Methods and compositions comprising a SHP2 inhibitor and a PD-l1 binding antagonist

Abstract

Provided herein are combination therapies comprising an SHP2 inhibitor (e.g., Compound 1) and a PD-L1 binding antagonist (e.g., acterizumab), and methods of using such combination therapies.

Description

Technical Field

[0001] Provided herein are combination therapies comprising a 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

[0003] This application incorporates by reference a computer readable form (CRF) of a sequence listing in ASCII text format submitted via EFS-Web. The sequence listing text file submitted via EFS-Web, named P37266_SEQ_LISTING_ST26.txt, has a file size of 18 kilobytes and was created on April 25, 2023. Background Art

[0004] Protein tyrosine phosphorylation plays a central role in the pathogenesis of cancer. SSHP2 (protein tyrosine phosphatase-2 containing Src homology 2 domain) is a protein tyrosine phosphatase encoded by the PTPN11 gene; it serves as a central node of multiple intracellular oncogenic signaling pathways such as RAS / Raf / MAPK, PI3K / AKT, Jak / STAT and PD-1 / PDL-1 pathways (J Med Chem. 2020; 63: 11368-11396). SHP2 gain-of-function mutations and / or overexpression are associated with genetic developmental diseases (such as Noonan syndrome) and various types of cancer (such as breast cancer, melanoma, non-small cell lung adenocarcinoma (NSCL) and other cancers) (Eur J Med Genet. 2015; 58 (10): 509-25; Pharmacol Res. 2020; 152: 104595-104605). Under basal conditions, SHP2 exists in an autoinhibited conformation, in which the catalytic activity of SHP2 is suppressed. Somatic missense mutations in SHP2, which have been detected in leukemias and, to a lesser extent, in solid tumors, destabilize the autoinhibited conformation of SHP2, leading to aberrant overactivation.

[0005] Therefore, there is a need for effective therapies and combination therapies to treat cancers such as lung cancer, head and neck cancer, and other solid tumors. Summary of the invention

[0006] Provided herein are solutions to these and other problems in the art.

[0007] In one aspect, provided herein is a combination therapy comprising (a) Compound 1 or a pharmaceutically acceptable salt thereof as described herein and (b) a PD-L1 binding antagonist as described herein.

[0008] On the other hand, provided herein is a method for treating lung cancer, head and neck cancer, or melanoma in a patient in need thereof, the method comprising administering an effective amount of a combination therapy during a treatment period, the combination therapy comprising (a) Compound 1 or a pharmaceutically acceptable salt thereof and (b) a PD-L1 binding antagonist, as described herein. In one embodiment, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, melanoma is BRAF wild-type (WT) melanoma.

[0009] On the other hand, provided herein is a method for treating lung cancer, head and neck cancer, or 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, as described herein. In one embodiment, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, melanoma is BRAF wild-type (WT) melanoma.

[0010] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof as described herein and atezolizumab for the treatment of lung cancer, head and neck cancer, or melanoma as described herein (U1). In one embodiment, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, melanoma is BRAF wild-type (WT) melanoma.

[0011] In yet another aspect, provided herein is a combination therapy comprising Compound 1 as described herein or a pharmaceutically acceptable salt thereof and atezolizumab for the manufacture of a medicament (U5) for the treatment of lung cancer, head and neck cancer, or melanoma. In one embodiment, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, melanoma is BRAF wild-type (WT) melanoma.

[0012] In yet another aspect, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof as described herein and atezolizumab is provided herein for the treatment of lung cancer, head and neck cancer, or melanoma. In one embodiment, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, melanoma is BRAF wild-type (WT) melanoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] To facilitate identification of the discussion of any particular element or act, the most significant digit(s) in a reference number refers to the figure number in which the element is first introduced.

[0014] Figure 1 The effects of compound 1 and anti-PD-L1 combination therapy on individual tumor volumes of EMT6 mammary carcinoma in BALB / c mice are illustrated.

[0015] Figure 2 Comparative analysis of compound 1 and anti-PD-L1 combination therapy on the growth of EMT6 breast cancer in BALB / c mice is illustrated.

[0016] Figure 3 AUC-based growth of individual tumors of EMT6 breast cancer in BALB / c mice is illustrated for Compound 1 and anti-PD-L1 combination therapy.

[0017] Figure 4 A illustrates the volume and MHC-I expression of individual EMT6 tumors after seven days of treatment.

[0018] Figure 4 B illustrates that after seven days of treatment, compound 1 + / - anti-PD-L1 group treatment increased the MFI of MHC-I and PD-L1 in tumors relative to the vehicle group (MHC-I (p=0.0354, p=0.0044) PD-L1 (p=0.0127, p=0.0018)).

[0019] Figure 5 A illustrates that the TAM population in the tumor microenvironment was reduced in the compound 1 + / - anti-PD-L1 group compared to the vehicle group (P = 0.0072, P = 0.0098). MDSCs were reduced in the tumor microenvironment of mice treated with compound 1 + / - anti-PD-L1 group relative to the vehicle group (p = 0.0058, p = 0.0083).

[0020] Figure 5 B illustrates that the frequency of CD8 T cell population increased in the tumor microenvironment of mice treated with Compound 1 + / - anti-PD-L1 group compared to the vehicle group (P=0.0058, p=0.008). The frequency of CD4 T cell population and NK cells increased in the tumor microenvironment of mice treated with Compound 1 + / - anti-PD-L1 compared to the vehicle group (CD4 (p=0.0067, p=0.002) and NK (p=0.013, p=0.024)).

[0021] Figure 6A illustrates that the frequency of CD8 populations expressing IFNg or TNFa increased in the compound 1 + / - anti-PD-L1 group compared to the vehicle group (IFNg (p = 0.0002, p = 0.0001), TNFa (p = 0.0016, p = 0.0035)). Relative to the vehicle, the frequency of CD8 expressing GZMB increased in mice treated with the compound 1 + anti-PD-L1 group (p = 0.0137). Compared with the vehicle group, the multifunctionality (co-expression of IFNg and TNFa) of the CD8 population was observed in the compound 1 + / - anti-PD-L1 group (P = 0.0008, P = 0.0011).

[0022] Figure 6 B illustrates that mice treated with Compound 1 + anti-PD-L1 increased the total number of CD8 T cell populations expressing activation markers (KI-67 ((p=0.0127), CD69 (p=0.0009), ICOS (p=0.001)) compared to the vehicle group. DETAILED DESCRIPTION

[0023] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. See, for example: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Methods, devices and materials similar or equivalent to any method, device and material described herein can be used in the practice of the present invention.

[0024] The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present disclosure.All references cited herein are incorporated by reference in their entirety.

[0025] As used herein and unless otherwise specified, when the terms "about" and "approximately" refer to a dose, amount or weight percentage of an ingredient of a composition or dosage form, it means a dose, amount or weight percentage known to those of ordinary skill in the art that provides a pharmacological effect equivalent to that obtained from the specified dose, amount or weight percentage. The equivalent dose, amount or weight percentage may be within the range of 30%, 20%, 15%, 10%, 5%, 1% or less of the specified dose, amount or weight percentage.

[0026] "Compound 1" refers to a compound having the following structure:

[0027]

[0028] A compound having the chemical name (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine.

[0029] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals such as, for example, humans, as appropriate.

[0030] The compounds of the present invention can be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts formed with inorganic acids and organic acids, which retain the biological effectiveness and properties of free alkalis and are not unexpected biologically or otherwise, and the inorganic acids are such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and the organic acids can be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic acid and sulfonic acid 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, dihydronaphthoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0031] The term "pharmaceutical base addition salts" includes those derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Specific base addition salts are ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary amines and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, 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.

[0032] 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, saccharin, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), naphthalene disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanesulfonate (ethane-1,2-disulfonate). sulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothiocyanate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, oxalate, malonate, toluenesulfonate (2-m-benzenesulfonate), naphthalenesulfonate (2-naphthalenesulfonate), camphorsulfonate (camphor-10-sulfonate, for example, (1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzamido)acetate), orotate, ditoluate (p-xylene-2-sulfonate) and pamoate (2,2'-dihydroxy-1,1'-dinaphthomethane-3,3'-dicarboxylate).

[0033] The terms "inhibit" and "reduce", or any variation of these terms, include any measurable reduction or complete inhibition to achieve the desired result. For example, the activity can be reduced by 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 any range derivable therein, compared to normal.

[0034] The terms "PD-L1 binding antagonist", "PD-L1 inhibitor" and "PD-L1 blocking antibody" are used interchangeably herein and refer to molecules that reduce, block, inhibit, eliminate or interfere with signal transduction generated by the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and / or B7-1). In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that reduce, block, inhibit, eliminate or interfere with signal transduction generated by the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and / or B7-1). In one instance, the PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by signaling through PD-L1 mediated by or through cell surface proteins expressed on T lymphocytes, thereby rendering the dysfunctional T cells less dysfunctional (e.g., improving the response of effectors to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1. In some instances, the 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, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, 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 aspect, the PD-L1 binding antagonist is atezolizumab.

[0035] The terms "programmed death ligand 1" and "PD-L1" refer to native sequence human PD-L1 polypeptides herein. Native sequence PD-L1 polypeptides are provided under Uniprot Accession No. Q9NZQ7. For example, native sequence PD-L1 may have an amino acid sequence as described in Uniprot Accession No. Q9NZQ7-1 (isoform 1). In another example, native sequence PD-L1 may have an amino acid sequence as described in Uniprot Accession No. Q9NZQ7-2 (isoform 2). In yet another example, native sequence PD-L1 may have an amino acid sequence as described in Uniprot Accession No. Q9NZQ7-3 (isoform 3). PD-L1 is also referred to in the art as "programmed cell death 1 ligand 1", "PDCD1LG1", "CD274", "B7-H" and "PDL1".

[0036] When referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain), the Kabat numbering system is generally used (e.g., Kabat et al., Sequences of Immunological Interest. 5th ed., U.S. Department of Health and Human Services, National Institutes of Health, Bethesda, Maryland (1991)). When referring to residues in the constant region of the immunoglobulin heavy chain, the "EU numbering system" or "EU index" is generally used (e.g., the EU index reported by Kabat et al., supra). The "EU index as described by Kabat" refers to the residue numbering of the human IgG1 EU antibody.

[0037] For the purposes of this article, "atezolizumab" is an Fc-engineered, humanized, aglycosylated IgG1κ 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 comprises a single amino acid substitution (asparagine to alanine) (N297A) at position 297 on the heavy chain, using EU numbering of amino acid residues in the Fc region, which results in an aglycosylated antibody with minimal binding to Fc receptors. Atezolizumab is also described in the following literature: WHO Drug Information (International Nonproprietary Names of Medicinal Substances), Proposed INN: List 112, Volume 28, Issue 4, published on January 16, 2015 (see page 485).

[0038] In some instances, 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 comprising 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 comprising the sequence of SEQ ID NO: 2; or (c) a VH as described in (a) and a VL as described in (b).

[0039] In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:

[0040] (a) the following heavy chain (VH) amino acid sequence:

[0041] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGT LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:1), and

[0042] (b) the following light chain (VL) amino acid sequence:

[0043] DIQMTQSPSSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:2).

[0044] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one instance, the cancer is lung cancer. In another instance, the cancer is non-small cell lung cancer (NSCLC). In one instance, the cancer is head and neck cancer. In another instance, the cancer is head and neck squamous cell carcinoma (HNSCC). In one instance, the cancer is melanoma. In another instance, the cancer is BRAF wild type (WT) melanoma.

[0045] As used herein, "treatment" 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). Treatment can be first-line treatment (e.g., the patient may not have been previously treated or has not received prior systemic therapy), or second-line or subsequent treatment. For example, if one or more symptoms associated with a cancer described herein are alleviated or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating symptoms caused by the disease, improving the quality of life of patients suffering from the disease, reducing the dose of other drugs required to treat the disease, and / or prolonging the patient's survival, the patient is successfully "treated".

[0046] The term "delaying progression" of a disease means postponing, hindering, slowing, slowing, stabilizing and / or slowing the progression of a cancer as described herein. Such a delay may be of varying lengths of time, depending on the history of the cancer as described herein and / or the patient being treated. It will be apparent to one skilled in the art that a substantial or significant delay may actually encompass prevention, in that the patient will not develop the cancer.

[0047] Herein, "effective amount" refers to the amount of therapeutic agents described herein (e.g., atezolizumab and / or compound 1) to achieve a therapeutic effect. In some instances, the effective amount of a therapeutic agent or combination of therapeutic agents is the amount of an agent or combination of agents that reaches a clinical endpoint provided herein. The effective amount herein may vary according to factors such as the patient's disease state, age, sex, and weight, and the ability of the agent to cause an expected response in the patient. The effective amount is also the amount in which the beneficial effects of the treatment exceed any toxic or deleterious effects of the treatment. In some embodiments, an effective amount of a drug may have the following effects: reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down or stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down or stop) tumor metastasis; inhibit (i.e., slow down or stop) tumor growth; and / or alleviate one or more of the symptoms associated with the disease. The effective amount may be administered once or multiple times. The effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein may be an amount sufficient to treat directly or indirectly.

[0048] “Objective response rate” or “ORR” is the percentage of patients who have a confirmed complete response or partial response as determined by the investigator according to RECIST v1.1 within two consecutive 3- to 4-week periods.

[0049] “Duration of response” or “DOR” is the time from the first documented objective response to disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.

[0050] “Progression-free survival” or “PFS” is the time from enrollment to the date of the first documented disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.

[0051] As used herein, "complete response" and "CR" refer to the disappearance of all target lesions and, if applicable, normalization of tumor marker levels.

[0052] As used herein, "partial response" and "PR" refer to the persistence of one or more non-target lesions and / or (if applicable) the maintenance of tumor marker levels above normal limits. PR may also refer to a 30% decrease in the sum of the diameters of target lesions, the appearance of new lesions in the absence of CR, and clear progression of non-target lesions.

[0053] "Administration period" or "cycle" refers to a time period including the administration of one or more agents described herein (e.g., Compound 1 and Atezolizumab) and an optional time period not including the administration of one or more agents described herein. For example, a cycle can be 21 days in total and includes the administration of one or more agents described herein (e.g., Compound 1 and Atezolizumab) on each day of the cycle. In another example, the length of the cycle can be 28 days in total and includes the administration of one or more agents described herein (e.g., Compound 1 and Atezolizumab) for 21 days and a seven-day rest period. "Rest period" refers to a time period in which at least one of the agents described herein (e.g., Compound 1 and Atezolizumab) is not administered. In one embodiment, the rest period refers to a time period in which any agent described herein (i.e., Compound 1 and Atezolizumab) is not administered. In some cases, the rest period provided herein may include the administration of another agent that is not Compound 1 or Atezolizumab. In such cases, the administration of another agent during the rest period should not interfere with or impair the administration of the agent described herein. In one case, the cycle used herein refers to a 21-day cycle without a rest period.

[0054] A "dosing regimen" refers to a period of administration of an agent described herein that comprises one or more cycles, wherein each cycle may include administration of an agent described herein at a different time or in a different amount.

[0055] "QD" refers to once daily administration of an agent described herein.

[0056] "BID" refers to administration of an agent described herein twice daily.

[0057] "Q3W" refers to administration of an agent described herein once every three weeks.

[0058] "PO" refers to oral administration of an agent described herein.

[0059] "IV" refers to intravenous administration of any agent described herein.

[0060] Graded adverse events refer to severity grading levels determined by NCI CTCAE. In one embodiment, adverse events are graded according to the following table.

[0061]

[0062] The term "patient" refers to a human patient. The patient can be an adult.

[0063] The term "antibody" herein specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies) and antibody fragments, as long as they exhibit the desired biological activity. In one instance, the antibody is a full-length monoclonal antibody.

[0064] As used herein, the term IgG "isotype" or "subclass" refers to any subclass of immunoglobulins defined by the chemical and antigenic characteristics of the immunoglobulin constant region.

[0065] According to the amino acid sequence of its heavy chain constant domain, antibodies (immunoglobulins) can be divided into different categories.Immunoglobulins are mainly divided into five categories: IgA, IgD, IgE, IgG and IgM, and some of them can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.The heavy chain constant domains corresponding to different classes of immunoglobulins are respectively referred to as α, γ, ε, γ and μ.The subunit structure and three-dimensional configuration of different types of immunoglobulins are well known and generally described in, for example, the following documents: Abbas et al. Cellular and Mol.Immunology, 4th edition (WB Saunders, Co., 2000).Antibodies can be part of larger fusion molecules, which are formed by covalent or non-covalent association of antibodies with one or more other proteins or peptides.

[0066] The terms "full length antibody", "intact antibody" and "whole antibody" are used interchangeably herein to refer to an antibody in its substantially intact form rather than an antibody fragment as defined below. The term refers to an antibody that contains an Fc region.

[0067] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, which comprises at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, the antibody produced by the host cell may undergo post-translational cleavage of one or more (particularly one or two) amino acids from the C-terminus of the heavy chain. Therefore, the antibody produced by the host cell by expressing a specific nucleic acid molecule encoding a full-length heavy chain may include a full-length heavy chain, or the antibody may include a cleavage variant of the full-length heavy chain. This may be a situation where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (K447) or C-terminal glycine (G446) and lysine (K447) in the Fc region may be present or may not be present. If not otherwise indicated, the amino acid sequence of the heavy chain including the Fc region is represented herein as having no C-terminal lysine (K447). On the one hand, the heavy chain including the Fc region as specified herein is included in the antibody disclosed herein, and the heavy chain includes an additional C-terminal glycine-lysine dipeptide (G446 and K447). On the one hand, the heavy chain including the Fc region as specified herein is included in the antibody disclosed herein, and the heavy chain includes an additional C-terminal glycine residue (G446). On the one hand, the heavy chain including the Fc region as specified herein is included in the antibody disclosed herein, and the heavy chain includes an additional C-terminal lysine residue (K447). In one embodiment, the Fc region contains a single amino acid substitution N297A of the heavy chain. Unless otherwise provided herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also referred to as the EU index), as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0068] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. Naked antibodies can be present in pharmaceutical compositions.

[0069] "Antibody fragments" include a portion of an intact antibody, preferably including its antigen binding region. In some cases, the antibody fragments described herein are antigen binding fragments. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0070] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, that is, except for possible variant antibodies (e.g., containing naturally occurring mutations or produced during the production of monoclonal antibody preparations, such variants are usually present in small amounts), the individual antibodies comprising the population have identity and / or bind to the same epitope. Contrary to the polyclonal antibody preparations that typically include different antibodies for different determinants (epitopes), each monoclonal antibody in the monoclonal antibody preparation is directed to a single determinant on the antigen. Therefore, the modifier "monoclonal" represents that the feature of the antibody is obtained from a substantially homogeneous antibody population, and should not be interpreted as requiring antibody to be produced by any ad hoc method. For example, the monoclonal antibody according to the present invention can be prepared by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals comprising all or part of human immunoglobulin loci.

[0071] As used herein, the term "hypervariable region" or "HVR" refers to individual regions of an antibody variable domain that are hypervariable in sequence and determine antigen binding specificity, such as the "complementarity determining region" ("CDR").

[0072] Typically, antibodies contain 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:

[0073] (a) hypervariable loops occurring at the following amino acid residues: 26 to 32 (L1), 50 to 52 (L2), 91 to 96 (L3), 26 to 32 (H1), 53 to 55 (H2), and 96 to 101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

[0074] (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

[0075] (c) Antigenic contact points occur at the following amino acid residues: 27c to 36 (L1), 46 to 55 (L2), 89 to 96 (L3), 30 to 35b (H1), 47 to 58 (H2), and 93 to 101 (H3) (MacCallum et al., J. Mol. Biol. 262:732-745 (1996)).

[0076] Unless otherwise indicated, CDRs are determined according to the method described in Kabat et al., supra. One skilled in the art will appreciate that CDR names may also be determined according to the method described in Chothia, supra, the method described in McCallum, supra, or any other scientifically accepted naming system.

[0077] "Framework" or "FR" refers to the variable domain residues excluding the complementarity determining regions (CDRs). The FR of a variable domain is usually composed of the following four FR domains: FR1, FR2, FR3, and FR4. Therefore, CDR and FR sequences usually appear in the following sequence in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

[0078] The term "variable domain residue numbering as described in Kabat" or "amino acid position numbering as described in Kabat" and variations thereof refer to the numbering system for the heavy chain variable domain or light chain variable domain used for the compilation of antibodies proposed in the above-mentioned document by Kabat et al. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening or insertion of the FR or HVR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion fragment after residue 52 of H2 (residue 52a according to Kabat numbering) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat numbering). The Kabat numbering of the residues of a given antibody can be determined by aligning the antibody sequence with a region of homology to a "standard" Kabat numbering sequence.

[0079] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0080] As used herein, "in combination with" means that in addition to administering one treatment modality, another treatment modality is administered, for example, a treatment regimen comprising administering a PD-1 axis binding antagonist (e.g., atezolizumab) and Compound 1 or a pharmaceutically acceptable salt thereof. Thus, "in combination with" means administering another treatment modality before, during, or after administering one treatment modality to a patient.

[0081] A drug that is administered "concurrently" with one or more other drugs is administered during the same treatment cycle, on the same day of treatment with the one or more other drugs, and optionally at the same time as the one or more other drugs. For example, for a cancer treatment given every three weeks, the concurrently administered drugs are each administered on Day 1 of the three-week cycle.

[0082] Combination therapy

[0083] Provided herein are combination therapies (compositions) comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist.

[0084] In some cases, 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 case herein, the isolated anti-PD-L1 antibody can bind to human PD-L1 (e.g., human PD-L1 shown in UniProtKB / Swiss-Prot accession number Q9NZQ7-1, or a variant thereof). In some cases, 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 cases, the anti-PD-L1 antibody is a monoclonal antibody. In some cases, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv and (Fab')2 fragments. In some cases, the anti-PD-L1 antibody is a humanized antibody. In some cases, 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, envolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosilimab, lodalimab, 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 that can be used in the methods of the present invention and methods for their preparation are described in International Patent Application Publication No. WO2010 / 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 is an anti-PD-L1 antibody. In a more preferred embodiment, the anti-PD-L1 antibody is atezolizumab.

[0085] In some instances, the anti-PD-L1 antibody comprises:

[0086] (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

[0087] (b) 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.

[0088] In one embodiment, the anti-PD-L1 antibody comprises:

[0089] (a) a heavy chain variable region (VH) comprising the following amino acid sequence:

[0090] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:9), and

[0091] (b) a light chain variable region (VL) comprising the following amino acid sequence:

[0092] DIQMTQSPSSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 10).

[0093] In some instances, 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, or comprising the sequence of, SEQ ID NO:9; (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, or comprising the sequence of, SEQ ID NO:10; or (c) a VH as described in (a) and a VL as described in (b).

[0094] In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:

[0095] (a) the following heavy chain amino acid sequence:

[0096] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGT LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:1), and

[0097] (b) the following light chain amino acid sequence:

[0098] DIQMTQSPSSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:2).

[0099] In some instances, 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).

[0100] In some instances, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60-7).Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1κ anti-PD-L1 antibody described in WO 2011 / 066389 and US 2013 / 034559 (MedImmune, AstraZeneca).

[0101] In some instances, 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 WO 2007 / 005874.

[0102] In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly). In some cases, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody. In some cases, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camel phage display library.

[0103] In some cases, the anti-PD-L1 antibody comprises a cleavable portion or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen-binding domain to bind its antigen, e.g., by removing a non-binding steric portion. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0104] In some instances, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or heavy chain variable domains and light chain variable domains from an anti-PD-L1 antibody described in US20160108123, WO 2016 / 000619, WO 2012 / 145493, U.S. Pat. No. 9,205,148, WO 2013 / 181634, or WO 2016 / 061142.

[0105] In a further specific aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In yet another specific aspect, minimal effector function comes from an "effectorless Fc mutation" or a glycosylation mutation. In a further case, the effectorless Fc mutation is an N297A or D265A / N297A substitution in the constant region. In a further case, the effectorless Fc mutation is an N297A substitution in the constant region. In some cases, the isolated anti-PD-L1 antibody is glycosylated. The glycosylation of the antibody is typically N-linked or O-linked. N-linked refers to the carbohydrate moiety being attached 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 enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in the polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid (most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used). Glycosylation sites may be conveniently removed from antibodies by altering the amino acid sequence to remove one of the above tripeptide sequences (for N-linked glycosylation sites). Mutations may be made by substituting an asparagine, serine, or threonine residue within a glycosylation site for another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

[0106] 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 can be used to treat certain types of lung cancer, head and neck cancer, and / or melanoma as 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 a free base. In another embodiment, Compound 1 is a pharmaceutically acceptable salt of Compound 1.

[0107] In one aspect, provided herein is a combination therapy (e.g., a composition) comprising Compound 1 or a pharmaceutically acceptable salt thereof, administered QD on Days 1 to 21 of the first 21-day cycle; and an anti-PD-L1 antibody.

[0108] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof administered QD on Days 1 to 21 of the first 21-day cycle, and Atezolizumab administered Q3W on Day 1 of the first 21-day cycle.

[0109] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof administered QD on Days 1 to 21 of the first 21-day cycle, and Atezolizumab administered Q2W on Day 1 of the first 21-day cycle. In one such embodiment, Atezolizumab is administered Q2W in an amount of 840 mg. In one such embodiment, Atezolizumab is administered Q2W according to the package insert.

[0110] In one embodiment of the combination therapy described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered in the form of a fixed dose QD administration. In one embodiment, administration is by oral (PO), wherein Compound 1 or a pharmaceutically acceptable salt thereof is formulated in a tablet or capsule. In one such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is formulated (and administered) in a film-coated tablet. In another such embodiment, Compound 1 is administered in a capsule.

[0111] In one embodiment of the combination therapies described herein, 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 g, 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 administration of Compound 1 or a pharmaceutically acceptable salt thereof.

[0112] In one embodiment of the combination therapy described herein, 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 administration of Compound 1 or a pharmaceutically acceptable salt thereof.

[0113] In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD 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. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered BID 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. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 20 mg, 40 mg, 50 mg, 60 mg, or 80 mg. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered BID in an amount of about 20 mg, 40 mg, 50 mg, 60 mg, or 80 mg.

[0114] In one embodiment of the combination therapies described herein, the PD-L1 binding antagonist is administered according to the package insert. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab.

[0115] As a general proposition, a therapeutically effective amount of a PD-L1 binding antagonist (e.g., atezolizumab) administered to a human will be in the range of about 0.01 mg / kg to about 50 mg / kg of patient body weight, whether by one or more administrations.

[0116] In some exemplary embodiments, the PD-L1 binding antagonist is administered, for example, 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, administered daily, weekly, every two weeks, every three weeks, or every four weeks.

[0117] In one case, 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 cases, the PD-L1 binding antagonist can be administered every three weeks at a dose of about 1000 mg to about 1400 mg (e.g., about 1100 mg to about 1300 mg every three weeks, e.g., about 1150 mg to about 1250 mg every three weeks).

[0118] In a preferred embodiment, the combination therapy described herein comprises Compound 1 or a pharmaceutically acceptable salt thereof as described herein and Atezolizumab, wherein Atezolizumab is administered intravenously to the 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 or a pharmaceutically acceptable salt thereof as described herein and Atezolizumab, wherein Atezolizumab is administered intravenously to the patient at a dose of about 1200 mg Q3W.

[0119] In one embodiment, the combination therapy described herein is used to treat lung cancer. In a specific embodiment, the combination therapy comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein the combination therapy is used to treat lung cancer. In one such embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In one such embodiment, the NSCLC is locally advanced or metastatic NSCLC. In another such embodiment, the NSCLC does not have EGFR or ALK changes.

[0120] In one embodiment, the combination therapy described herein is used to treat head and neck cancer. In one such embodiment, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In a specific embodiment, the combination therapy comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein the combination therapy is used to treat HNSCC. In one such embodiment, HNSCC is recurrent or metastatic HNSCC involving the oropharynx, oral cavity, larynx, or hypopharynx.

[0121] In one embodiment, the combination therapy described herein is used to treat melanoma. In a specific embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein the combination therapy is used to treat melanoma. In one such embodiment, the melanoma is locally advanced or metastatic (e.g., recurrent or newborn IV stage) melanoma. In another such embodiment, the melanoma is unresectable locally advanced (e.g., stage III) skin melanoma. In such embodiments, the melanoma is BRAF WT melanoma.

[0122] In yet another aspect, provided herein is a combination therapy for treating lung cancer as described herein, wherein the combination therapy comprises 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.

[0123] In yet another aspect, provided herein is a combination therapy for treating head and neck cancer as described herein, wherein the combination therapy comprises 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.

[0124] In yet another aspect, provided herein is a combination therapy useful for treating a melanoma as described herein, wherein the combination therapy comprises 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 melanoma is a BRAF WT melanoma.

[0125] In yet another aspect, provided herein is a combination therapy for treating lung cancer as described herein, wherein the combination therapy comprises 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 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 such embodiment, the lung cancer is NSCLC as described herein.

[0126] In yet another aspect, provided herein is a combination therapy for treating head and neck cancer as described herein, wherein the combination therapy comprises 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 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.

[0127] In yet another aspect, provided herein is a combination therapy useful for treating a melanoma as described herein, wherein the combination therapy comprises 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 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 a BRAF WT melanoma.

[0128] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab for the treatment of lung cancer, 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.

[0129] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab for the treatment of head and neck cancer, 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.

[0130] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab for the treatment of melanoma, 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 melanoma is a BRAF WT melanoma.

[0131] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab for the treatment of lung cancer, 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 such embodiment, the lung cancer is NSCLC as described herein.

[0132] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab for treating head and neck cancer, 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.

[0133] In yet another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab for treating melanoma, 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 a BRAF WT melanoma.

[0134] Treatment

[0135] 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. 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.

[0136] 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.

[0137] 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.

[0138] 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 a BRAF WT melanoma.

[0139] In one embodiment of the methods described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a fixed dose QD administration. In another embodiment of the methods described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a fixed dose BID administration. In one embodiment, it is administered orally (PO), wherein Compound 1 or a pharmaceutically acceptable salt thereof is formulated in tablets or capsules. In one embodiment, 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 150 mg, 20 mg to 250 mg, 20 mg to 20 ...50 mg, 20 mg to 200 mg, 20 mg to 150 mg, 20 mg to 250 mg, 20 mg to 250 mg, 20 mg to 250 mg, 20 mg to 250 mg, 20 mg to 250 mg, 20 mg to 25 Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of 20 to 100 mg, 20 to 80 mg, 20 to 75 mg, 20 to 60 mg, 20 to 40 mg, 40 to 250 mg, 40 to 200 mg, 40 to 150 mg, 40 to 100 mg, 40 to 80 mg, 40 to 60 mg, 60 to 250 mg, 60 to 200 mg, 60 to 150 mg, 60 to 100 mg or 60 to 80 mg.

[0140] In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet and administered QD in an amount of about 5 mg to 100 mg. 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.

[0141] In one embodiment of the methods described herein, 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, Compound 1 or a pharmaceutically acceptable salt thereof is administered BID in an amount of 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.

[0142] In one embodiment of the methods described herein, atezolizumab is administered, for example, 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, administered daily, weekly, every two weeks, every three weeks, or every four weeks.

[0143] In one case, atezolizumab is administered to a human at a dosage 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 cases, atezolizumab can be administered every three weeks at a dosage of about 1000 mg to about 1400 mg (e.g., about 1100 mg to about 1300 mg every three weeks, e.g., about 1150 mg to about 1250 mg every three weeks).

[0144] In a preferred embodiment of the methods 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.

[0145] In one embodiment, the methods described herein further include a run-in period. The length of the run-in period can be about 1 to 14 days. In one such embodiment, the run-in period includes 14 days. In another such embodiment, the run-in period is 14 days, and Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab are administered on the first day of the run-in period. In one such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered alone on the 8th day of the run-in period and is administered QD thereafter.

[0146] The method provided herein may include administering a combination therapy as described herein as part of a dosing regimen. In one such embodiment, the dosing regimen includes one or more cycles. In another embodiment, the dosing regimen includes at least two cycles. In another aspect provided herein, the dosing regimen includes 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20, 24, 30, 36, 42, 48, 54, 60, 66 or 72 cycles. In another embodiment, the dosing regimen includes about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, 2-12 or 2-6 cycles. In one embodiment, the dosing regimen includes administering a combination therapy as described herein with any number of cycles, until the desired response (e.g., PFS, OS, ORR and / or DOR) reaches the desired result (e.g., compared to a control group as described herein, PFS, OS, ORR and / or DOR improve). In another embodiment, the dosing regimen includes administering the combination therapy described herein in any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the dosing regimen includes administering the combination therapy as described herein in any number of cycles until disease progression.

[0147] In one embodiment of the methods described herein, a total of 1 to 50 doses of atezolizumab is administered to the patient, e.g., 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. dose, 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, 2 0 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. In a preferred embodiment, the dose is administered intravenously.

[0148] In certain embodiments, the therapeutic agents of the combination therapies described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab) may be administered in any suitable manner known in the art. For example, Atezolizumab may be administered sequentially (on different days) or simultaneously (on the same day or during the same treatment cycle) with Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, Atezolizumab is administered after administering Compound 1 or a pharmaceutically acceptable salt thereof. In some cases, Atezolizumab is administered after administering Compound 1, or its pharmaceutically acceptable salt may be administered on the same day. In one embodiment, Atezolizumab may 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 may be administered on the 1st day of each cycle, and then Atezolizumab may be administered on the 1st day of each cycle, wherein Compound 1 or a pharmaceutically acceptable salt thereof is then administered QD within the next 20 days of a 21-day cycle.

[0149] In a preferred embodiment, atezolizumab is administered intravenously. In one example, atezolizumab can be administered intravenously over 60 minutes; if the first infusion can be 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 rapid injection.

[0150] In one embodiment, atezolizumab is administered according to the following table:

[0151]

[0152]

[0153] 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, wherein the method comprises 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 as described herein QD and in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, Atezolizumab is administered as described herein Q3W 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 part of the introduction phase as described herein before 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.

[0154] Further provided herein is a method for treating lung cancer in a patient in need thereof, wherein the method comprises 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 as described herein QD and administered in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, Atezolizumab is administered as described herein Q3W and administered 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 a component of the introduction phase as described herein before 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. In one such embodiment, lung cancer is NSCLC as described herein.

[0155] Further provided herein is a method for treating head and neck cancer as described herein in a patient in need thereof, wherein the method comprises administering a treatment regimen to the patient, the 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 as described herein QD and in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, Atezolizumab is administered as described herein Q3W 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 part of the introduction phase as described herein before 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. In one embodiment, head and neck cancer is HNSCC as described herein.

[0156] Also provided herein is a method for treating a melanoma as described herein in a patient in need thereof, wherein the method comprises administering a treatment regimen to the patient, the 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 as described herein QD and in an amount as described herein (e.g., 5 mg to 100 mg). In another embodiment of such a method, Atezolizumab is administered as described herein Q3W 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 part of the introduction phase as described herein before 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. In one embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0157] In some cases, a treatment regimen as described herein comprises administration of one or more additional therapies, wherein the additional therapies are one or more side effect limiting agents (e.g., agents intended to reduce the occurrence and / or severity of therapeutic side effects, such as antiemetics, antacids, corticosteroids (e.g., prednisone or an equivalent, e.g., at a dose of 1 mg / kg / day to 2 mg / kg / day), hormone replacement medications, etc.).

[0158] In some embodiments of the methods described herein, the patient is assessed for PD-L1 positivity or PD-L1 status. In one embodiment, PD-L1 positivity or PD-L1 status is assessed by an IHC-based test. In one embodiment, the patient is PD-L1 positive. In one embodiment, the patient has NSCLC assessed to have a high PD-L1 status. In another embodiment, the patient has NSCLC assessed to have a low PD-L1 status. In one such embodiment, the patient has NSCLC with EGFR and ALK wild-type status.

[0159] The expression of PD-L1 in patients treated according to any of the methods and compositions described herein can be assessed. The method and the composition for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from a patient. In other examples, the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from a patient has been determined before or after treatment initiation. PD-L1 expression can be determined using any suitable method. 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, for example, a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archived tumor sample, a fresh tumor sample, or a frozen tumor sample.

[0160] For example, PD-L1 expression can be determined according to the percentage of tumor samples occupied by tumor-infiltrating immune cells expressing detectable PD-L1 expression levels, as the percentage of tumor-infiltrating immune cells expressing detectable PD-L1 expression levels in the tumor sample, and / or as the percentage of tumor cells expressing detectable PD-L1 expression levels in the tumor sample. It should be understood that in any of the foregoing examples, the percentage of tumor samples occupied by tumor-infiltrating immune cells can be the percentage of tumor area covered by tumor-infiltrating immune cells in a section of a tumor sample obtained from a patient, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., SP142 antibody). Any suitable anti-PD-L1 antibody can be used, including, for example, SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1L3N (CellSignaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics) and 9A11. In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263.

[0161] In some examples, a tumor sample obtained from a patient has a detectable PD-L1 expression level in less than 1% of tumor cells in the tumor sample, in 1% or more of tumor cells in the tumor sample, in 1% to less than 5% of tumor cells in the tumor sample, in 5% or more of tumor cells in the tumor sample, in 5% to less than 50% of tumor cells in the tumor sample, or in 50% or more of tumor cells in the tumor sample.

[0162] In some examples, a tumor sample obtained from a patient has a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, greater than 1% of the tumor sample, 1% to less than 5% of the tumor sample, greater than 5% of the tumor sample, 5% to less than 10% of the tumor sample, or greater than 10% of the tumor sample.

[0163] In some examples, tumor samples can be scored for PD-L1 positivity in tumor-infiltrating immune cells and / or tumor cells according to the diagnostic scoring criteria shown in Table A and / or Table B, respectively.

[0164] Table A. IHC diagnostic criteria for infiltrating immune cells (IC)

[0165]

[0166] Table B. Tumor cell (TC) IHC diagnostic criteria

[0167]

[0168] Also provided herein are methods of inhibiting tumor growth or producing tumor regression in patients described herein, which are performed by administering the combination therapy described herein. In one embodiment, provided herein is a method of inhibiting tumor growth in a patient in need thereof, which is performed 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.

[0169] In one embodiment, provided herein is a method of producing or improving tumor regression in a patient with lung cancer (e.g., NSCLC), head and neck cancer (e.g., HNSCC), or melanoma (e.g., BRAF WT melanoma) described 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.

[0170] Further provided herein is the use of a combination therapy (composition) described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating lung cancer (e.g., NSCLC), head and neck cancer (e.g., HNSCC), or melanoma (e.g., BRAF WT melanoma) as described herein.

[0171] In one embodiment is the use of a combination therapy (composition) as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating lung cancer as described herein (U1). In one such embodiment, the lung cancer is NSCLC. In some embodiments, NSCLC is locally advanced NSCLC or metastatic NSCLC as described herein.

[0172] In one embodiment is the use of a combination therapy (composition) as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating head and neck cancer as described herein (U2). In one such embodiment, the head and neck cancer is HNSCC as described herein.

[0173] In one embodiment is the use of a combination therapy (composition) as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating a melanoma as described herein (U3). In one embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0174] Further provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab as described herein for the treatment of lung cancer, head and neck cancer, or melanoma as described herein (U4), the combination therapy comprising a dosing regimen comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (ii) administering Atezolizumab Q3W on day 1 of the first 21-day cycle. In one such embodiment, the use comprises treating lung cancer. In one such embodiment, lung cancer is NSCLC as described herein. In another such embodiment, the use comprises treating head and neck cancer. In one such embodiment, head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises treating melanoma as described herein. In one such embodiment, melanoma is BRAF WT melanoma as described herein.

[0175] Further provided herein is the use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab as described herein for treating lung cancer, head and neck cancer, or melanoma as described herein (U5), the combination therapy comprising a dosing regimen comprising: (i) administering about 5 mg to 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 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 one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one such embodiment, the use comprises treating lung cancer. In one such embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the use comprises treating head and neck cancer. In one such embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises treating melanoma as described herein. In one such embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0176] Further provided herein is the use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab as described herein for the manufacture of a medicament (U6) for the treatment of lung cancer, head and neck cancer, or melanoma as described herein. In one such embodiment, the use comprises treating lung cancer. In one such embodiment, lung cancer is NSCLC as described herein. In another such embodiment, the use comprises treating head and neck cancer. In one such embodiment, head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises treating melanoma as described herein. In one such embodiment, melanoma is BRAF WT melanoma as described herein.

[0177] Further provided herein is the use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab as described herein for the manufacture of a medicament (U7), the medicament being used to treat lung cancer, head and neck cancer, or melanoma as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (ii) administering Atezolizumab Q3W on day 1 of the first 21-day cycle. In one such embodiment, the use comprises treating lung cancer. In one such embodiment, lung cancer is NSCLC as described herein. In another such embodiment, the use comprises treating head and neck cancer. In one such embodiment, head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises treating melanoma as described herein. In one such embodiment, melanoma is BRAF WT melanoma as described herein.

[0178] Further provided herein is the use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab as described herein for the manufacture of a medicament (U7), the medicament being used to treat lung cancer, head and neck cancer, or melanoma as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering about 5 mg to 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 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 one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one such embodiment, the use comprises treating lung cancer. In one such embodiment, lung cancer is NSCLC as described herein. In another such embodiment, the use comprises treating head and neck cancer. In one such embodiment, head and neck cancer is HNSCC as described herein. In another such embodiment, the use comprises treating melanoma as described herein. In one such embodiment, melanoma is BRAF WT melanoma as described herein.

[0179] In one embodiment, the combination therapy (composition) described herein comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, which is used for (U1) treating lung cancer as described herein. In one such embodiment, the lung cancer is NSCLC. In some embodiments, NSCLC is locally advanced NSCLC or metastatic NSCLC as described herein.

[0180] In one embodiment, the combination therapy (composition) described herein comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, which is used for (U2) treating head and neck cancer as described herein. In one such embodiment, the head and neck cancer is HNSCC as described herein.

[0181] In one embodiment, the combination therapy (composition) described herein comprises Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, which is used for (U3) treating a melanoma as described herein. In one such embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0182] Further provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab as described herein, for (U4) treating lung cancer, head and neck cancer, or melanoma as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (ii) administering Atezolizumab Q3W on day 1 of the first 21-day cycle. In one such embodiment, the treatment comprises treating lung cancer. In one such embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises treating head and neck cancer. In one such embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises treating a melanoma as described herein. In one such embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0183] Further provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab as described herein for (U5) treating lung cancer, head and neck cancer, or melanoma as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering about 5 mg to 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 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 one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one such embodiment, the treatment comprises treating lung cancer. In one such embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises treating head and neck cancer. In one such embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises treating a melanoma as described herein. In one such embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0184] Further provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab as described herein, which is used for (U6) the manufacture of a medicament for treating lung cancer, head and neck cancer, or melanoma as described herein. In one such embodiment, treatment comprises treating lung cancer. In one such embodiment, lung cancer is NSCLC as described herein. In another such embodiment, treatment comprises treating head and neck cancer. In one such embodiment, head and neck cancer is HNSCC as described herein. In another such embodiment, treatment comprises treating melanoma as described herein. In one such embodiment, melanoma is BRAF WT melanoma as described herein.

[0185] Further provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab as described herein, which is used for (U7) manufacturing a medicament for treating lung cancer, head and neck cancer, or melanoma as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (ii) administering Atezolizumab Q3W on day 1 of the first 21-day cycle. In one such embodiment, the treatment comprises treating lung cancer. In one such embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises treating head and neck cancer. In one such embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises treating a melanoma as described herein. In one such embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0186] Further provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab as described herein, which is used for (U7) manufacturing a medicament for treating lung cancer, head and neck cancer, or melanoma as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering about 5 mg to 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 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 one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one such embodiment, the treatment comprises treating lung cancer. In one such embodiment, the lung cancer is NSCLC as described herein. In another such embodiment, the treatment comprises treating head and neck cancer. In one such embodiment, the head and neck cancer is HNSCC as described herein. In another such embodiment, the treatment comprises treating a melanoma as described herein. In one such embodiment, the melanoma is a BRAF WT melanoma as described herein.

[0187] The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can improve efficacy while maintaining acceptable toxicity. A particular challenge is the need to distinguish the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof and Atezolizumab) is administered with a dosing regimen comprising a staggered dosing schedule. In one such embodiment, the patient has a reduced number or grade of adverse events (AEs) compared to a control (e.g., SOC therapy, treatment with a single agent described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof or Atezolizumab)).

[0188] As is generally known, when an adverse event occurs, there are four options: (1) continue the original treatment with optional concomitant therapy; (2) adjust the dosage of one or more agents in the dosing regimen; (3) suspend 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, where the administration of Atezolizumab is interrupted, the next administration of Compound 1 or a pharmaceutically acceptable salt thereof occurs on the same day that the administration of Atezolizumab is resumed.

[0189] 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, bone marrow suppression (e.g., thrombocytopenia and / or anemia), gastrointestinal toxicity (e.g., diarrhea, nausea and / or vomiting), rash, elevated liver transaminases, cardiomyopathy, ocular toxicity or phototoxicity. In another embodiment, patients described herein experience one or more of the following: infusion-related reactions (IRR) and immune-mediated hepatitis, pneumonia, colitis, pancreatitis, diabetes, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenia syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis and myositis. Immune-mediated reactions may involve any organ system and may lead to hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). In one such embodiment, the patient does not experience one or more of cardiac, pulmonary, renal, thromboembolic, or ocular toxicity.

[0190] In some embodiments, one or more concomitant therapies may also be administered to the patients described herein, including: (a) oral contraceptives; (b) hormone replacement therapy; (c) prophylactic or therapeutic anticoagulant therapy (such as stable doses of warfarin or low molecular weight heparin); vaccination (such as influenza, COVID-19), but live attenuated vaccines are not allowed; (d) megestrol acetate administered as an appetite stimulant; (e) mineralocorticoids (e.g., fludrocortisone); (f) medications for chronic obstructive pulmonary disease or asthma. (g) low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency; (h) palliative radiation therapy (e.g., to treat known bone metastases or relieve pain symptoms); (i) local therapy (e.g., surgery, stereotactic radiosurgery, radiation therapy, radiofrequency ablation); (j) premedication with antihistamines, antipyretics and / or analgesics (e.g., acetaminophen, ibuprofen, diphenhydramine) and / or H2 receptor antagonists (e.g., famotidine, cimetidine).

[0191] In certain embodiments, the patients described herein may not be taking concomitant therapy, which includes: (a) strong / 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) strong / moderate CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), Wort) and cyproterone acetate); (c) chemotherapy; (d) hormonal therapy; (e) immunotherapy; (f) radiation therapy; (g) herbal therapy; (h) live attenuated vaccines; systemic immune stimulants (e.g., interferon and IL-2); (i) proton pump inhibitors; (j) cannabidiol products; or (k) H2 blockers and antacids.

[0192] In one embodiment of the methods described herein, the patient described herein has a locally advanced or metastatic solid tumor (e.g., NSCLC, HNSCC, melanoma as described herein) that has (a) progressed after at least one available standard therapy, or (b) has been proven ineffective or intolerant to approved standard therapy, or is considered inappropriate.

[0193] In one embodiment of the methods described herein, the patient has lung cancer and has not previously received systemic therapy. In one such embodiment, the lung cancer is locally advanced or metastatic lung cancer as described herein.

[0194] In one embodiment of the methods described herein, the patient has NSCLC and has not previously received systemic therapy. In one such embodiment, the NSCLC is locally advanced or metastatic NSCLC as described herein.

[0195] In another embodiment of the methods described herein, the patient has NSCLC as described herein and without EGFR and / or ALK changes. In one such embodiment, a patient sample (e.g., a biopsy of a tumor tissue) is tested for EGFR and / or ALK changes. In another such embodiment, the patient is PD-L1 positive. In such embodiments, the patient is determined to be PD-L1 positive by performing an IHC analysis as described herein.

[0196] In one embodiment of the methods described herein, the patient described herein suffers from histologically confirmed recurrent or metastatic head and neck cancer. In one such embodiment, the head and neck cancer involves the oropharynx, oral cavity, larynx or hypopharynx. In one such embodiment, the head and neck cancer involves the oropharynx, oral cavity, larynx or hypopharynx that is considered unsuitable for curative therapy. In another embodiment of the methods described herein, the patient described herein suffers from head and neck cancer as described herein and has not previously received systemic therapy for the treatment of head and neck cancer. In another embodiment of the methods described herein, the patient described herein suffers from head and neck cancer and has been tested for the presence / absence of local human papillomavirus (HPV) for oropharyngeal cancer.

[0197] In one embodiment of the methods described herein, the patient described herein suffers from histologically confirmed recurrent or metastatic HNSCC. In one such embodiment, HNSCC involves the oropharynx, oral cavity, larynx or hypopharynx. In one such embodiment, HNSCC involves the oropharynx, oral cavity, larynx or hypopharynx that is considered unsuitable for curative therapy. In another embodiment of the methods described herein, the patient described herein suffers from HNSCC as described herein and has not previously received systemic therapy for the treatment of HNSCC. In another embodiment of the methods described herein, the patient described herein suffers from HNSCC and has received a test for the presence / absence of local human papillomavirus (HPV) for oropharyngeal cancer.

[0198] In one embodiment of the methods described herein, the patient described herein has a melanoma as described herein and has progressive disease on or after prior treatment comprising an anti-PD-1 or anti-PD-L1 therapy.

[0199] In one embodiment of the methods described herein, the patient described herein has a BRAFWT melanoma as described herein and has progressive disease on or after prior treatment comprising an anti-PD-1 or anti-PD-L1 therapy.

[0200] In one embodiment, the patients described herein have no known and untreated or active central nervous system (CNS) metastases (progression or need for anticonvulsant or corticosteroids for symptom control). Patients can be treated using the methods described herein, wherein such patients have a history of treated CNS metastases, wherein such patients: (1) have measurable or evaluable disease outside the CNS; (2) have no history of intracranial hemorrhage or spinal cord hemorrhage; (3) do not require ongoing corticosteroid treatment for CNS metastases, have discontinued corticosteroids two weeks prior to administration of the combination therapy as described herein, and have no ongoing symptoms caused by CNS metastases; (4) have not received stereotactic radiation within seven days prior to Day 1 of Cycle 1 as described herein or whole brain radiation within 14 days; and (5) have no evidence of transitional progression between completion of CNS-directed therapy and screening radiographic studies.

[0201] In one embodiment of the methods described herein, the patient described herein does not suffer from leptomeningeal disease or carcinomatous meningitis. In another embodiment, the patient described herein does not suffer from uncontrolled hypertension. In another embodiment, the patient described herein does not suffer from active tuberculosis infection. In another embodiment, the patient described herein is not receiving active HBV treatment.

[0202] In another embodiment of the methods described herein, the patient described herein does not have an ophthalmic disease including retinal vascular occlusion (RVO), central serous retinopathy (CSR), a predisposing factor for RVO or CSR, or a retinopathy at a screening ophthalmological examination.

[0203] In one embodiment of the methods described herein, the patient described herein has not undergone major surgery other than diagnostic surgery within 4 weeks prior to starting treatment as described herein.

[0204] In another embodiment of the methods described herein, the patients described herein do not have an active or history of an 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 granulomatosis, Sjögren's syndrome, syndrome), Guillain-Barre syndrome, or multiple sclerosis. In some embodiments, patients with such autoimmune diseases may be treated according to the methods described herein if they have:

[0205] ●These patients have a history of autoimmune-related hypothyroidism and are receiving thyroid replacement hormone therapy;

[0206] ●These patients have controlled type 1 diabetes and are receiving insulin therapy;

[0207] ● Patients had eczema, psoriasis, lichen simplex chronicus, or vitiligo with only dermatologic manifestations (e.g., patients with psoriatic arthritis were excluded) and (i) the rash had to cover less than 10% of the patient's body surface area, (ii) treatment was with low-potency topical corticosteroids alone, and (iii) no acute exacerbation of the underlying disease requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in the previous 12 months.

[0208] In another embodiment of the methods described herein, the patient has no history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or no evidence of active pneumonia on a screening chest computed tomography scan.

[0209] In another embodiment, the patient described herein has not been treated with chemotherapy, immunotherapy, or biological therapy as an anti-cancer therapy within three weeks prior to administration of the combination therapy described herein, or has not been treated with endocrine therapy within two weeks prior to administration of the combination therapy described herein, except for hormonal therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists to treat endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer).

[0210] In another embodiment of the methods described herein, the patient described herein has not received prior treatment with an H2 blocker or antacid within 14 days or five drug elimination half-lives, whichever is longer prior to initiation of treatment as described herein. In another embodiment of the methods described herein, the patient described herein has not received prior treatment with a mild or moderate CYP3A4 inhibitor or mild or moderate CYP3A4 inducer within 14 days or five drug elimination half-lives, whichever is longer prior to initiation of treatment as described herein.

[0211] Reagent test kit

[0212] The combination therapy described herein can be provided in the form of a kit comprising one or more of the agents described herein for administration. In one embodiment, the kit comprises Compound 1 or a pharmaceutically acceptable salt thereof for administration in combination with atezolizumab as described herein. In another embodiment, the kit comprises Compound 1 or a pharmaceutically acceptable salt thereof packaged with atezolizumab, wherein the kit comprises separate formulated doses of each agent.

[0213] Also provided herein is a product or kit comprising Compound 1 or a pharmaceutically acceptable salt thereof and a PD-L1 binding antagonist (e.g., atezolizumab). In some cases, the product further comprises a package insert comprising instructions for using the PD-L1 binding antagonist to treat lung cancer, head and neck cancer, or melanoma as described herein. In one such embodiment, lung cancer is NSCLC. In one such embodiment, the head and neck cancer is HNSCC. In one such embodiment, the melanoma is BRAF WT melanoma. In one embodiment, the product further comprises a package insert comprising instructions for using atezolizumab in combination with Compound 1 or a pharmaceutically acceptable salt thereof to treat NSCLC, HNSCC, or BRAF WT melanoma as described herein in a patient as described herein.

[0214] In some cases, the PD-L1 binding antagonist (e.g., atezolizumab) and compound 1 or a pharmaceutically acceptable salt thereof are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container can be formed of a variety of materials, such as glass, plastics (such as polyvinyl chloride or polyolefins) or metal alloys (such as stainless steel or Hastelloy). In some cases, the container holds the preparation, and the label on the container or associated with the container may indicate instructions for use. The product or kit may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some cases, the product further includes one or more other agents (e.g., additional chemotherapeutic agents and anti-tumor agents). Suitable containers for one or more reagents include, for example, bottles, vials, bags, and syringes.

[0215] Any article of manufacture or kit described herein may include instructions for administering Compound 1, or a pharmaceutically acceptable salt thereof, and / or a PD-L1 binding antagonist (e.g., atezolizumab) to a patient as described herein according to any of the methods described herein.

[0216] Implementation

[0217] Exemplary embodiments of the present invention are provided below.

[0218] Embodiment 1. A combination therapy comprising:

[0219] (a) Compound 1

[0220]

[0221] or a pharmaceutically acceptable salt thereof; and

[0222] (b) PD-L1 binding antagonists.

[0223] Embodiment 2. The combination therapy according to Embodiment 1, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0224] Embodiment 3. The combination therapy according to Embodiment 1 or 2, wherein the anti-PD-L1 antibody is atezolizumab.

[0225] Embodiment 4. The combination therapy according to Embodiment 3, 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 on Day 1 of the first 21-day cycle.

[0226] Embodiment 5. The combination therapy according to Embodiment 3, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered BID on Days 1 to 21 of the first 21-day cycle, and Atezolizumab is administered on Day 1 of the first 21-day cycle.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] Embodiment 9. The combination therapy according to any one of Embodiments 3 to 8, wherein atezolizumab is administered in an amount of about 800 mg to about 1400 mg Q3W.

[0231] 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.

[0232] 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 prior to the start of the first 21-day period, followed by administration of atezolizumab in an amount of 840 mg.

[0233] 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, said patient having lung cancer, head and neck cancer, or melanoma.

[0234] Embodiment 13. The combination therapy according to Embodiment 12, wherein the patient is PD-L1 positive.

[0235] Embodiment 14. The combination therapy according to Embodiment 12 or 13, wherein the patient is PD-L1 high.

[0236] Embodiment 15. The combination therapy according to any one of Embodiments 12 to 14, wherein the patient is PD-L1 low.

[0237] Embodiment 16. The combination therapy according to any one of Embodiments 13 to 15, wherein the PD-L1 positivity is determined by PD-L1 immunohistochemistry (IHC) assay.

[0238] 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.

[0239] Embodiment 18. A method of treating lung cancer, head and neck cancer, or melanoma in a patient in need thereof, the method comprising administering during a treatment period an effective amount of a combination therapy comprising:

[0240] (a) Compound 1

[0241]

[0242] or a pharmaceutically acceptable salt thereof; and

[0243] (b) PD-L1 binding antagonists.

[0244] Embodiment 19. The method according to Embodiment 18, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0245] Embodiment 20. The method according to embodiment 18, wherein the anti-PD-L1 antibody is atezolizumab.

[0246] Embodiment 21. The method according to embodiment 20, wherein the treatment period comprises:

[0247] (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and

[0248] (b) Atezolizumab is administered on Day 1 of the first 21-day cycle.

[0249] Embodiment 22. The method according to embodiment 20, wherein the treatment period comprises:

[0250] (a) administering Compound 1 or a pharmaceutically acceptable salt thereof BID on Days 1 to 21 of the first 21-day cycle; and

[0251] (b) Atezolizumab is administered on Day 1 of the first 21-day cycle.

[0252] Embodiment 23. The method according to any one of Embodiments 18 to 22, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet or capsule.

[0253] Embodiment 24. The method according to any one of Embodiments 18 to 23, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 100 mg.

[0254] Embodiment 25. The method of any one of Embodiments 18 to 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.

[0255] Embodiment 26. The method of any one of Embodiments 20 to 25, wherein atezolizumab is administered Q3W in an amount of about 800 mg to about 1400 mg.

[0256] Embodiment 27. The method of any one of Embodiments 20 to 26, wherein atezolizumab is administered in an amount of about 1200 mg on day 1 of each cycle.

[0257] Embodiment 28. The method according to any one of Embodiments 20 to 27, wherein the method further comprises a run-in period comprising administering Compound 1 or a pharmaceutically acceptable salt thereof prior to the start of the first cycle, followed by administration of atezolizumab in an amount of 840 mg.

[0258] Embodiment 29. The method according to embodiment 28, wherein the lead-in period comprises 1 to 14 days.

[0259] Embodiment 30. The method according to Embodiment 28 or 29, wherein the lead-in period is 14 days, and Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered on Day 1 of the lead-in period.

[0260] Embodiment 31. The method according to Embodiment 29 or 30, wherein QD administration of Compound 1 or a pharmaceutically acceptable salt thereof begins on Day 8 of the lead-in period.

[0261] Embodiment 32. The method according to any one of Embodiments 18 to 28, wherein the patient is PD-L1 positive.

[0262] Embodiment 33. The method according to any one of Embodiments 18 to 28 or 32, wherein the patient is PD-L1 high.

[0263] Embodiment 34. The method according to any one of Embodiments 18 to 28 or 32 to 33, wherein the patient is PD-L1 low.

[0264] 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 PD-L1 immunohistochemistry (IHC) assay.

[0265] Embodiment 36. The method according to any one of Embodiments 18 to 35, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0266] 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).

[0267] Embodiment 38. The method according to any one of Embodiments 18 to 35, wherein the melanoma is a BRAF WT melanoma.

[0268] Embodiment 39. A method of treating lung cancer, head and neck cancer, or 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.

[0269] Embodiment 40. The method according to Embodiment 39, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0270] Embodiment 41. The method according to Embodiment 39 or 40, wherein the anti-PD-L1 antibody is atezolizumab.

[0271] Embodiment 42. The method of embodiment 41, wherein:

[0272] (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD in an amount of about 5 mg to 100 mg on days 1 to 21 of the first 21-day cycle; and

[0273] (b) Atezolizumab was administered at 1200 mg on Day 1 of the first 21-day cycle.

[0274] Embodiment 43. The method of 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.

[0275] Embodiment 44. The method according to any one of Embodiments 39 to 43, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0276] 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).

[0277] Embodiment 46. The method of any one of Embodiments 39 to 43, wherein the melanoma is a BRAF WT melanoma.

[0278] Embodiment 47. Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating lung cancer, head and neck cancer or melanoma as described herein (U1).

[0279] Embodiment 48. The use according to Embodiment 47, further comprising a dosing regimen comprising: (a) QD administration of Compound 1 or a pharmaceutically acceptable salt thereof on Days 1 to 21 of the first 21-day cycle; and (b) administration of atezolizumab on Day 1 of the first 21-day cycle.

[0280] Embodiment 49. The use according to Embodiment 47 or 48, further comprising: (a) administering about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on Days 1 to 21 of the first 21-day cycle; and (b) administering about 1200 mg of Atezolizumab on Day 1 of the first 21-day cycle.

[0281] Embodiment 50. Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for the manufacture of a medicament (U5) for the treatment of lung cancer, head and neck cancer or melanoma.

[0282] Embodiment 51. The use according to Embodiment 50, further comprising: (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on Days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab Q3W on Day 1 of the first 21-day cycle.

[0283] Embodiment 52. The use according to Embodiment 50 or 51, further comprising: (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on Days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab on Day 1 of the first 21-day cycle.

[0284] Embodiment 53. The use according to any one of Embodiments 50 to 52, further comprising: (a) administering about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on Days 1 to 21 of the first 21-day cycle; and (b) administering about 1200 mg of atezolizumab on Day 1 of the first 21-day cycle.

[0285] Embodiment 54. The use according to any one of embodiments 50 to 53, wherein the dosing regimen comprises two or more cycles.

[0286] Embodiment 55. The 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.

[0287] Embodiment 56. The 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.

[0288] Embodiment 57. The use according to any one of Embodiments 47 to 56, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0289] Embodiment 58. The use according to any one of embodiments 47 to 56, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0290] Embodiment 59. The use according to any one of Embodiments 47 to 56, wherein the melanoma is a BRAF WT melanoma.

[0291] Embodiment 60. A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein the combination therapy is used to treat lung cancer, head and neck cancer, or melanoma.

[0292] Embodiment 61. The combination therapy according to Embodiment 60, wherein: (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD on Days 1 to 21 of the first 21-day cycle; and (b) Atezolizumab is administered Q3W on Day 1 of the first 21-day cycle.

[0293] Embodiment 62. The combination therapy according to Embodiment 60 or 61, wherein: (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD on Days 1 to 21 of the first 21-day cycle; and (b) Atezolizumab is administered on Day 1 of the first 21-day cycle.

[0294] Embodiment 63. A combination therapy according to any one of Embodiments 60 to 62, wherein: (a) about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered QD on Days 1 to 21 of the first 21-day cycle; and (b) about 1200 mg of atezolizumab is administered on Day 1 of the first 21-day cycle.

[0295] Embodiment 64. The combination therapy according to any one of Embodiments 60 to 63, wherein the dosing regimen comprises two or more cycles.

[0296] 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.

[0297] 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.

[0298] 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).

[0299] 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).

[0300] Embodiment 69. The combination therapy according to any one of Embodiments 60 to 66, wherein the melanoma is BRAF WT melanoma.

[0301] The following examples are presented by way of illustration and not limitation.

[0302] Examples

[0303] Example 1: In vitro and in vivo characterization

[0304] Drug. Compound 1 was prepared at a concentration of 60 mg / kg in 50 mM sodium citrate buffer (pH 3.0). 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 prepared as a solution in a buffer (pH 5.5) of 20 mM histidine acetate, 240 mM sucrose, and 0.02% Tween 20TM. The vehicle control for oral administration was 50 mM sodium citrate buffer (pH 3.0).

[0305] Cell lines. EMT6 breast cancer cell line was cultured in vitro, harvested in logarithmic growth phase, and resuspended in Matrigel containing medium at a 1:1 ratio (by volume). TM (BD Biosciences; San Jose, CA) in Hank's balanced salt solution (HBSS) for in vivo inoculation. Each animal was inoculated with 0.1 × 10 6 cells.

[0306] Mouse tumor model. Will carry 141 to 196mm 3 10.6-week-old Balb / c mice with tumors in the range of 1.5 to 2.5 mm were evenly divided into 4 study groups, with 10 mice in each group. At the start of dosing, the average tumor volume of all groups was 165 mm 3 . 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 each group received the treatment regimen described in Table 1. Mice were dosed for a total of 28 days or until the first sign of illness or were euthanized if weight loss was ≥20% of their body weight at the start of administration. The study extended beyond 28 days and examined the durability of the response after treatment was stopped and ended on day 102, where all remaining mice were euthanized.

[0307] Table 1. Treatment options

[0308]

[0309] Tumor and Body Weight Measurements. Tumor volume was measured in two perpendicular dimensions (length and width) using Ultra Cal-IV calipers (Model 54-10-111; Fred V. Fowler Co.; Newton, MA) and calculated according to the following formula:

[0310] Tumor size (mm 3 ) = (longer measurement value × shorter measurement value 2 )×0.5

[0311] Tumors that regressed >50% relative to their starting volume during the study were classified as partial responders (PR), while tumors whose final tumor volume corresponded to complete regression were classified as complete responders (CR). Animal body weights were measured using an Adventura Pro AV812 scale (Ohaus Corporation; Pine Brook, NJ), and the percent body weight change for each group was calculated and plotted (see Figure 4 ). Calculate the percent weight change using the following formula:

[0312] Weight change (%) = [(current weight / initial weight) - 1) × 100]

[0313] Growth analysis and group comparisons. Because tumors often grow exponentially, tumor volumes were natural log-transformed before analysis. Tumor growth was analyzed and compared using a custom function package in R (version 3.6.2); R Foundation for Statistical Computing; Vienna, Austria, which incorporates software from open source packages (e.g., lme4, mgcv, gamm4, multcomp, settings, 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). The mean tumor size was 0 (minimum) to 8 mm. 3 All raw tumor volume measurements (maximum) were judged to reflect the complete absence of tumor and were converted to 8 mm before natural log transformation. 3 A generalized additive mixed model (GAMM) was then applied to describe the changes in transformed tumor volume over time using regression splines with an automatically generated spline basis. This approach addressed both repeated measurements of the same subjects and graceful dropouts before the end of the study.

[0314] The percentage of tumor growth inhibition (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 reversely transformed to the original ratio, corrected for the initial tumor load and averaged in the same period. Positive values ​​represent anti-tumor effects, where 100% represents stagnation, and values>100% represent regression (negative values ​​represent tumor-promoting effects). The 95% confidence interval is a measure of variability based on the fitted model and data using parameterized bootstrapping. Growth contrast represents the difference in growth rate (time integral gain endpoint (endpoint Gain Integrated in Time, eGalT)) based on the area under the curve (AUC) between the treatment group and the reference group fitting. In order to calculate the growth rate based on AUC, the AUC value of the group is corrected for the initial tumor load and the slope is equivalently normalized. When the tumor shows logarithmic linear growth (i.e., fitting to a line on the natural logarithmic scale), the slope equivalent normalization of AUC causes the calculation of the fitted slope. In cases where tumors exhibit non-log linear growth (i.e., the fit is curved on a natural log scale), slope equivalent normalization results in the calculation of the constant log linear growth rate required to produce the baseline corrected AUC observed for the fit. Mathematically, this normalization is achieved by dividing each estimated baseline corrected AUC value by half the square of the common study period, yielding units of natural log 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 a measure of variability based on the fitted model and the data.

[0315] The growth rate of each individual tumor from the selected first day AUC to its final measurement time is calculated according to the AUC of the tumor volume profile within the time range after first performing a natural logarithm transformation on the tumor volume. In order to obtain the growth rate from AUC, the AUC is corrected for the initial tumor load associated with the period, and then the slope equivalent normalization is performed. In this normalization step, the baseline-corrected AUC value is divided by half of the square of the specified period. When the exponential growth on the original scale is linear on the natural logarithm scale, the default unit of the metric is natural logarithm unit / day. Positive values ​​represent growth, negative values ​​represent regression, and 0 indicates stagnation. The more positive the value, the faster the tumor grows. The more negative the value, the faster the tumor regression. For the purpose of group comparison, individual growth rates based on AUC are not calculated.

[0316] In Balb / c mice bearing EMT6 breast cancer, anti-tumor efficacy was assessed after treatment with a single agent, compound 1 (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 produce efficacy, with compound 1 causing 47% TGI and -0.033 GR relative to vehicle control, and anti-PD-L1 causing 30% TGI and -0.022 GR. In contrast, the combination of compound 1 and anti-PD-L1 showed an enhanced anti-tumor response close to tumor stasis after 20 days of dosing, and caused 92% TGI and -0.098 GR relative to vehicle control. In addition, sustained anti-tumor efficacy was observed after cessation of 28-day dosing treatment, with 1 / 10 PR and 5 / 10 CR (see Figure 1 , Figure 2 , Figure 3 All treatments were well tolerated as determined by percent body weight change.

[0317] Table 2. Summary of the effects of compound 1 and anti-PD-L1 combination therapy on EMT6 breast cancer in BALB / c mice

[0318]

[0319] CI = confidence interval; CR = complete responder; PR = partial responder; EOS = end of study; TGI = tumor growth inhibition; %TGI = percent tumor growth inhibition based on AUC (see data analysis section for equation). Vehicle control was 50 mM sodium citrate buffer (PH 3.0)

[0320] Tumor Immune Profiling. Anti-tumor immunity was assessed in EMT6 breast tumors by flow cytometric immune profiling of tumor cells and tumor-infiltrating immune cells after tumors were treated for 7 days with 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.

[0321] Tumor cells (CD45 negative cells) assessed for expression of MHC-I and PD-L1 revealed that the mean fluorescence intensity (MFI) expressed by MHC-I (p=0.0354 and p=0.0044, respectively) and PD-L1 (p=0.0127 and p=0.0018, respectively) were significantly increased in the treatment groups using compound 1 alone and in combination with anti-PD-L1 relative to the mean fluorescence intensity in the vehicle group (see Figure 4 ).

[0322] In tumors from mice treated with Compound 1 alone or in combination with anti-PD-L1 antibody, the frequencies of MDSCs (p=0.0058 and p=0.0083, respectively) and TAMs (p=0.0072 and p=0.0098, respectively) were decreased relative to the vehicle group ( Figure 5 A). In addition, in the tumor microenvironment of mice treated with compound 1 alone or in combination with anti-PD-L1, the frequency of the M1 macrophage population increased relative to the vehicle group (p=0.0033 and p=0.0162, respectively), while the M2 macrophage population was compensatory decreased (p=0.0036 and p=0.0007, respectively), with the M1 / M2 ratio increased in the combined treatment (p=0.0033). Bone marrow-derived dendritic cells (DCs) showed no changes in any treatment group. These data suggest that inhibition of SHP2 by compound 1 reduces tumor MDSCs and skews the phenotype of TAMs to become more pro-inflammatory.

[0323] Assessment of tumor infiltrating lymphocytes (TIL), including CD4 + and CD8 + T cell and NK cell populations to determine the effect of SHP2 inhibition on T cell and NK cell activity. In the compound 1 and anti-PD-L1 combination group, the number of mice treated with compound 1 alone or in combination with anti-PDL1 antibody increased compared to 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) ( Figure 5 B).

[0324] The activation status of TILs was assessed by evaluating 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 repeated stimulation conditions using PMA / ionomycin. Figure 6 A). CD8 T cells derived from tumors of mice treated with Compound 1 alone or in combination with anti-PD-L1 antibody relative to vehicle. + On T cells, the expression of IFNg and TNFa increased (IFNg, p = 0.0002 and p = 0.0001; TNFa, p = 0.0016 and p = 0.0035, respectively) ( Figure 6 A), which is consistent with these T cells being more active. In tumors from mice treated with compound 1 and anti-PD-L1, CD8 + The frequency of T cells also increased (p = 0.0137). Figure 6 A) Tumor-infiltrating CD8 + The polyfunctionality of T cells (expressing IFNg and TNFa) was increased (p=0.0008 and p=0.0011, respectively).

[0325] Markers of T cell activation and exhaustion were also assessed to determine whether inhibition of SHP2 by compound 1 alone or in combination with anti-PD-L1 antibodies altered CD8 + T cell phenotype. Tumors from mice treated with compound 1 and anti-PDL1 antibody showed CD8 + The total number of T cells increases ( Figure 6 B). These data demonstrate that inhibition of SHP2 by compound 1 alone or in combination with anti-PD-L1 results in a significant increase in NK cell and CD4+ and CD8+ T cell activation in EMT6 tumors.

[0326] Together, these studies showed that the inhibition of SHP2 by the combination of compound 1 at 60 mg / kg, QD and anti-PD-L1 antibodies exhibited significant antitumor activity in the EMT6 syngeneic tumor model. In addition to the increased antitumor activity observed during the 28-day dosing interval, there was also an increase in the number of durable responders at the end of the study (day 102), with 6 / 10 (60%) ORR and 5 / 10 (50%) CR. These data indicate that the combination of 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.

[0327] These data suggest that, relative to single agents alone, combining SHP2 inhibitor Compound 1 with an anti-PD-L1 antibody promotes anti-tumor immune responses through pharmacodynamic changes observed in tumor cells as well as in the tumor microenvironment that together promote deep and durable tumor suppression in a large population of animals.

[0328] Example 2 :

[0329] Compound 1 is a potent allosteric inhibitor of recombinant human SHP2 with a 50% inhibitory concentration (IC50) of 0.7 nM. It has been characterized in a number of nonclinical cancer models. Compound 1 has also been shown to be a potent inhibitor of SHP2 in cell-based assays. SHP2 inhibition in cells was determined by measuring ERK1 / 2 phosphorylation levels 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 showed that compound 1 selectively inhibits SHP2.

[0330] The antiproliferative effect of compound 1 has been evaluated in a variety of cancer cell lines using 2D formats and anchorage-independent 3D formats. In NSCLC, esophageal squamous cell carcinoma, colorectal cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma and other tumor cell lines tested in 2D or 3D formats, compound 1 inhibited proliferation in many cell lines at IC50 values ​​below 1 nM. Antiproliferative effects were seen in cell lines with various aberrations in the RAS / MAPK signaling pathway. These in vitro results suggest that compound 1 has the potential for broad antitumor effects in a variety of tumor types.

[0331] The in vivo anti-tumor activity of compound 1 has also been tested in a variety of xenograft models. Oral administration of a single agent compound 1 showed significant anti-tumor efficacy in human tumor xenograft models such as 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. Pharmacokinetics, pharmacodynamics, and efficacy comparisons showed that the degree and duration of SHP2 inhibition were directly correlated to 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.

[0332] 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 serve as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the size and quality of tumor-specific T cell responses, thereby improving antitumor activity. Atezolizumab has minimal binding to Fc receptors, thereby eliminating detectable Fc effector function and associated antibody-mediated clearance of activated effector T cells.

[0333] Atezolizumab has shown anti-tumor activity in both nonclinical models and in cancer patients, and is being studied as a potential treatment for a variety of malignancies. Atezolizumab is being studied as a single agent in advanced cancer and adjuvant therapy settings, as well as in combination with chemotherapy, targeted therapy, and cancer immunotherapy. Atezolizumab is approved (as a single agent and / or in combination with other anticancer therapies) for the treatment of locally advanced or metastatic urothelial carcinoma, NSCLC, small cell lung cancer, triple-negative breast cancer, melanoma, and hepatocellular carcinoma.

[0334] Rationale for combination therapy with atezolizumab. Supportive clinical data emerging in the field of cancer immunotherapy suggest that therapies focused on enhancing T cell responses to cancer can result in significant survival benefits for patients with advanced malignancies. The PD-L1 pathway serves as an immune checkpoint to temporarily suppress immune responses in states of chronic antigenic stimulation, such as chronic infection or cancer. Interruption of the PD-L1 pathway represents one approach to restore tumor-specific T cell immunity.

[0335] In nonclinical pharmacodynamics (PD) and efficacy studies, the combination of SHP2 inhibitor compound 1 (at 60 mg QD) and checkpoint inhibitors (anti-PD-L1) increased the inflammatory state of the tumor microenvironment in the EMT6 breast cancer syngeneic model, enabling the immune system to effectively intervene in the tumor, resulting in a stronger anti-tumor response. (See Example 1.) In tumor cells, compound 1 plus 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. In addition, the remaining TAMs were biased toward the pro-inflammatory M1 phenotype. Compound 1 alone and in combination with anti-PD-L1 also promoted the expression of CD4 + and CD8 + The combination of compound 1 and anti-PD-L1 boosted CD8 + Increases in T cell activation states, including increases in proliferative markers Ki-67 and CD69, and T cell maturation marker ICOS1. Compound 1 and anti-PD-L1 showed potent combination efficacy in the EMT6 tumor model, producing deeper and more durable responses relative to either single agent.

[0336] High PD-L1 expression can predict response to immune checkpoint inhibitor (CPI) therapy by promoting increased PD-L1 expression, antigen presentation on tumor cells, and enhancing CD8 +T cell infiltration and activation ability, SHP2 inhibition can synergize with PD-L1 blockade in tumors. Atezolizumab has shown activity in patients with advanced malignancies. Objective responses have been observed in a wide range of malignancies, including, for example, lung cancer (e.g., NSCLC), urothelial carcinoma, RCC, melanoma (e.g., BRAF WT melanoma), colorectal cancer, head and neck cancer (e.g., HNSCC), gastric cancer, breast cancer and sarcoma.

[0337] Patients with disease-specific malignancies that are responsive to anti-PD-1 / PD-L1 activity may benefit from the combination therapies described herein. PD-L1-positive NSCLC and PD-L1-positive metastatic head and neck squamous cell carcinoma (HNSCC) are responsive to anti-PD-1 / PD-L1 agents and single-agent anti-PD-1 / PD-L1 therapy in the first-line setting, which is a recognized standard of care and has been shown to provide benefit. Despite multiple types of treatments for these diseases (e.g., chemotherapy, immunotherapy), these patients still suffer from incurable disease, representing a high unmet need.

[0338] BRAF in the second-line or later metastatic setting V600 Patients with wild-type (BRAF WT) melanoma will also be treated. These patients have incurable disease and have no approved treatments following treatment with anti-PD-L1 therapy (with or without anti-CTLA4 therapy). Typically, these patients may be treated with additional CPI therapy. Studies have shown a range of response rates (4% to 36%), suggesting that retreatment may provide some limited benefit. Adding compound 1 to atezolizumab may provide additional anti-tumor activity.

[0339] Atezolizumab was generally well tolerated. Adverse events of potential immune-mediated causes consistent with immunotherapeutic agents have been observed and include rash, influenza-like illness endocrinopathies, hepatitis or transaminase elevations, pneumonitis, colitis, and myasthenia gravis.

[0340] Compound 1 and atezolizumab will be administered until unacceptable toxicity or loss of clinical benefit is determined by the investigator after comprehensive assessment of radiographic data and clinical status (e.g., worsening of symptoms, such as pain secondary to disease). Treatment with Compound 1 and atezolizumab may continue unless radiographic disease progression is evident.

[0341] In one embodiment, treatment with the combination of Compound 1 and atezolizumab described herein will consist of a 14-day lead-in period followed by a treatment period as described herein. During the lead-in period, patients will receive treatment on Days 1 and 8, as outlined below:

[0342] Day 1: Compound 1 tablet 60 mg PO QD followed by atezolizumab 840 mg IV

[0343] Day 8: Compound 1 capsule 60 mg PO QD

[0344] After the 14-day run-in period, patients will enter the treatment period. Beginning on Day 1 of Cycle 1, patients will be treated in 21-day cycles as outlined below:

[0345] Compound 1 capsules (at the indicated dose, e.g., 20 mg, 40 mg, 60 mg) POQD on Days 1 to 21 of each cycle

[0346] ●Atezolizumab 1200 mg IV on day 1 of each cycle

[0347] The activity of Compound 1 in combination with atezolizumab will be assessed for ORR, DOR, PFS, PFS rate, and OS rate according to RECIST v1.1.

[0348] Inclusion Criteria: Patients must meet the following treatment criteria as described herein:

[0349] ● Age ≥ 18 years old when signing the informed consent form

[0350] ●Measurable disease according to RECIST v1.1

[0351] ECOG performance status of 0 or 1

[0352] Life expectancy ≥12 weeks

[0353] ●Achieve adequate hematologic and end-organ function within 14 days prior to initiation of treatment:

[0354] ○ANC≥1.5×10 9 / L(1500 / mL)

[0355] ○WBC ≥ 2,500 / mL

[0356] ○Lymphocyte count ≥ 0.5 × 10 9 / L(500 / mL)

[0357] ○ Platelet count ≥100×10 9 / L(100,000 / mL)

[0358] ○Hemoglobin ≥90 g / L (9 g / dL)

[0359] ○ Serum albumin ≥25 g / L (2.5 g / dL)

[0360] ○AST, ALT, and ALP ≤ 2.5 × ULN, except in the following cases:

[0361] ■Patients with documented liver metastases: AST and ALT ≤ 5x ULN

[0362] ■Patients with documented liver or bone metastases: ALP ≤ 5x ULN

[0363] ○Total bilirubin ≤1.5×ULN, except in the following cases:

[0364] ■ Patients with known Gilbert's disease: Total bilirubin ≤ 3 × ULN

[0365] ○ Measured or calculated creatinine clearance ≥ 50 mL / min (calculated by using the Cockcroft-Gault formula):

[0366]

[0367] Negative HIV test at screening

[0368] Negative hepatitis B surface antigen (HBsAg) at screening

[0369] ●A positive result for hepatitis B surface antibody (HBsAb) at screening or a negative result for HBsAb at screening and the following:

[0370] ○Total hepatitis B core antibody (HBcAb) is negative

[0371] ○ Total HBcAb test positive followed by quantitative HBV DNA <500 IU / mL

[0372] ○ HBV DNA testing is required for patients with negative HBsAg test, negative HBsAb test, and positive total HBcAb test.

[0373] ●A negative hepatitis C virus (HCV) antibody test at screening; or a positive HCV antibody test at screening and a negative HCV RNA test later

[0374] ○ Patients who test positive for HCV antibodies should undergo HCV RNA testing.

[0375] ● Histologically confirmed locally advanced or metastatic solid tumors that have progressed after at least one available standard therapy; or for which approved standard therapy has proven ineffective or intolerant; standard therapy is considered inappropriate; or the investigational agent is the recognized standard of care Additional inclusion criteria for NSCLC

[0376] Histologically confirmed locally advanced or metastatic NSCLC

[0377] ●No prior systemic therapy for locally advanced or metastatic NSCLC (adjuvant therapy allowed)

[0378] ●Availability of representative tumor samples suitable for determination of EGFR and ALK alterations and PD-L1 status as assessed by central or local laboratory testing

[0379] ● No EGFR and ALK alterations or other known oncogenic driver mutations for which patients would be eligible for targeted therapeutics

[0380] PD-L1 positive

[0381] Additional inclusion criteria for HNSCC

[0382] Histologically confirmed recurrent or metastatic HNSCC involving the oropharynx, oral cavity, larynx, or hypopharynx, who is considered not amenable to curative therapy

[0383] ● Results of local human papillomavirus (HPV) status testing for known oropharyngeal cancer ● No prior systemic therapy for recurrent or metastatic HNSCC ● Availability of a representative tumor specimen suitable for determination of PD-L1 status as assessed by IHC-based testing at a central or local laboratory

[0384] PD-L1 positive

[0385] Additional inclusion criteria for melanoma

[0386] ● Histologically confirmed locally advanced or metastatic (recurrent or de novo stage IV) or unresectable locally advanced (stage III) cutaneous BRAF WT melanoma (as documented by a local validated test under the Clinical Laboratory Improvement Amendments (CLIA) or equivalent certified laboratory) that has progressed during or after treatment including anti-PD-1 or anti-PD-L1 therapy as defined by the American Joint Committee on Cancer, 8th edition ● Patients must have progressive disease at study entry.

[0387] Exclusion criteria: Patients who met any of the following criteria were excluded:

[0388] ●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:

[0389] o Measurable disease as determined by RECIST v1.1 must be present outside the CNS.

[0390] oThe patient had no history of intracranial or spinal hemorrhage.

[0391] o Patients have not received stereotactic radiotherapy within 7 days prior to treatment, whole brain radiotherapy within 14 days prior to treatment, or neurosurgery within 28 days prior to treatment

[0392] Resection

[0393] oNo ongoing need for corticosteroids as treatment for CNS disease.

[0394] oIf the patient is receiving anticonvulsant therapy, the dose must be considered stable.

[0395] o Metastases are limited to the cerebellum or supratentorial regions (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).

[0396] o No evidence of progression between completion of CNS-directed therapy and initiation of study treatment.

[0397] Leptomeningeal disease or carcinomatous meningitis

[0398] History or evidence of ophthalmologic disease during the screening eye examination, including retinal vascular occlusion (RVO), central serous retinopathy (CSR), predisposing factors for RVO or CSR, or retinopathy

[0399] Uncontrolled high blood pressure

[0400] Left ventricular ejection fraction < institutional lower limit of normal or < 50%

[0401] ● History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins ● Known allergy to Chinese hamster ovary cell products or to any component of atezolizumab formulation ● Known allergy or hypersensitivity to any component of Compound 1 formulation

[0402] Uncontrolled pleural effusion or ascites requiring repeated drainage procedures (monthly or more frequently)

[0403] Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

[0404] Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol / L, calcium >12 mg / dL, or corrected calcium >ULN)

[0405] Active or history of autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody Sjögren's syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, except for the following:

[0406] ○ Patients taking thyroid replacement hormone with a history of autoimmune-related hypothyroidism were eligible for this study.

[0407] ○ Patients with type 1 diabetes who were on an insulin regimen were eligible for the study.

[0408] ○ Those who only meet the following all Patients with the conditions eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatological manifestations only (e.g., patients with psoriatic arthritis were excluded) were eligible for the study:

[0409] ■The rash must cover < 10% of the body surface area

[0410] ■Disease is well controlled at baseline and requires only low-potency topical corticosteroids.

[0411] ■No acute exacerbation of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in the past 12 months

[0412] A history of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active lung inflammation on chest computed tomography (CT) scan

[0413] ●History of radiation pneumonitis (fibrosis) that allows for radiographic field

[0414] Active pulmonary tuberculosis

[0415] ●Major surgical procedures other than diagnostic procedures within 4 weeks prior to treatment

[0416] ●Prior allogeneic stem cell or solid organ transplantation

[0417] ●Current use of antiviral therapy for HBV

[0418] ● Treatment with chemotherapy, immunotherapy, biological therapy, or investigational agents as anticancer therapy within 3 weeks or 5 drug elimination half-lives (whichever is shorter) prior to treatment; or endocrine therapy within 2 weeks prior to treatment, except for the use of gonadotropin-releasing hormone agonists or antagonists for the treatment of endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer,

[0419] Hormone therapy for hormone receptor-positive breast cancer

[0420] ●Treatment with a strong CYP3A4 inhibitor or strong CYP3A4 inducer within 14 days or five drug elimination half-lives (whichever is longer) prior to treatment

[0421] ● Therapeutic oral or IV antibiotic treatment within 2 weeks prior to starting study drug

[0422] ● History of malignancy within 5 years before screening (except for cancers investigated in this study and malignancies with negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer,

[0423] Ductal carcinoma in situ or stage I uterine cancer)

[0424] History or presence of ECG abnormalities

[0425] ●Received live attenuated vaccine within 4 weeks before treatment

[0426] ●QT interval corrected by using the Fridericia formula (QTcF) >440 ms, as demonstrated by at least two ECGs taken >30 minutes apart

[0427] History of or risk factors for ventricular arrhythmias, such as structural heart disease (eg, severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary artery disease (ischemia confirmed by symptoms or diagnostic testing), clinically significant electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia), or a family history of unexplained sudden death or long QT syndrome

[0428] ●Currently receiving medications known to prolong the QT interval

[0429] ● Treatment with H2 blockers or antacids within 14 days or 5 drug elimination half-lives (whichever is longer) prior to starting study drug

[0430] ● Treatment with a mild or moderate CYP3A4 inhibitor or mild or moderate CYP3A4 inducer (see section 4.4.2.4 for details) within 14 days or 5 drug elimination half-lives (whichever is longer) prior to treatment

[0431] ● Treatment with any herbal remedy within 14 days or 5 drug elimination half-lives (whichever is longer) prior to treatment

[0432] Patients with a history of any immunodeficiency or autoimmune disease listed in the table below are excluded from participation in the study. Exceptions to this exclusion may be patients with a history of solid medical conditions such as atopic disease or childhood arthralgias, where the clinical suspicion of autoimmune disease is low. Patients with a history of autoimmune-related hypothyroidism who are receiving a stable dose of thyroid replacement hormone may be eligible for this study. In addition, transient autoimmune manifestations of acute infectious diseases that resolve after treatment of the infectious agent (e.g., acute Lyme arthritis) are not excluded.

[0433]

[0434] Study treatment formulation, packaging and handling. Compound 1 will be provided in capsules (10 mg and 25 mg) and tablets (20 mg). Compound 1 will be administered orally in capsules or tablets. During the treatment period, Compound 1 should be taken at about the same time every day on the 1st to 21st day of each 21-day cycle. Capsules or tablets should be swallowed whole and should not be chewed, crushed or opened. Missed doses can be taken within 4 hours after the scheduled administration time. If a dose of Compound 1 is missed (i.e., not taken within 4 hours after the scheduled administration time) or if vomiting occurs when taking the dose, administration should be resumed at the next scheduled dose.

[0435] Unless otherwise indicated, compound 1 should be taken with about 240 mL of water in an empty stomach state (1 hour before or 2 hours after a meal or snack). Patients will self-administer on an outpatient basis. Patients will receive compound 1 until unacceptable toxicity or loss of clinical benefit is determined by the investigator after a comprehensive assessment of radiographic data and clinical status (see Section 3.1.3 for details).

[0436] Atezolizumab will be provided as an IV formulation in a 1200 mg / 20 mL vial. Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle following administration of Compound 1. Atezolizumab administration should begin approximately 30 minutes after oral administration of Compound 1. Administration of Atezolizumab will be performed in a monitored environment with immediate access to trained personnel and adequate equipment and medications to control possible severe reactions. Atezolizumab infusions will be administered as outlined herein. Dose adjustments of Atezolizumab are not permitted.

[0437] Where patients described herein participate in a 14-day run-in period as described herein, such patients will receive atezolizumab administered by IV infusion at a fixed dose of 840 mg on Day 1 of the run-in period. During the treatment period of the dose-finding and expansion phases, all patients will 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.

[0438] Atezolizumab will be administered after administration of Compound 1. Atezolizumab infusion should begin 30 minutes after Compound 1 administration.

[0439] Administration of atezolizumab will occur in a monitored environment with immediate access to trained personnel and adequate equipment and medications to manage severe reactions that may occur. Atezolizumab infusion will be administered according to the instructions outlined in Table 3.

[0440] Administration of the first and subsequent atezolizumab infusions

[0441]

[0442]

[0443] Permitted Therapies. Patients were allowed to use the following therapies during the study:

[0444] Oral contraceptive pills

[0445] Hormone replacement therapy

[0446] ●Prophylactic or therapeutic anticoagulation (eg, stable doses of warfarin or low molecular weight heparin)

[0447] ● Vaccination, but live attenuated vaccines are not allowed

[0448] Megestrol acetate

[0449] Mineralocorticoids (eg, fludrocortisone)

[0450] Inhaled or low-dose corticosteroids

[0451] Low-dose corticosteroids

[0452] Palliative radiation therapy (eg, to treat known bone metastases or relieve painful symptoms) is outlined as follows:

[0453] ●Premedication with antihistamines, antipyretics, and / or analgesics may be administered only for the second and subsequent atezolizumab infusions at the investigator's discretion.

[0454] Patients who experience infusion-related symptoms may receive symptomatic treatment with acetaminophen, ibuprofen, diphenhydramine, and / or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications according to local standard practice. Severe infusion-related events manifested as dyspnea, hypotension, asthma, bronchospasm, tachycardia, decreased oxygen saturation, or respiratory distress should be treated clinically with supportive therapy (e.g., supplemental oxygen and b2-adrenergic agonists).

[0455] Use therapy with caution. Systemic corticosteroids, immunosuppressive drugs, and TNF-α inhibitors may attenuate the potential beneficial immunologic effects of atezolizumab therapy. Therefore, alternative agents, including antihistamines, should be considered in the setting of routine administration of systemic corticosteroids, immunosuppressive drugs, or TNF-α inhibitors.

[0456] Prohibited Therapies. The following concomitant therapies are prohibited as described below:

[0457] ●Investigational therapy (except for study therapy specified in the protocol) is prohibited within 3 weeks or 5 drug elimination half-lives before treatment.

[0458] ● Concomitant therapies intended for the treatment of cancer (including but not limited to chemotherapy, hormone therapy, immunotherapy, radiotherapy and herbal therapies), whether approved by health authorities or experimental, are prohibited before and during treatment.

[0459] ●Live attenuated vaccines

[0460] Systemic immunostimulants (including but not limited to interferon and IL-2)

[0461] Proton pump inhibitors

[0462] Cannabidiol products

[0463] ●Strong CYP3A4 inhibitors or strong CYP3A4 inducers

[0464] For all patients in the run-in period, the following concomitant therapies are prohibited within 14 days or 5 drug elimination half-lives (whichever is longer) prior to the run-in period:

[0465] H2 blockers and antacids

[0466] ●Mild or moderate CYP3A4 inhibitors or mild or moderate CYP3A4 inducers

[0467] ●All herbal remedies

[0468] Risks Associated with Compound 1. Administration of Compound 1 has been 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.

[0469] Risks associated with inhibitors of the MAPK pathway class. Administration of MAPK pathway inhibitors has been associated with cardiomyopathy, retinopathy, cardiomyopathy, CPK increases, thromboembolic events, phototoxicity, and reproductive toxicity. Nonclinical safety studies of Compound 1 did not show evidence of cardiac, pulmonary, renal, thromboembolic, or ocular toxicity.

[0470] Risks Associated with Atezolizumab. Atezolizumab has been associated with risks such as: infusion-related reactions (IRR) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenia gravis or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis. Immune-mediated reactions may involve any organ system and may result in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).

[0471] Adverse events. Adverse events are defined herein to refer to any unfavorable medical events in clinical study individuals who administer the medicaments described herein with the combination therapy described herein, regardless of causal attribution. The terms "serious" and "critical" are not synonymous. Severity refers to the intensity of the adverse event (e.g., according to mild, moderate or severe, or according to NCICTCAE rating; see Section 5.3.3); the event itself may have relatively minor medical significance (such as severe headache, without any further findings).

[0472] Adverse events to monitor include peripheral edema, diarrhea, dyspnea, hepatitis or elevated ALT or AST, pneumonia, any thromboembolic event, systemic lupus erythematosus, events suggestive of a hypersensitivity reaction (e.g., IRR, CRS, HLH, and MAS), nephritis, ocular toxicity (e.g., uveitis, retinitis, optic neuritis), cardiac disease (e.g., atrial fibrillation, myocarditis, pericarditis), vasculitis, autoimmune hemolytic anemia, and serious skin reactions (e.g., Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal necrolysis).

[0473] Throughout the specification and claims, the words "comprise," "comprises," and "comprising" are used in a non-exclusive sense, unless the context requires otherwise. It should be understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" the embodiments.

[0474] Where ranges of values ​​are provided, it is understood that, unless the context clearly dictates otherwise, each intervening value to one-tenth of the unit of the lower limit and any other stated or intervening value in the stated range is encompassed herein. The upper and lower limits of these smaller ranges may also be independently included in smaller ranges, and any explicitly excluded limits within the stated ranges are also encompassed herein. Where the stated range includes one or both limits, ranges excluding either or both of the included limits are also encompassed herein.

[0475] For those skilled in the art to which the present invention relates, many variations and other embodiments of the present invention set forth herein will come to mind with the benefit of the above description and the teachings presented in the associated drawings. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, and variations and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, these terms are used only in a general and descriptive sense and not for the purpose of limitation.

Claims

1. A combination therapy comprising: (a) Compound 1 or a pharmaceutically acceptable salt thereof; and (b) PD-L1 binding antagonists.

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

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

4. The combination therapy according to claim 3, 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 on Day 1 of the first 21-day cycle.

5. The combination therapy according to claim 3, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered 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 therapy according to any one of claims 1 to 5, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet or capsule.

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

8. The combination therapy according to any one of claims 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.

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

10. The combination therapy according to any one of claims 3 to 9, wherein atezolizumab is administered in an amount of about 1200 mg on day 1 of each cycle.

11. The combination therapy according to any one of claims 5 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered prior to the start of the first 21-day cycle, followed by administration of atezolizumab in an amount of 840 mg.

12. The combination therapy according to any one of claims 1 to 11, wherein the combination therapy is administered to a patient in need thereof, said patient having lung cancer, head and neck cancer, or melanoma.

13. The combination therapy of claim 12, wherein the patient is PD-L1 positive.

14. The combination therapy according to claim 12 or 13, wherein the patient is PD-L1 high.

15. The combination therapy according to any one of claims 12 to 14, wherein the patient is PD-L1 low.

16. The combination therapy according to any one of claims 13 to 15, wherein the PD-L1 positivity is determined by PD-L1 immunohistochemistry (IHC) assay.

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

18. A method of treating lung cancer, head and neck cancer, or melanoma in a patient in need thereof, the method 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) PD-L1 binding antagonists. The method of claim 18 , wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

20. The method of claim 18, wherein the anti-PD-L1 antibody is atezolizumab.

21. The method of claim 20, wherein the treatment period comprises: (a) QD administration of Compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab on Day 1 of the first 21-day cycle.

22. The method of claim 20, wherein the treatment period comprises: (a) administering Compound 1 or a pharmaceutically acceptable salt thereof BID on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab on Day 1 of the first 21-day cycle.

23. The method of any one of claims 18 to 22, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet or capsule.

24. The method of any one of claims 18 to 23, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to 100 mg.

25. The method of any one of claims 18 to 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.

26. The method of any one of claims 20 to 25, wherein atezolizumab is administered Q3W in an amount of about 800 mg to about 1400 mg.

27. The method of any one of claims 20 to 26, wherein atezolizumab is administered in an amount of about 1200 mg on day 1 of each cycle.

28. The method according to any one of claims 20 to 27, wherein the method further comprises a lead-in period comprising administering Compound 1 or a pharmaceutically acceptable salt thereof before the start of the first cycle, followed by administration of atezolizumab in an amount of 840 mg.

29. The method according to claim 28, wherein the lead-in period comprises 1 to 14 days.

30. The method according to claim 28 or 29, wherein the lead-in period is 14 days, and Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered on day 1 of the lead-in period.

31. The method of claim 28 or 29, wherein QD administration of Compound 1 or a pharmaceutically acceptable salt thereof begins on day 8 of the lead-in period.

32. The method of any one of claims 18 to 28, wherein the patient is PD-L1 positive.

33. The method of any one of claims 18 to 28 or 32, wherein the patient is PD-L1 high.

34. The method of any one of claims 18 to 28 or 32 to 33, wherein the patient is PD-L1 low.

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

36. The method of any one of claims 18 to 35, wherein the lung cancer is non-small cell lung cancer (NSCLC).

37. The method of any one of claims 18 to 35, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

38. The method of any one of claims 18 to 35, wherein the melanoma is a BRAF WT melanoma.

39. A method of treating lung cancer, head and neck cancer, or 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.

40. The method of claim 39, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

41. The method of claim 39 or 40, wherein the anti-PD-L1 antibody is atezolizumab.

42. The method of claim 41, wherein: (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD in an amount of about 5 mg to 100 mg on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab at 1200 mg on day 1 of the first 21-day cycle.

43. The method of any one of claims 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.

44. The method of any one of claims 39 to 43, wherein the lung cancer is non-small cell lung cancer (NSCLC).

45. The method of any one of claims 39 to 43, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

46. ​​The method of any one of claims 39 to 43, wherein the melanoma is a BRAF WT melanoma.

47. Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab for treating lung cancer, head and neck cancer, or melanoma as described herein.

48. The use according to claim 47, further comprising a dosing regimen comprising: (a) QD administration of Compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab on Day 1 of the first 21-day cycle.

49. The use according to claim 47 or 48, further comprising: (a) administering about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (b) administering about 1200 mg of atezolizumab on day 1 of the first 21-day cycle.

50. Use of a combination therapy 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.

51. The use according to claim 50, further comprising: (a) QD administration of Compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab Q3W on Day 1 of the first 21-day cycle.

52. The use according to claim 50 or 51, further comprising: (a) QD administration of Compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab on Day 1 of the first 21-day cycle.

53. The use according to any one of claims 50 to 52, further comprising: (a) administering about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (b) administering about 1200 mg of atezolizumab on day 1 of the first 21-day cycle.

54. The use according to any one of claims 50 to 53, wherein the dosing regimen comprises two or more cycles.

55. The use according to any one of claims 47 to 54, wherein Compound 1 is administered in an amount of about 5 mg to 100 mg.

56. The use according to any one of claims 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.

57. The use according to any one of claims 47 to 56, wherein the lung cancer is non-small cell lung cancer (NSCLC).

58. The use according to any one of claims 47 to 56, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

59. The use according to any one of claims 47 to 56, wherein the melanoma is a BRAF WT melanoma.

60. A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab, wherein the combination therapy is used to treat lung cancer, head and neck cancer, or melanoma.

61. The combination therapy according to claim 60, wherein: (a) QD administration of Compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab Q3W on Day 1 of the first 21-day cycle.

62. The combination therapy according to claim 60 or 61, wherein: (a) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (b) administering atezolizumab on Day 1 of the first 21-day cycle.

63. The combination therapy according to any one of claims 60 to 62, wherein: (a) administering about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (b) administering about 1200 mg of atezolizumab on day 1 of the first 21-day cycle.

64. The combination therapy of any one of claims 60 to 63, wherein the dosing regimen comprises two or more cycles.

65. The combination therapy of any one of claims 60 to 64, wherein Compound 1 is administered in an amount of about 5 mg to 100 mg.

66. The combination therapy of any one of claims 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.

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

68. The combination therapy of any one of claims 60 to 66, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

69. The combination therapy of any one of claims 60 to 66, wherein the melanoma is a BRAF WT melanoma.

Images