EP4669674A1

EP4669674A1 - METHOD FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER WITH ANTI-PD-1 ANTIBODIES

Info

Publication number: EP4669674A1
Application number: EP24760805.2A
Authority: EP
Inventors: Gregory Michael LUBINIECKI; Maria Catherine PIETANZA
Original assignee: Merck Sharp and Dohme LLC
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2023-02-22
Filing date: 2024-02-16
Publication date: 2025-12-31
Also published as: WO2024177899A1

Abstract

The invention relates to methods for treating non-small cell lung cancer in a human patient comprising administering an anti-PD-1 antibody or antigen binding fragment thereof (e.g., pembrolizumab) in specific amounts to the patient every three or six weeks, wherein the anti-PD-1 antibody or antigen binding fragment thereof is administered in combination with chemotherapy as a neoadjuvant treatment and following the neoadjuvant treatment, the patient is administered the anti-PD-1 antibody or antigen binding fragment thereof as an adjuvant treatment.

Description

METHODS FOR TREATING NON-SMAEL CELL LUNG CANCER WITH ANT1-PD-1

ANTIBODIES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/486.357 filed February 22, 2023, the entire contents of which is incorporated by reference herein.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing (25663-SEQLIST-27OCT2023.xml; Size: 36,864 bytes; and Date of Creation: October 27, 2023) are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0003] The invention relates to methods for treating non-small cell lung cancer in a human patient comprising administering an anti-PD-1 antibody or antigen binding fragment thereof (e.g.. pembrolizumab) in specific amounts to the patient every three or six weeks, wherein the anti-PD-1 antibody or antigen binding fragment thereof is administered in combination with chemotherapy as a neoadjuvant treatment and following the neoadjuvant treatment, the patient is administered the anti-PD-1 antibody or antigen binding fragment thereof as an adjuvant treatment.

BACKGROUND OF THE INVENTION

[0004] PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and up- regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology, 8:239-245 (2007)).

[0005] Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues. In large sample sets of e.g., ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment (Dong et al., Nat Med. 8(8):793-800 (2002); Yang et al. Invest Ophthalmol Vis Sa. 49: 2518-2525 (2008); Ghebeh et al. Neoplasia 8:190-198 (2006); Hamanishi et al., Proc. Natl. Acad. Sci. USA 104: 3360-3365 (2007); Thompson et al.. Cancer 5: 206-211 (2006) ; Nomi et al.. Clin. Cancer Research 13:2151-2157 (2007); Ohigashi et al., Clin. Cancer Research 11: 2947-2953 (2005); Inman et al., Cancer 109: 1499-1505 (2007); Shimauchi et al. Int. J. Cancer 121:2585-2590 (2007); Gao et al. Clin. Cancer Research 15: 971-979 (2009); Nakanishi J. Cancer Immunol Immunother. 56: 1173- 1182 (2007); and Hino et al., Cancer 00: 1-9 (2010)).

[0006] Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma (Ghebeh et al., BMC Cancer. 8:5714-15 (2008); Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and to correlate with poor prognosis in renal cancer (Thompson et al., Clinical Cancer Research 15: 1757-1761 (2007)). Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.

[0007] Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers (Brahmer et al., N Engl J Med

2012, 366: 2455-65; Garon et al. N Engl J Med 2015, 372: 2018-28; Hamid et al., N Engl J Med

2013, 369: 134-44; Robert et al., Lancet 2014, 384: 1109-17; Robert et al., N Engl J Med 2015, 372: 2521-32; Robert et al, N Engl J Med 2015, 372: 320-30; Topalian et al, N Engl J Med 2012, 366: 2443-54; Topalian et al, J Clin Oncol 2014, 32: 1020-30; Wolchok et al. N Engl J Med 2013, 369: 122-33). Immune therapies targeting the PD-1 axis include monoclonal antibodies directed to the PD-1 receptor (KEYTRUDA® (pembrolizumab), Merck Sharp & Dohme LLC., Rahway, NJ, USA; OPDIVO® (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ, USA, and LIBTAYO® (cemiplimab), Regeneron Pharmaceuticals, Inc., Tarrytown. NY, USA) and also those that bind to the PD-L1 ligand (MPDL3280A;

TECENTRIQ® (atezolizumab), Genentech, San Francisco, CA, USA; IMFINZI® (durvalumab), AstraZeneca Pharmaceuticals LP, Wilmington, DE; BAVENCIO® (avelumab), Merck KGaA, Darmstadt, Germany; JEMPERLI® (dostarlimab). GlaxoSmithKline Biologies LLC, Philadelphia. PA, USA). Both therapeutic approaches have demonstrated anti-tumor effects in numerous cancer types.

[0008] Lung cancer is the most common malignancy in the world, with an estimated global incidence in 2020 of 2.2 million new cases and an associated 1.8 million deaths. NSCLC represents approximately 85% of all lung cancers. For patients with Stage I to IIIA NSCLC, surgical resection is the standard treatment, which includes lobectomy, pneumonectomy, and mediastinal lymph node dissection/ sampling depending on the extent of the disease and the cardiopulmonary reserve of the patient. Patients with Stage I1IB disease are considered potentially operable if the metastases are limited to the N2 lymph nodes. In practice, fewer than 10% of patients with clinical Stage IIIB disease undergo surgery. 5-year OS rates for patients with surgically treated NSCLC remain unsatisfactory, ranging from approximately 20% (Stage IIIA) to 55% (Stage I), with many patients experiencing disease recurrence largely due to the presence of residual micrometastases.

SUMMARY OF THE INVENTION

[0009] The present disclosure provides a method of treating non-small cell lung cancer in a human patient comprising administering to the patient a PD-1 antibody, or antigen binding fragment thereof, in combination with chemotherapy as a neoadjuvant treatment, and administering to the patient a PD-1 antibody, or antigen binding fragment thereof as an adjuvant treatment after the neoadjuvant treatment. In some embodiments, the PD-1 antibody, or antigen binding fragment thereof comprises (a) light chain (LC) complementarity determining regions (CDRs) LC-CDR1, LC-CDR2 and LC-CDR3 comprising a sequence of amino acids as set forth in SEQ ID NOs: 1, 2 and 3, respectively, and heavy chain (HC) CDRs HC-CDR1, HC-CDR2 and HC-CDR3 comprising a sequence of amino acids as set forth in SEQ ID NOs: 6. 7 and 8, respectively; or (b) light chain CDRs LC-CDR1, LC-CDR2 and LC-CDR3 comprising a sequence of amino acids as set forth in SEQ ID NOs: 11, 12 and 13, respectively, and heavy chain CDRs HC-CDR1, HC-CDR2 and HC-CDR3 comprising a sequence of amino acids as set forth in SEQ ID NOs: 14, 15 and 16, respectively. In some embodiments, the antibody or antigen binding fragment thereof is administered every three weeks. In some embodiments, the antibody or antigen binding fragment thereof is administered every six w eeks. In embodiments of the invention, the antibody or antigen-binding fragment is pembrolizumab or an antigen-binding fragment thereof. In a further embodiment, the anti -PD-1 antibody is pembrolizumab.

[0010] In embodiments of the invention, the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg. In other embodiments of the invention, the antibody or antigen binding fragment thereof is administered at a dose of 400 mg.

[0011] In embodiments of the invention, the PD-1 antibody administered as an adjuvant treatment is administered as a monotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows the study design of a Phase III study described in Example 1.

[0013] Figure 2 shows the timeline and phases of the study design described in Example 1.

[0014] Figure 3 shows a Kaplan-Meier plot of event-free survival based on investigator assessment in the ITT population comparing the two study arms of the Phase III clinical trial as described in Example 1.

[0015] Figure 4 shows a Kaplan-Meier plot of overall survival in the ITT population comparing the two study arms of the Phase III clinical trial as described in Example 1.

[0016] Figure 5 shows a Kaplan-Meier plot of event-free survival based on investigator assessment by pCR status in the ITT population comparing the two arms of the Phase III clinical trial as described in Example 1.

[0017] Figure 6 shows the Kaplan-Meier plot of event-free survival based on investigator assessment by mPR status in the ITT population comparing the two arms of the Phase III clinical trial as described in Example 1.

[0018] Figure 7 shows amino acid sequences of the light chain and heavy chain for an exemplary anti-PD-1 monoclonal antibody useful in the invention (SEQ ID NOs: 5 and 10, respectively). Light chain and heavy chain variable regions are underlined (SEQ ID NOs: 4 and 9, respectively) and CDRs are bold.

DETAILED DESCRIPTION

Abbreviations

As used throughout the specification and appended claims, the following abbreviations apply:

AE adverse event

AEOSI adverse event of special interest

AJCC American Joint Committee on Cancer

ALP alkaline phosphatase

ALT alanine aminotransferase

APaT all participants as treated

APrS all participants receiving surgery

AST aspartate aminotransferase

BICR blinded independent central review

BIPR blinded independent pathologic review

CI confidence interval COVID-19 coronavirus disease caused by severe acute respiratory syndrome coronavirus 2

CSR clinical study report

CT clinical trial

CTCAE common terminology criteria for adverse events

DFS disease-free survival

ECG electrocardiogram

ECOG Eastern Cooperative Oncology Group

EFS event-free survival

EMA European Medicines Agency

EORTC European Organization for Research and Treatment of Cancer

EQ-5D-5L European Quality of Life Five Dimensions 5 Level Questionnaire

ERC Ethics Review Committee

EU European Union

EudraCT European Union Drug Regulating Authorities Clinical Trials Database

FAS full analysis set

FDA Food and Drug Administration

HR hazard ratio

HRQoL health-related quality of life

IA interim analysis

ICH International Council for Harmonization (of Technical Requirements for

Registration of Pharmaceuticals for Human Use)

IgG4 immunoglobulin G4

IMP Investigational Medicinal Product

IND Investigational New Drug

ITT intent-to-treat

IV intravenous

KM Kaplan-Meier

LS least squares

MedDRA Medical Dictionary for Regulatory Activities mPR maj or pathological response

NIMP noninvestigational medicinal product

NSCLC Non-small cell lung cancer

PET positron emission tomography mPR major pathological response

NAC neoadjuvant chemotherapy

NCI National Cancer Institute

NR not reached

OS overall survival pCR pathological complete response

PD progressive disease

PD-1 programmed cell death protein 1

PD-L1 programmed death-ligand 1

PD-L2 programmed death-ligand 2

PRO patient-reported outcome or participant-reported outcome

PS Performance scale

QA quality assurance

QLQ quality of life questionnaire

QoL quality of life

Q3W every 3 weeks

RECIST Response Evaluation Criteria in Solid Tumors

RMST restricted mean survival time

RT radiation therapy

SAE serious adverse event sSAP supplementary⁷ statistical analysis plan

SD standard deviation

TPS tumor proportion score

UICC Union for International Cancer Control

ULN upper limit of normal

WHO World Health Organization

Definitions

[0019] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0020] 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. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0021] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0022] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0023] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and/or values.

[0024] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0025] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

[0026] The terms “administration” or “administer” refers to the act of injecting or otherw ise physically delivering a substance as it exists outside the body (e.g.. an anti-PD-1 antibody) into a patient or subject, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery⁷, and/or any other methods of physical delivery' described herein or know n in the art.

[0027] The term “subject” (alternatively “patient”) as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g.. pigs), ovine (e.g. sheep), capra (e.g, goats), equine (e.g., horses), canine (e.g., domestic dogs), feline (e.g., house cats), lagomorph (e.g., rabbits), rodent (e.g., rats or mice), and Procyon lotor (e.g., raccoons). In particular embodiments, the subject is human. [0028] The term ‘‘subject in need thereof' as used herein refers to a subject diagnosed with or suspected of having cancer as defined herein.

[0029] As used herein, the term ‘'antibody'’ refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies, and may include post-translational modifications thereof (e.g., C-terminal Lysine clipping in the heavy chain, conversion of glutamine or glutamic acid to pyroglutamate) that may occur when an antibody is recombinantly expressed in host cells (e.g., CHO cells), or during purification/storage. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic. As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, fusion proteins comprising an antigen binding fragment thereof that competes with the intact antibody for specific.

[0030] In general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The variable regions of each hght/heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy' chains are typically’ classified as mu, delta, gamma, alpha, or epsilon, and define the antibody’s isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0031] “Variable regions” or “V region” or “V chain” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. A '‘variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.”

[0032] Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs). which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C- terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. As referred to herein the light chain CDRs are CDRL1, CDRL2 and CDRL3. respectively, and the heavy chain CDRs are CDRH1, CDRH2 and CDRH3, respectively. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al. ; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al.. (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al.. (1987) J Mol. Biol. 196:901- 917 or Chothia, et al., (1989) Nature 342:878-883.

[0033] A “CDR” refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH P-sheet framework, or one of three hypervariable regions (LI, L2, or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability⁷ within the antibody variable domains. CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved -sheet framework, and thus are able to adapt to different conformations. Both terminologies are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (AL Lazikani et al.. 1997, J. Mol. Biol. 273:927-48; Morea et a/., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is similarly well known to those skilled in the art. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art and shown below⁷ in Table 1. In some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In yet other embodiments, the CDRs are as defined by the AbM numbering system. In still other embodiments, the CDRs are as defined by the Chothia numbering system. In yet other embodiments, the CDRs are as defined by the Contact numbering system.

Table 1. Correspondence between the CDR Numbering Systems

[0034] ‘‘Chimeric antibody ” refers to an antibody in which a portion of the heavy and/or light chain contains sequences derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species (e.g, mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0035] “Human antibody” refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0036] “Humanized antibody” refers to forms of antibodies that contain sequences from nonhuman (e.g, murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefix “hum”, “hu” or “h” may be added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.

[0037] “Monoclonal antibody” or “mAb” or “Mab”. as used herein, refers to a population of substantially homogeneous antibodies, z.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods {see. e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0038] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability' to bind specifically to the antigen, e.g., fragments that retain one or more CDR regions and the ability to bind specifically to the antigen. An antibody that “specifically binds to” PD-1 is an antibody that exhibits preferential binding to PD-1 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity'. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or binding fragments thereof, will bind to the target protein with an affinity that is at least two-fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins. [0039] Antigen binding portions include, for example, Fab, Fab’. F(ab’)2, Fd, Fv, fragments including CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the antigen (e.g, PD-1). An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g, IgGl, IgG2, IgG3, IgG4. IgAl, and IgA2. The heavy -chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0040] An "antigen" is a structure to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, an antigen is associated with a cell, for example, is present on or in a cell, for example, a cancer cell.

[0041] An "intact" antibody is one comprising an antigen-binding site as well as a CL and at least heavy chain constant regions, CHI, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0042] As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory' immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.

[0043] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral route or parenteral route of administration. The term “enteral route” of administration refers to the administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route. “Parenteral route” of administration refers to a route of administration other than enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal. epidural and intrastemal, subcutaneous, or topical administration. The therapeutic agents and compositions of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. A suitable route and method of administration may vary depending on a number of factors such as the specific therapeutic agent being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the patient, and can be readily selected by a person skilled in the art.

[0044] “Chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytoxic/antitumor antibiotics, topoisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth. Chemotherapeutic agents useful in the treatment methods of the invention include cytostatic and/or cytotoxic agents. [0045] The term “variant” when used in relation to an antibody (e.g., an anti-PD-1 antibody) or an amino acid region within the antibody may refer to a peptide or polypeptide comprising one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and/or additions as compared to a native or unmodified sequence. For example, a variant of an anti-PD-1 antibody may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native or previously unmodified anti-PD-1 antibody. Variants may be naturally occurring or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants. In specific embodiments, an antibody variant (e.g, an anti-PD-1 antibody variant) at least retains the antibody functional activity. In some embodiments, an anti-PD-1 antibody variant binds to PD-1 and/or is antagonistic to PD-1 activity.

[0046] “Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity /hydrophilicity, backbone conformation and rigidity’, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and/or specificity. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology) of the Gene, The Benjamin/ Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 2 below.

Table 2. Exemplary Conservative Amino Acid Substitutions [0047] ’’Homology" refers to sequence similarity between two polypeptide sequences when they are optimally aligned. When a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, <?.g., if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position. The percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if 8 of 10 of the positions in two sequences are matched when the sequences are optimally aligned then the two sequences are 80% homologous. Generally, the comparison is made when two sequences are aligned to give maximum percent homology. For example, the comparison can be performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.

[0048] The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W„ et al.. (1993) Nature Genet. 3:266-272; Madden. T.L.. et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17: 149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., “A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure. (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., “Matrices for detecting distant relationships.’’ in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S.. et al.. (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul, S.F., etal., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S„ et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S„ et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob.

22:2022-2039; and Altschul. S.F. “Evaluating the statistical significance of multiple distinct local alignments.” in Theoretical and Computational Methods in Genome Research (S. Suhai, ed ), (1997) pp. 1-14, Plenum, New’ York.

[0049] “RECIST 1. 1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured. [0050] "Sustained response” means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.

[0051] "Non-responder patient”, when referring to a specific anti-tumor response to a treatment described herein, means the patient did not exhibit an anti-tumor response.

[0052] “Responder patient” when referring to a specific anti-tumor response to a treatment described herein, means the patient exhibited an anti-tumor response.

[0053] “Treat” or “treating” cancer as used herein means to administer an anti -human PD-1 monoclonal antibody or antigen binding fragment thereof, to a subject having cancer or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, comprising administration by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and/or any other methods of physical delivery described herein or known in the art. Typically, the agent(s) of the treatment method are administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting the progression of such symptom(s) by any clinically measurable degree. The amount of the agent(s) of the treatment method that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability⁷ of the therapeutic combination to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. “Treatment” may include one or more of the following: inducing/increasing an antitumor immune response, decreasing the number of one or more tumor markers, halting or delaying the growth of a tumor or blood cancer or progression of disease such as cancer, stabilization of disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, decreasing the level of one or more tumor markers, ameliorating or abrogating the clinical manifestations of disease, reducing the severity⁷ or duration of the clinical symptoms, prolonging the survival or patient relative to the expected survival in a similar untreated patient, and inducing complete or partial remission of a cancerous condition, wherein the disease is cancer, more specifically, non-small cell lung cancer. [0054] As used herein, “adjuvant treatment’⁷ means adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. Adjuvant treatment is treatment given after the main treatment to reduce the chance of cancer.

[0055] As used herein, “neoadjuvant treatment” is a treatment given as a first step to provide immediate disease control by killing cancer cells at the primary tumor site and those that have metastasized from it. An added benefit of neoadjuvant treatment may be a decrease in the size of the tumor to be resected, the main treatment.

[0056] The amount of a therapeutic agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. [0057] Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50: 1 S-10S (2009)). For example, with respect to tumor grow th inhibition, according to NCI standards, a T/C 42% is the minimum level of anti-tumor activity. A T/C < 10% is considered a high anti-tumor activity level, with T/C (%) = Median tumor volume of the treated/Median tumor volume of the control x 100. In some embodiments, the treatment achieved by a therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria. The treatment regimen for a therapy of the disclosure that is effective to treat a cancer patient may van- according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi²-test, the U-test according to Mann and Whitney, the Kruskal -Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test. [0058] “PD- 1 antagonist⁷’ means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1. B7H1, B7-4. CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the treatment methods, medicaments and uses of the invention in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0059] ■■Pembrolizumab" (formerly known as MK-3475, SCH 900475 and lambrolizumab) alternatively referred to herein as “pembro,” is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences and CDRs described in Table 3. Pembrolizumab has been approved by the U.S. FDA as described in the Prescribing Information for KEYTRUDA® (Merck & Co., Inc., Rahway, NJ USA; initial U.S. approval 2014, updated February 2023). The term pembrolizumab includes mAb’s having a structure as described above (7d.) but which do not include the C-terminal lysine in the heavy chain.

[0060] “Pembrolizumab variant” as used herein means a monoclonal antibody that comprises heavy chain and light chain sequences that are identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six. five, four, three, two or one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e g., the variant positions are located in the FR regions or the constant region, and optionally has a deletion of the C-terminal lysine residues of the heavy chain. In other words, pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively. A pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0061] “Platinum-containing chemotherapy” (also known as platins) refers to the use of chemotherapeutic agent(s) used to treat cancer that are coordination complexes of platinum. Platinum-containing chemotherapeutic agents are alkylating agents that crosslink DNA, resulting in ineffective DNA mismatch repair and generally leading to apoptosis. Examples of platins include cisplatin, carboplatin, and oxaliplatin.

PD-1 antagonists or anti-human PD-1 monoclonal antibodies useful in the invention [0062] Examples of mAbs that bind to human PD-1 , useful in the treatment methods, compositions, and uses of the invention, are described in US 7,521,051, US 8,008,449, and US 8,354,509. Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the treatment methods, compositions, and uses of the invention include: pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab), a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 7, and the humanized antibodies h409Al l, h409A16 and h409A17, which are described in WO 2008/156712.

[0063] Provided herein are PD-1 antagonists or anti -human PD-1 monoclonal antibodies that can be used in any of the methods, compositions, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks binding of PD-L1 to PD-1 and preferably also blocks binding of PD-L2 to PD-1.

[0064] Any monoclonal antibodies that bind to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and block the interaction between PD-1 and its ligand PD-L1 or PD-L2 can be used. In some embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1. In other embodiments, the antihuman PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L2. In yet other embodiments, the anti -human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.

[0065] Any monoclonal antibodies that bind to a PD-L1 polypeptide, a PD-L1 polypeptide fragment, a PD-L1 peptide, or a PD-L1 epitope and block the interaction between PD-L1 and PD-1 can also be used.

[0066] In certain embodiments, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD), PDR001 (U.S. Pat. No. 9,683,048). BGB-A317 (U.S. Pat. No. 8,735,553), and MGA012 (MacroGemcs. Rockville, MD). In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In another embodiment, the anti-human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti -human PD-1 monoclonal antibody is cemiplimab. In one embodiment, the anti -human PD-1 monoclonal antibody is dostarlimab. In yet another embodiment, the anti -human PD-1 monoclonal antibody is pidilizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is AMP-514. In another embodiment, the anti-human PD-1 monoclonal antibody is PDR001. In yet another embodiment, the anti -human PD-1 monoclonal antibody is BGB-A317. In still another embodiment, the anti-human PD-1 monoclonal antibody is MGA012.

[0067] In some embodiments, an anti -human PD-1 antibody or antigen binding fragment thereof for use in the methods and uses of the invention comprises three light chain CDRs of CDRL1, CDRL2 and CDRL3 and/or three heavy chain CDRs of CDRH1, CDRH2 and CDRH3. [0068] In one embodiment of the invention, CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 1 or a variant of the amino acid sequence as set forth in SEQ ID NO: 1, CDRL2 has the amino acid sequence as set forth in SEQ ID NO: 2 or a variant of the amino acid sequence as set forth in SEQ ID NO:2, and CDRL3 has the amino acid sequence as set forth in SEQ ID NO:3 or a variant of the amino acid sequence as set forth in SEQ ID NO:3.

[0069] In one embodiment, CDRH1 has the amino acid sequence as set forth in SEQ ID NO:6 or a variant of the amino acid sequence as set forth in SEQ ID NO:6, CDRH2 has the amino acid sequence as set forth in SEQ ID NO:7 or a variant of the amino acid sequence as set forth in SEQ ID NO:7, and CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 8 or a variant of the amino acid sequence as set forth in SEQ ID NO: 8.

[0070] In one embodiment, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.

[0071] In an alternative embodiment of the invention, CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 11 or a variant of the amino acid sequence as set forth in SEQ ID NO: 11, CDRL2 has the amino acid sequence as set forth in SEQ ID NO: 12 or a variant of the amino acid sequence as set forth in SEQ ID NO: 12, and CDRL3 has the amino acid sequence as set forth in SEQ ID NO: 13 or a variant of the amino acid sequence as set forth in SEQ ID NO: 13.

[0072] In one embodiment, CDRH1 has the amino acid sequence as set forth in SEQ ID NO: 16 or a variant of the amino acid sequence as set forth in SEQ ID NO: 16, CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 17 or a variant of the amino acid sequence as set forth in SEQ ID NO: 17. and CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 18 or a variant of the amino acid sequence as set forth in SEQ ID NO: 18.

[0073] In one embodiment, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.

[0074] In an alternative embodiment, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18.

[0075] In a further embodiment of the invention, CDRL1 has the amino acid sequence as set forth in SEQ ID NO:21 or a variant of the amino acid sequence as set forth in SEQ ID NO:21, CDRL2 has the amino acid sequence as set forth in SEQ ID NO:22 or a variant of the amino acid sequence as set forth in SEQ ID NO:22, and CDRL3 has the amino acid sequence as set forth in SEQ ID NO:23 or a variant of the amino acid sequence as set forth in SEQ ID NO:23.

[0076] In yet another embodiment, CDRH1 has the amino acid sequence as set forth in SEQ ID NO:24 or a variant of the amino acid sequence as set forth in SEQ ID NO:24, CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 25 or a variant of the amino acid sequence as set forth in SEQ ID NO:25, and CDRH3 has the amino acid sequence as set forth in SEQ ID NO:26 or a variant of the amino acid sequence as set forth in SEQ ID NO:26.

[0077] In another embodiment, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO:24. SEQ ID NO:25 and SEQ ID NO:26.

[0078] Some anti-human PD-1 antibody and antigen binding fragments of the invention comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:4 or a variant of the amino acid sequence as set forth in SEQ ID NO: 4, and the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 9 or a variant of the amino acid sequence as set forth in SEQ ID NO:9. In further embodiments, the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 14 or a variant of the amino acid sequence as set forth in SEQ ID NO: 14, and the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 19 or a variant of the amino acid sequence as set forth in SEQ ID NO: 19. In further embodiments, the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:27 or a variant of the amino acid sequence as set forth in SEQ ID NO:27 and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:28 or a variant of the amino acid sequence as set forth in SEQ ID NO:28, the amino acid sequence as set forth in SEQ ID NO: 29 or a variant of the amino acid sequence as set forth in SEQ ID NO:29, or the amino acid sequence as set forth in SEQ ID NO:30 or a variant of the amino acid sequence as set forth in SEQ ID NO:30. In such embodiments, a light chain variable region or heavy chain variable region sequence is identical to the reference sequence except having one, two, three, four or five amino acid substitutions. In some embodiments, the substitutions are in the framework region (/.e., outside of the CDRs). In some embodiments, one, two, three, four or five of the amino acid substitutions are conservative substitutions.

[0079] In one embodiment of the methods, kits or uses of the invention, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NON and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 14 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 19. In one embodiment of the methods of the invention, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:28 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27. In a further embodiment, the anti-human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:29 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27. In another embodiment, the antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:30 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27.

[0080] In another embodiment, the methods, kits or uses of the invention comprise an antihuman PD-1 antibody or antigen binding protein that has a VL domain and/or a VH domain with at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VL domains or VH domains described above, and exhibits specific binding to PD-1. In another embodiment, the anti -human PD-1 antibody or antigen binding protein of the methods the invention comprises VL and VH domains having up to 1, 2, 3. 4. or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0081] In any of the embodiments above, the PD-1 antagonist may be a full-length anti-PD-1 antibody or an antigen binding fragment thereof that specifically binds human PD-1. In certain embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. Any isotype of IgG can be used, including IgGi, IgGz. IgGa, and IgG4. Different constant domains may be appended to the VL and VH regions provided herein. For example, if a particular intended use of an antibody (or fragment) of the invention were to call for altered effector functions, a heavy chain constant domain other than IgGl may be used. Although IgGl antibodies provide for long half-life and for effector functions, such as complement activation and antibody -dependent cellular cy totoxicity', such activities may not be desirable for all uses of the antibody. In such instances an IgG4 constant domain, for example, may be used.

[0082] In embodiments of the invention, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 10. In alternative embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 15 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:20. In further embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:32 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody⁷ comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:33 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In yet additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:34 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In some methods of the invention, the PD-1 antagonist is pembrolizumab or a pembrolizumab biosimilar. In some methods of the invention, the PD-1 antagonist is nivolumab or anivolumab biosimilar. [0083] Ordinarily, amino acid sequence variants of the anti-PD-1 antibodies and antigen binding fragments of the invention will have an amino acid sequence having at least 75% amino acid sequence identity with the amino acid sequence of a reference antibody or antigen binding fragment (e.g. heavy chain, light chain, VH, VL, or humanized sequence), more preferably at least 80%. more preferably at least 85%, more preferably at least 90%. and most preferably at least 95, 98, or 99%. Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the anti-PD-1 residues, after aligning the sequences and introducing gaps, if necessary', to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. None of N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence shall be construed as affecting sequence identity⁷ or homology⁷.

[0084] Sequence identity refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences. The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et l., (1993) Nature Genet. 3:266-272; Madden, T.L., et al.. (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17: 149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.). pp. 345- 352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3." M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S.. et al., (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul, S.F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S„ et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S„ et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S.F. "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York. [0085] Likewise, either class of light chain can be used in the compositions and methods herein. Specifically, kappa, lambda, or variants thereof are useful in the present compositions and methods of the invention.

Table 3. Exemplary PD-1 Antibody Sequences

Table 4. Additional PD-1 Antibodies and Antigen Binding Fragments Useful in the Methods and Uses of the Invention.

Anti-PD-1 antibody dosing

[0086] In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is administered subcutaneously or intravenously, on a weekly, biweekly, triweekly, every 4 weeks, every 5 weeks, every 6 weeks, monthly, bimonthly, or quarterly basis at about 10, about 20, about 50, about 80, about 100, about 200. about 300, about 400, about 500, about 1000 or about 2500 mg/subject.

[0087] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is from about 0.01 mg/kg to about 50 mg/kg, from about 0.05 mg/kg to about 25 mg/kg, from about 0. 1 mg/kg to about 10 mg/kg, from about 0.2 mg/kg to about 9 mg/kg. from about 0.3 mg/kg to about 8 mg/kg. from about 0.4 mg/kg to about 7 mg/kg, from about 0.5 mg/kg to about 6 mg/kg, from about 0.6 mg/kg to about 5 mg/kg, from about 0.7 mg/kg to about 4 mg/kg, from about 0.8 mg/kg to about 3 mg/kg, from about 0.9 mg/kg to about 2 mg/kg. from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.0 mg/kg to about 2.0 mg/kg. from about 1.0 mg/kg to about 3.0 mg/kg, or from about 2.0 mg/kg to about 4.0 mg/kg.

[0088] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is from about 10 mg to about 500 mg, from about 25 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg. from about 150 mg to about 250 mg, from about 175 mg to about 250 mg, from about 200 mg to about 250 mg, from about 150 mg to about 240 mg, from about 175 mg to about 240 mg, or from about 200 mg to about 240 mg. In some embodiments, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

[0089] In another embodiment of the invention, the PD-1 antagonist in the therapy is pembrolizumab, or a pembrolizumab variant, which is administered in a liquid medicament at a dose selected from the group consisting of 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg/kg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, or 10 mg/kg Q3W. In other embodiments, the PD-1 antagonist in the therapy is pembrolizumab, or a pembrolizumab variant, which is administered in a liquid medicament at a flat dose such as 200 mg Q3W or 400 mg Q6W.

[0090] In some embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg/kg pembrolizumab once every three or six weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once even’ three weeks. In one embodiment, the human patient is administered 2 mg/kg pembrolizumab once every three weeks. In one embodiment, the human patient is administered 400 mg pembrolizumab once every three weeks.

[0091] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab and the human patient is administered 400 mg pembrolizumab once every six weeks.

[0092] In some embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg. about 480 mg, or about 2 mg/kg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 400 mg pembrolizumab once every' six weeks. In one embodiment, the human patient is administered 480 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered 2 mg/kg pembrolizumab once every six weeks. [0093] In some embodiments, pembrolizumab is provided as a liquid medicament that comprises 25 mg/ml pembrolizumab, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5. In other embodiments, pembrolizumab is provided as a liquid medicament that comprises about 125 to about 200 mg/mL of pembrolizumab, or an antigen binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof; about 7% (w/v) sucrose; and about 0.02 % (w/v) polysorbate 80.

[0094] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg pembrolizumab once every three weeks. In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 400 mg pembrolizumab once every’ six weeks.

[0095] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes. In other embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0096] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In embodiments of the invention, the amount of pembrolizumab administered subcutaneously to the patient is from 320 mg to 420 mg, from 340 mg to 420 mg, from 345 mg to 415 mg, from 350 mg to 410 mg, from 355 mg to 405 mg, from 360 mg to 400 mg, from 365 mg to 395 mg. from 370 mg to 390 mg. from 375 mg to 385 mg, or from 379 mg to 381 mg. In one embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 280 mg to about 450 mg. In a further embodiment of the invention, pembrolizumab is administered by subcutaneous injection at a dose of about 300 mg to about 450 mg. In yet a further embodiment of the invention, pembrolizumab is administered subcutaneously at a dose of about 320 mg to about 450 mg.

[0097] In embodiments of the invention, pembrolizumab is administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 130 mg/rnL. In embodiments of the invention, pembrolizumab administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 165 mg/mL. In embodiments of the invention, pembrolizumab is administered subcutaneously to the patient in two injections. In embodiments of the invention, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in one pre-filled syringe. In embodiments of the invention, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in two pre-filled syringe.

[0098] In one embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection at a dose that is at least about 1.6 times higher than a 200 mg or a 2 mg/kg dose. In one embodiment, the subcutaneous dose is administered once every three weeks. In one embodiment, the subcutaneous dose is administered once every six weeks. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 63%. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 64%. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 66%.

[0099] In one embodiment of the methods, compositions, kits and uses described herein, the selected dose of pembrolizumab is administered subcutaneously to the patient with a human hyaluronidase.

[0100] In one embodiment of the methods, compositions, kits and uses described herein, the selected dose of pembrolizumab and human hyaluronidase is administered subcutaneously to the patient, wherein the amount is 380 mg to about 410 mg. In one embodiment, the amount of pembrolizumab administered subcutaneously to the patient is 395 mg. In one embodiment, the patient is subcutaneously administered a dose of about 380 mg to about 410 mg of pembrolizumab and a human hyaluronidase every three weeks. In one embodiment, the patient is subcutaneously administered a dose of about 395 mg of pembrolizumab and a human hyaluronidase every three weeks.

[0101] In one embodiment of the methods, compositions, kits and uses described herein, the selected dose of pembrolizumab and human hyaluronidase is administered subcutaneously to the patient, wherein the selected dose of pembrolizumab is from about 760 mg to about 790 mg. In one embodiment, the amount of pembrolizumab administered subcutaneously to the patient is 790 mg. In one embodiment, the patient is subcutaneously administered a dose of about 760 mg to about 790 mg of pembrolizumab and a human hyaluronidase every' six weeks.

[0102] In one embodiment of the methods, compositions, kits and uses described herein, the human hyaluronidase is one of the following: Hyall, Hyal2, Hyal3, Hyal4, HyalPSl, and PH20/SPAM1. Recombinant forms of these hyaluronidases with modifications, mutations, addition, truncations can be used in the disclosed methods, uses, compositions, and kits. See, e.g., U.S. Patent Nos.7, 767, 429, 8,431,380, 7,871,607, International Publication No. WO 2020/022791, U.S. Patent Publication No. US2006/0104968 and European Patent 1858926, and in numerous other patents and publications, incorporated herein by reference in its entirety. Exemplary of such agents is the known agent PEGPH20 or rHuPH20. The methods, uses, compositions and kits of the invention encompass the use of any human hyaluronidase or fragments thereof, or variants or fragments thereof. In a preferred embodiment, the hyaluronidase is HP46 in WO 2020/022791. In this embodiment, the hyaluronidase has amino acid residue substitutions consisting of: T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T, and residues F38 to F468 compared to wild-type human PH20.

[0103] In other embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab, the human patient is administered about 240 mg or about 3 mg/kg nivolumab, and nivolumab is administered once every two weeks. In one specific embodiment, the human patient is administered about 240 mg nivolumab once every two weeks. In one specific embodiment, the human patient is administered about 3 mg/kg nivolumab once every two weeks. In other embodiments of the methods, compositions, kits and uses described herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab, the human patient is administered about 480 mg nivolumab once every four weeks.

[0104] In yet other embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab, the human patient is administered about 350 mg cemiplimab once every three weeks.

Methods and Uses of the Invention

[0105] The invention provides a method of treating non-small cell lung cancer (NSCLC) in a human patient comprising administering to the patient a PD-1 antibody, or antigen binding fragment thereof, in combination with chemotherapy as neoadjuvant treatment, and following the neoadjuvant treatment, administering to the patient a PD-1 antibody, or antigen binding fragment thereof as an adjuvant treatment.

[0106] In some embodiments, the PD-1 antibody or antigen binding fragment thereof is administered perioperatively.

[0107] In some embodiments, the PD-1 antibody, or antigen binding fragment thereof, is administered as an adjuvant treatment as a single agent. In some embodiments, the PD-1 antibody, or antigen binding fragment thereof, is administered as a monotherapy. [0108] In some embodiments, the anti-PD-1 antibody, or antigen binding fragment thereof, administered in the neoadjuvant treatment is administered every three weeks for 4 cycles.

[0109] In some embodiments, the anti-PD-1 antibody, or antigen binding fragment thereof, administered in the adjuvant treatment is administered every' three weeks for 13 cycles.

[0110] In some embodiments, the patient has resectable Stage II, IIIA or IIIB NSCLC. In particular embodiments, the patient has resectable Stage II NSCLC. In other particular embodiments, the patient has resectable Stage IIIA NSCLC. In other particular embodiments, the patient has resectable Stage IIIB NSCLC. In other particular embodiments, the patient has resectable T3-4N2 NSCLC.

[0111] In some embodiments, the patient has a PD-L1 expression tumor proportion score (TPS) of < 50%. In some embodiments, the patient has a PD-L1 expression TPS of > 50%.

[0112] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.

[0113] In some embodiments, the patient has a complete or partial response following the treatment. In particular embodiments, the patient has a complete response. In particular embodiments, the patient has a partial response. In other embodiments, the patient has a stable disease. In some embodiments, the patient has a duration of response of at least three months. [0114] The some embodiments, the patient has a complete resection. In particular embodiments, the patient had a lung lobectomy surgery. In particular embodiments, the patient had a bilobectomy. In particular embodiments, the patient had a pneumonectomy.

[0115] In some embodiments, the chemotherapy is platinum-containing chemotherapy. In other embodiments, the chemotherapy is cisplatin doublet. In particular embodiments, the cisplatin is administered at a dose of 75 mg/m² In particular embodiments, the cisplatin is administered Q3W on day 1 of the treatment cycle. In some embodiments, the chemotherapy is gemcitabine. In particular embodiments, the gemcitabine is administered at a dose of 1000 mg/m². In particular embodiments, the gemcitabine is administered Q3W on days 1 and 8 of the cycle. In particular embodiments, the gemcitabine is administered to patients with squamous NSCLC. In some embodiments, the chemotherapy is pemetrexed. In particular embodiments, pemetrexed is administered at a dose of 500 mg/m². In particular embodiments, pemetrexed is administered Q3W on day 1 of the treatment cycle. In particular embodiments, the pemetrexed is administered to patients with nonsquamous NSCLC.

[0116] In some embodiments, the method of treating additionally comprises radiotherapy. [0117] In some embodiments, a population of patients is treated by the methods herein, and wherein the population of patients have an event-free survival (EFS) rate at month 6 of 85% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the population of patients have an EFS rate at month 12 of 70% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the population of patients have an EFS rate at month 18 of 65% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the population of patients have an EFS rate at month 24 of 60% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the population of patients have an EFS rate at month 30 of 55% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the population of patients have an EFS rate at month 36 of 50% or greater.

[0118] In some embodiments, a population of patients is treated by the methods herein, wherein the median overall survival in the population is at least or about 48 months. In particular embodiments, a population of patients is treated by the methods herein, wherein the median overall survival in the treated population ranges from 30 to 48 months following the treatment. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival rate in the treated population at month 30 is 75% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 30 is 70% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 36 is 75% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 36 is 70% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 36 is 65% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 42 is 70% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 42 is 65% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 48 is 70% or greater. In particular embodiments, a population of patients is treated by the methods herein, wherein the overall survival in the treated population at month 48 is 65% or greater. [0119] In some embodiments, a population of patients is treated by the methods herein, wherein the mPR rate in the treated population is at least 25%. In particular embodiments, a population of patients is treated by the methods herein, wherein the mPR rate in the treated population is at least 30%.

[0120] In some embodiments, a population of patients is treated by the methods herein, wherein the pCR rate in the treated population is at least 15%. In particular embodiments, a population of patients is treated by the methods herein, wherein the pCR rate in the treated population is at least 18%.

Neoadjuvant Therapy

[0121] The use of neoadjuvant chemotherapy in early-stage NSCLC was limited by the acceptance of adjuvant chemotherapy as standard recommended treatment. A meta-analysis of 15 randomized controlled studies (2385 patients) showed that neoadjuvant chemotherapy significantly improves overall survival and recurrence-free survival in resectable NSCLC. Comparison between pre-operative or post-operative chemotherapy, while limited in power, demonstrated similar survival rates. Pre-operative chemotherapy may provide benefits such as reduced tumor size, increased operability', and diminished micrometastases.

[0122] Using immune checkpoint inhibitors in the neoadjuvant setting, while the primary tumor remains in situ, may offer similar advantages as neoadjuvant chemotherapy. Additionally, T cell activation may be greater during neoadjuvant administration compared with the adjuvant setting after surgery, as surgery may trigger a temporary' immunosuppressive stress response. Recently, neoadjuvant treatment with nivolumab plus chemotherapy showed a statistically significant improvement in EFS and pCR compared to chemotherapy alone in the Phase 3, open-label study, CheckMate-81 . The study led to FDA approval of nivolumab in the neoadjuvant setting, in combination with platinum-doublet chemotherapy in adult patients with resectable NSCLC (tumors >4 cm or node positive). However, in this neoadjuvant treatment study with nivolumab plus chemotherapy, an exploratory analysis of EFS by pCR status showed less pronounced benefits in patients with no pCR following neoadjuvant treatment (HR 0.84; 95% CL 0.61 to 1.17) compared to the overall study population (HR 0.63; 95% CI, 0.43 to 0.91), suggesting that subsequent treatment in the adjuvant setting may be needed to further enhance and consolidate the antitumor immune response to micrometastatic disease and prevent disease recurrence. Adjuvant Therapy

[0123] Given the poor survival statistics among patients with early-stage NSCLC that has been resected with curative intent, adjuvant chemotherapy with up to 4 cycles of a platinum-based doublet has been utilized to reduce the risk of disease recurrence. This is standard recommended treatment for patients with Stage II or III NSCLC. and for those with Stage IB NSCLC whose resected tumors were >4 cm. A meta-analysis of numerous studies has shown an absolute OS and DFS benefit at 5 years of approximately 5% with adjuvant chemotherapy in early-stage NSCLC.

[0124] In recent years, adjuvant treatments beyond chemotherapy have been explored to reduce the risk of recurrence and improve long-term survival for early-stage NSCLC, including immunotherapy and targeted therapy.

[0125] For patients with actionable tumor mutations, a number of targeted therapies as adjuvant treatments have been evaluated and demonstrated clinically meaningful benefits. Recently, results from the Phase 3 AD AURA study showed that osimertinib improved DFS in patients ith Stage IB-IIIA NSCLC and led to the approval of osimertinib in several countries for the adjuvant treatment of patients with early-stage EGFR-mutated lung cancer (exon 19 deletions or exon 21 L858R mutations).

[0126] A recent study (IMpowerOlO) evaluating the anti-PD-Ll antibody atezolizumab demonstrated improvement in DFS compared with best supportive care when given as adjuvant therapy following surgery and chemotherapy in participants with Stage II-IIIA NSCLC.

[0127] The results of KEYNOTE-091 show ed that adjuvant treatment with pembrolizumab monotherapy provides a statistically significant and clinically meaningful improvement in DFS compared with placebo in participants with Stage IB (T2a >4 cm), Stage II, or Stage IIIA NSCLC (defined using AJCC seventh edition) following complete resection. These data support the benefit of pembrolizumab as adjuvant therapy for early-stage NSCLC following complete resection and, if indicated, adjuvant chemotherapy.

[0128] It is shown herein that perioperative treatment (neoadjuvant followed by adjuvant treatment) with chemotherapy /pembrolizumab and pembrolizumab unexpectedly resulted in statistically significant and clinically meaningful improvement in EFS compared with chemotherapy/placebo and placebo as described in the Examples. The overall survival hazard ratio is more favorable for participants in the pembrolizumab arm as compared with participants in the placebo arm. EXAMPLES

[0129] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. [0130] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0131] All references (e.g.. publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Example 1: Administration of Platinum Doublet Chemotherapy +/- Pembrolizumab (MK- 3475) as Neoadjuvant/Adjuvant Therapy for Participants with Resectable Stage II, IIIA, and Resectable IIIB Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE 671)

[0132] The example in this section is offered by way of illustration, and not by way of limitation.

[0133] Pembrolizumab in combination with neoadjuvant chemotherapy followed by single agent pembrolizumab after surgery was evaluated in KEYNOTE-671 to address the unmet need for improved survival outcomes in patients with resectable NSCLC. The Phase 111 Study evaluates the concomitant neoadjuvant platinum doublet chemotherapy plus pembrolizumab (Q3W x 4 cycles) followed by surgery' and adjuvant pembrolizumab (Q3W x 13 cycles) versus concomitant neoadjuvant platinum doublet chemotherapy plus placebo (Q3W x 4 cycles) followed by surgery and adjuvant placebo (Q3W x 13 cycles) in participants with resectable Stage II or IIIA-B (T3-4N2) NSCLC. A total of approximately 786 participants were randomized in a 1 : 1 ratio to receive pembrolizumab plus chemotherapy (pembrolizumab arm) or placebo plus chemotherapy (placebo arm). Stratification factors were disease stage (II vs III), PD-L1 expression (TPS <50% vs >50%), histology (squamous vs nonsquamous), and region (East Asia vs non-East Asia). Route of Administration for the study is IV infusion. Primary endpoints are EFS and OS. Secondary endpoints are mPR, pCR, safety, PROs. I. Study Design (see Figure 1 and Figure 2):

Participants:

Stages II through IIIA-B (N2) NSCLC

Biopsy of suspicious hilar or mediastinal lymph node(s).

ECOG PS 0-1.

Able to undergo planned surgery' (lobectomy, bilobectomy, or pneumonectomy).

Stratification:

Stages (II, III)

TPS (<50%, > 50%)

Histology (Squamous, Non-squamous) Region (East Asia, non-East Asia) Randomization (1 : 1, N=786)

Arm A: Cisplatin doublet (Q3W x 4 cycles), pembrolizumab (200 mg Q3W x 4 cycles)

Arm B: Cisplatin doublet (Q3W x 4 cycles), placebo (Q3W x 4 cycles)

After surgery', Arm A: pembrolizumab (200 mg Q3W x 13 cycles, RT if: microscopic residual disease or gross residual disease)

After surgery, Arm B: placebo (Q3W x 13 cycles. RT if: microscopic residual disease or gross residual disease).

(Residual disease: Primary' tumor - positive margin at bronchus, pulmonary' vessels, or structures abutting primary tumor. Mediastinal lymph node - extracapsular extension)

[0134] If a participant did not undergo surgery due to refusal, physician decision, medical illness, or any reason other than local progression or metastatic disease, they were to receive RT and continue to the adjuvant phase. Only participants with microscopic residual disease or gross residual disease in the tumor bed after surgery were to undergo RT.

Table 5: Study Design

II. Eligibility Criteria:

[0135] The study included male and female participants >18 years of age with previously untreated and pathologically confirmed resectable Stage II or IIIA-B (N2) NSCLC who were able to undergo study therapy, including necessary surgery, had an Eastern Cooperative Oncol ogy Group (ECOG) status of 0 to 1, and adequate organ function.

Inclusion Criteria:

[0136] Have previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC.

[0137] Be able to undergo protocol therapy, including necessary surgery'. A positron emission tomography (PET) scan may be utilized as a surrogate for pathologic staging of N1 lymph nodes for participants with T2b and T4 tumors. [0138] If male, must agree to use contraception or practice abstinence as well as refrain from donating sperm during the treatment period and for the time needed to eliminate each study intervention after the last dose of study intervention.

[0139] If female, may participate if not pregnant or breastfeeding, and at least one of the following conditions apply: 1) not a woman of childbearing potential (WOCBP); or 2) a WOCBP who agrees to follow contraceptive guidance during the treatment period and for the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period.

[0140] Have available formalin-fixed paraffin embedded (FFPE) tumor tissue sample blocks for submission. If blocks are not available, have unstained slides for submission for central programmed death -ligand 1 (PD-L1) testing.

[0141] Have an Eastern Cooperative Oncology’ Group (ECOG) performance status of 0 to 1 within 10 days of randomization.

[0142] Have adequate organ function.

Exclusion Criteria:

[0143] Has one of the following tumor locations/types: 1) NSCLC involving the superior sulcus; 2) Large cell neuro-endocrine cancer (LCNEC); or 3) Sarcomatoid tumor.

[0144] Has a history of (non-infectious) pneumonitis /interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.

[0145] Has an active infection requiring systemic therapy.

[0146] Has had an allogenic tissue/sold organ transplant.

[0147] Has a known severe hypersensitivity (> Grade 3) to pembrolizumab, its active substance and/or any of its excipients.

[0148] Has a known severe hypersensitivity (> Grade 3) to any of the study chemotherapy agents and/or to any of their excipients.

[0149] Has an active autoimmune disease that has required systemic treatment in past 2 years.

[0150] Has a know n history of human immunodeficiency virus (HIV) infection.

[0151] Has a known history' of Hepatitis B or Hepatitis C.

[0152] Has a known history of active tuberculosis. [0153] Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate.

[0154] Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial.

[0155] Has received prior therapy with an anti-PD-1, anti-PD-Ll, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor.

[0156] Has received prior systemic anti-cancer therapy including investigational agents for the current malignancy prior to randomization/allocation.

[0157] Has received prior radiotherapy within 2 weeks of start of trial treatment.

[0158] Has received a live vaccine within 30 days prior to the first dose of trial drug.

[0159] Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.

[0160] Has a diagnosis of immunodeficiency or is receiving either systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.

[0161] Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.

III. Objectives and Endpoints

Table 6: Objectives and Endpoints

IV. Study Results

Participant Disposition:

[0162] Pembrolizumab arm: 397 participants were randomized and 396 were treated; 42 (10.6%) are ongoing, 160 (40.4%) completed study treatment, and 194 (49.0%) discontinued study intervention. [0163] Placebo arm: 400 participants were randomized and 399 were treated; 45 (11.3%) are ongoing, 141 (35.3%) completed study treatment, and 213 (53.4%) discontinued study intervention.

[0164] A total of 160 participants (40.4%) in the pembrolizumab arm and 141 (35.3%) in the placebo arm completed study treatment. The most frequent reason for discontinuation of study treatment is AEs (21.0%) in the pembrolizumab arm and progressive disease (24.6%) in the placebo arm. At the time of the data cutoff for interim analysis, 42 participants in the pembrolizumab arm and 45 in the placebo arm remained on study treatment.

[0165] The proportion of participants who were discontinued from the study is similar in the 2 treatment arms (20.9% in the pembrolizumab arm and 28.0% in the placebo arm) with the most common reason for both arms cited as death (18.9% pembrolizumab arm and 25.0% placebo arm).

[0166] During neoadjuvant treatment, 54 (13.6%) participants in the pembrolizumab arm and 64 (16.0%) participants in the placebo arm discontinued permanently from all study treatments. The most frequent reason for discontinuation is AEs (6.1%) in the pembrolizumab arm and progressive disease (6.5%) in the placebo arm.

[0167] A total of 325 participants in the pembrolizumab arm and 317 of participants in the placebo arm underwent in-study surgery after neoadjuvant treatment. Of those participants, 5 in the pembrolizumab group (1.5%) and 15 in the placebo group (4.7%) were found unresectable during surgery. A total of 35 participants in the pembrolizumab arm and 53 of participants in the placebo arm underwent radiotherapy. In the pembrolizumab arm 18 (4.5%) participants underwent both in-study surgery and radiotherapy, compared to 35 (8.8%) participants in the placebo arm.

[0168] In the adjuvant phase, the number of participants who discontinued study treatment is similar between the treatment arms. The most frequent reason for discontinuation of pembrolizumab is AEs and the most frequent reason for discontinuation of placebo is progressive disease. A similar number of participants completed adjuvant study medication (55.2% pembrolizumab arm and 52.8% placebo arm).

[0169] Disposition of participants in the APaT population is similar to disposition of the ITT population. Table 7: Disposition of Participants (ITT Population) Table 8: Consort Table (ITT Population)

Table 9: Participant Characteristics (ITT Population)

Table 10: Summary of Drug Exposure Combined Phases (Neo-adjuvant/Surgery + Adjuvant) (APaT Population)

Primary Endpoints

[0170] Perioperative treatment (neoadjuvant followed by adjuvant treatment) with pembrolizumab + chemotherapy/pembrolizumab resulted in a statistically significant and clinically meaningful improvement in EFS by investigator assessment compared with placebo + chemotherapy/placebo in participants with resectable Stage II, IIIA, or IIIB (T3-4N2) NSCLC (HR: 0.58; 95% CI: 0.46, 0.72; p<0.00001); the median EFS was not reached for the pembrolizumab arm and 17.0 months for the placebo arm. [0171] The EFS benefit observed in the pembrolizumab arm over the placebo arm is consistent across all prespecified subgroups including disease stage, histology, and PD-L1 expression. Results from a sensitivity' analysis of EFS by BICR were consistent with the primary EFS analysis.

[0172] The point estimate for the OS HR is more favorable for participants in the pembrolizumab arm compared with participants in the placebo arm (median NR vs 45.5 months; HR: 0.73; 95% CI: 0.54, 0.99; ?=0.02124), however, only -46% of the total events needed for the OS final analysis (177 of 386 events) is observed at interim analysis, and the boundary for statistical significance was not crossed. OS will continue to be tested at next interim analysis.

Secondary Endpoints

[0173] There is a statistically significant and clinically meaningful improvement in mPR based on blinded independent pathological review (B1PR) in the pembrolizumab arm compared with the placebo arm, with an mPR rate of 30.2% versus 11.0% (difference: 19.2%; 95% CI: 13.9, 24.7; 0.00001).

[0174] There is a statistically significant and clinically meaningful improvement in pCR based on BIPR in the pembrolizumab arm compared with the placebo arm, with a pCR rate of 18. 1% versus 4.0% (difference: 14.2%; 95% CI: 10.1, 18.7; /XO.00001).

[0175] Participants in both the pembrolizumab arm and placebo arm maintained health-related quality of life (HRQoL).

Neoadjuvant/Surgery Phase

[0176] The median duration of exposure to study treatments in the neoadj uvant/surgery phase is similar between the pembrolizumab arm (106.0 days) and placebo arm (106.0 days).

[0177] The median duration of exposure to study drugs (corresponding to the protocol-specified 4 cycles of neoadjuvant therapy) and each individual drug component in the neoadj uvant/surgery phase were similar between the pembrolizumab arm and placebo arm.

[0178] Radiotherapy was administered to 35 participants in the pembrolizumab arm (median duration: 41.0 days) and 53 participants in the placebo arm (median duration: 43.2 days). The median dose delivered was 6000 centigray in both arms. More participants in the placebo arm received radiotherapy due to the fact that more participants in this arm had R1 and R2 resection and slightly more did not have surgery. In the pembrolizumab arm 18 (4.5%) participants underwent both in-study surgery and radiotherapy, compared to 35 (8.8%) participants in the placebo arm.

Adjuvant Phase

[0179] The median duration of exposure to pembrolizumab in the adjuvant phase is similar compared with placebo (253.0 days [range: 1.0 to 336.0 days] vs 252.0 days [range: 1.0 to 387.0 days]).

Surgery

[0180] In the ITT population, 325 (81.9%) participants in the pembrolizumab arm and 317 (79.3%) participants in the placebo arm underwent in-study surgery; 320 (86.0%) were resectable in the pembrolizumab arm and 302 (75.5%) were resectable in the placebo arm.

[0181] Among participants who underwent in-study surgery, 5 participants in the pembrolizumab group (1.5%) and 15 in the placebo group (4.7%) were found unresectable during the surgery' procedure. The type of surgery and surgery outcome were generally consistent between the treatment arms. The majority' of participants (78.8% pembrolizumab and 75.1% placebo) underw ent lung lobectomy. The majority of participants (92.0% pembrolizumab and 84.2% placebo) had complete resection (R0).

[0182] A total of 71 (17.9%) participants in the pembrolizumab arm did not undergo in study surgery and 82 (20.5%) in the placebo arm. The most common reason for not undergoing surgery is AEs for the pembrolizumab arm and progressive disease for the placebo arm.

Duration of Follow-up

[0183] The median follow-up duration for the ITT population is similar between the 2 treatment groups (22.1 months in the pembrolizumab arm and 21.4 months in the placebo arm).

Table 11: Summary of Follow-up Duration (ITT Population)

V. Efficacy and Other Evaluations

Efficacy Results

[0184] Treatment with pembrolizumab + chemo therapy /pembrolizumab resulted in a statistically significant and clinically meaningful improvement in EFS by investigator assessment compared with placebo + chemotherapy /placebo in participants with resectable Stage II, IIIA, or IIIB (T3- 4N2) NSCLC. Based on early results, the OS favors pembrolizumab + chemotherapy/pembrolizumab over placebo + chemotherapy/placebo, although the data were not sufficiently mature to declare a statistically significant result at the time of interim analysis. Overall survival will continue to be tested at the next interim analysis.

Primary Efficacy Endpoints

1. Event-free Survival

[0185] EFS is formally tested with the multiplicity-adjusted, one-sided p-value boundary’ of 0.00462 at interim analysis. Treatment with pembrolizumab + chemotherapy/pembrolizumab resulted in a statistically significant and clinically meaningful improvement in EFS by investigator assessment compared with placebo + chemotherapy/placebo in participants with resectable Stage II. IIIA, or IIIB (T3-4N2) NSCLC (HR: 0.58; 95% CI: 0.46, 0.72; /?<0.00001), representing a 42% reduction in the risk of EFS event (progression/recurrence. inability to resect tumor, or death) in the pembrolizumab arm versus the placebo arm.

[0186] Median EFS was not reached in the pembrolizumab arm and 17.0 months in the placebo arm. The EFS rate is higher in the pembrolizumab group compared to the placebo group over time.

[0187] The KM plot in Figure 3 showed that the pembrolizumab arm curve separated from the placebo arm curve at approximately Month 5 and remained separated over time. The most frequent type of first EFS event in both arms is progression/recurrence.

[0188] The EFS benefit of pembrolizumab over placebo is consistent across all prespecified subgroups, including PD-L1 expression, histology, and disease stage. Results from a sensitivity analysis of EFS by BICR were consistent with the primary EFS analysis.

[0189] See Table 12A, Table 12B, and Figure 3 for analysis of event-free survival based on investigator assessment. Table 12A: Analysis of Event-Free Survival (Primary Censoring Rule) Based on Investigator Assessment (ITT Population) Table 12B: Number of participants at risk in reference to Figure 3:

Event-free Survival Sensitivity Analyses

[0190] Prespecified sensitivity analyses for EFS were conducted in the ITT population to evaluate the robustness of EFS results. Results in each sensitivity' analysis were consistent with the primary analysis. Specifically, a sensitivity analysis using BICR assessment is conducted using the same censoring rules as the primary analysis. The EFS HR is 0.66 (95% CI: 0.52, 0.83; p = 0.00013). Additionally, a sensitivity analysis is performed using the primary censoring rule with the exception that events occurring after 2 consecutive missed disease assessments or after new' anti-cancer therapy, if any, were censored at the last disease assessment prior to the earlier date of >2 consecutive missed disease assessments and new anti-cancer therapy. Based on the investigator assessment, the EFS HR with this sensitivity analysis is 0.58 (95% CI: 0.46, 0.72; p < 0.00001).

2. Overall Survival (OS)

[0191] OS is defined as the time from start of study treatment to date of death due to any cause. OS is a primary endpoint.

[0192] OS is formally tested with the multiplicity -adjusted, one-sided /i- value boundary of 0.00093.

[0193] As of the database cutoff date for interim analysis, a total of 76 OS events were observed, and the median OS was not reached in the pembrolizumab arm. A total of 101 events were observed, and the median OS is 45.5 (95% CI: 42.0, NR) months for the placebo arm. The point estimate of the OS HR favored the pembrolizumab arm over the placebo arm (HR: 0.73; 95% CI: 0.54, 0.99; p=0.02124) as shown in Table 13A, Table 13B and Figure 4. However, due to the relative early time of the analysis with respect to the OS endpoint (information fraction of approximately 46% [177 of the 386 events needed for the final analysis]), the observed / value did not cross the multiplicity-adjusted, one-sided /?- value boundary at interim analysis. OS will continue to be tested at next interim analysis.

[0194] The estimated difference in RMST for the pembrolizumab arm versus the placebo arm is 1.12 (95% CI: -0.45, 2.68) at Month 36, 1.91 (95% CI: -0.08, 3.91) at Month 42 and 3.10 (95% CI: -0.62, 5.58) at Month 48, favoring the pembrolizumab arm.

Table 13A: Analysis of Overall Survival, (ITT Population)

Table 13B: Number of participants at risk in reference to Figure 4:

Secondary Efficacy Endpoints

1. Major Pathological Response

[0195] There is a statistically significant and clinically meaningful improvement in mPR based on BIPR in the pembrolizumab arm compared with the placebo arm. The mPR rate is 30.2% for the pembrolizumab arm and 11.0% for the placebo arm, with a difference in response rates of 19.2% (95% CI: 13.9, 24.7; p<0.00001) (See Table 14).

[0196] The treatment differences for the pembrolizumab arm compared with the placebo arm across all prespecified subgroups were consistent with the findings in the ITT population.

[0197] Major pathological response results by investigator assessment were consistent with those provided by BIPR.

Table 14: Analysis of Major Pathological Response Based on BIPR Assessment (ITT Population)

2. Pathological Complete Response

[0198] There is a statistically significant and clinically meaningful improvement in pCR based on BIPR in the pembrolizumab arm compared with the placebo arm. The pCR rate is 18.1% for the pembrolizumab arm and 4.0% for the placebo arm, with a difference in response rates of 14.2% (95% CI: 10.1, 18.7; / O.OOOOl). See Table 15.

[0199] The treatment differences for the pembrolizumab arm compared with the placebo arm across all prespecified subgroups were consistent with the findings in the ITT population.

[0200] The pCR results by investigator assessment consistent with those provided by BIPR.

Table 15: Analysis of Pathological Complete Response Based on BIPR Assessment (ITT

Population)

[0201] Participants in both the pembrolizumab arm and placebo arm maintained health-related quality of life (HRQoL).

Efficacy Conclusions

[0202] Efficacy results are summarized in Table 16 and 17. Pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment and continued as monotherapy in adjuvant treatment reduces the risk of EFS event (progression/recurrence, inability to resect tumor, or death) in patients with resectable Stage II. IIIA. or IIIB (T3-4N2) NSCLC.

[0203] OS in participants treated with pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as adjuvant monotherapy is more favorable than neoadjuvant chemotherapy plus placebo followed by adjuvant placebo, although the data is not sufficiently mature to declare a statistically significant result at the time of interim analysis.

[0204] Treatment with pembrolizumab in combination with neoadjuvant chemotherapy provides a statistically significant and clinically meaningful improvement in both mPR and pCR based on BIPR when compared with neoadjuvant chemotherapy alone.

[0205] Based on the results from this study, the treatment regimen of pembrolizumab + chemotherapy followed by pembrolizumab monotherapy has a manageable safety profile during the combined (neoadj uvant/surgery + adjuvant) phases.

Table 16: Summary of KEYNOTE-671 Primary Results

Table 17: Summary of KEYNOTE-671 Secondary Endpoints

[0206] This Phase III study (KEYNOTE-671) is designed to demonstrate that the complete regimen of pembrolizumab given with chemotherapy for 4 cycles prior to surgery followed by 13 cycles of pembrolizumab after surgery confers a long-term benefit in patients with Stage II-III resectable NSCLC. Although pure neoadjuvant, and pure adjuvant treatment regimens with ICI were recently approved, KEYNOTE-671 evaluated whether pembrolizumab given in combination with neoadjuvant chemotherapy and as monotherapy in the adjuvant phase provides additional benefits and should be considered as a viable regimen option for patients.

[0207] Results of an exploratory' unstratified subgroup analysis of EFS in patients who have and who have not achieved pCR or mPR, showed clear evidence of a treatment effect in both groups (pCR/no pCR; mPR/no mPR) (See Table 18, Figure 5, Figure 6). In the subgroup of participants who did not achieve pCR (which includes the majority of participants in the pembrolizumab arm [325/397] and placebo arm [384/400]), the HR for EFS is 0.69 (95% CI: 0.55, 0.85) and the median EFS is more than doubled in the pembrolizumab arm compared with the placebo arm (34.1 versus 15.2 months). The K-M curve separated at approximately month 4 and remained separated over time, showing the long-term benefit in participants who received the penoperative treatment regimen and, suggesting that the benefit of pembrolizumab may extend beyond the scope of purely neoadjuvant therapy. Table 18. Analysis of Event-Free Survival Based on Investigator Assessment by pCR or mPR Status (ITT Population)

Example 2: Administration of Platinum Doublet Chemotherapy +/- Pembrolizumab (MK- 3475) as Neoadjuvant/Adjuvant Therapy for Participants with Resectable Stage II, IIIA, and Resectable IIIB Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE 671) - Interim Analysis 1 and Interim Analysis 2 data.

[0208] Example 2 provides Interim Analysis 1 and Interim Analysis 2 data for Keynote-671 as a follow up on to Example 1, which provided Interim Analysis 1.

[0209] Neoadjuvant pembrolizumab + cisplatin-based chemotherapy (neoadjuvant pembro + chemo), resection, and adjuvant (adj) pembro (pembro arm; n=397) significantly improved EFS. OS, pCR, and mPR and had an expected safety profile versus neoadjuvant placebo (pbo) + chemo, resection and adjuvant pbo (pbo arm; n=400) in patients (pts) with resectable stage II, IIIA, or IIIB (N2) NSCLC. [0210] Interim Analysis 1: perioperative pembrolizumab regimen significantly improved EFS (HR 0.58, P < 0.00001), mPR (30.2% vs 11.0%, P < 0.00001), and pCR (18.1% vs 4.0%, P < 0.00001) (Wakelee H et al. N Engl J Med 2023;389:491-503)

[0211] Interim Analysis 2: perioperative pembrolizumab regimen significantly improved OS (HR 0.72, P = 0.00517); EFS benefit maintained (Spicer J et al. Abstr LBA56 presented at ESMO Congress 2023).

[0212] Median time from randomization to the data cutoff date (second interim analysis) was 36.6 mo (range, 18.8-62.0). With 254 (31.9%) deaths, OS was significantly improved in the pembro arm (HR 0.72 [95% CI 0.56-0.93]; P = 0.00517). Median OS was not reached (NR) (95% CI NR-NR) in the pembro arm vs 52.4 mo (95% CI 45.7-NR) in the placebo arm; 36-mo OS rates were 71.3% vs 64.0%. EFS continued to be improved in the pembro arm (HR 0.59 [95% CI 0.48-0.72]; median [95% CI] 47.2 mo [32.9-NR] vs 18.3 mo [14.8-22.1]; 36-mo rate, 54.3% vs 35.4%). Treatment-related AEs were grade >3 in 45.2% of pts in the pembro arm vs 37.8% in the placebo arm, led to discontinuation of all treatment in 20.2% vs 9.3%, and led to death in 1.0% vs 0.8% (no new treatment-related deaths since the first interim analysis). (Spicer J et al. Abstr LBA56 presented at ESMO Congress 2023).

[0213] AE profile for interim analysis 1 and 2 were as expected based on the known profiles of the individual treatment components. (Wakelee H et al. N Engl J Med 2023;389:491-503 and Spicer J et al. Abstr LBA56 presented at ESMO Congress 2023).

[0214] Results led to perioperative pembrolizumab regimen being approved by the US FDA and included as a category 1 recommendation in the NCCN guidelines.

Claims

WHAT IS CLAIMED IS:

1. A method of treating non-small cell lung cancer (NSCLC) in a human patient comprising administering to the patient an anti-PD-1 antibody, or antigen binding fragment thereof, in combination with chemotherapy as a neoadjuvant treatment, and administering to the patient the anti-PD-1 antibody, or antigen binding fragment thereof as an adjuvant treatment after the neoadjuvant treatment, wherein the anti-PD-1 antibody or antigen binding fragment thereof comprises light chain complementarity determining regions (CDRs) comprising a sequence of amino acids as set forth in SEQ ID NOs: 1, 2 and 3 and heavy chain CDRs comprising a sequence of amino acids as set forth in SEQ ID NOs: 6, 7 and 8.

2. The method of claim 1, wherein the anti-PD-1 antibody, or antigen binding fragment thereof is an anti-PD-1 monoclonal antibody.

3. The method of claim 2, wherein the anti-PD-1 monoclonal antibody administered as an adjuvant treatment is administered as a monotherapy.

4. The method of any one of claims 2-3, wherein the anti-PD-1 monoclonal antibody is administered to the patient at a dose of about 200 mg once every three weeks.

5. The method of any one of claims 2-3, wherein the anti-PD-1 monoclonal antibody is administered to the patient at a dose of about 400 mg once every six weeks.

6. The method of any one of claims 1-5, wherein the anti-PD-1 monoclonal antibody is administered to the patient by an IV infusion.

7. The method of any one of claims 1-6, wherein the anti-PD-1 monoclonal antibody is administered to the patient by an IV infusion over about 30 minutes on day 1 of each treatment cycle.

8. The method of any one of claims 1-7, wherein the anti-PD-1 antibody, or antigen binding fragment thereof, is pembrolizumab.

9. The method of claim 8, wherein the pembrolizumab administered as a neoadjuvant treatment is administered every three weeks for 4 cycles.

10. The method of any one of claims 8-9, wherein the pembrolizumab administered as an adjuvant treatment is administered every three weeks for 13 cycles.

11. The method of any one of claims 1-10, wherein the patient has resectable Stage II, IIIA or IIIB NSCLC.

12. The method of any one of claims 1-11, wherein the patient has resectable Stage II NSCLC.

13. The method of any one of claims 1-11. wherein the patient has resectable Stage IIIA-B NSCLC.

14. The method of any one of claims 1-10, wherein the patient has resectable T3-4N2 NSCLC.

15. The method of any one of claims 1-14, wherein the patient has a PD-L1 expression tumor proportion score (TPS) of < 50%.

16. The method of any one of claims 1-14. wherein the patient has a PD-L1 expression tumor proportion score (TPS) of > 50%.

17. The method of any one of claims 1-16, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1.

18. The method of any one of claims 1-17, wherein the patient has a complete response following the treatment.

20. The method of any one of claims 1-17, wherein the patient has a partial response following the treatment.

21. The method of any one of claims 1-17 or 19, wherein the patient has a stable disease following the treatment.

22. The method of any one of claims 1-20. wherein the patient has a duration of response of at least three months.

23. The method of any one of claims 1-21, wherein the patient had a complete lung resection after neoadjuvant treatment.

24. The method of any one of claims 1-21, wherein the patient had a lung lobectomy surgery.

25. The method of any one of claims 1-21. wherein the patient had a bilobectomy.

26. The method of any one of claims 1-21, wherein the patient had a pneumonectomy.

27. The method of any one of claims 1-25. wherein the chemotherapy is platinum- containing chemotherapy.

28. The method of any one of claims 1-26, wherein the chemotherapy is cisplatin doublet.

29. The method of any one of claims 1-25, wherein the chemotherapy is gemcitabine.

30. The method of any one of claims 1-25. wherein the chemotherapy is pemetrexed.

31. The method of any one of claims 1-29, wherein the treatment further comprises radiotherapy.

32. The method of any one of claims 2-30. wherein the anti-PD-1 monoclonal antibody is administered peri operatively.

33. The method of any one of claims 1-31. wherein a population of patients is treated by the method, and wherein the population of patients has an event-free survival (EFS) rate at month 6 of 85% or greater.

34. The method of any one of claims 1-32. wherein a population of patients is treated by the method, and wherein the population of patients has an event-free survival (EFS) rate at month 12 of 70% or greater.

35. The method of any one of claims 1-33. wherein a population of patients is treated by the method, and wherein the population of patients has an event-free survival (EFS) rate at month 18 of 65% or greater.

36. The method of any one of claims 1-34. wherein a population of patients is treated by the method, and wherein the population of patients has an event-free survival (EFS) rate at month 24 of 60% or greater.

37. The method of any one of claims 1-35, wherein a population of patients is treated by the method, and wherein the population of patients has an event-free survival (EFS) rate at month 30 of 55% or greater.

38. The method of any one of claims 1-36, wherein a population of patients is treated by the method, and wherein the population of patients has an event-free survival (EFS) rate at month 36 of 50% or greater.

39. The method of any one of claims 1-37, wherein a population of patients is treated by the method, and wherein the median overall survival in the treated population is at least or about 48 months following the treatment.

40. The method of any one of claims 1-37, wherein a population of patients is treated by the method, and wherein the median overall survival in the treated population ranges from 30 to 48 months following the treatment.

41. The method of any one of claims 1-37. wherein a population of patients is treated by the method, and wherein the median overall survival rate in the treated population at month 30 is 70% or greater.

42. The method of any one of claims 1-33 or 37. wherein a population of patients is treated by the method, and wherein the overall survival rate in the treated population at month 36 is 70% or greater.

43. The method of any one of claims 1-33 or 36-37, wherein a population of patients is treated by the method, wherein the overall survival rate in the treated population at month 42 is 65% or greater.

44. The method of any one of claims 1-33 or 36-38, wherein a population of patients is treated by the method, wherein the overall survival rate in the treated population at month 48 is 65% or greater.

45. The method of any one of claims 1-39, wherein a population of patients is treated by the method, wherein the major pathological response (mPR) rate in the treated population is at least 25%.

46. The method of any one of claims 1-42, wherein a population of patients is treated by the methods, wherein the pathological complete response (pCR) rate in the treated population is at least 15%.

47. The method of any one of claims 1-43, wherein the anti-PD-1 antibody, or antigenbinding fragment thereof, is pembrolizumab.

48. The method of any one of claims 2-7 or 11-45, wherein the anti-PD-1 monoclonal antibody is a pembrolizumab variant.

49. The method of any one of claims 1-3 or 6-47, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered as part of a composition, wherein the composition comprises 130 mg/mL of the anti-PD-1 antibody or antigen-binding fragment thereof.

50. The method of any one of claims 1-3, or 6-47, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered as part of a composition, wherein the composition comprises 165 mg/mL of the anti-PD-1 antibody or antigen-binding fragment thereof.

51. Use of an anti-PD-1 antibody, or antigen binding fragment thereof, in a method of treating cancer, according to any one of claims 1-50.