CN114601924A

CN114601924A - Methods of treating squamous non-small cell lung cancer with anti-PD-1 antibodies or antigen-binding fragments thereof

Info

Publication number: CN114601924A
Application number: CN202111512201.6A
Authority: CN
Inventors: 周辉; 王树彦; 孙路尧
Original assignee: Innovent Biologics Suzhou Co Ltd
Current assignee: Innovent Biologics Suzhou Co Ltd
Priority date: 2020-12-09
Filing date: 2021-12-08
Publication date: 2022-06-10

Abstract

The present invention relates to the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of squamous non-small cell lung cancer. The invention also provides single pharmaceutical dosage units and kits comprising an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof. The invention also provides the use of said single pharmaceutical dosage unit or kit of parts for the manufacture of a medicament for the treatment of squamous non-small cell lung cancer, preferably squamous non-small cell lung cancer which is advanced or metastatic squamous non-small cell lung cancer with failure of first-line platinum-containing chemotherapy.

Description

Methods of treating squamous non-small cell lung cancer with anti-PD-1 antibodies or antigen-binding fragments thereof

Technical Field

The present invention relates to a method of treating squamous non-small cell lung cancer with an anti-PD-1 antibody or antigen-binding fragment thereof, and to the use of an anti-PD-1 antibody or antigen-binding fragment thereof for the manufacture of a medicament for the treatment of squamous non-small cell lung cancer.

Background

With the increase of the average life span and the change of life style of human beings, malignant tumors have become a serious threat to the health of Chinese people, and constitute a serious disease threatening life. Especially lung cancer, the morbidity and mortality of the lung cancer are the first of malignant tumors due to the large smoking population. Statistics in 2015 indicate that the incidence and mortality of lung cancer in China are 73.3 million and 60.0 million respectively, which is the most worldwide [ http:// globocan. The effective treatment means of the advanced lung squamous carcinoma is less, the first-line standard treatment is platinum combined chemotherapy, and the second-line treatment is still chemotherapy mainly comprising docetaxel. Second line therapy has limited efficacy, with a median survival time of about 6 months [ Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versals in Advanced Squamous-Cell Non-Small-Cell Lung cancer. N Engl J Med 2015,373:123-135], and there is a great unmet medical need. In recent years, the research on the effect of activating the human autoimmune system by inhibiting immune check points to attack tumor cells is rapidly advanced, and the immune check point inhibitor (PD-1/PD-L1 inhibitor) provides a new clinical treatment approach for treating non-small cell lung cancer (NSCLC) including squamous cell lung carcinoma.

Immune checkpoints are a class of immunosuppressive molecules. Their physiological function is to modulate the magnitude and breadth of the immune response, thereby avoiding the development of autoimmunity. Tumor cells often use the properties of immune checkpoints to evade attack by immune cells. The currently clinically verified immune checkpoint comprises CTLA-4 and PD-1/PD-L1, wherein the immune checkpoint inhibitor targeting PD-1/PD-L1 has better clinical application prospect due to better safety and wider indications.

PD-1 is mainly expressed in activated T cells and has two ligands, PD-L1 and PD-L2, of which PD-L1 is the main ligand, and expression can be seen in activated T cells, antigen presenting cells and tumor cells [ Nat Rev Immunol 2008,8:467-477 ]. The binding of PD-1/PD-L1 plays an important role in regulating T cell activation and maintaining peripheral immune tolerance. When the T cell does not express PD-1, the T cell interacts with the antigen presenting cell, so that the T cell activates and expands and secretes activated cell factors, and the T cell acts on the tumor cell to kill the tumor cell; the activated T cells start to express PD-1, and after the activated T cells are combined with ligand PD-L1 on antigen presenting cells or tumor cells, the inhibition signals transmitted by the PD-1 can inhibit the proliferation of the T cells and the secretion of activated cytokines, so that the functions of the T cells are reduced, and most tumor cells escape from immune cell attack through the mechanism; if the interaction between PD-1 and PD-L1 is blocked with a drug, the activity of T cells and the ability to kill cancer cells can be restored [ Journal of Clinical Investigation 2015,125:3384-3391 ].

Aiming at the problem that the effect of the existing docetaxel on treating the second-line squamous non-small cell lung cancer is limited, for example, the median total survival time is short, the research of an immune checkpoint inhibitor on the treatment strategy of the second-line squamous non-small cell lung cancer is urgently needed.

Disclosure of Invention

The present invention provides a method of treating squamous non-small cell lung cancer, the method comprising administering to an individual an anti-PD-1 antibody or antigen-binding fragment thereof.

In a preferred embodiment of the present invention, the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises VH CDR1-3, VL CDR1-3, HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively, and LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively.

In a preferred embodiment of the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region and the heavy chain comprises a heavy chain variable region, wherein the light chain variable region has the amino acid sequence as set forth in SEQ ID NO: 8, and the heavy chain variable region has an amino acid sequence shown as SEQ ID NO: 7.

In a preferred embodiment of the invention, the PD-1 antibody or antigen-binding fragment thereof comprises a light chain having the amino acid sequence as set forth in SEQ ID NO: 10 and the heavy chain has the amino acid sequence shown as SEQ ID NO: 9, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the invention, the anti-PD-1 antibody is cedilizumab.

The anti-PD-1 antibody or an antigen-binding fragment thereof is prepared according to WO2017/025016A 1.

In a preferred embodiment of the invention, the squamous non-small cell lung cancer is advanced or metastatic squamous non-small cell lung cancer that failed first-line platinum-containing chemotherapy.

In a preferred embodiment of the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every two to four weeks at a dose selected from the group consisting of 100-300 mg.

In a preferred embodiment of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 100mg, 150mg, 200mg, 250mg, 300 mg.

In a preferred embodiment of the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every three weeks at a dose of 200 mg.

In a preferred embodiment of the invention, the individual is a human, preferably, the individual achieves an Objective Remission Rate (ORR) of 27.6% after administration of the anti-PD-1 antibody or antigen-binding fragment thereof; median overall survival (Median OS) reached 11.79 months; median survival time (Median PFS) reached 4.30 months; the disease control rate DCR reaches 68.3%; median sustained remission DoR reached 12.45 months.

The administration routes of the present invention include intravenous drip, intravenous injection, oral administration, subcutaneous injection, etc.; preferably, the route of administration is intravenous drip.

The present invention also provides a single pharmaceutical dosage unit comprising an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof, preferably, 100-300mg of an anti-PD-1 antibody or antigen-binding fragment thereof; more preferably, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is included.

In a preferred embodiment of the invention, the anti-PD-1 antibody in a single pharmaceutical dosage unit provided by the invention is sildenumab.

The invention also provides a kit of parts comprising an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof as described above and further comprising a package insert printed with instructions for using the anti-PD-1 antibody or antigen-binding fragment thereof in an individual.

The invention also provides the use of a single pharmaceutical dosage unit or kit as described above in the manufacture of a medicament for the treatment of squamous non-small cell lung cancer, preferably advanced or metastatic squamous non-small cell lung cancer that failed first-line platinum-containing chemotherapy.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.

The term "about," when used in conjunction with a numerical value, is intended to encompass a numerical value within a range having a lower limit that is 5% less than the stated numerical value and an upper limit that is 5% greater than the stated numerical value.

The term "and/or" should be understood to mean any one of the options or a combination of any two or more of the options.

As used herein, the term "comprising" or "comprises" is intended to mean including the stated elements, integers or steps, but not excluding any other elements, integers or steps. When the term "comprising" or "includes" is used herein, unless otherwise specified, it also encompasses the presence of stated elements, integers or steps. For example, when referring to an antibody variable region "comprising" a particular sequence, it is also intended to encompass antibody variable regions consisting of that particular sequence.

As used herein, the term "antibody" refers to a polypeptide comprising at least a light or heavy chain immunoglobulin variable region that specifically recognizes and binds an antigen. The term encompasses a variety of antibody structures, including, but not limited to, monoclonal, polyclonal, single or multi-chain antibodies, monospecific or multispecific antibodies (e.g., bispecific antibodies), fully human or chimeric antibodies or humanized antibodies, full length antibodies, and antibody fragments, so long as they exhibit the desired antigen binding activity.

As will be understood by those skilled in the art, a "whole antibody" (used interchangeably herein with "full length antibody", "whole antibody" and "whole antibody") comprises at least two heavy chains (H) and two light chains (L). 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 3 domains CH1, CH2, and CH 3. 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 variable region is the domain of the heavy or light chain of an antibody that is involved in binding the antibody to its antigen. The constant regions are not directly involved in binding of antibodies to antigens, but exhibit a variety of effector functions. The light chains of antibodies can be classified into one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains. The heavy chains of antibodies can be divided into 5 major different types depending on the amino acid sequence of their heavy chain constant region: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into subclasses, e.g., IgG1, IgG2, IgG3 and IgG4, IgA1, and IgA 2. The heavy chain constant regions corresponding to different antibody types are referred to as α, δ, ε, γ, and μ, respectively. The term "isotype" refers to the type of antibody determined by the constant region of the antibody heavy chain. See, e.g., Fundamental Immunology, ch.7(Paul, w. ed., second edition, Raven Press, n.y. (1989)), which is incorporated herein by reference in its entirety for all purposes.

The term "antigen-binding portion" of an antibody (used interchangeably herein with "antibody fragment" and "antigen-binding fragment") refers to a molecule that is not an intact antibody, comprising the portion of the intact antibody that is used to bind the antigen to which the intact antibody binds. As understood by those skilled in the art, the antigen-binding portion of an antibody typically comprises amino acid residues from a "complementarity determining region" or "CDR". Antigen-binding fragments can be prepared by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Antigen binding fragments include, but are not limited to, Fab, scFab, Fab ', F (ab ') 2, Fab ' -SH, Fv, single chain Fv, diabodies (diabodies), triabodies (triabodies), tetrabodies (tetrabodies), minibodies (minibodies), single domain antibodies (sdabs). For a more detailed description of antibody fragments, see: basic Immunology (Fundamental Immunology), edited by w.e.paul, Raven Press, n.y. (1993); shorea et al (editors), antibody drug research and applications, national institutes of health press (2013); hollinger et al, PNAS USA 90: 6444-; hudson et al, nat. Med.9: 129-.

In the context of the present invention, the percent amino acid sequence identity is determined for an antibody sequence by optimally aligning a candidate antibody sequence with a reference antibody sequence, in a preferred embodiment, optimally according to the Kabat numbering convention. Herein, without specifying a comparison window (i.e. the target antibody region to be compared), it will be suitable for alignment over the full length of the reference antibody sequence. In some embodiments, for antibodies, the sequence identity may be distributed over the entire heavy chain variable region and/or the entire light chain variable region, or the percent sequence identity may be limited to the framework regions only, while the sequences of the corresponding CDR regions remain 100% identical.

Similarly, with respect to antibody sequences, based on the alignment, candidate antibodies having amino acid changes in the target antibody region relative to a reference antibody can be determined.

In the present invention, "conservative substitution" refers to an amino acid change resulting in the substitution of an amino acid with a chemically similar amino acid. Amino acid modifications such as substitutions can be introduced into the antibodies of the invention by standard methods known in the art, for example, site-directed mutagenesis and PCR-mediated mutagenesis.

Conservative substitution tables providing functionally similar amino acids are well known in the art. In a preferred aspect, the conservatively substituted residue is from conservative substitutions a, preferably the preferred conservatively substituted residues shown in table a.

TABLE A

Original residues	Exemplary substitutions	Preferred conservative substitutions
			Ala(A)	Val；Leu；Ile	Val
Arg(R)	Lys；Gln；Asn	Lys
			Asn(N)	Gln；His；Asp；Lys；Arg	Gln
Asp(D)	Glu；Asn	Glu
			Cys(C)	Ser；Ala	Ser
Gln(Q)	Asn；Glu	Asn
			Glu(E)	Asp；Gln	Asp
Gly(G)	Ala	Ala
			His(H)	Asn；Gln；Lys；Arg	Arg
Ile(I)	Leu; val; met; ala; phe; norleucine	Leu
			Leu(L)	Norleucine; ile; val; met; ala; phe (Phe)	Ile
Lys(K)	Arg；Gln；Asn	Arg
			Met(M)	Leu；Phe；Ile	Leu
Phe(F)	Trp；Leu；Val；Ile；Ala；Tyr	Tyr
			Pro(P)	Ala	Ala
Ser(S)	Thr	Thr
			Thr(T)	Val；Ser	Ser
Trp(W)	Tyr；Phe	Tyr
			Tyr(Y)	Trp；Phe；Thr；Ser	Phe
Val(V)	Ile; leu; met; phe; ala; norleucine	Leu

"complementarity determining regions" or "CDR regions" or "CDRs" are regions of amino acids in the variable region of an antibody that are primarily responsible for binding to an epitope of an antigen. The CDRs of the heavy and light chains are commonly referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2 and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2 and LCDR 3.

A "variable region" or "variable domain" is a domain in the heavy or light chain of an antibody that is involved in the binding of the antibody to its antigen. The heavy chain variable region (VH) and the light chain variable region (VL) may be further subdivided into hypervariable regions (HVRs, also known as Complementarity Determining Regions (CDRs)) with more conserved regions (i.e., Framework Regions (FRs)) interposed therebetween. Each VH and VL consists of three CDRs and 4 FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR 4. In some cases, a single VH or VL domain is sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen can be isolated by screening libraries of complementary VL or VH domains using VH or VL domains from antibodies that bind the antigen (see, e.g., Portolano, S. et al, J.Immunol.150(1993) 880-.

It is known in the art that one or more residues in one or both of the two variable regions (i.e., VH and/or VL) may be modified, e.g., residue modifications, particularly conservative residue substitutions, to one or more CDR regions and/or to one or more framework regions, while the modified antibody still substantially retains at least one biological property (e.g., antigen binding ability) of the antibody molecule prior to the modification. For example, residues from a CDR region may be mutated to improve one or more binding properties (e.g., affinity) of the antibody. The antibody binding properties or other functional properties of the mutated antibody may be assessed in vitro or in vivo assay assays. Preferably, conservative substitutions are introduced. Preferably, the residues introduced in the CDR regions are not changed by more than 1, 2, 3, 4 or 5. Furthermore, framework region residues may be mutated, for example to improve the properties of the antibody. For example, one or more framework residues may be "back-mutated" to the corresponding germline sequence residue.

The term "treatment" as used herein refers to a slowing, arresting or reversing of the progression of squamous non-small cell lung cancer in a subject as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease. Treatment may include, for example, reducing symptom severity, number of symptoms, or frequency of recurrence, e.g., tumor growth inhibition, tumor growth retardation, or regression of existing tumors.

The term "single pharmaceutical dosage unit" as used herein means a single pharmaceutical dosage form, including injections, tablets, and lyophilized powders, that is administered to a patient at the time of a dosing regimen.

As used herein, the term "effective amount" is generally an amount sufficient to reduce the severity and/or frequency of symptoms, eliminate symptoms and/or underlying causes, prevent the appearance of symptoms and/or their underlying causes, and/or ameliorate damage caused by or associated with a disease state (e.g., lung disease). In some embodiments, the effective amount is a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" is an amount sufficient to treat a disease state or condition, particularly a state or condition associated with the disease state, or to otherwise prevent, hinder, delay or reverse the progression of the disease state or any other undesirable condition associated with the disease in any way. A "prophylactically effective amount" is an amount that, when administered to a subject, will have a predetermined prophylactic effect, e.g., prevent or delay the onset (or recurrence) of the disease state, or reduce the likelihood of the onset (or recurrence) of the disease state or associated symptoms. A complete therapeutic or prophylactic effect does not necessarily occur as a result of administration of one dose, but may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations.

The term "administering" as used herein means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., by injection or infusion.

The term "dose" as used herein is the amount of drug that elicits a therapeutic effect. Unless otherwise indicated, the dosage is related to the amount of drug in free form. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased proportionally to the amount of the drug in free form. For example, the dosage will be stated in a product package or product information sheet.

The term "adverse event" (AE) generally refers to any undesirable medical event that occurs after administration of a drug to a subject in a clinical trial. Adverse events are not necessarily causal to treatment. Thus, an adverse event may be any adverse and undesirable sign (including abnormal findings), symptom or disease that has a temporal correlation with the use of a drug (including study drug), whether or not it is drug related (ICH-GCP definition). A medical treatment may have one or more related AEs, and each AE may have the same or different level of severity.

The term "Overall Survival (OS)" refers to the period from the random period to death due to any cause. Subjects who survived the last visit had OS scored as data loss at the time of the last visit. Subjects who were missed their OS were data loss as the last confirmed survival time before the missed visit. The OS of data erasure is defined as the time from random grouping to erasure.

The term "Progression Free Survival (PFS)" refers to the time from randomization to first disease Progression (imaging), and if the patient died for any reason before disease Progression, to death. Subjects who did not develop disease progression or death had the date of the last imaging evaluation as the date of deletion. Subjects who had not been evaluated imagewise after baseline were censored with randomized dates. Analysis of PFS median progression free survival (mPFS) and 95% CI were estimated using Kaplan-Meier and plotted as a survival graph.

The term "Objective Response Rate (ORR)" refers to the proportion of patients whose tumors have shrunk to a certain extent and are maintained for a certain period of time, including cases of CR and PR. Solid tumor remission evaluation criteria (RECIST 1.1 criteria) were used to assess objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline, and the criteria for efficacy assessment are divided into Complete Remission (CR), Partial Remission (PR), Stable (SD), Progression (PD) according to RECIST 1.1 criteria.

The term "Disease Control Rate (DCR)" refers to the percentage of confirmed complete remission, partial remission, and stable Disease (. gtoreq.8 weeks) cases among patients with evaluable efficacy.

The term "duration of remission (DoR)" refers to the duration of remission in a subject in remission (CR or PR): the first remission date to the time of disease progression or death, subjects without PD or death were censored at the last imaging evaluation date. Median sustained remission (mDoR) and 95% CI were estimated using Kaplan-Meier and plotted as a survival graph.

The term "Complete Response (CR)": all target lesions disappeared and no new ones appeared.

The term "Partial mitigation (PR)": the sum of the target lesion diameters is reduced by at least 30% from baseline levels.

The term "Progressive Disease (PD)": the diameter and relative increase is at least 20% with respect to the minimum of the sum of all measured target lesion diameters throughout the experimental study (baseline values are referenced if the baseline measurement is minimal).

The term "Stable Disease (SD)": the target lesion was decreased to a degree that did not reach PR and increased to a degree that did not reach PD levels, between which the minimum of the sum of the diameters was considered for the study.

Drawings

FIG. 1 is the difference in OS between IBI308 versus docetaxel;

FIG. 2 is the difference in PFS for IBI308 versus docetaxel;

figure 3 is the difference in ORR for IBI308 versus docetaxel.

Detailed Description

The invention is further illustrated by the following non-limiting examples.

Example 1

Test antibodies and other drugs

The anti-PD-1 antibody used in the present invention was Xindilizumab (10 mL: 100mg) produced by Xinda biopharmaceutical (Suzhou) Co., Ltd.

Docetaxel: specification: 20mg/0.5mL, 40mg/1mL, or 80mg/2mL

Group entry criteria

1. A cytological or histological diagnosis of squamous non-small cell lung cancer;

2. locally advanced, metastatic or recurrent (i.e., stage IIIB, IIIC or iv not meeting the criteria for radical chemoradiotherapy) NSCLC (8 th edition by UICC/AJCC staging system), four cases are possible:

1) disease progression (RECIST v1.1) during or after first-line platinum-containing chemotherapy (including during maintenance chemotherapy), first-line therapy allowing one of the drugs to be discontinued, reduced or replaced between the same;

2) failure to tolerate the toxicity of a first-line platinum-containing chemotherapy regimen (receiving at least a full cycle of treatment), necessitating a change to another systemic treatment regimen;

3) the disease relapse or metastasis occurs within 6 months after the platinum-containing neoadjuvant/adjuvant chemotherapy (before and after radical operation) or sequential/synchronous radical radiotherapy and chemotherapy (platinum-containing scheme) is finished;

4) the disease relapse or metastasis is more than 6 months after the platinum-containing neoadjuvant/adjuvant chemotherapy (before and after radical operation) or sequential/synchronous radical radiotherapy and chemotherapy (platinum-containing scheme) is finished, and the disease progress occurs after or during the platinum-containing scheme chemotherapy for the relapse or metastasis;

3. at least one measurable lesion (RECIST v 1.1);

4. male or female is more than or equal to 18 years old and less than or equal to 75 years old;

an ECOG PS score of 0 or 1;

6. the expected life cycle is more than or equal to 12 weeks;

7. vital organ and bone marrow function meets the following requirements (except for patients treated with any cells and growth factors within the first 2 weeks of randomization):

1) blood routine: absolute Neutrophil Count (ANC) of 1.5X 109/L or more, Platelet (PLT) of 100X 109/L or more, Hemoglobin (HGB) of 90g/L or more (transfusion with components cannot be used within 1 week before randomization);

2) liver function: serum Total Bilirubin (TBIL) is less than or equal to 1.5 times of Upper Limit of Normal (ULN), alanine Aminotransferase (ALT) and/or aspartate Aminotransferase (AST) is less than or equal to 2.5 times of ULN, and serum Albumin (ALB) is more than or equal to 2.8g/dL

3) Renal function: serum creatinine (Cr) is less than or equal to 1.5 × ULN, or creatinine clearance is more than or equal to 40mL/min (using standard Cockcroft-Gault formula): female: CrCl ═ ((140-years) × body weight (kg)) × 0.85/(72 × serum creatinine (mg/dL)) male: CrCl ═ ((140-years) × body weight (kg) × 1.00)/(72 × serum creatinine (mg/dL))

8. The subject and the sexual partner of the subject need to take a medically approved contraceptive (e.g., an intrauterine device, a contraceptive, or a condom, etc.) during the study treatment period and within 6 months after the study treatment period;

9. written informed consent was signed and protocol-specified visits and related procedures could be followed.

Method of administration

Experimental groups: the sillimumab (also referred to herein as IBI308) was administered every three weeks for a dosing cycle of 200mg per intravenous drip. The drug is administered through an on-line filter with 0.2-1.2 μm (infusion time is recommended to be controlled within 30-60 minutes) until disease progression, death, intolerance of toxicity, withdrawal of informed consent, initiation of new anti-tumor therapy or termination of therapy for other reasons as prescribed by the regimen.

Control group: docetaxel 75mg/m2 was instilled intravenously, Q3W, until disease progression, death, intolerance of toxicity, withdrawal of informed consent, initiation of new anti-tumor therapy or other cause prescribed by the regimen was discontinued.

Results of the experiment

First, safety outcomes of IBI308 vs docetaxel in advanced or metastatic squamous non-small cell lung cancer with failure of first-line platinum-containing chemotherapy:

the experimental statistics were analyzed using the safety analysis set (SS) for 290 patients (experimental group 145, control group 145) in the total group from 08/25 days in 2017 (first informed consent signing date) to 31/7/2020 (data expiration date). The SS pool was included in 274 subjects, with 144 in the fudilitumab group and 130 in the docetaxel group. IBI308 has good safety compared to docetaxel, with a lower incidence of adverse events associated with study drug class 3 and above, and no new adverse reaction safety signal was observed.

Second, the efficacy results of IBI308 versus docetaxel in advanced or metastatic squamous non-small cell lung cancer with failure of first-line platinum-containing chemotherapy:

experimental statistics from 25 days 08/2017 (first informed consent and sign date) to 31 days 7/2020 (data expiration date), 290 patients (145 experimental groups and 145 control groups) were enrolled, 280 patients (145 experimental groups and 135 control groups) were included in the effectiveness analysis, and the data analysis revealed that the experimental groups all showed better therapeutic benefit than the control groups in os (optimal summary), PFS, ORR, DCR and DoR.

In terms of OS, when experimental group IBI308 was treated for 6 months, OS reached 76%, and control group docetaxel 61%; at 12 months of treatment, OS was 49% in IBI308 group and 38% in docetaxel group. Wherein the median os (media os), IBI308 group was 11.79 months, docetaxel group was only 8.25 months; HR was 0.74 (FIG. 1).

In terms of PFS, PFS reached 42% at 6 months of experimental group IBI308 treatment, 16% for control docetaxel; at 12 months of treatment, PFS was 21% in the IBI308 group and only 2% in the docetaxel group. Wherein the median pfs (media pfs), IBI308 group was 4.30 months, docetaxel group was only 2.79 months; HR was 0.52 (fig. 2).

In ORR, DCR, DoR, the ORR of IBI308 group was 27.6%, the docetaxel group was only 5.2%; DCR was 68.3% for IBI308 group and only 42.2% for docetaxel group; median dor (media dor) for group IBI308 was 12.45 months, with docetaxel only at 4.14 months (table 1 and fig. 3).

The above safety and efficacy experimental results show that the anti-PD-1 antibody IBI308 exhibits better therapeutic effects (Median survival Median OS, longer Median progression-free survival Median PFS; significantly improved ORR, DCR and Median DoR) and good safety in treating advanced or metastatic squamous non-small cell lung cancer that fails platinum-containing chemotherapy at the first-line, i.e., in second-line squamous non-small cell lung cancer, compared to docetaxel.

Sequence listing

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Gly Leu Ile Ile Pro Met Phe Asp Thr Ala Gly Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Ala Ile Thr Val Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Glu His Ser Ser Thr Gly Thr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 8

<211> 107

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 8

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Ser Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn His Leu Pro Phe

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 9

<211> 447

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 9

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Ile Pro Met Phe Asp Thr Ala Gly Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Ala Ile Thr Val Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Glu His Ser Ser Thr Gly Thr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 10

<211> 214

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> synthetic construct

<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Ser Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn His Leu Pro Phe

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

Claims

1. A method of preventing or treating squamous non-small cell lung cancer in an individual, comprising administering to the individual an anti-PD-1 antibody or antigen-binding fragment thereof comprising VH CDR1-3, VL CDR1-3, HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

2. The method of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region and the heavy chain comprises a heavy chain variable region, wherein the light chain variable region has the amino acid sequence as set forth in SEQ ID NO: 8, and the heavy chain variable region has an amino acid sequence shown as SEQ ID NO: 7.

3. The method of claim 2, wherein the light chain has the amino acid sequence set forth in SEQ ID NO: 10 and the heavy chain has the amino acid sequence shown as SEQ ID NO: 9, or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the anti-PD-1 antibody is certolizumab.

5. The method of any one of claims 1-4, wherein the squamous non-small cell lung cancer is advanced or metastatic squamous non-small cell lung cancer that failed first-line platinum-containing chemotherapy.

6. The method according to any one of claims 1 to 5, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every two to four weeks at a dose selected from the group consisting of 100-300 mg; preferably 100mg, 150mg, 200mg, 250mg or 300 mg; more preferably 200mg, administered once every three weeks.

7. The method of any one of claims 1 to 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered by intravenous drip, intravenous injection, oral administration, subcutaneous injection, preferably by intravenous drip.

8. The method of any one of claims 1-7, wherein the individual is a human; preferably, the individual has an objective tumor remission rate, ORR, of 27.6% following administration of the anti-PD-1 antibody or antigen-binding fragment thereof; median overall survival (Median OS) reached 11.79 months; median survival time (Median PFS) reached 4.30 months; the disease control rate DCR reaches 68.3%; median sustained remission DoR reached 12.45 months.

9. A single pharmaceutical dosage unit comprising a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof according to any one of claims 1-8, preferably comprising 100-300mg of an anti-PD-1 antibody or antigen-binding fragment thereof; preferably, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is included.

10. The single drug dosage unit of claim 9, wherein the anti-PD-1 antibody is cedilizumab.

11. A kit of parts comprising a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof according to any one of claims 1-10, preferably 100mg of an anti-PD-1 antibody or antigen-binding fragment thereof; preferably, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is included; preferably, further comprising a package insert printed with instructions for using the anti-PD-1 antibody or antigen-binding fragment thereof in an individual.

12. Use of a single pharmaceutical dosage unit according to claims 9-10 or a kit of parts according to claim 11 for the preparation of a medicament for the treatment of squamous non-small cell lung cancer, preferably, said squamous non-small cell lung cancer is advanced or metastatic squamous non-small cell lung cancer that has failed first-line platinum-containing chemotherapy.