Methods and Compositions Comprising an SHP2 Inhibitor and a PD-L1 Binding Antagonist

Abstract

A combination therapy comprising an SHP2 inhibitor (e.g., Compound 1) and a PD-L1 binding antagonist (e.g., atezolizumab), and methods of using such combination therapies are provided herein. In another aspect, a method of treating lung cancer, head and neck cancer, or melanoma in a patient in need of treatment for lung cancer, head and neck cancer, or melanoma, comprising administering, during a treatment period, an effective amount of a combination therapy comprising (a) Compound 1 or a pharmaceutically acceptable salt thereof, and (b) a PD-L1 binding antagonist, as described herein, is provided herein.

Description

Technical Field

[0001] The present disclosure provides a combination therapy comprising an SHP2 inhibitor (e.g., Compound 1) and a PD-L1 binding antagonist (e.g., atezolizumab), and methods of using such combination therapies.

[0002] Sequence Listing This application incorporates by reference a computer-readable format (CRF) of a sequence listing in ASCII text format submitted via EFS-Web. The sequence listing text file, titled P37266_SEQ_LISTING_ST26.txt, having a file size of 18 kilobytes, was created on April 25, 2023.

Background Art

[0003] Protein tyrosine phosphorylation plays a central role in the etiology of cancer. SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is a protein tyrosine phosphatase encoded by the PTPN11 gene and functions as a central node in several intracellular oncogenic signaling pathways such as the RAS / Raf / MAPK, PI3K / AKT, Jak / STAT, and PD-1 / PDL-1 pathways (J Med Chem. 2020;63:11368-11396). The acquisition and / or overexpression of functional mutations in SHP2 are associated with genetic developmental disorders (e.g., Noonan syndrome) and various types of cancer (e.g., breast cancer, melanoma, non-small cell lung adenocarcinoma (NSCL), and others) (Eur J Med Genet. 2015;58(10):509-25; Pharmacol Res. 2020;152:104595-104605). Under basal conditions, SHP2 exists in an auto-inhibited conformation with its catalytic activity suppressed. Somatic missense mutations in SHP2, detected more rarely in leukemia and even more rarely in solid tumors, destabilize the auto-inhibited conformation of SHP2, thereby resulting in abnormal overactivation. Therefore, there is a need for effective treatment methods and combination therapies for treating cancers such as lung cancer, head and neck cancer, and other solid tumors.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0005] This specification provides solutions to these and other problems in the art.

[0006] In one aspect, a combination therapy is provided herein that includes (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof, and (b) a PD-L1 binding antagonist described herein.

[0007] In another aspect, a method for treating lung cancer, head and neck cancer, or melanoma in a patient in need of treatment for lung cancer, head and neck cancer, or melanoma, the method comprising administering, during a treatment period, an effective amount of a combination therapy comprising (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof, and (b) a PD-L1 binding antagonist is provided herein. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the melanoma is BRAF wild-type (WT) melanoma.

[0008] In another aspect, provided herein is a method of treating lung cancer, head and neck cancer, or melanoma in a patient in need of treatment for lung cancer, head and neck cancer, or melanoma, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 described herein or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the melanoma is BRAF wild-type (WT) melanoma.

[0009] In yet another aspect, provided herein is the use (U1) of a combination therapy comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof and atezolizumab for treating lung cancer, head and neck cancer, or melanoma described herein. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the melanoma is BRAF wild-type (WT) melanoma.

[0010] In yet another aspect, provided herein is the use (U5) of a combination therapy comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof and atezolizumab for manufacturing a medicament for treating lung cancer, head and neck cancer, or melanoma. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the melanoma is BRAF wild-type (WT) melanoma.

[0011] In yet another aspect, provided herein is a combination therapy comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof and atezolizumab for use in the treatment of lung cancer, head and neck cancer or melanoma. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the melanoma is BRAF wild-type (WT) melanoma.

Brief Description of the Drawings

[0012] To facilitate easy identification of any particular element or act, the most significant digit of a reference number refers to the figure number in which that element is first introduced.

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Figure 6B

Mode for Carrying Out the Invention

[0022] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. For example, see Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). In the practice of the present invention, any methods, devices, and materials similar or equivalent to those described herein can be used.

[0023] The following definitions are provided to facilitate understanding of certain terms frequently used in this specification and are not meant to limit the scope of the present disclosure. All references mentioned in this specification are incorporated by reference in their entirety.

[0024] As used in this specification, unless otherwise specified, the terms “about” and “approximately” when referring to the dosage, amount, or weight percentage of a component of a composition or dosage form mean a dosage, amount, or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage. Equivalent dosages, amounts, or weight percentages can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dosage, amount, or weight percentage.

[0025] “Compound 1” has the structure:

Chemical formula

[0026] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse side effects, allergic reactions, or other adverse reactions when appropriately administered to animals, such as humans.

[0027] The compounds of the present invention may be in the form of salts such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" mean salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., which retain the biological effectiveness and properties of the free base and are salts that are biologically or otherwise desirable. Organic acids may be selected from the classes of aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acids of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0028] The term "pharmaceutically acceptable basic addition salts" includes those derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Specific basic addition salts are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0029] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, phthalate (e.g., 2-phthalate or 3-phthalate), napadisylate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esilate, malonate, mesitylate (2-mesitylenesulfonate), naphthylate (2-naphthalenesulfonate), camsylate (camphor 10-sulfonate, e.g., (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2’-dihydroxy-1,1’-dinaphthylmethane-3,3’-dicarboxylate).

[0030] The terms "inhibit" and "reduce / decrease", or any variation of these terms, include any measurable reduction / decrease or complete inhibition to achieve the desired result. For example, about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or a decrease of any of these range variables, a decrease in activity compared to normal may exist.

[0031] The terms "PD-L1 binding antagonist", "PD-L1 inhibitor", and "PD-L1 blocking antibody" are used interchangeably herein and refer to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, such as PD-1 and / or B7-1. In some examples, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific embodiment, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some examples, a PD-L1 binding antagonist includes an anti-PD-L1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, such as PD-1 and / or B7-1. In one example, a PD-L1 binding antagonist reduces a negative co-stimulatory signal mediated by or through a cell surface protein expressed on a T lymphocyte via PD-L1-mediated signaling such that dysfunctional T cells are prevented from becoming dysfunctional (e.g., enhancing an effector response to antigen recognition). In some examples, a PD-L1 binding antagonist binds to PD-L1. In some examples, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, rodaplimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab.

[0032] The terms "programmed death ligand 1" and "PD-L1" as used herein refer to the native sequence human PD-L1 polypeptide. The native sequence PD-L1 polypeptide is provided by Uniprot accession number Q9NZQ7. For example, the native sequence PD-L1 may have the amino acid sequence set forth in Uniprot accession number Q9NZQ7-1 (isoform 1). In another example, the native sequence PD-L1 may have the amino acid sequence set forth in Uniprot accession number Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have the amino acid sequence set forth in Uniprot accession number Q9NZQ7-3 (isoform 3). PD-L1 is also commonly referred to in the art as "programmed cell death 1 ligand 1", "PDCD1LG1", "CD274", "B7-H", and "PDL1".

[0033] The Kabat numbering system is generally used when referring to residues in the variable domains (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in the constant region of the immunoglobulin heavy chain (e.g., the EU index reported in Kabat et al. supra). The "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies.

[0034] For the purposes of this specification, "atezolizumab" is a Fc-engineered humanized non-glycosylated IgG1 kappa immunoglobulin that binds to PD-L1 and comprises the heavy chain sequence of SEQ ID NO: 1 and the light chain sequence of SEQ ID NO: 2. Atezolizumab contains a single amino acid substitution (asparagine to alanine) (N297A) at position 297 on the heavy chain using the EU numbering of Fc region amino acid residues, resulting in a non-glycosylated antibody with minimal binding to Fc receptors. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, issued on January 16, 2015 (see page 485).

[0035] In some examples, the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to the sequence of SEQ ID NO: 1 or the sequence of SEQ ID NO: 1, (b) a VL comprising an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to the sequence of SEQ ID NO: 2 or SEQ ID NO: 2, or (c) the VH described in (a) and the VL described in (b).

[0036] In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises: (a) Heavy chain (VH) amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 1), and (b) Light chain (VL) amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2).

[0037] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one example, the cancer is lung cancer. In another example, the cancer is non-small cell lung cancer (NSCLC). In one example, the cancer is head and neck cancer. In another example, the cancer is head and neck squamous cell carcinoma (HNSCC). In one example, the cancer is melanoma. In another example, the cancer is BRAF wild-type (WT) melanoma.

[0038] As used herein, "treating" includes effective cancer treatment with an effective amount of a therapeutic agent (e.g., atezolizumab or Compound 1) or a combination of therapeutic agents (e.g., atezolizumab and Compound 1). The treatment can be first-line treatment (e.g., the patient may not have been previously treated or may not have received prior systemic therapy) or second-line treatment or subsequent therapy. For example, the treatment is successful if one or more symptoms associated with the cancer described herein, including, but not limited to, reduction (or destruction) of cancer cell proliferation, alleviation of symptoms resulting from the disease, improvement in the quality of life of the diseased person, reduction in the dosage of other drug therapies required for treatment of the disease, and / or prolongation of the patient's survival period, are alleviated or eliminated.

[0039] The term "delaying the progression" of a disease refers to delaying, preventing, retarding, slowing, stabilizing, and / or postponing the onset of the cancer described herein. This delay can be of various durations depending on the cancer being treated herein and / or the patient's medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively encompass prevention in the sense that the patient does not develop cancer.

[0040] As used herein, "effective amount" refers to the amount of a therapeutic agent (e.g., atezolizumab and / or Compound 1) described herein that achieves a therapeutic result. In some examples, the effective amount of a therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves a clinical endpoint provided herein. The effective amount herein can vary depending on factors such as the patient's disease state, age, gender, and weight, as well as the ability of the agent to elicit the desired response in the patient. The effective amount is also one in which the therapeutically beneficial effects exceed any toxic or detrimental effects of the treatment. In some embodiments, an effective amount of a drug can have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., delaying or stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., delaying or stopping) tumor metastasis, inhibiting (i.e., delaying or stopping) tumor growth, and / or reducing one or more of the symptoms associated with the disease. The effective amount can be administered in one or more administrations. The effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein can be an amount sufficient to directly or indirectly achieve a therapeutic treatment.

[0041] "Objective response rate" or "ORR" is determined by the investigator in charge of the clinical trial according to RECIST v1.1, 3 and refers to the percentage of patients with confirmed complete or partial response at two consecutive opportunities separated by 4 weeks.

[0042] "Duration of response" or "DOR" refers to the time from the first occurrence of a recorded objective response to the earlier of disease progression, as determined by the investigator in charge of the clinical trial according to RECIST v1.1, or death from any cause.

[0043] "Progression-free survival" or "PFS" refers to the time from registration to the earlier of the occurrence of the first recorded disease progression or death from any cause, as determined by the investigator in charge of the clinical trial using RECIST v1.1.

[0044] As used herein, "complete response" and "CR" refer to the disappearance of all target lesions and, if applicable, normalization of tumor marker levels.

[0045] As used herein, "partial response" and "PR" refer to the persistence of one or more non-target lesions and / or, if applicable, maintenance above the normal limits of tumor marker levels. PR can also refer to a 30% reduction in the sum of the diameters of target lesions in the absence of CR, new lesions, and definite progression in non-target lesions. 3

[0046] "Treatment period" or "cycle" refers to a period that includes administration of one or more of the agents described herein (e.g., Compound 1 and atezolizumab), and any period that does not include administration of one or more of the agents described herein. For example, a cycle can be a total of 21 days, with each day of the cycle including administration of one or more of the agents described herein (e.g., Compound 1 and atezolizumab). In another example, a cycle can be a total of 28 days, including administration of one or more of the agents described herein (e.g., Compound 1 and atezolizumab) over a 21-day period and a 7-day drug-free period. "Drug-free period" refers to a period during which at least one of the agents described herein (i.e., Compound 1 and atezolizumab) is not administered. In one embodiment, the drug-free period refers to a period during which none of the agents described herein (i.e., Compound 1 and atezolizumab) are administered. The drug-free periods provided herein can, in some examples, include administration of another agent that is not Compound 1 or atezolizumab. In such cases, administration of another agent during the drug-free period should not interfere with or be detrimental to the administration of the agents described herein. In one example, a cycle as used herein refers to a 21-day cycle without a drug-free period.

[0047] "Dosing regimen" refers to the treatment period of the agents described herein, including one or more cycles, where each cycle can include administration of the agents described herein a different number of times or in different amounts.

[0048] "QD" refers to administering the agent described in this specification once a day.

[0049] "BID" refers to administering the agent described in this specification twice a day.

[0050] "Q3W" refers to administering the agent described in this specification once every three weeks.

[0051] "PO" refers to oral administration of the agent described in this specification.

[0052] "IV" refers to intravenous administration of any agent described in this specification.

[0053] Grading of adverse events refers to the severity grading scale established by NCI CTCAE. In one embodiment, adverse events are graded according to the following table.

Table 3

[0054] The term "patient" refers to a human patient. The patient may be an adult.

[0055] The term "antibody" specifically includes monoclonal antibodies (such as full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired biological activity. In one example, the antibody is a full-length monoclonal antibody.

[0056] As used herein, the terms IgG "isotype" or "subclass" mean any of the immunoglobulin subclasses defined by the chemical and antigenic properties of their constant regions.

[0057] Depending on the amino acid sequences of the constant domains of those heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these may be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, γ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known and are generally described, for example, in Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000). An antibody may be part of a larger fusion molecule formed by covalent or non-covalent binding of the antibody to one or more other proteins or peptides.

[0058] The terms "full-length antibody", "intact antibody", and "whole antibody" are used interchangeably herein to refer to an antibody in its substantially intact form that is not an antibody fragment as described below. This term refers to an antibody that includes the Fc region.

[0059] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by a host cell may be subject to post-translational cleavage of one or more, particularly one or two amino acids from the C-terminus of the heavy chain. Thus, an antibody produced by a host cell upon expression of a particular nucleic acid molecule encoding a full-length heavy chain may contain the full-length heavy chain or a cleaved variant of the full-length heavy chain. This is also true when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Thus, the C-terminal lysine (K447), or the C-terminal glycine (G446) and lysine (K447) of the Fc region may or may not be present. The amino acid sequence of the heavy chain containing the Fc region is shown herein without the C-terminal lysine (K447) unless otherwise indicated. In one embodiment, the heavy chain containing the Fc region as specified herein and included in the antibodies disclosed herein contains an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one embodiment, the heavy chain containing the Fc region as specified herein and included in the antibodies disclosed herein contains an additional C-terminal glycine residue (G446). In one embodiment, the heavy chain containing the Fc region as specified herein and included in the antibodies disclosed herein contains an additional C-terminal lysine residue (K447). In one embodiment, the Fc region contains a single amino acid substitution N297A in the heavy chain. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering scheme (also called the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0060] "Naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. A naked antibody may be present in a pharmaceutical composition.

[0061] "Antibody fragment" includes a portion of an intact antibody, preferably including the antigen-binding region thereof. In some instances, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments include Fab, F(ab’) 2 , and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0062] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a collection of substantially homogeneous antibodies, i.e., the individual antibodies comprising the collection are identical and / or bind the same epitope, except for possible variant antibodies that may be present in minor amounts, including, for example, naturally occurring mutations or mutations occurring during production of the monoclonal antibody preparation. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous collection of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be made by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.

[0063] As used herein, the terms "hypervariable region" or "HVR" refer to each region of an antibody variable domain that is hypervariable in sequence and that determines antigen-binding specificity, e.g., the "complementary determining regions" (CDRs).

[0064] Generally, an antibody contains six CDRs, three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include, (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2) and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2) and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)).

[0065] Unless otherwise indicated, CDRs are determined according to Kabat et al., supra. One of ordinary skill in the art will understand that the CDR designations can be determined according to Chothia, supra, MacCallum, supra, or any other scientifically approved nomenclature system.

[0066] "Framework" or "FR" refers to the variable domain residues outside the complementarity determining regions (CDRs). The FRs of the variable domain generally consist of four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences generally occur in the following sequence in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

[0067] The term "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat", and variations thereof, refer to the numbering system used for the heavy chain variable domain or the light chain variable domain of the antibody compilation in Kabat et al., (supra). Using this numbering scheme, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to deletions or insertions in the FR or HVR of the variable domain. For example, the heavy chain variable domain may contain a single amino acid insertion (residue 52a according to Kabat) after residue 52 of H2, and residues inserted after residue 82 of the heavy chain FR (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment in the homologous regions between the antibody's sequence and the sequence numbered by "standard" Kabat.

[0068] The term "package insert" is used to refer to the instructions normally included in the commercial package of a therapeutic product, and contains information regarding indications, uses, dosages, administrations, combination therapies, contraindications, and / or warnings for such a therapeutic product.

[0069] As used herein, "in combination with" refers to the administration of a treatment regimen that includes, in addition to another treatment modality, one treatment modality, e.g., the administration of a PD-1 axis-binding antagonist (e.g., atezolizumab) and Compound 1 or a pharmaceutically acceptable salt thereof. Thus, "in combination with" refers to the administration of one treatment modality before, during, or after the administration of another treatment modality to a patient.

[0070] A drug administered "simultaneously" with one or more other drugs is administered on the same treatment day as the one or more other drugs, and, if necessary, at the same time as the one or more other drugs, during the same treatment cycle. For example, in the case of a cancer therapy administered every three weeks, the drugs administered simultaneously are each administered on day 1 of the three-week cycle.

[0071] Combination therapy Provided herein is a combination therapy (composition) comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist.

[0072] In some examples, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any of the examples herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, such as human PD-L1 as shown in UniProtKB / Swiss-Prot accession number Q9NZQ7-1, or a variant thereof. In some examples, the anti-PD-L1 antibody can inhibit the binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1. In some examples, the anti-PD-L1 antibody is a monoclonal antibody. In some examples, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab fragment, Fab’-SH fragment, Fv fragment, scFv fragment, and (Fab’)2 fragment. In some examples, the anti-PD-L1 antibody is a humanized antibody. In some examples, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, rodaplimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. Examples of anti-PD-L1 antibodies useful in the methods of the present invention and methods for making them are described in International Publication No. WO 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety. In a preferred embodiment, the PD-L1 binding antagonist comprises an anti-PD-L1 antibody. In a more preferred embodiment, the anti-PD-L1 antibody is atezolizumab.

[0073] In some examples, the anti-PD-L1 antibody is, (a) The HVR-H1, HVR-H2, and HVR-H3 sequences of GFTFSDSWIH (SEQ ID NO: 3), AWISPYGGSTYYADSVKG (SEQ ID NO: 4), and RHWPGGFDY (SEQ ID NO: 5), respectively, and (b) It includes the HVR-L1, HVR-L2, and HVR-L3 sequences of RASQDVSTAVA (SEQ ID NO: 6), SASFLYS (SEQ ID NO: 7), and QQYLYHPAT (SEQ ID NO: 8), respectively.

[0074] In one embodiment, the anti-PD-L1 antibody is (a) A heavy chain variable region (VH) comprising the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 9), and (b) A light chain variable region (VL) comprising the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 10).

[0075] In some examples, the anti-PD-L1 antibody is (a) an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to the sequence of SEQ ID NO: 9, or a VH domain comprising the sequence of SEQ ID NO: 9; (b) an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to the sequence of SEQ ID NO: 10, or a VL domain comprising the sequence of SEQ ID NO: 10; or it comprises the VH of (a) and the VL of (b).

[0076] In one embodiment, the anti-PD-L1 antibody includes atezolizumab comprising the following: (a) Heavy chain amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 1), and (b) Light chain amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2).

[0077] In some examples, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

[0078] In some examples, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PD-L1 antibody (MedImmune, AstraZeneca) described in International Publication No. WO 2011 / 066389 and U.S. Patent Application Publication No. 2013 / 034559.

[0079] In some examples, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in International Publication No. WO 2007 / 005874.

[0080] In some examples, the anti-PD-L1 antibody is LY3300054 (Eli Lilly). In some examples, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody. In some examples, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camel phage display library.

[0081] In some examples, the anti-PD-L1 antibody is composed of a cleavable site or linker that, when cleaved (e.g., by proteases in the tumor microenvironment), activates the antibody antigen-binding domain to enable binding of its antigen, e.g., by removing a non-binding steric moiety. In some examples, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0082] In some examples, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs), and / or the heavy chain variable domain and the light chain variable domain from an anti-PD-L1 antibody described in US Patent Application Publication No. 20160108123, International Publication No. 2016 / 000619, International Publication No. 2012 / 145493, US Patent No. 9,205,148, International Publication No. 2013 / 181634, or International Publication No. 2016 / 061142.

[0083] In a still further specific embodiment, the anti-PD-L1 antibody has reduced or minimal effector function. In an even more specific embodiment, the minimal effector function results from a "Fc mutation without effector" or a glycosylation mutation. In a still further instance, the Fc mutation without effector is an N297A or D265A / N297A substitution within the constant region. In a still further example, the effectorless Fc mutation is an N297A substitution within the constant region. In some examples, the isolated anti-PD-L1 antibody is non-glycosylated. Glycosylation of an antibody is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid other than proline) are recognition sequences for the enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of a sugar, N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. Removal of glycosylation sites from an antibody is conveniently achieved by modifying the amino acid sequence such that one of the above-described tripeptide sequences (for N-linked glycosylation sites) is removed. This modification can be done by substitution of the asparagine, serine, or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

[0084] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab. In one embodiment, the combination therapy described herein is useful for the treatment of certain types of lung cancer, head and neck cancer, and / or melanoma described herein. In one embodiment, the lung cancer is NSCLC. In one embodiment, the head and neck cancer is HNSCC. In one embodiment, the melanoma is BRAF WT melanoma. In one embodiment, Compound 1 is the free base. In another embodiment, Compound 1 is a pharmaceutically acceptable salt of Compound 1.

[0085] In one aspect, provided herein is a combination therapy (e.g., a composition) comprising Compound 1 or a pharmaceutically acceptable salt thereof, which is administered QD on days 1 to 21 of the first 21-day cycle, and an anti-PD-L1 antibody.

[0086] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof, which is administered QD on days 1 to 21 of the first 21-day cycle, and atezolizumab, which is administered Q3W on day 1 of the first 21-day cycle.

[0087] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof, which is administered QD on days 1 to 21 of the first 21-day cycle, and atezolizumab, which is administered Q2W on day 1 of the first 21-day cycle. In such an embodiment, atezolizumab is administered Q2W in an amount of 840 mg. In such an embodiment, atezolizumab is administered Q2W in accordance with the package insert.

[0088] In one embodiment of the combination therapy described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed dose QD. In one embodiment, the administration is oral (PO), and Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or a capsule. In such an embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is formulated (and administered) as a film-coated tablet. In another such embodiment, Compound 1 is administered as a capsule.

[0089] In one embodiment of the combination therapy described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 125 mg, 5 mg to 120 mg, 5 mg to 110 mg, 5 mg to 100 mg, 5 mg to 80 mg, 5 mg to 75 mg, 5 mg to 60 mg, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 20 mg, 5 mg to 10 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 150 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 75 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 250 mg, 40 mg to 200 mg, 40 mg to 150 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 60 mg, 60 mg to 250 mg, 60 mg to 200 mg, 60 mg to 150 mg, 60 mg to 100 mg, or 60 mg to 80 mg QD.

[0090] In one embodiment of the combination therapy described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 125 mg, 5 mg to 120 mg, 5 mg to 110 mg, 5 mg to 100 mg, 5 mg to 80 mg, 5 mg to 75 mg, 5 mg to 60 mg, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 20 mg, 5 mg to 10 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 150 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 75 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 250 mg, 40 mg to 200 mg, 40 mg to 150 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 60 mg, 60 mg to 250 mg, 60 mg to 200 mg, 60 mg to 150 mg, 60 mg to 100 mg, or 60 mg to 80 mg BID.

[0091] In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg or 150 mg QD. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg or 150 mg BID. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg, 40 mg, 50 mg, 60 mg or 80 mg QD. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg, 40 mg, 50 mg, 60 mg or 80 mg BID.

[0092] In one embodiment of the combination therapy described herein, the PD-L1 binding antagonist is administered in accordance with the package insert. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab.

[0093] As a general proposition, the therapeutically effective amount of a PD-L1 binding antagonist (e.g., atezolizumab) administered to humans will range from about 0.01 mg / kg to about 50 mg / kg of the patient's body weight, whether by one or more administrations.

[0094] In some exemplary embodiments, the PD-L1 binding antagonist is administered at a dosage of about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, or about 0.01 mg / kg to about 1 mg / kg, and is administered, for example, daily, weekly, every two weeks, every three weeks, or every four weeks.

[0095] In one example, the PD-L1 binding antagonist is administered to a human at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg. In some examples, the PD-L1 binding antagonist can be administered at a dose of about 1000 mg to about 1400 mg every three weeks (e.g., about 1100 mg to about 1300 mg every three weeks, e.g., about 1150 mg to about 1250 mg every three weeks).

[0096] In a preferred embodiment, the combination therapy described herein comprises Compound 1 described herein or a pharmaceutically acceptable salt thereof and atezolizumab, and atezolizumab is intravenously administered to a patient at a dose of about 840 mg every two weeks, about 1200 mg every three weeks, or about 1680 mg every four weeks. In a preferred embodiment, the combination therapy described herein comprises Compound 1 described herein or a pharmaceutically acceptable salt thereof and atezolizumab, and atezolizumab is administered to the patient intravenously at a dose of about 1200 mg Q3W.

[0097] In one embodiment, the combination therapy described herein is used to treat lung cancer. In a particular embodiment, the combination therapy comprises Compound 1 described herein or a pharmaceutically acceptable salt thereof and atezolizumab, and the combination therapy is for treating lung cancer. In such an embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). In such an embodiment, the NSCLC is locally advanced or metastatic NSCLC. In another such embodiment, the NSCLC has no EGFR or ALK alterations.

[0098] In one embodiment, the combination therapy described herein is used to treat head and neck cancer. In such an embodiment, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In a particular embodiment, the combination therapy comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, and the combination therapy is for treating HNSCC. In such an embodiment, the HNSCC is recurrent or metastatic HNSCC including the hypopharynx, oral cavity, larynx, or hypopharynx.

[0099] In one embodiment, the combination therapy described herein is used to treat melanoma. In a particular embodiment, the combination therapy comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, and the combination therapy is for treating melanoma. In such an embodiment, the melanoma is locally advanced melanoma or metastatic (e.g., recurrent or de novo stage IV) melanoma. In another such embodiment, the melanoma is unresectable locally advanced (e.g., stage III) cutaneous melanoma. In such an embodiment, the melanoma is BRAF WT melanoma.

[0100] In yet another aspect, provided herein is a combination therapy useful for treating lung cancer described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD on days 1 to 21 of the first 21-day cycle, and atezolizumab is administered Q3W on day 1 of the first 21-day cycle. In one embodiment, the lung cancer is NSCLC.

[0101] In yet another aspect, provided herein is a combination therapy useful for treating head and neck cancer described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD on days 1 to 21 of the first 21-day cycle, and atezolizumab is administered Q3W on day 1 of the first 21-day cycle. In one embodiment, the head and neck cancer is HNSCC.

[0102] In yet another aspect, provided herein is a combination therapy useful for the treatment of melanoma described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W on day 1 of the first 21-day cycle. In one embodiment, the melanoma is BRAFT WT melanoma.

[0103] In yet another aspect, provided herein is a combination therapy useful for the treatment of lung cancer described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W in an amount of about 1200 mg on day 1 of the first 21-day cycle. In such an embodiment, the lung cancer is NSCLC as described herein.

[0104] In yet another aspect, provided herein is a combination therapy useful for the treatment of head and neck cancer described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W in an amount of about 1200 mg on day 1 of the first 21-day cycle. In one embodiment, the head and neck cancer is HNSCC.

[0105] In yet another aspect, provided herein is a combination therapy useful for the treatment of melanoma described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W in an amount of about 1200 mg on day 1 of the first 21-day cycle. In one embodiment, the melanoma is BRAFT WT melanoma.

[0106] In yet another aspect, provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of lung cancer and atezolizumab, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W on day 1 of the first 21-day cycle. In one embodiment, the lung cancer is NSCLC.

[0107] In yet another aspect, provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of head and neck cancer and atezolizumab, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W on day 1 of the first 21-day cycle. In one embodiment, the head and neck cancer is HNSCC.

[0108] In yet another aspect, provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of melanoma and atezolizumab, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W on day 1 of the first 21-day cycle. In one embodiment, the melanoma is BRAF T WT melanoma.

[0109] In yet another aspect, provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of lung cancer and atezolizumab, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered Q3W in an amount of about 1200 mg on day 1 of the first 21-day cycle. In such an embodiment, the lung cancer is the NSCLC described herein.

[0110] In yet another aspect, provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of head and neck cancer and atezolizumab, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg on days 1 to 21 of the first 21-day cycle, and atezolizumab is administered Q3W in an amount of about 1200 mg on day 1 of the first 21-day cycle. In one embodiment, the head and neck cancer is HNSCC.

[0111] In yet another aspect, provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of melanoma and atezolizumab, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg on days 1 to 21 of the first 21-day cycle, and atezolizumab is administered Q3W in an amount of about 1200 mg on day 1 of the first 21-day cycle. In one embodiment, the melanoma is BRAF T WT melanoma.

[0112] Method of treatment Also provided herein are methods of treating patients in need of treatment for lung cancer (e.g., NSCLC), head and neck cancer (e.g., HNSCC) or melanoma (e.g., BRAF T WT melanoma). In one embodiment, the method comprises administering an effective amount of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist. In another embodiment, the method comprises administering an effective amount of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab.

[0113] In one aspect, provided herein is a method of treating lung cancer in a patient in need thereof, the method comprising administering an effective amount of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist. In another aspect, provided herein is a method of treating lung cancer in a patient in need thereof, the method comprising administering an effective amount of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab. In one embodiment, the lung cancer is NSCLC.

[0114] In one aspect, provided herein is a method of treating head and neck cancer in a patient in need thereof, the method comprising administering an effective amount of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist. In another aspect, provided herein is a method of treating head and neck cancer in a patient in need thereof, the method comprising administering an effective amount of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab. In one embodiment, the head and neck cancer is HNSCC.

[0115] In one aspect, provided herein is a method of treating melanoma in a patient in need thereof, the method comprising administering an effective amount of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist. In another aspect, provided herein is a method of treating melanoma in a patient in need thereof, the method comprising administering an effective amount of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab. In one embodiment, the melanoma is BRAF T WT melanoma.

[0116] In one embodiment of the method described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed dose of QD administration. In another embodiment of the method described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed dose of BID administration. In one embodiment, the administration is oral (PO), and Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 125 mg, 5 mg to 120 mg, 5 mg to 110 mg, 5 mg to 100 mg, 5 mg to 80 mg, 5 mg to 75 mg, 5 mg to 60 mg, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 20 mg, 5 mg to 10 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 150 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 75 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 250 mg, 40 mg to 200 mg, 40 mg to 150 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 60 mg, 60 mg to 250 mg, 60 mg to 200 mg, 60 mg to 150 mg, 60 mg to 100 mg, or 60 mg to 80 mg QD.

[0117] In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet and administered in an amount of about 5 mg to 100 mg QD. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 10 mg. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 20 mg. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 40 mg. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 60 mg. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 80 mg.

[0118] In one embodiment of the method described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 125 mg, 5 mg to 120 mg, 5 mg to 110 mg, 5 mg to 100 mg, 5 mg to 80 mg, 5 mg to 75 mg, 5 mg to 60 mg, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 20 mg, 5 mg to 10 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 150 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 75 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 250 mg, 40 mg to 200 mg, 40 mg to 150 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 60 mg, 60 mg to 250 mg, 60 mg to 200 mg, 60 mg to 150 mg, 60 mg to 100 mg, or 60 mg to 80 mg BID.

[0119] In one embodiment of the method described herein, atezolizumab is administered at a dose of about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, or about 0.01 mg / kg to about 1 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks.

[0120] In one example, atezolizumab is administered to humans at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg. In some examples, atezolizumab can be administered at a dose of about 1000 mg to about 1400 mg every three weeks (for example, about 1100 mg to about 1300 mg every three weeks, for example, about 1150 mg to about 1250 mg every three weeks).

[0121] In a preferred embodiment of the method described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered as described herein, and atezolizumab is administered intravenously to the patient at a dose of about 1200 mg Q3W.

[0122] In one embodiment, the method described herein further includes a priming period. The priming period can be about 1 to 14 days in length. In such an embodiment, the priming period includes 14 days. In another such embodiment, the priming period is 14 days, and compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered on the first day of the priming period. In such an embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered alone on the eighth day of the priming period and then administered QD thereafter.

[0123] The methods provided herein may include administration of the combination therapies described herein as part of a dosing regimen. In such an embodiment, the dosing regimen may include one or more cycles. In another embodiment, the dosing regimen includes at least 2 cycles. In another aspect, the dosing regimens provided herein include 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles. In yet another embodiment, the dosing regimen includes from about 2 to 72, 2 to 66, 2 to 60, 2 to 54, 2 to 48, 2 to 42, 2 to 36, 2 to 30, 2 to 24, 2 to 18, 2 to 12, or 2 to 6 cycles. In one embodiment, the dosing regimen includes administration of any number of cycles of the combination therapies described herein until a desired response (e.g., PFS, OS, ORR, and / or DOR) reaches a desired outcome (e.g., an increase in PFS, OS, ORR, and / or DOR as compared to a control described herein). In another embodiment, the dosing regimen includes administration of any number of cycles of the combination therapies described herein until toxicity develops or the patient experiences one or more adverse events (AEs) that otherwise prevent further dosing. In yet another embodiment, the dosing regimen includes administration of any number of cycles of the combination therapies described herein until disease progression.

[0124] In one embodiment of the method described herein, a patient is administered a total of 1 to 50 doses, for example, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 50 doses, 40 to 45 doses, or 45 to 50 doses of atezolizumab. In a preferred embodiment, the dose is administered intravenously.

[0125] In certain embodiments, the therapeutic agents of the combination therapies described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof, and atezolizumab) can be administered by any suitable method known in the art. For example, atezolizumab can be administered sequentially (on different days) or simultaneously (on the same day or during the same treatment cycle) as Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, atezolizumab is administered after the administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some examples, atezolizumab is administered after the administration of Compound 1, or a pharmaceutically acceptable salt thereof can be administered on the same day. In one embodiment, atezolizumab can be administered on the same day after administering Compound 1 or a pharmaceutically acceptable salt thereof. For example, Compound 1 or a pharmaceutically acceptable salt thereof can be administered on Day 1 of each cycle before administering atezolizumab on Day 1 of each cycle, and then Compound 1 or a pharmaceutically acceptable salt thereof is administered QD for the next 20 days of a 21-day cycle.

[0126] In a preferred embodiment, atezolizumab is administered intravenously. In one example, atezolizumab can be administered intravenously over 60 minutes, and if a first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes. In some examples, the PD-1 axis-binding antagonist is not administered as an intravenous push or bolus.

[0127] In one embodiment, atezolizumab is administered according to the following table. [Table 4]

[0128] Also provided herein is a method for treating lung cancer (e.g., NSCLC), head and neck cancer (e.g., HNSCC), or melanoma (e.g., BRAF WT melanoma) in a patient in need thereof, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist (e.g., atezolizumab). In another embodiment of such a method, Compound 1 or a pharmaceutically acceptable salt thereof is administered at the QD described herein and in the amounts described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, atezolizumab is administered at the Q3W described herein and in the amounts described herein (e.g., 1200 mg). In another such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered as components of the priming period described herein prior to the start of the treatment regimen. In such a method, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab may be administered as described herein.

[0129] Furthermore, provided herein is a method for treating lung cancer in a patient in need of treatment for lung cancer, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist (e.g., atezolizumab). In another embodiment of such a method, Compound 1 or a pharmaceutically acceptable salt thereof is administered at QD as described herein and in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, atezolizumab is administered at Q3W as described herein and in an amount as described herein (e.g., 1200 mg). In another such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered as components of a priming period as described herein prior to the start of the treatment regimen. In such a method, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab can be administered as described herein. In one such embodiment, the lung cancer is NSCLC as described herein.

[0130] Still further, provided herein is a method for treating head and neck cancer in a patient in need of treatment for head and neck cancer as described herein, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist (e.g., atezolizumab). In another embodiment of such a method, Compound 1 or a pharmaceutically acceptable salt thereof is administered at QD as described herein and in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, atezolizumab is administered at Q3W as described herein and in an amount as described herein (e.g., 1200 mg). In another such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered as components of a priming period as described herein prior to the start of the treatment regimen. In such a method, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab can be administered as described herein. In one embodiment, the head and neck cancer is HNSCC as described herein.

[0131] Also provided herein is a method for treating melanoma in a patient in need of treatment of melanoma described herein, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist (e.g., atezolizumab). In another embodiment of such a method, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD as described herein and in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, atezolizumab is administered Q3W as described herein and in an amount as described herein (e.g., 1200 mg). In another such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered as components of an acclimation period as described herein prior to the start of the treatment regimen. In such a method, Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab can be administered as described herein. In one embodiment, the melanoma is BRAF WT melanoma as described herein.

[0132] In some examples, the treatment regimen described herein includes administration of one or more additional therapies, the additional therapies being one or more side effect limiting agents (e.g., agents intended to reduce the occurrence and / or severity of side effects of the treatment, e.g., antiemetics, gastric acid suppressants, corticosteroids (e.g., prednisone or equivalents, e.g., at a dose of 1 to 2 mg / kg / day), hormone replacement agent(s), etc.).

[0133] In some embodiments of the methods described herein, a patient is evaluated for PD-L1 positivity or PD-L1 status. In one embodiment, PD-L1 positivity or PD-L1 status is evaluated by a test based on IHC. In one embodiment, the patient is PD-L1 positive. In one embodiment, the patient has NSCLC that was evaluated in the PD-L1 high state. In another embodiment, the patient has NSCLC that was evaluated in the PD-L1 low state. In such an embodiment, the patient has NSCLC in the EGFR and ALK wild-type state.

[0134] The expression of PD-L1 can be evaluated in a patient treated according to any of the methods and compositions for use described herein. The methods and compositions for use can include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the patient. In other examples, the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the patient has been determined before or after the start of treatment. PD-L1 expression can be determined using any suitable approach. For example, PD-L1 expression can be determined as described in U.S. Patent Application Publication Nos. 2018 / 0030138 and 2018 / 0037655. Any suitable tumor sample can be used, such as a formalin-fixed paraffin-embedded (FFPE) tumor sample, a stored tumor sample, a fresh tumor sample, or a frozen tumor sample.

[0135] For example, the expression of PD-L1 can be determined in terms of the percentage of tumor samples containing tumor-infiltrating immune cells expressing a detectable PD-L1 expression level, as the percentage of tumor-infiltrating immune cells in tumor samples expressing a detectable PD-L1 expression level, and / or as the percentage of tumor cells in tumor samples expressing a detectable PD-L1 expression level. In any of the foregoing examples, it should be understood that the percentage of tumor samples composed of tumor-infiltrating immune cells can be with respect to the percentage of the tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the patient (e.g., as evaluated by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody)). For example, any suitable anti-PD-L1 antibody including SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11 may be used. In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263.

[0136] In some examples, the tumor sample obtained from the patient has a detectable PD-L1 expression level in less than 1% of the tumor cells in the tumor sample, 1% or more of the tumor cells in the tumor sample, less than 1% to 5% of the tumor cells in the tumor sample, 5% or more of the tumor cells in the tumor sample, less than 5% to 50% of the tumor cells in the tumor sample, or 50% or more of the tumor cells in the tumor sample.

[0137] In some examples, the tumor sample obtained from the patient has a detectable PD-L1 expression level in tumor-infiltrating immune cells constituting less than 1% of the tumor sample, more than 1% of the tumor sample, less than 1% to 5% of the tumor sample, more than 5% of the tumor sample, less than 5% to 10% of the tumor sample, or more than 10% of the tumor sample.

[0138] In some examples, tumor samples can be scored for PD-L1 positivity in tumor-infiltrating immune cells and / or tumor cells according to the criteria for diagnostic assessment shown in Table A and / or Table B, respectively.

[0139]

Table A

[0140]

Table B

[0141] Also provided herein are methods of inhibiting tumor growth or causing tumor regression in the patients described herein by administering the combination therapies described herein. In one embodiment, a method of inhibiting tumor growth in a patient in need thereof is provided herein by administering a combination therapy comprising administering compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab in one or more 21-day cycles as described herein.

[0142] In one embodiment, a method of causing or improving tumor regression in a patient having lung cancer (e.g., NSCLC), head and neck cancer (e.g., HNSCC), or melanoma (e.g., BRAF WT melanoma) as described herein is provided herein by administering a combination therapy comprising administering compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab in one or more 21-day cycles as described herein.

[0143] Further provided herein is the use of the combination therapy (composition) described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for the treatment of lung cancer (e.g., NSCLC), head and neck cancer (e.g., HNSCC), or melanoma (e.g., BRAF WT melanoma) as described herein.

[0144] In one embodiment, provided herein is the use (U1) of the combination therapy (composition) described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the treatment of lung cancer described herein. In such an embodiment, the lung cancer is NSCLC. In some embodiments, the NSCLC is locally advanced NSCLC or metastatic NSCLC as described herein.

[0145] In one embodiment, provided herein is the use (U2) of the combination therapy (composition) described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the treatment of head and neck cancer described herein. In such an embodiment, the head and neck cancer is HNSCC as described herein.

[0146] In one embodiment, provided herein is the use (U3) of the combination therapy (composition) described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the treatment of melanoma described herein. In one embodiment, the melanoma is BRAFT WT melanoma as described herein.

[0147] Further provided herein is the use (U4) of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the treatment of lung cancer, head and neck cancer, or melanoma described herein, the use comprising a dosing regimen comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of a first 21-day cycle; and (ii) administering atezolizumab Q3W on day 1 of a first 21-day cycle. In such an embodiment, the use comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the use comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises the treatment of melanoma described herein. In such an embodiment, the melanoma is BRAFT WT melanoma as described herein.

[0148] Further provided herein is the use (U5) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the treatment of lung cancer, head and neck cancer, or melanoma described herein, comprising a dosing regimen comprising: (i) administering about 5 to 100 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering about 1200 mg of atezolizumab Q3W on day 1 of the first 21-day cycle. In such an embodiment, the dosing regimen comprises more than 2 cycles as described herein. In such an embodiment, the use comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the use comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0149] Also provided herein is the use (U6) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the manufacture of a medicament for the treatment of lung cancer, head and neck cancer, or melanoma described herein. In such an embodiment, the use comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the use comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0150] Further provided herein is the use (U7) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the manufacture of a medicament for the treatment of lung cancer, head and neck cancer, or melanoma described herein, the use comprising a dosing regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle, and (ii) administering atezolizumab Q3W on day 1 of the first 21-day cycle. In such an embodiment, the use includes the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the use includes the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the use includes the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0151] Further provided herein is the use (U7) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, for the manufacture of a medicament for the treatment of lung cancer, head and neck cancer, or melanoma described herein, the use comprising a dosing regimen including (i) administering from about 5 to 100 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle, and (ii) administering about 1200 mg of atezolizumab Q3W on day 1 of the first 21-day cycle. In such an embodiment, the dosing regimen includes two or more cycles as described herein. In such an embodiment, the use includes the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the use includes the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the use includes the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0152] In one embodiment, provided herein is a combination therapy (composition) described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U1) in the treatment of lung cancer described herein. In such an embodiment, the lung cancer is NSCLC. In some embodiments, the NSCLC is locally advanced NSCLC or metastatic NSCLC as described herein.

[0153] In one embodiment, provided herein is a combination therapy (composition) described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U2) in the treatment of head and neck cancer described herein. In such an embodiment, the head and neck cancer is HNSCC as described herein.

[0154] In one embodiment, provided herein is a combination therapy (composition) described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U3) in the treatment of melanoma described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0155] Further provided herein is a combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U4) in the treatment of lung cancer, head and neck cancer, or melanoma described herein, the combination therapy comprising a dosing regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of a first 21-day cycle, and (ii) administering atezolizumab Q3W on day 1 of the first 21-day cycle. In such an embodiment, the treatment includes the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment includes the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment includes the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0156] Furthermore, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U5) in the treatment of lung cancer, head and neck cancer, or melanoma described herein, the combination therapy comprising a dosing regimen comprising: (i) administering about 5-100 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (ii) administering about 1200 mg of atezolizumab Q3W on day 1 of a first 21-day cycle. In such an embodiment, the dosing regimen comprises more than 2 cycles as described herein. In such an embodiment, the treatment comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0157] Furthermore, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U6) in the manufacture of a medicament for the treatment of lung cancer, head and neck cancer, or melanoma described herein. In such an embodiment, the treatment comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0158] Further provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U7) in the manufacture of a medicament for the treatment of lung cancer, head and neck cancer, or melanoma described herein, the combination therapy comprising a dosing regimen comprising: (i) administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (ii) administering atezolizumab Q3W on day 1 of a first 21-day cycle. In such an embodiment, the treatment comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0159] Further provided herein is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use (U7) in the manufacture of a medicament for the treatment of lung cancer, head and neck cancer, or melanoma described herein, the combination therapy comprising a dosing regimen comprising: (i) administering about 5 to 100 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (ii) administering about 1200 mg of atezolizumab Q3W on day 1 of a first 21-day cycle. In such an embodiment, the dosing regimen comprises 2 or more cycles as described herein. In such an embodiment, the treatment comprises the treatment of lung cancer. In such an embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises the treatment of head and neck cancer. In such an embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises the treatment of melanoma as described herein. In such an embodiment, the melanoma is BRAF WT melanoma as described herein.

[0160] The development of combination treatments has challenges, including, for example, the selection of agents for combination therapies that may lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapies described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof, and atezolizumab) are administered in a dosing regimen that includes a staggered dosing schedule. In such an embodiment, the patient has a reduction in the number or grade of adverse events (AEs) comparable to a control (e.g., treatment with SOC therapy, treatment with one agent described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof, or atezolizumab) alone).

[0161] When an adverse event occurs, it is generally understood that there are four options: (1) continue treatment as is with any concomitant therapy; (2) adjust the dose of one or more agents in the dosing regimen; (3) temporarily interrupt the administration of one or more agents in the dosing regimen; or (4) discontinue the administration of one or more agents in the dosing regimen. In one embodiment, the amount of Compound 1 or a pharmaceutically acceptable salt thereof is not changed. In another embodiment, the amount of atezolizumab administered is not changed. In one embodiment, if the administration of atezolizumab is interrupted, the next administration of Compound 1 or a pharmaceutically acceptable salt thereof is on the same day that the administration of atezolizumab is resumed.

[0162] Patients described herein may experience one or more adverse events (AEs) such as those described herein. In one embodiment, patients described herein experience peripheral edema, myelosuppression (e.g., thrombocytopenia and / or anemia), gastrointestinal toxicity (e.g., diarrhea, nausea and / or vomiting), rash, elevated liver transaminases, myocarditis, ophthalmic toxicity or phototoxicity. In another embodiment, patients described herein experience one or more of infusion-related reactions (IRR) and immune-mediated hepatitis, interstitial pneumonia, colitis, pancreatitis, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis and myositis. Immune-mediated reactions can involve any organ system and can result in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). In such an embodiment, the patient does not experience one or more of cardiotoxicity, pulmonary toxicity, nephrotoxicity, thromboembolic toxicity, or ophthalmic toxicity.

[0163] In some embodiments, one or more combination therapies can also be administered to the patients described herein, including: (a) oral contraceptives; (b) hormone replacement therapy; (c) prophylactic or therapeutic anticoagulation therapy (e.g., a stable dose of warfarin or low molecular weight heparin); vaccination (influenza, COVID-19, etc.), provided that live attenuated vaccines are not permitted; (d) megestrol acetate administered as an appetite stimulant; (e) mineralocorticoids (e.g., fludrocortisone); (f) inhaled or low-dose corticosteroids administered for chronic obstructive pulmonary disease or asthma; (g) low-dose corticosteroids administered for orthostatic hypotension or adrenal insufficiency; (h) palliative radiation therapy (e.g., treatment of known bone metastases or symptomatic relief of pain); (i) local therapies (e.g., surgery, stereotactic radiosurgery, radiation therapy, radiofrequency ablation); (j) premedication with antihistamines, antipyretics and / or analgesics (e.g., acetaminophen, ibuprofen, diphenhydramine), and / or H 2 receptor antagonists (e.g., famotidine, cimetidine).

[0164] In certain embodiments, the patients described herein are not to receive combination therapy including (a) potent / moderate CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or grapefruit supplements); (b) potent / moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone); (c) chemotherapy; (d) hormonal therapy; (e) immunotherapy; (f) radiation therapy; (g) herbal therapy); (h) live attenuated vaccines; systemic immune activators (e.g., interferon and IL-2); (i) proton pump inhibitors; (j) cannabidiol products; or (k) H 2 blockers and antacids.

[0165] In one embodiment of the methods described herein, the patients described herein have a locally advanced or metastatic solid tumor (e.g., NSCLC, HNSCC, melanoma as described herein) having any of the following: (a) progressing after at least one available standard therapy, or (b) for which an approved standard therapy has been proven ineffective or unacceptable or is considered inappropriate.

[0166] In one embodiment of the methods described herein, the patient has lung cancer and has not received prior systemic therapy. In such an embodiment, the lung cancer is locally advanced or metastatic lung cancer as described herein.

[0167] In one embodiment of the methods described herein, the patient has NSCLC and has not received prior systemic therapy. In such an embodiment, the NSCLC is the locally advanced or metastatic NSCLC described herein.

[0168] In another embodiment of the methods described herein, the patient has NSCLC as described herein and has no EGFR and / or ALK alterations. In such an embodiment, a patient sample (e.g., a biopsy of tumor tissue) is tested for the presence or absence of EGFR and / or ALK alterations. In another such embodiment, the patient is PD-L1 positive. In such an embodiment, the patient is determined to be PD-L1 positive by performing IHC analysis as described herein.

[0169] In one embodiment of the methods described herein, the patient described herein has histologically confirmed recurrent or metastatic head and neck cancer. In such an embodiment, the head and neck cancer includes the oropharynx, oral cavity, larynx, or hypopharynx. In such an embodiment, the head and neck cancer includes the oropharynx, oral cavity, larynx, or hypopharynx that is considered not suitable for curative therapy. In another embodiment of the methods described herein, the patient described herein has head and neck cancer as described herein and has not received prior systemic therapy for treating the head and neck cancer. In another embodiment of the methods described herein, the patient described herein has head and neck cancer and has been tested for the presence / absence of local human papillomavirus (HPV) for oropharyngeal cancer.

[0170] In one embodiment of the methods described herein, the patient described herein has histologically confirmed recurrent or metastatic HNSCC. In such an embodiment, the HNSCC includes the hypopharynx, oral cavity, larynx, or hypolarynx. In such an embodiment, the HNSCC includes the hypopharynx, oral cavity, larynx, or hypolarynx that is considered not suitable for curative therapy. In another embodiment of the methods described herein, the patient described herein has the HNSCC described herein and has not received prior systemic therapy for treating the HNSCC. In another embodiment of the methods described herein, the patient described herein has HNSCC and has been tested for the presence / absence of local human papillomavirus (HPV) for hypopharyngeal cancer.

[0171] In one embodiment of the methods described herein, the patient described herein has the melanoma described herein and the disease is progressing either during or after pretreatment comprising anti-PD-1 or anti-PD-L1 therapy.

[0172] In one embodiment of the methods described herein, the patient described herein has the BRAF T WT melanoma described herein and the disease is progressing either during or after pretreatment comprising anti-PD-1 or anti-PD-L1 therapy.

[0173] In one embodiment, the patient described herein does not have known untreated or active central nervous system (CNS) metastases (either progressive or requiring anticonvulsants or corticosteroids for palliative therapy). If the patient has a history of CNS metastases that have been treated, the methods described herein may be used for treatment, and such patients have the following: (1) measurable or evaluable disease outside the CNS; (2) no history of intracranial or spinal cord hemorrhage; (3) no ongoing need for corticosteroids as treatment for CNS metastases, with corticosteroids discontinued two weeks prior to administration of the combination therapy described herein and no ongoing symptoms attributable to CNS metastases; (4) no stereotactic radiation within 7 days or whole brain radiation within 14 days prior to day 1 of cycle 1 described herein; and (5) no evidence of interim progression between completion of CNS-directed therapy and screening radiologic studies.

[0174] In one embodiment of the methods described herein, the patient described herein does not have leptomeningeal disease or carcinomatous meningitis. In another embodiment, the patient described herein does not have uncontrolled hypertension. In another embodiment, the patient described herein does not have active tuberculosis infection. In another embodiment, the patient described herein is not being actively treated for HBV.

[0175] In another embodiment of the methods described herein, the patient described herein does not have an ophthalmic disease including retinal vein occlusion (RVO), central serous retinopathy (CSR), a predisposition to RVO or CSR, or retinopathy at the time of screening ophthalmic examination.

[0176] In one embodiment of the methods described herein, the patient described herein has not received a major surgical procedure other than for diagnosis within 4 weeks prior to the start of treatment described herein.

[0177] In another embodiment of the methods described herein, the patient described herein does not have an active autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain - Barré syndrome, or multiple sclerosis, or a history thereof. In some embodiments, a patient having such an autoimmune disease can be treated according to the methods described herein if: · such a patient has a history of autoimmune - related hypothyroidism and is being treated with thyroid replacement hormone; · such a patient has controlled type 1 diabetes and is being treated with an insulin regimen; · such a patient has eczema, psoriasis, lichen simplex chronicus, or vitiligo with only skin symptoms (e.g., patients with psoriatic arthritis are excluded), (i) the rash covers less than 10% of the patient's body surface area, (ii) the treatment uses only low - potency topical corticosteroids, and (iii) there has been no occurrence of an acute exacerbation of an underlying disease requiring psoralen + ultraviolet A irradiation, methotrexate, retinoids, biological agents, oral calcineurin inhibitors, or high - potency or oral corticosteroids within the past 12 months.

[0178] In another embodiment of the methods described herein, the patient does not have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug - induced interstitial pneumonia or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on screening by chest computed tomography scan.

[0179] In another embodiment, the patient described herein has not been treated with chemotherapy, immunotherapy, or biological therapy as an anticancer therapy within 3 weeks prior to administration of the combination therapy described herein, except for hormone therapy using a gonadotropin-releasing hormone (GnRH) agonist or antagonist for an endocrine-sensitive cancer (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer), or has not received endocrine therapy within 2 weeks prior to administration of the combination therapy described herein.

[0180] In another embodiment of the method described herein, the patient described herein has not received pretreatment with an H 2 blocking agent or antacid within 14 days prior to the treatment described herein or within the longer of the two periods of 5 drug elimination half-lives. In another embodiment of the method described herein, the patient described herein has not received pretreatment with a mild or moderate CYP3A4 inhibitor or a mild or moderate CYP3A4 inducer within 14 days prior to the treatment described herein or within the longer of the two periods of 5 drug elimination half-lives.

[0181] Kit The combination therapy described herein can be provided as a kit containing one or more of the agents described herein for administration. In one embodiment, the kit contains Compound 1 or a pharmaceutically acceptable salt thereof for administration in combination with atezolizumab described herein. In another embodiment, the kit contains Compound 1 or a pharmaceutically acceptable salt thereof packaged together with atezolizumab, and the kit contains separately formulated dosages of each agent.

[0182] Also provided herein are articles of manufacture or kits comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist (e.g., atezolizumab). In some examples, the article of manufacture further comprises a package insert containing instructions for using the PD-L1 binding antagonist for treating lung cancer, head and neck cancer, or melanoma as described herein. In such an embodiment, the lung cancer is NSCLC. In such an embodiment, the head and neck cancer is HNSCC. In such an embodiment, the melanoma is BRAF WT melanoma. In one embodiment, the article of manufacture further comprises a package insert containing instructions for using atezolizumab in combination with Compound 1 or a pharmaceutically acceptable salt thereof for treating NSCLC, HNSCC, or BRAF WT melanoma as described herein in a patient as described herein.

[0183] In some examples, the PD-L1 binding antagonist (e.g., atezolizumab) and Compound 1 or a pharmaceutically acceptable salt thereof are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container can be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy). In some examples, the container holds the formulation, and the label on the container or a label associated with the container can indicate instructions for use. The article of manufacture or kit can further comprise other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes, and a package insert with instructions for use. In some examples, the article of manufacture further comprises one or more other agents (e.g., additional chemotherapeutic or anti-neoplastic agents). Suitable containers for the one or more agents include, for example, bottles, vials, bags, and syringes.

[0184] Any of the manufactured products or kits described herein may include instructions for administering to a patient a compound 1 or a pharmaceutically acceptable salt thereof, and / or a PD-L1 binding antagonist (e.g., atezolizumab) according to any of the methods described herein.

[0185] Embodiment Exemplary embodiments of the present invention are provided below.

[0186] Embodiment 1. A combination therapy comprising: (a) Compound 1

Chemical formula

[0187] Embodiment 2. The combination therapy according to Embodiment 1, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0188] Embodiment 3. The combination therapy according to Embodiment 1 or 2, wherein the anti-PD-L1 antibody is atezolizumab.

[0189] Embodiment 4. The combination therapy according to Embodiment 3, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered on day 1 of the first 21-day cycle.

[0190] Embodiment 5. The combination therapy according to Embodiment 3, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered BID from day 1 to day 21 of the first 21-day cycle, and atezolizumab is administered on day 1 of the first 21-day cycle.

[0191] Embodiment 6. The combination therapy according to any one of Embodiments 1 to 5, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

[0192] Embodiment 7. The combination therapy according to any one of Embodiments 1 to 6, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 100 mg.

[0193] Embodiment 8. The combination therapy according to any one of Embodiments 1 to 7, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg or 100 mg.

[0194] Embodiment 9. The combination therapy according to any one of Embodiments 3 to 8, wherein atezolizumab is administered Q3W in an amount of about 800 mg to about 1400 mg.

[0195] Embodiment 10. The combination therapy according to any one of Embodiments 3 to 9, wherein atezolizumab is administered in an amount of about 1200 mg on Day 1 of each cycle.

[0196] Embodiment 11. The combination therapy according to any one of Embodiments 5 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered before the start of the first 21-day cycle, and then atezolizumab is administered in an amount of 840 mg.

[0197] Embodiment 12. The combination therapy according to any one of Embodiments 1 to 11, wherein the combination therapy is administered to a patient in need thereof, and the patient has lung cancer, head and neck cancer, or melanoma.

[0198] Embodiment 13. The combination therapy according to Embodiment 12, wherein the patient is PD-L1 positive.

[0199] Embodiment 14. The combination therapy according to Embodiment 12 or 13, wherein the patient is PD-L1-high.

[0200] Embodiment 15. The combination therapy according to any one of Embodiments 12 to 14, wherein the patient is PD-L1-low.

[0201] Embodiment 16. The combination therapy according to any one of Embodiments 13 to 15, wherein the PD-L1 positivity is determined by a PD-L1 immunohistochemistry (IHC) assay.

[0202] Embodiment 17. The combination therapy according to any one of Embodiments 12 to 15, wherein the patient has non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), or BRAF WT melanoma.

[0203] Embodiment 18. A method for treating lung cancer, head and neck cancer, or melanoma in a patient in need of treatment for lung cancer, head and neck cancer, or melanoma, comprising administering, during a treatment period, (a) Compound 1

Chemical formula

[0204] Embodiment 19. The method according to Embodiment 18, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0205] Embodiment 20. The method according to Embodiment 18, wherein the anti-PD-L1 antibody is atezolizumab.

[0206] Embodiment 21. The treatment period is (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of a first 21-day cycle, and (b) administering atezolizumab on day 1 of the first 21-day cycle, The method according to Embodiment 20.

[0207] Embodiment 22. The treatment period is (a) administering Compound 1 or a pharmaceutically acceptable salt thereof BID on days 1 to 21 of a first 21-day cycle, and (b) Administering atezolizumab on the first day of the first 21-day cycle, and The method according to embodiment 20, comprising

[0208] Embodiment 23. The method according to any one of embodiments 18-22, wherein compound 1 or a pharmaceutically acceptable salt thereof is orally administered as a tablet or capsule.

[0209] Embodiment 24. The method according to any one of embodiments 18-23, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 100 mg.

[0210] Embodiment 25. The method according to any one of embodiments 18-24, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg or 100 mg.

[0211] Embodiment 26. The method according to any one of embodiments 20-25, wherein atezolizumab is administered Q3W in an amount of about 800 mg to about 1400 mg.

[0212] Embodiment 27. The method according to any one of embodiments 20-26, wherein atezolizumab is administered in an amount of about 1200 mg on the first day of each cycle.

[0213] Embodiment 28. The method according to any one of embodiments 20-27, further comprising a priming period that includes administering compound 1 or a pharmaceutically acceptable salt thereof before the start of the first cycle, followed by administering atezolizumab in an amount of 840 mg.

[0214] Embodiment 29. The method according to embodiment 28, wherein the priming period includes 1 to 14 days.

[0215] Embodiment 30. The method according to embodiment 28 or 29, wherein the priming period is 14 days, and compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered on the first day of the priming period.

[0216] Embodiment 31. The method according to Embodiment 29 or 30, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered QD starting from the 8th day of the acclimation period.

[0217] Embodiment 32. The method according to any one of Embodiments 18 to 28, wherein the patient is PD-L1 positive.

[0218] Embodiment 33. The method according to any one of Embodiments 18 to 28 or 32, wherein the patient is PD-L1-high.

[0219] Embodiment 34. The method according to any one of Embodiments 18 to 28 or 32 to 33, wherein the patient is PD-L1-low.

[0220] Embodiment 35. The method according to any one of Embodiments 18 to 28 or 32 to 34, wherein the PD-L1 positivity is determined by a PD-L1 immunohistochemistry (IHC) assay.

[0221] Embodiment 36. The method according to any one of Embodiments 18 to 35, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0222] Embodiment 37. The method according to any one of Embodiments 18 to 35, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0223] Embodiment 38. The method according to any one of Embodiments 18 to 35, wherein the melanoma is BRAF WT melanoma.

[0224] Embodiment 39. A method for treating lung cancer, head and neck cancer, or melanoma in a patient in need of treatment for lung cancer, head and neck cancer, or melanoma, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist.

[0225] The method according to embodiment 39, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0226] The method according to embodiment 39 or 40, wherein the anti-PD-L1 antibody is atezolizumab.

[0227] Embodiment 42. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 5 mg to 100 mg on days 1 to 21 of the first 21-day cycle, (b) Atezolizumab is administered in an amount of 1200 mg on day 1 of the first 21-day cycle, The method according to embodiment 41.

[0228] Embodiment 43. The method according to any one of embodiments 39 to 42, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg or 100 mg.

[0229] Embodiment 44. The method according to any one of embodiments 39 to 43, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0230] Embodiment 45. The method according to any one of embodiments 39 to 43, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0231] Embodiment 46. The method according to any one of embodiments 39 to 43, wherein the melanoma is BRAF WT melanoma.

[0232] Embodiment 47. Use (U1) of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating the lung cancer, head and neck cancer, or melanoma described herein.

[0233] Embodiment 48. A dosing regimen, comprising: (a) administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (b) administering atezolizumab on day 1 of said first 21-day cycle; The use according to embodiment 47, further comprising a dosing regimen.

[0234] Embodiment 49. (a) Administering about 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of said first 21-day cycle; and (b) administering about 1200 mg of atezolizumab on day 1 of said first 21-day cycle; The use according to embodiment 47 or 48, further comprising.

[0235] Embodiment 50. Use (U5) of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for the manufacture of a medicament for treating lung cancer, head and neck cancer, or melanoma.

[0236] Embodiment 51. (a) Administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (b) administering atezolizumab Q3W on day 1 of said first 21-day cycle; The use according to embodiment 50, further comprising a dosing regimen.

[0237] Embodiment 52. (a) Administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (b) administering atezolizumab on day 1 of said first 21-day cycle; The use according to embodiment 50 or 51, further comprising a dosing regimen.

[0238] Embodiment 53. (a) Administering about 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (b) administering about 1200 mg of atezolizumab on day 1 of said first 21-day cycle; The use according to any one of embodiments 50 to 52, further comprising.

[0239] Use according to any one of Embodiments 50 to 53, wherein the dosing regimen includes two or more cycles.

[0240] Use according to any one of Embodiments 47 to 54, wherein Compound 1 is administered in an amount of about 5 mg to 100 mg.

[0241] Use according to any one of Embodiments 47 to 55, wherein Compound 1 is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg or 100 mg.

[0242] Use according to any one of Embodiments 47 to 56, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0243] Use according to any one of Embodiments 47 to 56, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0244] Use according to any one of Embodiments 47 to 56, wherein the melanoma is BRAF WT melanoma.

[0245] A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for use in the treatment of lung cancer, head and neck cancer, or melanoma.

[0246] The combination therapy according to Embodiment 60, wherein (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and (b) atezolizumab is administered Q3W on day 1 of the first 21-day cycle.

[0247] The combination therapy according to Embodiment 60 or 61, wherein (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD from day 1 to day 21 of the first 21-day cycle, and (b) atezolizumab is administered on day 1 of the first 21-day cycle.

[0248] Embodiment 63. (a) From day 1 to day 21 of the first 21-day cycle, about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered QD, and (b) on day 1 of the first 21-day cycle, about 1200 mg of atezolizumab is administered. The combination therapy according to any one of Embodiments 60 to 62.

[0249] Embodiment 64. The combination therapy according to any one of Embodiments 60 to 63, wherein the dosing regimen includes two or more cycles.

[0250] Embodiment 65. The combination therapy according to any one of Embodiments 60 to 64, wherein Compound 1 is administered in an amount of about 5 mg to 100 mg.

[0251] Embodiment 66. The combination therapy according to any one of Embodiments 60 to 65, wherein Compound 1 is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg or 100 mg.

[0252] Embodiment 67. The combination therapy according to any one of Embodiments 60 to 66, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0253] Embodiment 68. The combination therapy according to any one of Embodiments 60 to 66, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0254] Embodiment 69. The combination therapy according to any one of Embodiments 60 to 66, wherein the melanoma is BRAFT WT melanoma.

[0255] The following examples are presented by way of illustration and not limitation.

Examples

[0256] Example 1: In vitro and in vivo property evaluation

[0257] Agents. Compound 1 was formulated in 50 mM sodium citrate buffer (pH 3.0) at a concentration of 60 mg / kg. Anti-PD-L1 mAb (Mu IgG2a anti-PD-L1, hereinafter referred to as anti-PD-L1) and anti-gp120 isotype control (Mu IgG1 anti-gp120; hereinafter referred to as isotype control) were formulated as solutions in a buffer of 20 mM histidine acetate, 240 mM sucrose, 0.02% Tween 20™, pH 5.5. The oral administration vehicle control was 50 mM sodium citrate buffer, pH 3.0.

[0258] Cell lines. EMT6 breast cancer cell lines were cultured in vitro, harvested in the logarithmic growth phase, and resuspended in Hank's balanced salt solution (HBSS) containing Matrigel™ (BD Biosciences; San Jose, CA) at a volume ratio of 1:1 for in vivo inoculation. Each animal was inoculated with 0.1×10 6 cells at a volume of 100 μL into the mammary gland (5, left).

[0259] Mouse tumor models. 10.6-week-old Balb / c mice with tumors in the range of 141 - 196 mm 3 were evenly distributed into four study groups consisting of 10 mice each. The average tumor volume across all groups was 165 mm 3 at the start of dosing. The average starting weight was 19.94 g. All concentrations were calculated based on an average body weight of 20 g and adjusted for a 10% weight loss or gain. Mice in various groups received the treatment regimens described in Table 1. The mice were dosed for a total of 28 days, or until the first signs of illness, or until euthanasia if the weight loss was more than 20% of the starting weight at the start of dosing. This study was extended beyond 28 days to check the persistence of the response after discontinuation of treatment and ended on day 102, and all remaining mice were euthanized.

[0260]

Table 1

[0261] Measurement of tumor and body weight. Tumor volume was measured in two perpendicular dimensions (length and width) using an Ultra Cal-IV caliper (model 54-10-111; Fred V. Fowler Co.; Newton, Massachusetts), and tumor volume was calculated according to the following formula: Tumor size (mm 3 ) = (longer measurement × shorter measurement 2 ) × 0.5

[0262] Tumors that regressed by more than 50% relative to their starting volume during the study were classified as partial responders (PR), and tumors with a final tumor volume corresponding to complete regression were classified as complete responders (CR). Animal body weight was measured using an Adventura Pro AV812 scale (Ohaus Corporation; Pine Brook, New Jersey), and the rate of change in body weight for each group was calculated and plotted (see Figure 4). Percent weight change was calculated using the following formula. Weight change (%) = [(current weight / initial weight) - 1] × 100

[0263] Growth analysis and group comparison. Since tumors generally exhibit exponential growth, tumor volume was subjected to natural logarithm transformation prior to analysis. Analysis and comparison of tumor growth were performed using a customized function package in R (version 3.6.2) (R Foundation for Statistical Computing; Vienna, Austria), which integrates software from open-source packages (e.g., lme4, mgcv, gamm4, multcomp, setting, and plyr) and several packages from the tidyverse (e.g., magrittr, dplyr, tidyr, and ggplot2) (Forrest et al.; Cancer Res 2020;80(22):5089-97). All raw tumor volume measurements from 0 (minimum) to 8 mm 3 (maximum) were judged to reflect complete tumor absence and set to 8 mm prior to natural logarithm transformation 3It was converted. Subsequently, a generalized additive mixed model (GAMM) was applied to describe the change in the transformed tumor volume over time using a regression spline with automatically generated spline bases. This approach addresses both repeated measurements from the same study subjects and moderate dropout before the end of the study.

[0264] Tumor growth inhibition rate (TGI) represents the percentage difference between the area under the curve (AUC) of the treatment group and the reference group after the tumor volume is inverse-transformed to the original scale, correcting for the starting tumor burden and averaging over a common period. Positive values indicate an anti-tumor effect, 100% indicates stasis, and values above 100% indicate regression (negative values indicate a tumor-promoting effect). The 95% confidence interval is based on the fitted model and variability measurements of the data using parametric bootstrapping. Growth contrast represents the difference in growth rate (endpoint Gain Integrated in Time (eGalT)) based on the area under the curve (AUC) between the fits of the treatment group and the reference group. To calculate the AUC-based growth rate, the group AUC values were corrected for the starting tumor burden and subjected to gradient-equivalent normalization. When the tumor shows log-linear growth (i.e., the fit is a line on the natural logarithm scale), gradient-equivalent normalization of the AUC results in the calculation of the gradient of the fit. When the tumor shows non-log-linear growth (i.e., the fit is curved on the natural logarithm scale), gradient-equivalent normalization results in the calculation of a constant log-linear growth rate necessary to obtain the observed baseline-corrected AUC for fitting. Mathematically, this normalization is achieved by dividing each estimated baseline-corrected AUC value by half of the square of the common study period, resulting in units of natural logarithm units per day. The vehicle control corresponds to a growth contrast (GR) value of 0. The more negative the GR value, the greater the anti-tumor effect. The 95% confidence interval is based on the fitted model and variability measurements of the data.

[0265] The growth rate of each individual tumor from the selected Day 1 AUC to its final measurement time point is calculated from the AUC of the tumor volume profile in this time range after first subjecting the tumor volume to a natural logarithm transformation. To obtain the growth rate from the AUC, the AUC is corrected to account for the tumor burden associated with this period and then subjected to gradient equivalent normalization. The baseline-corrected AUC value is divided by half of the square of the period specified in this normalization step. The default unit of this metric is natural logarithm units per day, since an exponential increase on the original scale is linear on the natural logarithm scale. Positive values indicate growth, negative values indicate regression, and 0 indicates stasis. The more positive the value, the faster the tumor is growing. The more negative the value, the faster the regression of the tumor. Growth rates based on individual AUCs are not calculated for the purpose of group comparison.

[0266] The anti-tumor effect was evaluated in Balb / c mice bearing EMT6 breast cancer after treatment with compound 1 as a single agent (60 mg / kg, PO, QD), anti-PD-L1 (10 mg / kg, IV, first dose, then 5 mg / kg, IP, twice a week), or a combination of compound 1 and anti-PD-L1. Single-agent treatment did not result in efficacy, with compound 1 resulting in 47% TGI and -0.033 GR relative to the vehicle control, and anti-PD-L1 resulting in 30% TGI and -0.022 GR. In contrast, the combination of compound 1 and anti-PD-L1 showed enhanced anti-tumor response approaching tumor stasis after 20 days of dosing, resulting in 92% TGI and -0.098 GR relative to the vehicle control. Furthermore, a sustained anti-tumor effect was observed after discontinuation of 28 days of dosing treatment using 1 / 10 PR and 5 / 10 CR (see Figures 1, 2, and 3). As determined by the rate of change in body weight, all treatments had good tolerability.

[0267]

Table 2

[0268] Tumor immune profiling. Anti-tumor immunity was evaluated in EMT6 breast tumors by flow cytometry immune profiling of tumor cells and tumor-infiltrating immune cells after 7 days of treatment with either vehicle and isotype control antibody, single-agent compound 1 (60 mg / kg, PO, QD), anti-PD-L1 antibody (10 mg / kg, IV, first dose, then 5 mg / kg, IP, twice weekly), or a combination of compound 1 and anti-PD-L1.

[0269] Tumor cells (CD45-negative cells) evaluated for MHC-I and PD-L1 expression showed a significant increase in the mean fluorescence intensity (MFI) of the expression of both MHC-I (p = 0.0354 and p = 0.0044, respectively) and PD-L1 (p = 0.0127 and p = 0.0018, respectively) in the compound 1 alone and combination with anti-PD-L1 treatment groups compared to the vehicle group (see Figure 4).

[0270] In tumors from mice treated with compound 1 alone or in combination with anti-PD-L1 antibody, the frequencies of MDSC (p = 0.0058 and p = 0.0083, respectively) and TAM (p = 0.0072 and p = 0.0098, respectively) were decreased compared to the vehicle group (Figure 5A). Furthermore, compared to the vehicle group, there were increases in the frequencies of the M1 population of macrophages (p = 0.0033 and p = 0.0162, respectively) and compensatory decreases in the M2 population of macrophages (p = 0.0036 and p = 0.0007, respectively), as well as an increase in the M1 / M2 ratio in the combination (p = 0.0033) in the tumor microenvironment of mice treated with compound 1 alone or in combination with anti-PD-L1. Myeloid-derived dendritic cells (DC) showed no changes in any treatment group. These data demonstrate that SHP2 inhibition by compound 1 reduces tumor MDSC and skews the phenotype of TAM to be more pro-inflammatory.

[0271] To determine the effect of SHP2 inhibition on T and NK cell activity, CD4 + and CD8 +Tumor-infiltrating lymphocytes (TILs) containing T cells and NK cell populations were evaluated. In the combination group of Compound 1 and anti-PD-L1, in mice treated with Compound 1 alone or in combination with an anti-PDL1 antibody, compared with the vehicle group (CD8, p = 0.0058 and p = 0.008; CD4, p = 0.0067 and p = 0.002; NK, p = 0.013 and p = 0.024 respectively), there was an increase (Figure 5B).

[0272] The activation state of TILs was evaluated by assessing the expression of cytokines and effector molecules including interferon gamma (IFNg), tumor necrosis factor alpha (TNFa), and granzyme B (GZMB) from tumor-derived T cells under restimulation conditions using PMA / ionomycin (Figure 6A). Tumor-derived CD8 from mice treated with Compound 1 alone or in combination with an anti-PD-L1 antibody + The expression of both IFNg and TNFa on tumor-derived CD8 T cells increased compared to the vehicle group (IFNg, p = 0.0002 and p = 0.0001; TNFa, p = 0.0016 and p = 0.0035 respectively) (Figure 6A), consistent with these T cells being more active. The frequency of CD8 T cells expressing GZMB in tumors from mice treated with Compound 1 and anti-PD-L1 + also increased compared to the vehicle group (p = 0.0137). (Figure 6A). Tumor-infiltrating CD8 + The multifunctionality of T cells (expressing IFNg and TNFa) increased when mice were treated with Compound 1 alone or in combination with an anti-PD-L1 antibody compared to the vehicle group (p = 0.0008 and p = 0.0011 respectively).

[0273] Markers of T cell activation and exhaustion were also evaluated to determine whether SHP2 inhibition by Compound 1 alone or in combination with an anti-PD-L1 antibody changed the phenotype of CD8 T cells within the tumor. + Tumors from mice treated with Compound 1 and an anti-PDL1 antibody expressed the activation markers Ki-67 (p = 0.0127), CD69 (p = 0.0009), and ICOS (p = 0.001) on CD8 +An increase in the total number of T cells was shown (Figure 6B). These data demonstrate that SHP2 inhibition by compound 1 alone or in combination with anti-PD-L1 results in a significant increase in NK cell as well as CD4+ and CD8+ T cell activation in EMT6 tumors.

[0274] These studies collectively demonstrate that SHP2 inhibition by compound 1 at 60 mg / kg, QD in combination with an anti-PD-L1 antibody demonstrates significant antitumor activity in the EMT6 syngeneic tumor model. In addition to the increase in antitumor activity observed during the 28-day dosing interval, there was also an increase in the number of durable responders with an ORR of 6 / 10 (60%) and a CR of 5 / 10 (50%) at the end of the study (day 102). These data demonstrate that combining the SHP2 inhibitor compound 1 with an anti-PD-L1 antibody is a well-tolerated and effective combination regimen in the EMT6 syngeneic tumor model.

[0275] These data demonstrate that combining the SHP2 inhibitor compound 1 with an anti-PD-L1 antibody promotes the antitumor immune response through pharmacodynamic changes observed in tumor cells and a tumor microenvironment that collectively promotes profound and sustained tumor inhibition in a significant number of animals compared to single-agent alone.

[0276] Example 2:

[0277] Compound 1 is a potent allosteric inhibitor of recombinant human SHP2 with an inhibitory concentration of 50% (IC50) of 0.7 nM. This has been characterized in a number of preclinical cancer models. Compound 1 has also been demonstrated to be a potent inhibitor of SHP2 in cell-based assays. SHP2 inhibition in cells was determined by measuring the level of ERK1 / 2 phosphorylation at Thr202 / Tyr204 with an IC50 value of 1.3 nM in EGFR-amplified KYSE-520 cells. A comprehensive evaluation of selectivity against a panel of kinases, receptors, ion channels and transporters demonstrated that compound 1 selectively inhibits SHP2.

[0278] The anti-proliferative effect of Compound 1 has been evaluated in multiple cancer cell lines using 2D and anchorage-independent 3D formats. Among a panel of NSCLC, esophageal squamous cell carcinoma, colorectal cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma, and other tumor cell lines tested in 2D or 3D assays, Compound 1 inhibited the growth of a number of cell lines with IC50 values of less than 1 nM. The anti-proliferative effect was seen in cell lines with various abnormalities in the RAS / MAPK signaling pathway. These in vitro results suggest that Compound 1 has the potential for broad anti-tumor effects across various tumor types.

[0279] Compound 1 has also been tested for in vivo anti-tumor activity in multiple xenograft models. Oral administration of the single agent Compound 1 showed significant anti-tumor effects in human tumor xenograft models of, for example, KRAS-mutant NSCLC (NCI-H358) and EGFR-amplified esophageal squamous cell carcinoma (KYSE-520). Dose-dependent anti-tumor activity was observed at well-tolerated dose levels. Comparisons of pharmacokinetics, pharmacodynamics, and efficacy showed that the extent and duration of SHP2 inhibition correlated directly with the level of anti-tumor activity. Overall, these in vitro and in vivo studies support the clinical evaluation of Compound 1 as an anti-tumor agent.

[0280] Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80, both of which function as inhibitory receptors expressed on T cells). Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity. Atezolizumab has minimal binding to Fc receptors and thus eliminates detectable Fc effector functions and associated antibody-mediated clearance of activated effector T cells.

[0281] Atezolizumab has shown antitumor activity in both preclinical models and cancer patients and is being investigated as a potential treatment for a wide variety of malignancies. Atezolizumab has been studied as a single agent in advanced cancer, as well as in the context of adjuvant therapy, and in combination with chemotherapy, targeted therapy, and cancer immunotherapy. Atezolizumab is approved for the treatment of locally advanced or metastatic urothelial carcinoma, NSCLC, small cell lung carcinoma, triple-negative breast cancer, melanoma, and hepatocellular carcinoma (as a single agent and / or in combination with other anticancer therapies).

[0282] Rationale for combination therapy with atezolizumab. Promising clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T cell responses against cancer can provide significant survival benefits in patients with advanced malignancies. The PD-L1 pathway functions as an immune checkpoint that transiently weakens the immune response in chronic antigen-stimulated states such as chronic infections and cancer. Interruption of the PD-L1 pathway represents one route to restore tumor-specific T cell immunity.

[0283] In preclinical pharmacodynamics (PD) and efficacy studies, the SHP2 inhibitor compound 1 (at 60 mg QD) in combination with checkpoint inhibition (anti-PD-L1) resulted in an increase in the inflammatory state of the tumor microenvironment in the EMT6 breast cancer syngeneic model, enabling effective engagement of the immune system against the tumor to result in a stronger antitumor response. (See Example 1). In tumor cells, compound 1 + anti-PD-L1 increased tumor MHC I and PD-L1 expression. Compound 1 alone or in combination with anti-PD-L1 resulted in a decrease in MDSC and TAM. Furthermore, the remaining TAM were skewed towards the pro-inflammatory M1 phenotype. Compound 1 alone and in combination with anti-PD-L1 promoted an increase in CD4 + and CD8 + T cells as well as NK cells present in the tumor. The combination of compound 1 and anti-PD-L1 resulted in an increase in the proliferative markers Ki-67 and CD69 as well as the T cell maturation marker ICOS1, in CD8 +The activation state of T cells was promoted. Compound 1 and anti-PD-L1 showed potent combination efficacy in the EMT6 tumor model, resulting in a deeper and more sustained response than either monotherapy.

[0284] High PD-L1 expression can predict the response to immune checkpoint inhibitor (CPI) therapy. Its ability to increase PD-L1 expression, antigen presentation to tumor cells, and CD8 + By promoting the infiltration and enhanced activation of CD8 T cells, SHP2 inhibition can synergize with PD-L1 blockade in tumors. Atezolizumab has demonstrated activity in patients with advanced malignancies. Objective responses have been observed across a wide range of malignancies, including, for example, lung cancer (e.g., NSCLC), urothelial cancer, RCC, melanoma (e.g., BRAF WT melanoma), colorectal cancer, head and neck cancer (e.g., HNSCC), gastric cancer, breast cancer, and sarcoma.

[0285] Patients with disease-specific malignancies responsive to anti-PD-1 / PD-L1 activity are likely to benefit from the combination therapies described herein. PD-L1-positive NSCLC and PD-L1-positive metastatic head and neck squamous cell carcinoma (HNSCC) in the first-line treatment setting are responsive to anti-PD-1 / PD-L1 agents, and single-agent anti-PD-1 / PD-L1 therapy is a recognized standard treatment regimen shown to provide benefit. Multiple treatment types are available for these diseases (chemotherapy, immunotherapy), but these patients have high unmet needs with incurable diseases.

[0286] BRAF in the context of second-line or later metastatic treatment V600Patients with wild-type (BRAF WT) melanoma are also treated. These patients have a terminal disease and there is no approved therapy after the use of anti-PD-L1 therapy, regardless of the presence or absence of anti-CTLA4 treatment. Typically, these patients may be treated with additional CPI treatment. Studies have shown a response rate range of 4% - 36%, indicating that retreatment may provide some limited benefit. The addition of Compound 1 to atezolizumab may provide additional anti-tumor activity.

[0287] Atezolizumab was generally well tolerated. Immune-mediated adverse events (including rash, endocrinopathy of influenza-like disease, hepatitis or hypertransaminasemia, interstitial pneumonia, colitis, and myasthenia gravis) that may be consistent with the immunotherapy agent were observed.

[0288] Compound 1 and atezolizumab are administered until unacceptable toxicity or loss of clinical benefit, as determined by the principal investigator after integrated assessment of radiographic data and clinical status (e.g., symptomatic worsening such as pain secondary to the disease). Treatment with Compound 1 and atezolizumab may continue beyond obvious radiographic disease progression.

[0289] In one example, treatment with the combination of Compound 1 and atezolizumab described herein consists of a 14-day run-in period followed by the treatment period described herein. During the run-in period, the patient is treated on Day 1 and Day 8 as outlined below. · Day 1: Compound 1 tablet 60 mg PO QD, followed by atezolizumab 840 mg IV · Day 8: Compound 1 capsule 60 mg PO QD

[0290] Upon completion of the 14-day run-in period, the patient enters the treatment period. Starting on Day 1 of Cycle 1, the patient is treated in 21-day cycles as outlined below. · Compound 1 capsule (assigned dose, e.g., 20 mg, 40 mg, 60 mg), PO QD on Days 1 - 21 of each cycle · 1200 mg of atezolizumab IV on the first day of each cycle

[0291] The activity of Compound 1 in combination with atezolizumab was evaluated according to RECIST v1.1 for ORR, DOR, PFS, PFS rate, and OS rate.

[0292] Selection criteria: Patients must meet the following criteria for the treatment described herein: · 18 years of age or older at the time of signing the informed consent documents · Measured disease by RECIST v1.1 · ECOG performance status 0 or 1 · Life expectancy of 12 weeks or more · Adequate hematologic and end-organ function obtained within 14 days before treatment initiation: o ANC ≧ 1.5×10 9 / L (1500 / mL) o WBC ≧ 2,500 / mL o Lymphocyte count ≧ 0.5×10 9 / L (500 / mL) o Platelet count ≧ 100×10 9 / L (100,000 / mL) o Hemoglobin ≧ 90 g / L (9 g / dL) o Serum albumin ≧ 25 g / L (2.5 g / dL) o AST, ALT, and ALP ≦ 2.5×ULN, except for the following exceptions. · Patients with documented liver metastases: AST and ALT ≦ 5×ULN · Patients with documented liver or bone metastases: ALP ≦ 5×ULN o Total bilirubin ≦ 1.5×ULN, except for the following exceptions. · Patients with known Gilbert's disease: Total bilirubin ≦ 3×ULN o Measured or calculated creatinine clearance ≧ 50 mL / min (calculated using the Cockcroft-Gault formula):

Number

[0293] Additional selection criteria for NSCLC · Histologically confirmed locally advanced or metastatic NSCLC · No prior systemic therapy for locally advanced or metastatic NSCLC (adjuvant therapy is allowed) · Availability of a representative tumor specimen suitable for determination of EGFR and ALK alterations and PD-L1 status evaluated by central laboratory or on-site laboratory testing · Absence of EGFR and ALK alterations or other known oncogenic driver mutations for which the patient can access targeted therapeutic agents · PD-L1 positive

[0294] Additional selection criteria for HNSCC Histologically confirmed recurrent or metastatic HNSCC involving the oropharynx, oral cavity, larynx, or hypopharynx that is considered not suitable for curative therapy · Known results of local human papillomavirus (HPV) status testing for oropharyngeal cancer · No prior systemic therapy for recurrent or metastatic HNSCC · Availability of representative tumor specimens suitable for determination of PD-L1 status evaluated by IHC in a central laboratory or at the site laboratory · PD-L1 positive

[0295] Additional selection criteria for melanoma · Histologically confirmed locally advanced or metastatic (recurrent or de novo stage IV) or unresectable locally advanced (stage III) cutaneous BRAF WT melanoma that progressed during or after treatment with anti-PD-1 therapy or anti-PD-L1 therapy as defined by the 8th edition of the American Joint Committee on Cancer (AJCC) (demonstrated by a local efficacy trial in a CLIA (Clinical Laboratory Improvement Amendments)- or equivalently accredited laboratory) · The patient must have progressive disease at the time of study enrollment.

[0296] Exclusion criteria: Patients who meet any of the following criteria are excluded: · Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. · Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met: o Measurable disease by RECIST v1.1 must be present outside the CNS. o The patient has no history of intracranial or spinal cord hemorrhage. o The patient has not received stereotactic radiotherapy within 7 days prior to treatment, whole-brain radiotherapy within 14 days prior to treatment, or neurosurgical resection within 28 days prior to treatment There is no ongoing need for corticosteroids as a treatment for oCNS disease. oIf the patient is receiving antispasmodic therapy, the dose is considered stable. oMetastases are limited to the cerebellum or supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord). oThere is no evidence of intermediate progression between the completion of oCNS-directed treatment and the initiation of the investigational treatment. · Leptomeningeal disease or carcinomatous meningitis · History or findings of ophthalmic diseases including retinal vein occlusion (RVO), central serous retinopathy (CSR), predisposition to RVO or CSR, or retinopathy in screening ophthalmic examinations · Uncontrolled hypertension · Left ventricular ejection fraction below the lower limit within normal facilities or less than 50% · History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins · Known hypersensitivity to Chinese hamster ovary cell products or any component of the atezolizumab formulation · Known allergy or hypersensitivity to any component of the Compound 1 formulation · Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage treatment (once a month or more frequently) · History of clinically significant liver disease including viral or other hepatitis, current alcohol abuse, or cirrhosis · Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol / L, calcium > 12 mg / dL, or corrected calcium > ULN) · Active or history of autoimmune diseases or immunodeficiencies including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, provided that the following are excluded: oPatients with a history of autoimmune-related hypothyroidism taking thyroid replacement hormone are eligible for the study. Patients with controlled type 1 diabetes who are on an insulin regimen are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with only skin symptoms (e.g., patients with psoriatic arthritis are excluded) are eligible for the study if all of the following criteria are met: · The body surface area covered by the rash must be less than 10%. · The disease is well-controlled at baseline and requires only low-potency topical corticosteroids. · There has been no acute exacerbation of the underlying condition requiring psoralen + ultraviolet A irradiation, methotrexate, retinoids, biological agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the past 12 months. · A history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced interstitial pneumonia, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on screening chest computed tomography (CT) scan · A history of radiation-induced interstitial pneumonia (fibrosis) in the radiation field is acceptable. · Active tuberculosis · Major surgical procedures within 4 weeks prior to treatment other than for diagnosis · Prior allogeneic stem cell or solid organ transplantation · Current treatment with antiviral therapy for HBV · Treatment with the investigational drug as chemotherapy, immunotherapy, biological therapy, or anti-cancer therapy with a short half-life of either 3 weeks or 5 drug elimination half-lives prior to treatment; or endocrine therapy within 2 weeks prior to treatment, except for hormonal therapy with gonadotropin-releasing hormone agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer). · Treatment with a strong CYP3A4 inhibitor or a strong CYP3A4 inducer within 14 days prior to treatment or within the longer of 5 drug elimination half-lives. · Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to the start of the investigational drug. · History of malignancy within 5 years prior to screening, excluding malignancies where the cancer under investigation in this study and the risk of metastasis or death are negligible (e.g., 5-year OS rate > 90%), such as appropriately treated cervical intraepithelial neoplasia, non-melanoma skin cancer, localized prostate cancer, intraductal carcinoma in situ, or stage I uterine cancer · History or presence of abnormal ECG · Treatment with live attenuated vaccines within 4 weeks prior to treatment · QTcF > 440 ms, corrected using the Fridericia formula, demonstrated by at least two ECGs taken more than 30 minutes apart · History of ventricular arrhythmia or risk factors for ventricular arrhythmia such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (with ischemia demonstrated by symptoms or diagnostic tests), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or QT prolongation syndrome · Current treatment with medications known to prolong the QT interval · H within 14 days prior to the start of the study drug 2 Treatment with H blockers or antacids or the longer of 5 drug elimination half-lives · Treatment with mild or moderate CYP3A4 inhibitors or mild or moderate CYP3A4 inducers (see section 4.4.2.4 for details) within 14 days prior to treatment or the longer of 5 drug elimination half-lives · Treatment with any herbal therapy within 14 days prior to treatment or the longer of 5 drug elimination half-lives

[0297] Patients with a history of immunodeficiency or autoimmune diseases listed in the following table are excluded from participating in the study. Possible exceptions to this exclusion may be patients with a low clinical suspicion of autoimmune disease, a history of an entity such as atopic disease or juvenile arthralgia. Patients with a history of autoimmune-related hypothyroidism receiving a stable dose of thyroid replacement hormone may be eligible for this study. Furthermore, transient autoimmune symptoms of acute infectious diseases that resolve during treatment of the infectious agent are not excluded (e.g., acute Lyme arthritis).

Table 5

[0298] Study treatment formulation, packaging and handling. Compound 1 is supplied as capsules (10 mg and 25 mg) and tablets (20 mg). Compound 1 is administered orally in the form of capsules or tablets. During the treatment period, Compound 1 must be taken daily at approximately the same time on days 1 to 21 of each 21-day cycle. Capsules or tablets must be swallowed whole and must not be chewed, crushed or opened. A missed dose may be administered up to 4 hours after the scheduled dosing time. If a dose of Compound 1 is missed (i.e., not taken within 4 hours of the scheduled dosing time), or if vomiting occurs when that dose is taken, dosing must be resumed with the next scheduled dose.

[0299] Unless otherwise instructed, Compound 1 must be taken with approximately 240 mL of water in a fasting state (1 hour before or 2 hours after a meal or snack). Patients self-administer on an outpatient basis. Patients receive Compound 1 until unacceptable toxicity or loss of clinical benefit determined by the principal investigator after integrated assessment of radiographic data and clinical status (see Section 3.1.3 for details).

[0300] Atezolizumab is supplied as an IV formulation in 1200 mg / 20 mL vials. Atezolizumab is administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle following administration of Compound 1. The initiation of atezolizumab administration must be approximately 30 minutes after oral administration of Compound 1. Administration of atezolizumab is performed in a monitored setting with trained personnel and immediate access to appropriate equipment and medications for managing potentially serious reactions. Atezolizumab infusions are administered according to the instructions outlined in this specification. Dose modifications of atezolizumab are not permitted.

[0301] Patients described herein participate in the 14-day acclimation period described herein, and such patients receive atezolizumab administered by IV infusion at a fixed dose of 840 mg on Day 1 of the acclimation period. During the treatment periods of the dose-setting phase and the dose-escalation phase, all patients receive atezolizumab administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit.

[0302] Atezolizumab is administered after administration of Compound 1. Atezolizumab infusion must be initiated 30 minutes after administration of Compound 1.

[0303] Administration of atezolizumab is performed in a monitored setting with trained personnel and immediate access to appropriate equipment and medications for managing potentially serious reactions. Atezolizumab infusions are administered according to the instructions outlined in Table 3.

[0304] Administration of the first and subsequent atezolizumab infusions

Table 6

[0305] Permitted Treatments. Patients are permitted to use the following therapies during the study. · Oral contraceptives · Hormone replacement therapy · Preventive or therapeutic anticoagulant therapy (stable doses of warfarin or low molecular weight heparin, etc.) · However, vaccination with live attenuated vaccines is not permitted · Megestrol acetate · Mineralocorticoids (e.g., fludrocortisone) · Inhaled or low-dose corticosteroids · Low-dose corticosteroids · Palliative radiotherapy as outlined below (e.g., treatment of known bone metastases or symptomatic relief of pain): · Premedication with antihistamines, antipyretics, and / or analgesics may be administered at the discretion of the treating investigator only for subsequent infusions of atezolizumab

[0306] Patients experiencing infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and / or H 2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation, or tachypnea must be managed with clinically appropriate supportive therapy (e.g., oxygen supplementation and b 2 adrenergic agonists).

[0307] Caution is required for treatments. Systemic corticosteroids, immunosuppressive drugs, and TNF-a inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids, immunosuppressive drugs, or TNF-a inhibitors are administered routinely, alternatives including antihistamines should be considered

[0308] Prohibited treatments. The use of the following combination therapies is prohibited as described below: · Investigational treatments (other than the study treatments defined in the study protocol) are prohibited within 3 weeks prior to treatment or within 5 drug elimination half-lives Combination therapies for the treatment of cancer (including, but not limited to, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy), whether approved by health authorities or experimental, are prohibited before and during treatment. · Live vaccines, attenuated vaccines · Systemic immune stimulants (including, but not limited to, interferon and IL-2) · Proton pump inhibitors · Cannabidiol products · Potent CYP3A4 inhibitors or potent CYP3A4 inducers

[0309] For all patients during the titration period, the use of the following combination therapies is prohibited within the longer of 14 days before the titration period or 5 drug elimination half-lives. · H 2 blockers and antacids · Mild or moderate CYP3A4 inhibitors or mild or moderate CYP3A4 inducers · All herbal therapies

[0310] Risks associated with Compound 1. Administration of Compound 1 is associated with reversible and monitorable events including: peripheral edema, myelosuppression (e.g., thrombocytopenia, anemia), gastrointestinal toxicity (e.g., diarrhea, nausea and vomiting), elevated liver transaminases, and rash.

[0311] Risks associated with MAPK pathway class inhibitors. Administration of MAPK pathway inhibitors is associated with cardiomyopathy, retinopathy, cardiomyopathy, increased CPK, thromboembolic events, phototoxicity, and reproductive toxicity. Non-clinical safety studies with Compound 1 did not show evidence of cardiac, pulmonary, renal, thromboembolic, or ocular toxicity.

[0312] Risks associated with atezolizumab. Atezolizumab is associated with the following risks: infusion-related reactions (IRR) and immune-mediated hepatitis, interstitial pneumonia, colitis, pancreatitis, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis and myositis. Immune-mediated reactions may involve any organ system and can lead to hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).

[0313] Adverse events. As defined herein, adverse events refer to any untoward medical event in a clinical trial subject administered the agents described herein in combination therapy dh, regardless of the attribute of the cause. The terms "severe" and "serious" are not synonyms. Severity refers to the intensity of the adverse event (e.g., as evaluated as mild, moderate, or severe or by NCI CTCAE; see Section 5.3.3), and the event itself may have relatively minor medical significance (e.g., severe headache with no further findings).

[0314] Adverse events to be monitored include peripheral edema, diarrhea, dyspnea, hepatitis or elevated ALT or AST, interstitial pneumonia, any thromboembolic event, systemic lupus erythematosus, events suggesting hypersensitivity (e.g., IRR, CRS, HLH, and MAS), nephritis, ocular toxicity (e.g., uveitis, retinitis, optic neuritis), cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis), vasculitis, autoimmune hemolytic anemia and severe skin reactions (e.g., Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal necrolysis).

[0315] Throughout this specification and the claims, the words "comprise / comprises, and comprising" are used in a non-limiting sense, except where the context requires otherwise. Embodiments described herein are to be understood to include embodiments "consisting of" and / or "consisting essentially of".

[0316] When a range of values is provided, unless a different indication is clear from the context, each intervening value between the upper and lower limits of the range and any other stated value or intervening value within the stated range to one tenth of the unit of the lower limit is to be understood as being included in this specification. The upper and lower limits of these smaller ranges, which can be included independently in smaller ranges, are also included in this specification, subject to the specifically excluded limit values in the stated range. When one or both of the limit values are included in the stated range, ranges excluding either or both of those included limit values are also included in this specification.

[0317] Many modifications and other embodiments of the inventions described herein will come to mind to those skilled in the art to which these inventions pertain, having the benefit of the teachings presented in the foregoing description and the related drawings. Accordingly, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed, and that changes and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. (a) Compound 1 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, (b) PD-L1 binding antagonist, A combination that includes this.

2. The combination according to claim 1, wherein the PD-L1-binding antagonist is an anti-PD-L1 antibody.

3. The combination according to claim 1 or 2, wherein the anti-PD-L1 antibody is atezolizumab.

4. The combination according to claim 3, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of a first 21-day cycle, and atezolizumab is administered on day 1 of the first 21-day cycle.

5. The combination according to claim 3, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered via BID on days 1 to 21 of a first 21-day cycle, and atezolizumab is administered on day 1 of the first 21-day cycle.

6. The combination according to claim 1 or 2, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

7. The combination according to claim 1 or 2, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 100 mg.

8. The combination according to claim 1 or 2, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg.

9. The combination according to claim 3, characterized in that atezolizumab is administered in an amount of approximately 800 mg to approximately 1400 mg over Q3W.

10. The combination according to claim 3, characterized in that atezolizumab is administered in an amount of approximately 1200 mg on day 1 of each cycle.

11. The combination according to claim 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered before the commencement of the first 21-day cycle, followed by the administration of atezolizumab in an amount of 840 mg.

12. The combination according to claim 1 or 2, characterized in that the combination is administered to a patient who has lung cancer, head and neck cancer, or melanoma.

13. The combination according to claim 12, wherein the patient is PD-L1 positive.

14. The combination according to claim 12, wherein the patient is PD-L1-high.

15. The combination according to claim 12, wherein the patient is PD-L1-low.

16. The combination according to claim 13, wherein the PD-L1 positivity is determined by a PD-L1 immunohistochemistry (IHC) assay.

17. The combination according to claim 12, wherein the patient has non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), or BRAF WT melanoma.

18. For use in methods of treating lung cancer, head and neck cancer, or melanoma in patients requiring treatment for lung cancer, head and neck cancer, or melanoma, (a) Compound 1 【Transformation 5】 or a pharmaceutically acceptable salt thereof, (b) PD-L1 binding antagonist, A combination comprising the above, characterized in that the combination is administered during a treatment period.

19. The combination according to claim 18, wherein the PD-L1-binding antagonist is an anti-PD-L1 antibody.

20. The combination according to claim 18, wherein the anti-PD-L1 antibody is atezolizumab.

21. The aforementioned treatment period is, (a) administering compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, (b) Administering atezolizumab on day 1 of the first 21-day cycle, The combination according to claim 20, including the following:

22. The aforementioned treatment period is, (a) administering compound 1 or a pharmaceutically acceptable salt thereof as a BID on days 1 to 21 of the first 21-day cycle, (b) Administering atezolizumab on day 1 of the first 21-day cycle, The combination according to claim 20, including the following:

23. The combination according to any one of claims 18 to 22, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

24. The combination according to any one of claims 18 to 22, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 100 mg.

25. The combination according to any one of claims 18 to 22, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg.

26. The combination according to any one of claims 20 to 22, characterized in that atezolizumab is administered in an amount of approximately 800 mg to approximately 1400 mg over Q3W.

27. The combination according to any one of claims 20 to 22, characterized in that atezolizumab is administered in an amount of approximately 1200 mg on day 1 of each cycle.

28. The combination according to any one of claims 20 to 22, wherein the method further comprises a acclimatization period including administering compound 1 or a pharmaceutically acceptable salt thereof before the start of a first cycle, followed by the administration of atezolizumab in an amount of 840 mg.

29. The combination according to claim 28, wherein the break-in period includes 1 to 14 days.

30. The combination according to claim 28, wherein the acclimatization period is 14 days, and compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered on the first day of the acclimatization period.

31. The combination according to claim 28, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered via QD starting from the 8th day of the acclimatization period.

32. The combination according to any one of claims 18 to 22, wherein the patient is PD-L1 positive.

33. The combination according to any one of claims 18 to 22, wherein the patient is PD-L1-high.

34. The combination according to any one of claims 18 to 22, wherein the patient is PD-L1-low.

35. The combination according to any one of claims 18 to 22, wherein the PD-L1 positivity is determined by a PD-L1 immunohistochemistry (IHC) assay.

36. The combination according to any one of claims 18 to 22, wherein the lung cancer is non-small cell lung cancer (NSCLC).

37. The combination according to any one of claims 18 to 22, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

38. The combination according to any one of claims 18 to 22, wherein the melanoma is a BRAF WT melanoma.

39. A combination comprising compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 conjugated antagonist for use in methods of treating lung cancer, head and neck cancer, or melanoma in patients requiring treatment for lung cancer, head and neck cancer, or melanoma.

40. The combination according to claim 39, wherein the PD-L1-binding antagonist is an anti-PD-L1 antibody.

41. The combination according to claim 39 or 40, wherein the anti-PD-L1 antibody is atezolizumab.

42. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in doses of approximately 5 mg to 100 mg on days 1 to 21 of the first 21-day cycle. (b) Atezolizumab is administered in a dose of 1200 mg on day 1 of the first 21-day cycle, The combination described in claim 41.

43. The combination according to claim 39 or 40, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg.

44. The combination according to claim 39 or 40, wherein the lung cancer is non-small cell lung cancer (NSCLC).

45. The combination according to claim 39 or 40, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

46. The combination according to claim 39 or 40, wherein the melanoma is a BRAFT WT melanoma.

47. The combination is (a) Compound 1 or a pharmaceutically acceptable salt thereof at QD on days 1 to 21 of the first 21-day cycle, and (b) Atezolizumab on day 1 of the first 21-day cycle The combination according to claim 39, characterized in that it is administered in combination with the other.

48. The combination is (a) Approximately 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof at QD on days 1 to 21 of the first 21-day cycle, and (b) Approximately 1200 mg of atezolizumab on day 1 of the first 21-day cycle. The combination according to claim 39 or 47, characterized in that it is administered in combination with the other.

49. Use of a combination comprising compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for the manufacture of a pharmaceutical product for treating lung cancer, head and neck cancer, or melanoma.

50. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of the first 21-day cycle. (b) The use according to claim 49, characterized in that atezolizumab is administered Q3W on day 1 of the first 21-day cycle.

51. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of the first 21-day cycle. (b) The use according to claim 49 or 50, characterized in that atezolizumab is administered on day 1 of the first 21-day cycle.

52. (a) Compound 1 or a pharmaceutically acceptable salt of approximately 50 mg to 500 mg is administered as a QD on days 1 to 21 of the first 21-day cycle. (b) The use according to claim 49 or 50, characterized in that approximately 1200 mg of atezolizumab is administered on day 1 of the first 21-day cycle.

53. The use according to claim 49 or 50, wherein the drug regimen comprises two or more cycles.

54. The use according to claim 49 or 50, characterized in that compound 1 is administered in an amount of approximately 5 mg to 100 mg.

55. The use according to claim 49 or 50, characterized in that compound 1 is administered in an amount of approximately 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg.

56. The use according to claim 49 or 50, wherein the lung cancer is non-small cell lung cancer (NSCLC).

57. The use according to claim 49 or 50, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

58. The use according to claim 49 or 50, wherein the melanoma is a BRAFT WT melanoma.

59. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of the first 21-day cycle. (b) Atezolizumab is administered Q3W on day 1 of the first 21-day cycle, The combination described in claim 39.

60. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of the first 21-day cycle. (b) characterized in that atezolizumab is administered on day 1 of the first 21-day cycle, The combination according to claim 39 or 59.

61. (a) Compound 1 or a pharmaceutically acceptable salt of approximately 50 mg to 500 mg is administered as a QD on days 1 to 21 of the first 21-day cycle. (b) A characteristic feature is that approximately 1200 mg of atezolizumab is administered on day 1 of the first 21-day cycle. The combination according to claim 39 or 59.

62. The combination according to claim 39 or 59, wherein the drug regimen comprises two or more cycles.

63. The combination according to claim 39 or 59, characterized in that compound 1 is administered in an amount of approximately 5 mg to 100 mg.

64. (a) Compound 1 【Transformation 6】 A composition comprising (b) a pharmaceutically acceptable salt thereof, wherein the composition is administered in combination with a PD-L1 conjugating antagonist.

65. (a) A composition comprising a PD-L1 binding antagonist, wherein the composition comprises (b) compound 1 【Transformation 7】 A composition characterized by being administered in combination with a pharmaceutically acceptable salt thereof.

66. A method for treating lung cancer, head and neck cancer, or melanoma in patients requiring treatment for lung cancer, head and neck cancer, or melanoma, comprising: (a) Compound 1 【Transformation 8】 A composition comprising a pharmaceutically acceptable salt thereof, wherein the composition is administered in combination with (b) a PD-L1 conjugating antagonist during the treatment period.

67. A composition for treating lung cancer, head and neck cancer, or melanoma in a patient requiring treatment for lung cancer, head and neck cancer, or melanoma, comprising (a) a PD-L1 conjugating antagonist, wherein during the treatment period, (b) compound 1 【Chemistry 9】 A composition characterized by being administered in combination with a pharmaceutically acceptable salt thereof.

68. A composition comprising compound 1 or a pharmaceutically acceptable salt thereof for treating lung cancer, head and neck cancer, or melanoma in a patient requiring treatment for lung cancer, head and neck cancer, or melanoma, characterized in that the composition is administered in combination with a PD-L1 conjugating antagonist.

69. A composition comprising a PD-L1 conjugating antagonist for treating lung cancer, head and neck cancer, or melanoma in patients requiring treatment for lung cancer, head and neck cancer, or melanoma, characterized in that the composition is administered in combination with compound 1 or a pharmaceutically acceptable salt thereof.

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