in order to enhance the anti-angiogenesis or immune activation function of single drug, improve tumor microenvironment, improve clinical benefit and safety , would be a potential treatment option.

Overview

The present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody or antigen-binding fragment thereof and a multi-receptor tyrosine kinase (multi-RTK) inhibitor, and uses and methods 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-1 1 The antibody or antigen-binding fragment thereof comprises the light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and as 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.

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 sequence as SEQ ID. The sequence of NO:7 is identical to or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical amino acid sequences thereto, and the light chain variable region has a sequence that is identical to or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% with the sequence of SEQ ID NO: 8 or amino acid sequences of higher identity.

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

4. The pharmaceutical combination product of any one of Embodiments 1-3, wherein the multi-receptor tyrosine kinase inhibitor at least inhibits the tyrosine kinase activity of the following two or more 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 of embodiment 4, wherein the multi-receptor tyrosine kinase inhibitor can simultaneously inhibit the tyrosine kinase activities of receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R.

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

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

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

(ii) The single administered 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, eg, 150 mg, 200 mg, 250 mg, 300 mg or 350 mg.

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

(i) The single administration dose of anti-PD-1 antibody or antigen-binding fragment thereof 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, every three weeks One (Q3W) administration; and/or

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

10. The pharmaceutical combination 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, parenterally, such as by intravenous infusion; and/or

(ii) The multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof may be administered by the parenteral route or parenterally, eg orally in a solid dosage form such as a capsule or tablet.

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

12. The pharmaceutical combination according to any one of the preceding embodiments, wherein the period of administration of the pharmaceutical combination can be one week, two weeks, three weeks, one month, two months, three months, four months, five Monthly, half-yearly or longer, optionally, the duration of each dosing cycle can be the same or different, and the intervals between each dosing cycle can be the same or different.

13. The pharmaceutical combination product of any one of the preceding embodiments for use in the prevention or treatment of cancer in an individual in need thereof, wherein the cancer is a solid tumor selected from neuroendocrine tumors tumors (eg: neuroendocrine tumors and neuroendocrine carcinomas; pancreatic neuroendocrine tumors (pNET); non-pancreatic neuroendocrine tumors such as lung carcinoid, gastric carcinoid, duodenal carcinoid, jejunal carcinoid, ileal carcinoid tumor, colonic and rectal carcinoid 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 carcinoma) 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 carcinoma (eg, 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 thereof an effective amount of the pharmaceutical combination as defined in any one of the preceding embodiments, wherein the cancer is a solid tumor selected from neuroendocrine tumors (e.g. : Neuroendocrine tumors and neuroendocrine carcinomas; pancreatic neuroendocrine tumors (pNETs); non-pancreatic neuroendocrine tumors such as lung carcinoids, gastric carcinoids, duodenal carcinoids, jejunal carcinoids, ileal carcinoids, colon carcinoid tumors and rectal carcinoid 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 (eg esophageal squamous cell carcinoma); or the cancer is a hematological malignancy selected from leukemia or lymphoma.

15. The method of embodiment 14, wherein:

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

(ii) The single administered 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, eg, 150 mg, 200 mg, 250 mg, 300 mg or 350 mg.

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

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

(i) The single administration dose of anti-PD-1 antibody or antigen-binding fragment thereof 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, every three weeks One (Q3W) administration; and/or

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

18. The method according to any one of embodiments 14-17, wherein the period of administration of (i) and/or (ii) in 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 more, optionally, the duration of each dosing cycle can be the same or different, and the intervals between each dosing cycle can be the same or different.

19. Use of the pharmaceutical combination product of any one of embodiments 1-13 for the prevention or treatment of cancer in an individual suffering from or at risk of developing cancer, or in the preparation of Use in a medicament for the prevention or treatment of cancer in an individual 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 an anti-PD-1 antibody, and/or the cancer is refractory to a multi-receptor tyrosine kinase inhibitor for refractory cancer.

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

23. The kit of embodiment 22, comprising:

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

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

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

In each of the above-mentioned embodiments, the individual is a mammal, such as a human. In some preferred embodiments, the individual is an individual with or at risk of developing cancer, eg, a cancer patient.

In some more preferred embodiments, the individual includes individuals with a predicted low response rate to treatment with anti-PD-1 antibody alone, such as cancers with a predicted low response rate to treatment with anti-PD-1 antibody alone patient.

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

In other more preferred embodiments, the individual includes individuals who are expected to have a lower rate of response to treatment with a multi-receptor tyrosine kinase inhibitor alone, such as those with a multi-receptor tyrosine kinase inhibitor alone. Cancer patients with low expected response rates to treatment.

A cancer that is refractory to monotherapy with a multi-receptor tyrosine kinase inhibitor refers to a cancer that is expected to have a low response rate to treatment with a multi-receptor tyrosine kinase inhibitor alone.

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

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

Before the present invention is described in detail, it is to be understood that this invention is not limited to the particular methods and experimental conditions set forth in this specification, as such methods and conditions may vary. Additionally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention in any way.

definition

For easier understanding of the present invention, certain scientific and technical terms are specifically defined as follows. Unless explicitly defined otherwise elsewhere herein, technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Abbreviations for amino acid residues are standard 3-letter and/or 1-letter codes used in the art to refer to one of the 20 commonly used L-amino acids. As used herein (including the scope of claims), the singular forms include their corresponding plural forms, unless the context clearly dictates otherwise.

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

All numerical ranges herein should be understood to disclose each numerical value and subset of numerical values within that range, whether or not specifically disclosed otherwise. For example, any reference to a numerical range should be considered as a reference to each and every numerical value within the numerical range, such as each integer within the numerical range. The invention relates to all values falling within these ranges, all smaller ranges, and the upper or lower limit of the numerical range.

The term "and/or" when used in conjunction with two or more alternatives 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 "comprising" means the inclusion of that element, integer or step, but not the exclusion of any other element, integer or step. Herein, when the term "comprising" or "comprising" is used, unless otherwise indicated, the elements, integers or The situation of the steps. For example, reference to an antibody variable region that "comprises" a particular sequence is also intended to encompass antibody variable regions that consist of that particular sequence.

The term "antibody" refers to any form of antibody that possesses the desired biological activity. Accordingly, it is used in the broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies Synthetic antibodies, camelized single domain antibodies, and antigen-binding fragments of antibodies.

The term "antigen-binding fragment" includes fragments or derivatives of antibodies, typically including at least a fragment of the antigen-binding or variable region (eg, one or more CDRs) of the parent antibody, which retain at least some of the binding specificity of the parent antibody. sex. 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; ) and multispecific antibodies. A binding fragment or derivative typically retains at least 10% of its antigen-binding activity when the antigen-binding activity is expressed on a molar basis. Preferred binding fragments or derivatives retain at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the antigen binding affinity of the parent antibody. It is also contemplated that antigen-binding fragments of antibodies may include conservative or non-conservative amino acid substitutions that do not significantly alter their biological activity (referred to as "conservative variants" or "functionally conservative variants" of the antibody).

The term "humanized antibody" refers to a form of antibody that contains sequences from human and non-human (eg, murine, rat) antibodies. In general, humanized antibodies comprise substantially all of at least one, usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the hypervariable loops Framework (FR) regions are the framework regions of human immunoglobulin sequences. A humanized antibody optionally may comprise at least a portion of a human immunoglobulin constant region (Fc). A humanized form of a rodent antibody will typically contain the same CDR sequences of the parent rodent antibody, However, certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.

The terms "whole antibody", "full length antibody", "complete antibody" and "intact antibody" are used interchangeably herein to refer to a composition comprising at least two heavy (H) chains and two light chains interconnected by disulfide bonds (L) Glycoprotein. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2 and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions (complementarity determining regions (CDRs), with more conserved regions (framework regions (FR)) interposed therebetween. Each VH and VL consists of three CDRs and four FR composition, from the amino terminus to the carboxyl terminus, is arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, HCDR1, HCDR2 and HCDR3 represent the three CDRs of the heavy chain variable region in turn, LCDR1 , LCDR2 and LCDR3 in turn represent the 3 CDRs of the light chain variable region. The constant region is not directly involved in the binding of the antibody to the antigen, but shows a variety of effector functions. In a given VH or VL amino acid sequence, each The precise amino acid sequence boundaries of the CDRs 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 are equivalent to Hypervariable loops of non-human immunoglobulins, while all or substantially all frameworks (refer to -917 (1987) falling within these ranges); Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., USDepartment of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath) and Contact (University College London); North numbering scheme (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 invention can be bounded by those skilled in the art according to any scheme in the art (eg, different assignment systems or combinations). .

Although CDRs vary from antibody to antibody, only a limited number of amino acid positions within CDRs are directly involved in antigen binding. Using at least two of the Kabat, Chothia, AbM and Contact methods, the region of minimum overlap can be determined, thereby providing the "minimum binding unit" for antigen binding. The minimal binding unit can be a sub-portion of a CDR. As is known to those skilled in the art, the residues of the remainder of the CDR sequence can be determined from the structure and protein folding of the antibody. Accordingly, the present invention also contemplates variants of any of the CDRs presented herein. For example, in a variant of a CDR, the amino acid residues of the smallest binding unit may remain unchanged, while the remaining CDR residues as defined by Kabat or Chothia may 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 activities of tyrosine kinases include direct and indirect activities. Exemplary direct activities include, but are not limited to, association with target molecules or phosphorylation of target substrates (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 typically characterized by unregulated cell growth. Benign and malignant cancers as well as dormant tumors or micrometastases are included in this definition. 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 lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), multiple Sexual bone marrow Tumor, gastrointestinal (tract) cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma tumor, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, gastric cancer, bladder cancer, hepatocellular tumor, breast cancer, colon cancer, neuroendocrine tumor and head and neck cancer. The cancer is preferably advanced cancer, recurrent and/or refractory cancer, or cancer that is resistant to chemotherapy, more preferably advanced solid tumor, such as (hitologically or cytologically confirmed) unresectable or metastatic Advanced solid tumors.

The term "tumor" as applied to an individual diagnosed with or suspected of having cancer refers to a malignant or potentially malignant neoplasm or mass of tissue of any size, and includes both primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or areas of fluid. Different types of solid tumors are named for the type of cells that form them. Leukemia (cancer of the blood) does not usually form solid tumors (National Cancer Institute dictionary of Cancer Terms).

The terms "patient", "subject" or "patient" refer to any single individual in need of treatment or participation in clinical trials, epidemiological studies, or use as controls, including humans and mammals such as cattle, horses, dogs and cats .

A "therapeutically effective amount" of a drug or therapeutic agent refers to an amount of an active agent (eg, an antibody, soluble receptor, polypeptide, polynucleotide, small organic molecule, or other drug) effective to "treat" a disease or disorder in a patient or mammal . In the case of cancer, a therapeutically effective amount of an 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 tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumors growth; alleviate to some extent one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; reduce tumorigenicity, tumor frequency, or tumorigenic capacity; reduce tumor the number or frequency of cancer stem cells in the cell; differentiate tumorigenic cells into a non-tumorigenic state; or a combination of these effects. To the extent that the active agent prevents existing cancer cells from growing and/or kills existing cancer cells, it may be referred to as cytostatic and/or cytotoxic.

The term "dose" is the amount of drug that elicits a therapeutic effect. Dosages are related to the amount of drug in free form unless otherwise stated. If the drug is in the form of a pharmaceutically acceptable salt, the amount of drug is increased proportionally to the amount of drug in free form. For example, the dosage will be stated on the product packaging, in the product information sheet, or in the instructions included with the kit.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is non-toxic, biologically tolerable or otherwise biologically suitable for administration to treat or prevent disease. Including but not limited to acid addition salts or phosphonium addition salts such as: hydrochloride, hydrobromide, phosphate, sulfate, sulfite, nitrate, malate, maleate, fumaric acid salt, tartrate, succinate, citrate, lactate, mesylate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylates, stearate and salts of the formula _{HOOC- (CH 2) n-COOH} ( wherein n is 0-4) alkane-dicarboxylic acid formed.

The term "inhibit" means that a given molecule (eg, (i) an anti-PD-1 antibody or antigen-binding fragment thereof and/or (ii) a multireceptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof) causes a certain decrease in some parameters (eg PD-1 activity and/or VEGFR, FGFR1, CSF1R activity). For example, the term includes inhibition of activity by at least 5%, 10%, 20%, 30%, 40% or more. Therefore, suppression does not have to be 100%.

The term "treatment" refers to 1) a therapeutic measure that cures, slows, relieves the symptoms of and/or stops the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventive Sexual measures that prevent and/or slow the development of a pathological condition or disorder in an individual. Therefore, those in need of treatment include patients who have suffered from the disease, patients who are prone to suffer from the disease, and and those who want to prevent the disease. In certain embodiments, an individual is successfully "treated" for cancer by the methods of the invention, wherein the individual exhibits one or more of the following: a reduction in the number or complete disappearance of cancer cells; a reduction in tumor size; inhibition or lack of infiltration of cancer cells into peripheral organs including For example, cancer spreads to soft tissue and bone; inhibition or lack of tumor metastasis; inhibition or lack of tumor growth; alleviation of one or more symptoms associated with that particular cancer; reduction in morbidity and mortality; improvement in quality of life; reduction in tumorigenicity, tumorigenic frequency or tumorigenic capacity; reducing the number or frequency of cancer stem cells in a tumor; differentiating tumorigenic cells into a non-tumorigenic state; or a combination of the foregoing effects.

The term "prevention" includes the inhibition or delay of the onset or frequency of a disease or disorder or symptoms thereof, and generally refers to the administration of a drug prior to the onset of a sign or symptom, particularly in an at-risk individual.

The term "inhibiting tumor growth" refers to any mechanism by which tumor cell growth can be inhibited. In certain embodiments, tumor cell growth is inhibited by retarding 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 in 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 routes of administration of each active ingredient in the pharmaceutical combination of the present invention include oral, intravenous (eg, infusion (also known as infusion) infusion) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, topical or other parenteral routes of administration. The phrase "parenteral administration" as used herein refers to modes of administration other than parenteral and topical administration, usually by intravenous, and includes, without limitation, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular , intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, 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 and the like.

The term "continuous administration" refers to daily administration. In the case of continuous administration, the drug may be administered one or more times per day, eg, once daily, twice daily, three times daily, preferably once daily.

The terms "pharmaceutical combination" and "pharmaceutical combination" are used interchangeably herein to refer to a non-fixed combination or fixed combination, including but not limited to kits, pharmaceutical compositions. The term "non-fixed combination" means that the active ingredients (eg, anti-PD-1 antibodies, multi-receptor tyrosine kinase (multi-RTK) inhibitors) are present in separate entities simultaneously, without specific time constraints, or in the same or different administered to the patient sequentially at a time interval, wherein such administration provides prophylactically or therapeutically effective levels 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 pharmaceutical combination are administered at levels no greater than when they are used alone. The term "fixed combination" means that the two active agents are administered to a patient simultaneously in the form of a single entity. The doses and/or time intervals of the two active agents are preferably selected so that the combined use of the parts produces a greater effect in the treatment of a disease or condition than either component alone can achieve. The ingredients may each be in separate formulations, which may be the same or different.

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

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

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

The term "progression-free survival" or "PFS" is the time from a patient's first use of an investigational drug until disease progression or death from any cause.

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

The terms "liquid formulation" or "liquid composition" refer to formulations in liquid form. The liquid composition may be, for example, a composition comprising: (i) an anti-PD-1 antibody or antigen-binding fragment thereof described herein; (ii) an optional buffer; and (iii) a vehicle. "Buffer" means a pH buffer Punch. For example, the buffer may be selected from buffers known in the art for use in antibody formulations, such as histidine, glutamate, phosphate, acetate, citrate, or tris.

All numerical ranges herein should be understood to disclose each numerical value and subset of numerical values within that range, whether or not specifically disclosed otherwise. For example, any reference to a numerical range should be considered as a reference to each and every numerical value within the numerical range, such as each integer within the numerical range. The invention relates to all values falling within these ranges, all smaller ranges, and the upper or lower limit of the numerical range.

Technical and scientific terms that are not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which this 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, including definitions of terms, are incorporated herein.

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

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 comprises the same as SEQ ID NO:7 amino acid sequence identical to or at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the sequence, and the light chain variable region comprises or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the sequence of SEQ ID NO: 8 Amino acid sequences of high identity.

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

In some embodiments, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is toripalimab (also referred to herein as JS001 or toripalimab), which is comprised of the sequences shown in SEQ ID NOs: 9 and 10, respectively Humanized IgG4 mAbs with amino acid sequences of the light and heavy chains.

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

In some embodiments, the multi-receptor tyrosine kinase inhibitors in the pharmaceutical combinations of the present invention are described in WO2018090324A1 and other patent applications/patents of the same family, the entire contents of which (including definitions of terms) are incorporated herein by reference This article, for all purposes.

In some embodiments, the multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention is "surufatinib," also referred to herein as "HMPL-012," which inhibits receptors VEGFR1, VEGFR2 (KDR), The tyrosine kinases of VEGFR3, FGFR1 and CSF1R have strong inhibitory effects, with the median inhibitory concentrations of 2, 24, 1, 15, and 4 nM, respectively. 100 nM, showing good selectivity. "Surufatinib" is a compound having the structure of formula (I).

Surufatinib and pharmaceutically acceptable salts thereof herein are described in patent CN102070618, WO2011060746A1 and other patent applications/patents of the same family. In some embodiments, surufatinib is a crystalline form such as Form I or Form II as described in CN102070618, WO2011060746A1 and other patent applications/patents of the same family. The aforementioned patent applications/patents are incorporated herein by reference for all purposes.

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

The pharmaceutical combinations of the present invention may also contain one or more additional therapeutic agents. Additional therapeutic agents can be, for example, chemotherapeutic agents other than VEGR inhibitors, biotherapeutic agents, immunogenic Agents (eg, attenuated cancer cells, tumor antigens, antigen-presenting cells (such as dendritic cells pulsed with tumor-derived antigens or nucleic acids), immunostimulatory cytokines (eg, 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 Regimen

The choice of a dosing regimen (also referred to herein as an administration regimen) for the pharmaceutical combinations of the present invention depends on several factors, including the subject'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 within acceptable levels of side effects. Thus, the dosage and frequency of administration of each biotherapeutic agent and chemotherapeutic agent in the pharmaceutical combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and the characteristics of the patient. Guidance for selecting appropriate doses of antibodies, cytokines and small molecules is available. See, eg, 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 (2002 November). Determination of an appropriate dosage regimen can be made 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 will depend, for example, on the patient's clinical history (e.g., previous treatments). ), the type and stage of cancer being treated, and biomarkers of response to one or more of the therapeutic agents in the combination therapy.

Each therapeutic agent of the pharmaceutical combination of the present invention may be administered simultaneously (ie, in the same pharmaceutical composition), concurrently (ie, in separate pharmaceutical formulations, one after the other in any order), or sequentially in any order apply. The therapeutic agents in a pharmaceutical combination may be in different dosage forms (eg, one drug is a tablet or capsule and the other is a sterile liquid formulation) and/or on different dosing schedules (eg, chemotherapeutic agents are administered at least daily and biological Sequential administration is particularly useful when the therapeutic agent is administered less frequently (eg, once a week, once every two weeks, or once every three weeks).

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

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 may be administered by continuous infusion or by intermittent doses, and a single administration dose may range from about 0.01 to about 20 mg/kg, about 0.1 to about 10 mg/kg of the subject's body weight, or about 120mg to about 480mg fixed dose. For example, the dose can 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 body weight of the subject, or a fixed dose of about 120 mg, 240 mg, 360 mg or 480 mg. Dosage regimens are typically designed to achieve exposures that result in sustained receptor occupancy (RO) based on the Ab's typical pharmacokinetic properties. 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. 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 toripalimab, and the single administration dose is selected from about 1 to about 5 mg/kg body weight of the subject. In some embodiments, the single administration dose of toripalimab 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 subject's body weight, or 120 mg, Fixed doses of 240 mg and 480 mg administered intravenously. In some preferred embodiments, toripalimab is administered as a liquid drug, and selected doses of the drug are administered by intravenous infusion over a period of 30-60 minutes. In some embodiments, toripalimab is administered at 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) inhibitors in the pharmaceutical combinations of the present invention are administered at their approved or recommended doses and treatment is continued until a clinical effect is 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 surufatinib, and the 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 surufatinib 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 representative dosing regimen might be administration twice daily, once daily, once every two days, or once every three days. In some embodiments, surufatinib is administered to the individual once daily. In some embodiments, surufatinib is administered at a dose selected from about 125 mg, about 150 mg twice daily (BID). In other embodiments, surufatinib is administered at a dose of about 250 mg once daily.

The optimal dose of surufatinib in combination therewith can be identified by the dose of one of toripalimab. In one embodiment, toripalimab is administered at a fixed dose of about 240 mg Q3W, surufatinib is administered at a starting dose of about 250 mg QD, and if the patient tolerates this combination of doses, the The dose level of surufatinib was increased by 50 mg/day, and if the patient did not tolerate the starting dose combination, the dose level of surufatinib was decreased by 50 mg/day, and the number of dose reductions per patient should not exceed 2 times. The lowest dose level can be adjusted. Down to 150mg QD.

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

In some embodiments, surufatinib is administered orally within 1 hour after breakfast. Surufatinib can be administered before or after toripalimab is administered on the day of toripalimab administration.

The administration cycle of the anti-PD-1 antibody and/or multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention may be the same or different, and may be one week, two weeks, three weeks, one month, two months, three Months, four months, five months, half a year or more, optionally, the duration of each dosing cycle can be the same or different, and the intervals between each dosing cycle can be the same or different. For example, in some embodiments, toripalimab is a fixed dose of about 240 mg every three weeks One administration, and surufatinib was administered at a fixed dose of approximately 250 mg once daily, continuously, for a period of three weeks for both.

treatment or use

The present invention provides the aforementioned pharmaceutical combinations of the present invention for use in preventing and/or treating the severity of at least one symptom or sign of cancer or inhibiting cancer cell growth in an individual.

The present invention provides methods of preventing or treating cancer comprising administering to an individual in need thereof an effective amount of a pharmaceutical combination of the present invention. The effective amount includes a prophylactically 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 a medicament for preventing or treating cancer. The pharmaceutical combination of the present invention can be used before or after surgery to remove the tumor, and can be used before, during, or after radiation therapy.

In some embodiments, the pharmaceutical combination of the present invention is administered to a patient who has not been previously treated with a biotherapeutic or chemotherapeutic agent, ie, is naive. In other embodiments, the combination therapy is administered to patients who have not achieved a sustained response after prior treatment with a biotherapeutic or chemotherapeutic agent (ie, treatment-experienced).

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

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

The pharmaceutical combination of the present invention is useful for the treatment of cancers such as neuroendocrine tumors, biliary tract cancer, gastric cancer (eg gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, lung cancer (eg 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 (eg, esophageal squamous cell carcinoma); or a hematological malignancy 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 (eg, gastric adenocarcinoma and gastroesophageal junction adenocarcinoma), thyroid cancer, soft tissue sarcoma, endometrial cancer, or esophageal cancer (eg, esophageal squamous cell carcinoma). It should be noted that biliary tract cancer, gastric cancer, thyroid cancer, soft tissue sarcoma, endometrial cancer and esophageal cancer described in the present invention do not include biliary tract, stomach, thyroid, soft tissue, Cancers or tumors in areas such as the endometrial lining 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 neoplasms (NENs) are tumors derived from cells of the endocrine (hormonal) and nervous systems. Neuroendocrine tumors include tumors with diverse morphological, functional, and behavioral characteristics. Neuroendocrine tumors can be classified according to grade and differentiation. Generally well-differentiated neuroendocrine tumors are defined as neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine tumors are defined as neuroendocrine carcinomas (NECs). Refer to 2018 IARC / WHO 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 site of origin. In certain embodiments, the neuroendocrine tumor is selected from the group consisting of 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 thyroid, adrenal glands (eg, 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 has spread beyond the wall of the primary organ to adjacent tissues, such as fat, muscle, or lymph nodes. In certain embodiments, the neuroendocrine tumor has spread to tissues or organs distant from the primary organ, such as liver, bone, or lung.

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 a somatostatin analog. In certain embodiments, the tumor is resistant to treatment with a kinase inhibitor.

Pill box

The anti-PD-1 antibody or antigen-binding fragment thereof described herein and wherein the multi-receptor tyrosine kinase (multi-RTK) inhibitor or a pharmaceutically acceptable salt thereof can be used as a first container and a second container and Supplied in pillbox with package insert. The first container contains at least one dose of a formulation comprising an 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 or a pharmaceutically acceptable salt thereof. formulation, and the package insert or label contains instructions for using the formulation to treat cancer in a patient. The first and second containers can be Contains the same or different shapes (eg vials, syringes and bottles) and/or materials (eg plastic or glass). The kit may further contain other materials useful for administering the formulation, such as diluents, filters, IV bags and tubing, needles and syringes.

In some embodiments, the kit comprises:

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

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

In the above-mentioned embodiments, the single pharmaceutical dosage unit refers to a single pharmaceutical dosage form comprising the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention and/or comprising a multi-receptor of the present invention for a single administration to a patient A single drug dosage form of a tyrosine kinase inhibitor in vivo. The single pharmaceutical dosage form may be a dosage form for parenteral administration, such as a vial, ampule, prefilled needle or prefilled syringe for injection containing the drug in solution or lyophilized powder, or a dosage form for parenteral administration, For example, tablets, capsules, lozenges, powders, suspensions and the like for oral administration.

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

detailed description

Example 1 Anti-tumor synergistic effect of JS001 combined with surufatinib in MC38 tumor model

1.1 The purpose of the experiment:

In this experiment, human PD-1 transgenic mice were injected subcutaneously into mouse MC38 colon cancer cells to establish a tumor model, and the synergistic effect of JS001 and HMPL-012 in combination against tumors was evaluated by the size of the tumor and the body weight of the mice.

1.2 Drug sources

JS001 (Toripalimab), batch number 20171208, produced and provided by Suzhou Junmeng Biomedical Technology Co., Ltd. HMPL-012 (surufatinib), batch number 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 PBS-resuspended cells (5*10 ⁵ cells/0.1 ml/cell) were inoculated into transgenic B-hPD-1 C57bl/c cells mice (FIG Orsay from one hundred Jiangsu biological technology Co., Ltd.; female; 7-8W) the right axilla, 6 days until the tumor grew to a volume of approximately 123mm ^3, mice were randomized into 4 groups (group G1 , administration groups G2, G3 and G4), 12 in each group. Dosing began on the day of the grouping, and the specific dosing schedule is shown in Table 1.

1.4 Observation indicators and statistical analysis of data

Tumor volumes were measured twice weekly, animals were weighed weekly, and data were recorded.

If any one of the following conditions occurs in any mouse in the experiment, the mouse will be discontinued from the experiment and removed from data collection: (1) the tumor volume of the mouse exceeds 3000mm ³ ; (2) 3 the mouse has a severe tumor Ulcers and no scarring for three days; (3) mice develop abnormal movements or paralysis; (4) mice lose more than 20% of their body weight before the start of the experiment.

At the end of the experiment 25 days after the first administration, the mice were euthanized, and the tumor tissues were separated and photographed and weighed for measurement. The tumor weight and volume (terminal tumor volume) of mice in each group were measured, and the relative tumor growth inhibition rate TGI (%) was calculated. . The formula for calculating 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 = final tumor volume after administration in control group - final tumor volume in administration group after administration; Tvol _{control -} Tvol _predose = final tumor volume in control group after administration - tumor volume in control group before administration ( pre-dose tumor volume on day 7).

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

1.5 Experimental results

The experimental results are shown in Table 2 below and Figure 1, indicating that the test drug JS001 has a certain inhibitory effect on tumor growth at the level of 0.3mg/kg; the test drug surufatinib has a certain inhibitory effect on tumor growth at the dose level of 40mg/kg. Effect; compared with JS001 (0.3mg/kg) and surufatinib (40mg/kg) alone, JS001 (0.3mg/kg) combined with surufatinib (40mg/kg) was statistically more significant inhibit tumor growth.

Example 2 An open-label, single-arm, multicenter phase II clinical study evaluating the efficacy and safety of surufatinib combined with toripalimab in patients with advanced solid tumors

This study is an open-label, single-arm, multicenter phase II clinical study evaluating surufatinib combined with toripalimab in patients with advanced solid tumors who have failed standard therapy or who have no effective therapy.

2.1 Research purpose

The main purpose of this study was to evaluate the objective response rate (ORR) (RECIST 1.1 criteria) of surufatinib combined with toripalimab in patients with advanced solid tumors and to evaluate the safety and tolerability of some patients with safety introduction .

The secondary objectives of this study include: (1) To evaluate the ORR (irRECIST criteria), duration of response (DoR), progression-free survival (PFS), duration of response (DoR), and progression-free survival (PFS) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, Disease control rate (DCR) (RECIST1.1 criteria and irRECIST criteria) and overall survival (OS); (2) to evaluate surufatinib combined with toripalimab in patients with advanced solid tumors (safety induction (3) to evaluate the pharmacokinetics (PK) of surufatinib combined with toripalimab in patients with advanced solid tumors; (4) to evaluate the combination of surufatinib Immunogenicity of toripalimab in patients with advanced solid tumors; (5) Detection of PD-L1 expression in tumor tissue samples of patients, and related efficacy analysis (RECIST1.1 criteria and irRECIST criteria), in order to determine the advantages Crowd provides reference.

As well as exploratory purposes to study biomarkers for efficacy prediction and drug resistance mechanisms.

2.2 Research principles

According to the Investigator's Brochure, the recommended dose of toripalimab in current clinical studies is a fixed dose of 240 mg administered every three weeks. The recommended dose of surufatinib as a single agent is 300 mg, QD. In a phase I exploratory study of surufatinib in combination with toripalimab (NCT03879057), toripalimab remained at a fixed dose of 240 mg every three weeks; surufatinib explored 200 mg, 250 mg, and 300mg, QD, a total of 3 dose groups. DLT was not observed in 3 patients in 200mg group and 6 patients in 250mg group, and 1 DLT was observed in 7 patients in 300mg group, which was grade 3 hyperthyroidism and recovered after treatment. And the three dose groups also showed a certain anti-tumor effect. Although the safety and tolerability of the three dose groups were good, and all were clinically effective doses, in the same treatment time window, the 250 mg group had better efficacy and fewer adverse reactions. Therefore, based on the results of clinical drug safety, tolerability, and efficacy, the combined doses selected in this study are: surufatinib, 250 mg, QD; toripalimab, 240 mg, intravenous infusion, once every three weeks.

2.3 Research plan

The study plans to enroll 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 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 the safety lead-in part, 6 patients will receive a combination therapy of surufatinib and toripalimab every 3 weeks: surufatinib 250mg, QD, after meals orally + toripalimab , 240mg, intravenous infusion, Q3W.

1/6受試者出現DLT)才能繼續入組。若安全性導入部分患者安全性評估不能耐受，藥物安全評估委員會(SRC)將根據該部分患者安全性評估及索凡替尼聯合特瑞普利單抗I期研究推薦採用索凡替尼200mg，每日1次(QD)，餐後口服+特瑞普利單抗，240mg，靜脈滴注，每3週一次(Q3W)；或其他新的聯合給藥劑量。 The safety lead-in part plans to enroll 6 patients, who will be evaluated for patient safety by the Drug Safety Review Committee (SRC) within 28 days after the first dose (DLT observation period). Only when the observation period of DLT was completed in 6 patients and the safety was tolerable by SRC (

1/6 subjects had DLT) to continue enrolling. If the safety evaluation of some patients cannot be tolerated, the Drug Safety Review Committee (SRC) will recommend the use of surufatinib 200mg based on the safety evaluation of these patients and the phase I study of surufatinib combined with toripalimab , once a day (QD), after meals orally + toripalimab, 240 mg, intravenous infusion, once every 3 weeks (Q3W); or other new combined doses.

Definition of DLT: According to the evaluation criteria of NCI CTCAE version 5.0, within 28 days after the first dose (DLT observation period), the following toxic reactions related to surufatinib and/or toripalimab are judged by the investigator to occur. is 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 disturbances recovered to grade 2 or below within 7 days after supportive treatment;

˙Grade 3 endocrine lesions adequately controlled with hormone replacement therapy;

˙No clinically significant grade 3 drug-related laboratory abnormalities;

140mmHg，且舒張壓

90mmHg的高血壓； ˙ Systolic blood pressure can be controlled by drug treatment

140mmHg, and diastolic blood pressure

Hypertension of 90mmHg;

˙ Whether grade 3 or grade 4 infusion reaction is a DLT should be determined by the investigator and the sponsor through discussion.

2. Hematological toxicity:

˙Grade 4 isolated neutropenia with duration >3 days;

˙ Grade 3 or 4 febrile neutropenia;

˙Grade 3 thrombocytopenia with bleeding tendency;

˙Grade 4 thrombocytopenia;

˙ Grade 4 anemia.

3. Any life-threatening adverse events.

DLT-evaluable patients must meet all of the following criteria:

˙ Subjects received at least 1 cycle of toripalimab and 85% or more of the prescribed dose of surufatinib during the DLT observation period; adverse events that occurred during the DLT observation period have not been reported. No medical intervention was taken before confirmation of DLT (except for adverse events that allow treatment in the DLT definition and some grade 2 adverse events that recommend treatment according to the protocol);

˙Completed the safety evaluation of the entire DLT observation period or withdrawn early due to the occurrence of DLT.

Patients who do not meet the above conditions need to enroll new subjects to supplement to ensure that there are at least 6 DLT-evaluable patients in the safety lead-in part.

If a patient develops DLT during the DLT observation period, the investigator can decide whether to accept the follow-up study drug treatment, and the dose can be reduced according to the dose adjustment principle specified in the protocol (toripalimab does not allow dose adjustment) or drug withdrawal.

All patients will receive surufatinib in combination with toripalimab until disease progression, death, intolerable toxicity, patient voluntary request to discontinue study treatment or withdraw informed consent, initiation of new antitumor therapy, pregnancy, severe Violation of the research process stipulated in the protocol, the investigator decides to terminate the study treatment based on the best interests of the patient, or to be lost to follow-up, whichever occurs first, but the maximum duration of toripalimab treatment is 24 months.

During the study, investigators will perform tumor assessment using RECIST 1.1 and irRECIST criteria, and tumor imaging assessments will be performed every 6 weeks (±7 days) from the first dose for 48 weeks Afterwards, tumor imaging assessments were performed every 12 weeks (±7 days) until disease progression, death, intolerable toxicity, or other protocol-specified criteria for discontinuing study treatment, whichever occurred first. The first CR or PR should be confirmed after 4 weeks (±7 days).

Patients who discontinue study treatment for any reason other than disease progression (except for withdrawal of informed consent or death) should still go to the research center for tumor evaluation according to the visit plan specified in the study protocol until disease progression, death, initiation of new anti-tumor therapy Treatment, loss to follow-up, withdrawal of informed consent, and end of study, whichever occurred first. If the patient has not had a tumor evaluation within 28 days prior to discontinuation of study treatment/withdrawal from the study, a tumor evaluation should be performed at the time of discontinuation of study treatment/withdrawal from the study.

From the termination of study treatment (termination of surufatinib or toripalimab treatment, whichever occurs later), survival follow-up (telephone follow-up) is performed every 12 weeks, and anti-tumor treatment after disease progression is recorded. Until the death of the patient, loss of follow-up, withdrawal of informed consent, and the end of the study, whichever occurs first.

During the study, all SAEs (Severity Adverse Event, serious adverse events) were reported from the signing of the informed consent form to the first dose of the study drug; from the first dose of the study drug to the last dose of the study drug (surufatinib or the last dose of toripalimab, whichever occurs later), within 90 days after or before starting new antitumor therapy, record all AEs and report SAEs (including protocol-specified special adverse events); last dose 90 Days later or starting new antitumor therapy until the end of the study, only investigator-confirmed SAEs related to the study drug were reported. All AEs were graded NCI CTCAE version 5.0. All SAEs were followed up until the adverse events returned to the baseline state, the investigator judged that they were in a stable state, the patient started new anti-tumor therapy, lost to follow-up, withdrawn informed consent, and died, whichever came first.

This study was divided into 3 periods: screening period, treatment period and follow-up period, see Table 3.

Patients ended the trial in the following 5 conditions:

1) The patient withdraws informed consent and refuses to continue to provide information;

2) Screening failed;

3) death;

4) Patients lost to follow-up;

5) The entire clinical research section bundle.

2.4 Study population

About 16 domestic research centers including Peking University Cancer Hospital and Fudan University Affiliated Cancer Hospital.

The study target population is histologically or cytologically confirmed, failed standard therapy (disease progression after therapy or intolerable toxicity of therapy), no standard therapy or inability to receive standard therapy, and unresectable or metastatic advanced disease Cancer 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 systemic 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-small cell lung cancer and other tumors mainly);

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

3) There are clearly measurable lesions that meet the requirements of the solid tumor response evaluation criteria (RECIST 1.1 criteria); if the lesion that has received local therapy (radiotherapy, ablation, vascular intervention, etc.) in the past is the only lesion, there must be disease progression in the lesion. Clarify imaging evidence;

2.5 Treatment options

During the study period, on the day when surufatinib was combined with toripalimab, oral surufatinib was recommended first, followed by intravenous infusion of toripalimab. All patients will receive surufatinib and toripalimab in a 3-week cycle until disease progression, death, patient voluntary request to discontinue study treatment, intolerable toxicity, initiation of new antitumor therapy, pregnancy , Serious violation of the research process stipulated in the protocol, the investigator decides to terminate the study treatment or to be lost to follow-up based on the best interests of the patient, whichever occurs first, but the maximum duration of toripalimab treatment is 24 months.

Surufatinib: 250 mg, orally within 1 hour after breakfast, once daily continuously.

During the course of the study, every effort should be made to ensure that patients receive medication according to the study protocol. If a patient misses a dose in the morning, it can be taken any time before 10 p.m. on the same day. However, if the patient misses taking the prescribed medicine and fails to make up the medicine on the same day, he must take the prescribed medicine the next time, but the missed medicine will not need to be made up again. Missed medication must be reported to the investigator, and recorded on the CRF. If a patient vomits after taking the drug, a replacement dose is not recommended unless the full capsule is seen.

Vigorous exercise should be avoided during the trial; patients should avoid high concentrations of grapefruit juice and consumption of grapefruit and beverages containing this ingredient.

Toripalimab: 240 mg, intravenous infusion, Q3W, the first intravenous infusion time is at least 60 minutes. If the first infusion is well tolerated, the duration of the second infusion can be shortened to 30 minutes. If the 30-minute infusion is also well tolerated by the patient, all subsequent infusions can be completed within 30 minutes. It should not be administered as an intravenous bolus or a single bolus injection.

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

2.6 Dose Adjustment

2.6.1 Surufatinib

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 lowest dose level can be reduced to 150 mg/day. After a dose reduction, it cannot be returned to the previous dose level.

In order to recover the toxicity, unless otherwise specified, the treatment can generally be suspended for a maximum of 28 days. If the toxicity cannot be recovered to grade 1 or baseline for more than 28 days, it will be regarded as intolerance, and surufatinib will be permanently discontinued.

2.6.2 Toripalimab

During the treatment of toripalimab, the investigator may need to suspend or permanently discontinue the drug according to the safety and tolerability of the patient, and it is not recommended to increase or decrease the dose. Medication suspensions of up to 12 weeks are allowed, calculated from the time of the last dose. If a delay occurs during the every 3-week cycle of toripalimab treatment, all future dosing days will be delayed to ensure that the dosing interval between toripalimab treatment cycles is 21±3 days . Study dosing may be resumed when patients requiring delayed dosing meet the criteria for resumption of dosing. Tumor evaluation in all patients should continue as required by the protocol, with or without delayed dosing. If the patient did not meet the re-dosing criteria after a 12-week suspension, the study treatment toripalimab was permanently discontinued. For patients who meet the criteria for permanent discontinuation of treatment, if toripalimab is restarted, the investigator should discuss with the sponsor and fully consider the patient's benefit and immune-related adverse events have fully resolved.

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 (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, about 10-20 cases of thyroid adenocarcinoma, About 10-20 cases of cancer, about 10-20 cases of small cell lung cancer, about 10-20 cases of soft tissue sarcoma, about 10-20 cases of endometrial cancer and about 10-20 cases of esophageal squamous cell carcinoma, non-small cell There are about 10 to 20 cases of lung cancer, of which about 20 patients with the above tumors who have received immunotherapy in the past). The actual sample size may be adjusted appropriately based on the progress of the surufatinib combined with toripalimab study.

2.7.2 Statistical analysis method:

The results of this study were mainly descriptive statistical methods. The measurement data lists the number of people, the mean, the standard deviation, the median, the maximum value, and the minimum value. Count data and grade data list frequencies and percentages.

2.7.3 Effectiveness analysis:

The analysis of tumor efficacy-related indicators will be mainly based on the tumor efficacy evaluable population, defined as all patients who have used the study drug, have measurable lesions at baseline, and have at least one tumor evaluation after baseline. The ORR and DCR were calculated based on the evaluable population of tumor efficacy, and the 95% exact confidence interval (CI) was calculated by the Clopper-pearson method. In addition, a supportive analysis of tumor efficacy indicators will be performed based on the ITT set. The ITT (Intention-to-Treat, intention-to-treat) set was defined as all patients who received at least one study drug treatment. Analysis for PFS and OS will be based on the ITT set. For time-to-event variables including DoR, PFS, and OS, the Kaplan-Meier method was used to estimate medians, quartiles, and their 95% CIs, as well as PFS and OS probabilities at the time of interest, if data allowed. .

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

2.7.4 Security Analysis:

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 graded according to NCI CTCAE5.0. with international The Dictionary of Medical Terms (MedDRA) codes adverse events. Summarize the number and frequency of adverse events according to the Human System Organ Class and the corresponding preferred term. Changes before and after treatment will be compared for laboratory test results, vital signs, ECG, left ventricular ejection fraction, and ECOG. Clinically significant outliers are listed.

2.7.5 Pharmacokinetic analysis:

All patients who used study drug, had at least one PK sampling and analysis, and had no significant protocol deviations that impacted PK data were included in the PK analysis (ie, the PK analysis set). The non-compartmental model will be used to analyze the blood drug concentration data by Winnolin software, and calculate the relevant PK parameters, including: t _1/2 , T _max , C _max , AUC _0-∞ , AUC _0-t , CL/F , VZ/F, etc. Appropriate statistical tables and graphs will be used to describe the plasma concentration data and PK parameters.

2.7.6 Immunogenicity analysis:

The positive rates of toripalimab anti-drug antibody (ADA) and neutralizing antibody (NAb) were calculated and summarized using descriptive statistical analysis.

2.7.7 Biomarker analysis:

Results of descriptive statistical analyses of biomarkers that may correlate with disease prognosis will be provided and will be presented in a separate report.

2.8 Research results

2.8.1 Security Summary

The drug combination of surufatinib and toripalimab of the present invention In this clinical trial, as of February 25, 2020, a total of 3 patients with solid tumors were enrolled, all of whom have passed the DLT observation period and have not DLT was observed. Up to now, no adverse events of CTCAE grade 2 or above have occurred. No unexpected safety signals (adverse events) were observed and it was well tolerated. Some patients (2 cases) achieved partial remission after treatment, showing excellent antitumor activity.

2.8.2 Safety Analysis Results

3級(CTCAE v5.0)不良事件，其中33.8%的受試者發生

3級(CTCAE v5.0)治療相關的不良事件；26.1%的受試者發生嚴重不良事件，其中治療相關的嚴重不良事件發生率為15.3%。未觀察到任何意外的安全信號(不良事件)，具有良好的耐受性。不同瘤種和/或隊列的安全性分析結果詳見下表6。 The drug combination of surufatinib and toripalimab of the present invention In this clinical trial, a total of 157 solid tumor subjects were enrolled as of December 31, 2020, and 96.8% of the subjects developed experienced at least one adverse event; occurred in 42.7% of subjects

Grade 3 (CTCAE v5.0) adverse events, which occurred in 33.8% of subjects

Grade 3 (CTCAE v5.0) treatment-related adverse events; serious adverse events occurred in 26.1% of subjects, with treatment-related serious adverse events occurring in 15.3%. No unexpected safety signals (adverse events) were observed and it was well tolerated. The safety analysis results of different tumor types and/or cohorts are shown in Table 6 below.

2.8.3 Effectiveness Analysis Results

In the ITT cohort, as of December 31, 2020, a total of 139 subjects had been evaluated for efficacy, including 20 neuroendocrine carcinomas, 19 neuroendocrine tumors, 20 esophageal squamous cell carcinomas, 18 biliary tract carcinomas, There were 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, and 6 cases of endometrial carcinoma. Investigator-assessed best efficacy assessments according to RECIST 1.1 criteria are shown in Table 7.

Overall efficacy evaluation:

Among the 139 subjects who underwent efficacy evaluation, 1 subject achieved a complete response (CR), 27 subjects had a partial response (PR), and 20 subjects had a confirmed partial response (PR), the best response in 75 subjects was stable disease (SD), 1 subject could not be evaluable, ORR and confirmed ORR were 20.1% (95% CI 13.8%-27.8%) and 15.1% (95%), respectively % CI 13.8%-27.8%), DCR was 74.8% (95% CI 66%-81.2%).

Efficacy evaluation of each subgroup:

Among the 20 neuroendocrine cancer subjects who underwent efficacy evaluation, 5 subjects achieved partial remission (PR), 4 subjects were confirmed partial remission (PR), and 9 subjects were the best Efficacy was stable disease (SD), ORR and confirmed ORR were 25.0% (95% CI 8.7%-49.1%) and 20.0% (95% CI 5.7%-43.7%), respectively, and DCR (95% CI) was 70.0% ( 95%CI 45.7%-88.1%).

Of the 19 subjects with neuroendocrine tumors who underwent efficacy evaluation, 1 subject achieved a confirmed partial response (PR), and 16 subjects had stable disease (SD) as the best response, with a confirmed ORR of 5.3% (95% CI 0.1%-26.0%), DCR was 89.5% (95% CI 66.9%-98.7%).

Among the 20 subjects with esophageal squamous cell carcinoma who underwent efficacy evaluation, 1 subject achieved a confirmed complete response (CR), 5 subjects achieved a partial response (PR), and 4 subjects achieved a partial response (PR). To confirm partial response (PR), the best response in 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%), respectively -49.1%) with a DCR of 60.0% (95% CI 36.1%-80.9%).

Among the 18 subjects with biliary tract cancer who underwent efficacy evaluation, 3 subjects achieved confirmed partial response (PR), 8 subjects had the best response to stable disease (SD), and the confirmed ORR was 16.7% ( 95% CI 3.58%-41.4%), DCR was 61.1% (95% CI 35.8%-82.7%).

Among the 19 patients with small cell lung cancer who had been evaluated for efficacy, 3 patients achieved partial response (PR), 2 of which were confirmed partial response (PR), and 15 were the best Efficacy was stable disease (SD), ORR and confirmed ORR were 15.8% (95% CI 3.38%-39.6%) and 10.5% (1.3%-33.1%), respectively, and DCR was 94.7% (95% CI 74%-99.9%) ).

Among the 8 subjects with thyroid cancer who underwent efficacy evaluation, 2 subjects achieved confirmed partial response (PR), 5 subjects had the best response as stable disease (SD), and the confirmed ORR was 25.0% (95% CI 3.2%-65.1%) with a DCR of 87.5% (95% CI 47.4%-99.7%). Among the 14 subjects with soft tissue sarcoma who underwent efficacy evaluation, 1 subject achieved a confirmed partial response (PR), and 8 subjects had stable disease (SD) as the best response, with a confirmed ORR of 7.1% (95%). % CI 0.2%-33.9%), DCR was 64.3% (95% CI 35.1%-87.2%).

Among the 15 subjects with gastric adenocarcinoma and gastroesophageal junction adenocarcinoma who had been evaluated for efficacy, 5 subjects achieved partial remission (PR), of which 2 subjects were confirmed partial remission (PR), and 6 subjects achieved partial remission (PR). The best response in the patients was stable disease (SD), ORR and confirmed ORR were 33.3% (95% CI 11.8%-61.6%) and 13.3% (1.7%-40.5%), respectively, and DCR was 73.3% (95%) CI 44.9%-92.2%).

Among the 6 patients with endometrial cancer who underwent efficacy evaluation, 2 patients achieved partial response (PR), of which 1 patient was confirmed partial response (PR), and 2 patients were the most The best response was stable disease (SD), ORR and confirmed ORR were 33.3% (95% CI 4.3%-77.7%) and 16.7% (0.4%-64.1%), respectively, and DCR was 66.7% (95% CI 22.3%-95.7 %).

<110> Hutchison MEDIPHARMA LIMITED SHANGHAI JUNSHI BIOSCIENCES CO.,LTD.

<120> Drug combination of anti-PD-1 antibody and multi-receptor tyrosine kinase inhibitor and method of using the same

<130>

<150> CN 202010157668.2

<151> 2020-03-09

<150> CN 202110226817.0

<151> 2021-03-01

<160> 10

<170> SIPOSequenceListing 1.0

<210> 1

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 1

<210> 2

<211> 7

<212> PRT

<213> Artificial Sequence

<400> 2

<210> 3

<211> 9

<212> PRT

<213> Artificial Sequence

<400> 3

<210> 4

<211> 5

<212> PRT

<213> Artificial Sequence

<400> 4

<210> 5

<211> 17

<212> PRT

<213> Artificial Sequence

<400> 5

<210> 6

<211> 16

<212> PRT

<213> Artificial Sequence

<400> 6

<210> 7

<211> 112

<212> PRT

<213> Artificial Sequence

<400> 7

<210> 8

<211> 125

<212> PRT

<213> Artificial Sequence

<400> 8

<210> 9

<211> 219

<212> PRT

<213> Artificial Sequence

<400> 9

<210> 10

<211> 452

<212> PRT

<213> Artificial Sequence

<400> 10

Claims (15)

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 The antibody or antigen-binding fragment thereof comprises the light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 with amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and the amino acid sequences respectively The heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO:1, 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 comprises the same SEQ ID NO: The sequence of 7 is identical to or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical amino acid sequence with it, and is light The chain variable region comprises or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the sequence of SEQ ID NO: 8 identical amino acid sequences. 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 has at least 90%, 91%, 92%, 93%, 94% of the same sequence A heavy chain amino acid sequence of %, 95%, 96%, 97%, 98%, 99% or higher identity, and identical to or at least 90%, 91%, 92% identical to the sequence of SEQ ID NO: 10 %, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical light chain amino acid sequences. The pharmaceutical combination product according to any one of claims 1 to 3, wherein the multi-receptor tyrosine kinase inhibitor at least inhibits the tyrosine kinase activity of the following two or more receptors Properties: (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 activities of receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R. The pharmaceutical combination product according to claim 5, wherein the multi-receptor tyrosine kinase inhibitor is surufatinib. The pharmaceutical combination product of any one of claims 1 to 6, wherein (i) The single administration dose of anti-PD-1 antibody or antigen-binding fragment thereof is selected from about 1 mg/kg to about 5 mg/kg body weight of the individual, eg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg per kg body weight of the subject, or selected from a fixed dose of about 120 mg to about 480 mg, preferably 120 mg, 240 mg, 360 mg or 480 mg; and/or (ii) The single administered 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, eg, 150 mg, 200 mg, 250 mg, 300 mg or 350 mg. The pharmaceutical combination product of any one of claims 1 to 7, wherein (i) the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a frequency of once weekly, 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 the 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. The pharmaceutical combination product of any one of claims 1 to 8, wherein (i) the single administration dose of anti-PD-1 antibody or antigen-binding fragment thereof 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, with administered once every three weeks (Q3W); and/or (ii) The single administration dose of the multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is 200 mg, 250 mg or 300 mg, preferably 250 mg, administered continuously once a day (QD). The pharmaceutical combination product of any one of claims 1 to 9, wherein (i) the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a liquid dosage form such as an injection, parenterally, such as by intravenous infusion; and/or (ii) The multi-receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, can be administered via the parenteral route or parenterally, eg orally, in a solid dosage form such as a capsule or tablet. The pharmaceutical combination product according to any one of claims 1 to 10, wherein the administration period of (i) and/or (ii) in 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 duration of each dosing cycle can be the same or different, and the intervals between each dosing cycle can be the same or different. The pharmaceutical combination product of any one of claims 1 to 11 for preventing or treating cancer in an individual in need thereof, wherein the cancer is a solid tumor selected from neuroendocrine tumors (eg, neuroendocrine tumors; Neuroendocrine carcinoma; pancreatic neuroendocrine tumor (pNET); non-pancreatic neuroendocrine tumors such as lung carcinoid, gastric carcinoid, duodenal carcinoid, jejunal carcinoid, ileal carcinoid, colon carcinoid, and rectal carcinoid 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, intrauterine cancer Membrane 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 (eg esophageal squamous cell carcinoma); or the cancer is a hematological malignancy selected from leukemia or lymphoid tumor. A method of preventing or treating cancer, the method comprising administering an effective amount of the pharmaceutical combination product according to any one of claims 1 to 11 to an individual in need, wherein the cancer is a solid tumor selected from neuroendocrine tumors ( Examples: neuroendocrine tumors; neuroendocrine carcinomas; pancreatic neuroendocrine tumors (pNETs); non-pancreatic neuroendocrine tumors such as lung carcinoid, gastric carcinoid, duodenal carcinoid, jejunal carcinoid, colon and rectal carcinoid 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 the cancer is a hematological malignancy selected from leukemia or lymphoma. A kit comprising a pharmaceutical combination as claimed in any one of claims 1 to 11, preferably the kit comprises one or more single drug dosage units. The kit of claim 14, comprising: (1) One or more single drug dosage units comprising about 120 mg to about 480 mg, such as 120 mg, 240 mg, 360 mg or 480 mg, preferably 240 mg, of an anti-PD-1 antibody or antigen-binding fragment thereof ;and / or (2) One or more single drug dosage units comprising from about 150 mg to about 350 mg, such as 150 mg, 200 mg, 250 mg, 300 mg or 350 mg, preferably 250 mg, of a multi-receptor tyrosine kinase inhibitor agent or a pharmaceutically acceptable salt thereof.

Images