Combination therapies

Abstract

To provide combination therapies for treating KRas G12C cancers, in particular, to provide methods for treating cancer in a subject in need thereof.SOLUTION: Methods comprising administering to the subject a therapeutically effective amount of a combination of an agent that blocks Programmed Death-1 receptor (PD-1) and Programmed Death Ligand-1 (PD-L1) signaling and a KRAS G12C inhibitor of the following formula, kits comprising the compositions, and methods of use thereof are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to combination therapies useful for treating cancer. In particular, the present invention relates to therapeutically effective combinations of agents that disrupt programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) axis signaling ("PD-1 / PD-L1 inhibitors") and KRas G12C inhibitors, kits containing the compositions, and methods of use thereof. [Background technology]

[0002] Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch, cycling between inactive (GDP-bound) and active (GTP-bound) states, transducing upstream cellular signals received from multiple tyrosine kinases to downstream effectors to control various processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed over 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and result in constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single-nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177 doi:10.1158 / 1078-0432.CCR-11-3265, published online September 26, 2012).

[0004] Oncogenic KRas mutations create an immunosuppressive microenvironment that leads to resistance to immune checkpoint blockade (ICB) therapy, including anti-PD-1 and anti-PD-L1 inhibitors. Activated KRas has been shown to suppress the expression of interferon regulatory factor 2 (IRF2), which directly suppresses CXCL3 expression. This KRas-mediated suppression of IRF2 leads to increased expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs) and promotes their migration into the tumor microenvironment. The role of KRAS in regulating the immune microenvironment and primary ICB resistance in advanced colorectal cancer has been established. In colorectal cancer, anti-PD-1 resistance in KRAS-expressing tumors can be overcome by forced IRF2 expression or by CXCR2 inhibition. (See, e.g., Liao et al., (2019) Cancer Cell 35:559-572.)

[0005] Furthermore, oncogenic KRas signaling has been shown to promote tumor immune resistance to ICB therapy by stabilizing PD-L1 mRNA through repression of the AU-rich element-binding protein tristetraprolin (TTP), which negatively regulates PD-L1 expression via AU-rich elements in the 3'UTR of PD-L1 mRNA (see, e.g., Coelho et al., (2017) Immunity 47(6):1083-1099).

[0006] Oncogenic KRas has also been shown to impair antigen presentation by suppressing MHC I expression, thereby enabling tumor cells to evade cytotoxic T lymphocytes (see, e.g., El-Jawhari et al., (2014) Molecular Immunology 58(2):160-168), and KRas-activating mutations upregulate IL-8 expression in NSCLC, and IL-8 plays a role in cell growth and migration in KRas-associated NSCLC (see, e.g., Sunaga et al., (2012) Int. J. Cancer 130(8):1733-1744).

[0007] Thus, activated KRas G12C expression regulates many aspects of the immune system and contributes to the immunosuppressive tumor microenvironment of KRas G12C-associated tumors. Therefore, direct inhibition of KRas G12C-mediated cellular activity should reverse this reported immunosuppressive tumor microenvironment and thereby improve the clinical activity of immune checkpoint inhibitor therapy, including the PD-1 / PD-L1 pathway.

[0008] For all the aforementioned reasons, it is necessary to develop combination therapies using KRas G12C inhibitors and ICB therapy, including anti-PD-1 and anti-PD-L1 inhibitors, to treat KRas G12C-associated cancers that are resistant to ICB therapy.

Prior Art Documents

Non-Patent Documents

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Summary of the Invention

[0010] Note: There seems to be a small error in the translation of line ID=23 where "6169-6177 doi:10" was wrongly split into "6-169-6177 doi:10". It should be "6169-6177 doi:10". The above translation has been corrected accordingly.In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an agent that disrupts programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) axis signaling (a "PD-1 / PD-L1 inhibitor") and a KRAS G12C inhibitor of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is a 4- to 12-membered saturated or partially saturated monocyclic, bridged, or spiro ring, and the saturated or partially saturated monocyclic ring optionally contains one or more R 8 is replaced by Y is a bond, O, S, or NR 5 and R 1 teeth, [ka] and R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl optionally comprises one or more R 9 may be substituted with Z is C1-C4 alkylene; Each R 3 are independently C1-C3 alkyl, oxo, or haloalkyl; L is a bond, —C(O)—, or C1-C3 alkylene; R 4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl may optionally be one or more R 6 or R 7 may be substituted with Each R 5 are independently hydrogen or C1-C3 alkyl; R 6 is a cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of which may optionally be one or more R 7 may be substituted with Each R 7 are independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, and Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, and C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 )2, or heteroaryl, Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R11 is haloalkyl, R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2, or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is optionally substituted with one or more R 7 is replaced by m is zero or an integer from 1 to 2; p is 1 or 2; [ka] If is a triple bond, R A is absent, and R B exists and p is equal to 1 or or [ka] is a double bond, R A exists and R B exists and p is equal to 2 or R A , R B and the carbon atom to which they are attached may optionally be joined by one or more R 7 Forms a 5-8 membered partially saturated cycloalkyl substituted with

[0011] For use in the methods provided herein, the KRas G12C inhibitor compound of Formula I, having formula IA, [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L, and m are as defined in Formula I, and the piperazinyl ring is optionally R 8 is substituted with R 8 is as defined in Formula I.

[0012] For use in the methods provided herein, a KRas G12C inhibitor compound of Formula I having formula IB is [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 3 , R 4 , L, and m are as defined in Formula I; R 2 , optionally with one or more R 9 heterocyclylalkyl substituted with 9 is as defined in formula I, and the piperazinyl ring is optionally 8 wherein R 8 is as defined in Formula I).

[0013] In another aspect of the invention, a pharmaceutical combination is provided for use in a method, comprising a therapeutically effective amount of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one embodiment, the PD-1 / PD-L1 inhibitor binds to and / or inhibits the activity of the PD-1 receptor. In one embodiment, the PD-1 / PD-L1 inhibitor binds to and / or inhibits the signaling of a PD-L1 ligand.

[0014] In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer. In one embodiment, the PD-1 / PD-L1 inhibitor binds to and / or inhibits the activity of the PD-1 receptor. In one embodiment, the PD-1 / PD-L1 inhibitor binds to and / or inhibits PD-L1 ligand signaling.

[0015] Also provided is a method of treating a KRas G12C-associated cancer in a subject in need thereof, wherein the KRas G12C-associated cancer is resistant to treatment with a PD-1 / PD-L1 inhibitor, comprising administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0016] Also provided is a method of treating a subject identified or diagnosed with a KRas G12C-associated cancer and determined to have previously developed resistance to treatment with a PD-1 / PD-L1 inhibitor, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0017] Also provided is a method for suppressing resistance to treatment with a PD-1 / PD-L1 inhibitor in a subject having a KRas G12C-associated cancer, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0018] Also provided herein are methods of treating a subject identified or diagnosed with a KRAS G12C-associated cancer, comprising: (a) detecting resistance of the KRas G12C-associated cancer in the subject to treatment with a PD-1 / PD-L1 inhibitor previously administered to the patient; and (b) after (a), administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0019] Also provided herein is a method of treating a subject identified or diagnosed with a KRas G12C-associated cancer and determined to have previously developed resistance to treatment with a KRAS G12C inhibitor, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0020] Also provided herein are methods of treating a subject identified or diagnosed with a KRas G12C-associated cancer, comprising: (a) administering a KRAS G12C inhibitor as monotherapy until disease progression; and (b) following (a), administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0021] In some embodiments of the invention, the KRas G12C inhibitor compound and the PD-1 / PD-L1 inhibitor are the only active agents in the combinations and methods provided.

[0022] Examples of PD-1 / PD-L1 inhibitors that bind to and / or inhibit the activity of the PD-1 receptor and are suitable for the provided combinations and methods include nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), and tislelizumab, and biosimilars thereof. Examples of PD-1 / PD-L1 inhibitors that bind to and / or inhibit the activity of a PD-L1 ligand and are suitable for the provided combinations and methods include atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and biosimilars thereof.

[0023] Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising: (a) determining (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit) that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the combination induces a durable complete response in the patient compared to either the PD-1 / PD-L1 inhibitor or the KRas G12C inhibitor alone.

[0024] In one embodiment of this method, the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and the KRas G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered simultaneously. In one embodiment of this method, the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, is administered weekly for 3 weeks, and the KRas G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered daily for about 28 days.

[0025] Also provided herein are kits comprising a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Also provided are kits comprising a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating KRas G12C cancer.

[0026] In a related aspect, the present invention provides a kit comprising a dose of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in amounts effective to inhibit the growth of cancer cells in a subject. The kit, in some cases, includes an insert comprising instructions for administering the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The insert may provide the user with a set of instructions for using the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0027] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally where the previous treatment was unsuccessful, and / or the patient has undergone surgery, optionally where the surgery was unsuccessful, and / or the patient has been treated with a platinum-based chemotherapy agent, optionally where the patient has previously been determined to be non-responsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, optionally where the previous treatment with the kinase inhibitor was unsuccessful, and / or the patient has been treated with one or more other therapeutic agent(s). DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention relates to a combination therapy for treating KRas G12C cancer. In particular, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, a kit comprising the method, a kit comprising the composition, and a method of use thereof.

[0029] In one embodiment, the combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, induces a durable complete response in an animal having a KRas G12C-associated cancer compared to the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof administered as a single agent.

[0030] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0031] As used herein, "KRas G12C" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Cys.

[0032] As used herein, "KRas G12C inhibitor" refers to a compound of the present invention represented by Formula (I), Formula IA, and Formula IB described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitor of the present invention interacts with KRas G12C and irreversibly binds to it by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, thereby inhibiting the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof).

[0033] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has KRas G12C mutation.A non-limiting example of a KRas G12C-associated disease or disorder is KRas G12C-associated cancer.

[0034] As used herein, programmed cell death protein 1 (PD-1) is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily that suppresses immune responses by transmitting negative cell signals through interaction with its two ligands, PD-L1 or PD-L2.

[0035] As used herein, a "PD-1 / PD-L1 inhibitor" refers to an agent that can negatively regulate or inhibit all or part of PD-1 / PD-L1 axis signaling activity, including agents that block PD-1 or PD-L1. Examples include PD-1 and PD-L1 binding antagonists such as anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0036] As used herein, the term "PD-1 binding antagonist" refers to a PD-1 inhibitor, i.e., a molecule that reduces, blocks, inhibits, neutralizes, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. In some embodiments, a PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its binding partners. In certain aspects, a PD-1 inhibitor inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 inhibitors include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, neutralize, or prevent signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, a PD-1 inhibitor reduces negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes that mediate signaling through PD-1, rendering dysfunctional T cells less dysfunctional. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the PD-1 antibody is pembrolizumab or a biosimilar thereof. In one embodiment, the PD-1 antibody is cemiplimab or a biosimilar thereof. In one embodiment, the PD-1 antibody is tislelizumab or a biosimilar thereof.

[0037] As used herein, the term "PD-L1 binding antagonist" refers to a PD-L1 inhibitor, i.e., a molecule that reduces, blocks, inhibits, neutralizes, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, such as PD-1 and / or B7-1. In some embodiments, a PD-L1 inhibitor is a molecule that inhibits the binding of PD-L1 to its binding partners. In particular aspects, PD-L1 inhibitors inhibit the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, PD-L1 inhibitors include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, neutralize, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In one embodiment, the PD-L1 inhibitor reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediate PD-L1-mediated signaling, rendering dysfunctional T cells less dysfunctional. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In a specific aspect, the anti-PD-L1 antibody is avelumab or a biosimilar thereof. In another specific aspect, the anti-PD-L1 antibody is atezolizumab or a biosimilar thereof. In another specific aspect, the anti-PD-L1 antibody is durvalumab or a biosimilar thereof. In another specific aspect, the anti-PD-L1 antibody is BMS-936559 (BMS-936559) or a biosimilar thereof.

[0038] "Biosimilar" means an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody (e.g., nivolumab or pembrolizumab), and may optionally have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).

[0039] As used herein, "complete response" refers to a subject having a KRas G12C-associated cancer who has been treated with a combination of a PD-1 / PD-L1 inhibitor and a KRas G12C inhibitor of the present invention, where at some stage of treatment the treated tumor is no longer detectable by palpation, calibration, or standard therapeutic methods for detecting such tumors that eventually recur. The duration of complete response is typically measured in days.

[0040] As used herein, a "durable complete response" refers to a subject with a KRas G12C-associated cancer who has been treated with a combination of a PD-1 / PD-L1 inhibitor and a KRas G12C inhibitor of the present invention, wherein the treated tumor is no longer detectable by palpation, calibration, or standard therapeutic methods for detecting such tumors, the tumor does not recur due to anti-tumor immune memory induced in the subject, remains undetectable after treatment and / or in patient-derived animal models (PDX), and is difficult to re-challenge using tumor cells identical to the initial tumor type. The duration of a durable complete response is typically measured in weeks, months, or years.

[0041] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have tumor(s) that are positive for the KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has a KRas G12C mutation (e.g., if the tumor is identified as such using a regulatory approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0042] The term "pediatric patient" as used herein refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years (until their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0043] In some embodiments of any of the methods or uses described herein, assays used to determine whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample such as a paraffin-embedded biopsy sample or a biopsy sample from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient with one or more symptoms of a KRas G12C-associated cancer, and / or a patient at increased risk of developing a KRas G12C-associated cancer)) can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0044] The term "regulatory authority" refers to a national agency that approves pharmaceutical agents for medical use in that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0045] The term "amino" refers to -NH2.

[0046] The term "acyl" refers to -C(O)CH3.

[0047] The term "alkyl," as used herein, refers to straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, optionally substituted with 1, 2, or 3 substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0048] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl.

[0049] The term "haloalkyloxy" refers to -O-haloalkyl.

[0050] An "alkylene" group, as defined herein above, is an alkyl group that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0051] The term "alkoxy" refers to -OC1-C6 alkyl.

[0052] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, e.g., 3 to 8 carbons, and as a further example, 3 to 6 carbons, wherein the cycloalkyl group is further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0053] The term "heteroalkyl" refers to an alkyl group, as defined herein above, wherein one or more carbon atoms in the chain is replaced by a heteroatom selected from the group consisting of O, S, and N.

[0054] As used herein, the term "hydroxyalkyl" refers to -alkyl-OH.

[0055] The term "dihydroxyalkyl" refers to an alkyl group, as defined herein, in which two carbon atoms are each replaced with a hydroxyl group.

[0056] The term "alkylaminyl" means -NR x - refers to alkyl, R x is hydrogen. In one embodiment, R x is hydrogen.

[0057] The term "dialkylaminyl" refers to -N(R y )2, each R y is C1-C3 alkyl.

[0058] The term "alkylaminylalkyl" means -alkyl-NR x - refers to alkyl, R x is hydrogen. In one embodiment, R x is hydrogen.

[0059] The term "dialkylaminylalkyl" refers to -alkyl-N(Ry )2, each R y is C1-C4 alkyl, -alkyl-N(R y The alkyl in 2 may be optionally substituted with hydroxy or hydroxyalkyl.

[0060] An "aryl" group is a C-C alkyl group containing one to three aromatic rings, which may be optionally substituted. 14 In one embodiment, the aryl group is a C-C 10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0061] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which independently may be optionally substituted or unsubstituted. Examples of aralkyl groups include (C-C) alkyl (C-C 10 ) aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. An example of a substituted aralkyl is when an alkyl group is substituted with a hydroxyalkyl.

[0062] A "heterocyclyl" or "heterocyclic" group is a ring structure having about 3 to about 12 atoms, e.g., 4 to 8 atoms, in which one or more atoms are selected from the group consisting of N, O, and S, and the remainder of the ring atoms are carbon. A heterocyclyl can be a monocyclic, bicyclic, spirocyclic, or bridged ring system. A heterocyclic group optionally has an R on a carbon or ring nitrogen at one or more positions. 7 is substituted with R 7is as defined for Formula I. Heterocyclic groups are also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl, 1,1-dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane, and oxazabicycloheptane. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0063] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, attached to the remainder of the molecule via an alkyl linker, wherein the alkyl linker of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.

[0064] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 pi electrons shared in a circular array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, Indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthroline Anthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydropyrrolinyl thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0065] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, where the radical is on the alkyl group, either of which is independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0066] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a desired target, i.e., PD-1 / PD-L1 or KRas G12C. Such an amount can be administered as a single dose or according to a regimen, whereby it is effective.

[0067] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some way reduce symptoms, or to halt or reverse the progression of a condition, or to negatively regulate or inhibit the activity of PD-1 / PD-L1 or KRas G12C. Such an amount can be administered as a single dose or according to a regimen, whereby it is effective.

[0068] As used herein, a "therapeutically effective amount" of two compounds is an amount that synergistically increases the activity of the combination compared to the therapeutically effective amounts of each compound in the combination. For example, in vivo, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in a durable complete response in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in overall survival ("OS") in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in progression-free survival ("PFS") in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor growth regression in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor growth inhibition in a subject relative to treatment with a KRas G12C inhibitor alone.In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an improvement in stable disease duration in a subject compared to treatment with the KRas G12C inhibitor alone. The amount of each compound in the combination may be the same as or different from the therapeutically effective amount of each compound when administered alone as monotherapy, so long as the combination is synergistic. Such amounts may be administered as a single dose or according to a regimen whereby it is effective.

[0069] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0070] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical combination refers to any relief, permanent or temporary, lasting or transient, that can result from or be associated with administration of the combination.

[0071] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of a KRAS inhibitor or PD-1 / PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, or the length of treatment time with a combination therapy described herein) means that the parameter may vary above or below the numerical value listed for that parameter by as much as 10%. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. "About" used at the beginning of a list of parameters modifies the respective parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0072] Inhibitor Compounds In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0073] 1.PD-1 / PD-L1 inhibitors Programmed death protein 1 (PD-1) is an immunosuppressive receptor expressed primarily on activated T and B cells. PD-1 is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72). PD-1 contains a membrane-proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) and a membrane-distal tyrosine-based switch motif (ITSM). Two ligands that bind to PD-1, PD-L1 and PD-L2, have been identified and have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192:1027-34). PD-L1 is a ligand for PD-1 and is abundant in various human cancers (Dong et al. (2002) Nat. Med. 8:787-9). The interaction of PD-1 and PD-L1 results in a reduction of tumor-infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, and immune evasion by cancer cells (Dong et al. (2003) J. Mol. Med. 81:281-7).

[0074] Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked. For example, disruption of the PD-1 / PD-L1 interaction has been shown to increase T cell proliferation and cytokine production and block cell cycle progression.

[0075] Given that PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system, blocking the interaction between PD-1 and PD-L1 has attracted the attention of the pharmaceutical industry, leading to a new and innovative class of immune checkpoint therapies for a wide range of cancers. The PD-1 / PD-L1 pathway is a well-validated target for the development of antibody therapeutics for cancer treatment, and several anti-PD-1 and anti-PD-L1 antibodies have undergone human clinical trials for a wide variety of cancers, including NSCLC, renal cell carcinoma, melanoma, head and neck squamous cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, and other cancers. Exemplary anti-PD-1 antibodies include nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), and tislelizumab, as well as their biosimilars. Exemplary anti-PD-L1 antibodies include atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and their biosimilars.

[0076] Methods for producing agents that disrupt the PD-1 / PD-L1 signaling axis, including the antibodies described herein, are well known to those of skill in the art, and agents that disrupt the PD-1 / PD-L1 signaling axis can be obtained from a wide range of commercial suppliers in formats suitable for both research or approved human clinical use. Additionally, suitable agents that disrupt PD-1 / PD-L1 signaling for use in the compositions and methods disclosed herein, and methods for preparing such agents, as well as diagnostic and efficacy markers useful for monitoring treatment, are described in U.S. Patent Application Publication Nos. 2018 / 0327848, 2018 / 0237524, 2018 / 0148790, 2018 / 0111996, 2016 / 0 305947, 2016 / 0304969, 2016 / 0304606, 2015 / 0232555, 2015 / 0079109, 2014 / 0348743, 2014 / 0294852, 2014 / 0271684, 2014 / 0234296, 2013 / 0133091, 2011 / 0123550, and 2009 / 0217401.

[0077] 2. KRas G12C inhibitors In one embodiment, the KRas G12C inhibitor used in the method is a compound of formula (I), formula IA, or formula IB [ka] or a pharmaceutically acceptable salt thereof, wherein: X is a 4- to 12-membered saturated or partially saturated monocyclic, bridged, or spiro ring, and the saturated or partially saturated monocyclic ring optionally contains one or more R 8 is replaced by Y is a bond, O, S, or NR 5 and R 1 teeth, [ka] and R 2is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl optionally comprises one or more R 9 may be substituted with Z is C1-C4 alkylene; Each R 3 are independently C1-C3 alkyl, oxo, or haloalkyl; L is a bond, —C(O)—, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl may optionally be one or more R 6 or R 7 may be substituted with Each R 5 are independently hydrogen or C1-C3 alkyl; R 6 is a cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of which may optionally be one or more R 7 may be substituted with Each R 7 are independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, and Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5)2, wherein C1-C3 alkyl is optionally cyano, halogen, -OR 5 , -N(R 5 )2, or heteroaryl, Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl, R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2, or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is optionally substituted with one or more R 7 is replaced by m is zero or an integer from 1 to 2; p is 1 or 2; [ka] If is a triple bond, R A is absent, and R B exists and p is equal to 1 or or [ka] is a double bond, R A exists and R B exists and p is equal to 2 or R A , R B and the carbon atom to which they are attached may optionally be joined by one or more R 7 Forms a 5-8 membered partially saturated cycloalkyl substituted with

[0078] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula IA [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , L, and m are as defined in Formula I; R 11 is hydrogen, methyl, or hydroxyalkyl, and the piperidinyl ring is optionally 8 is substituted with R 8 is as defined in Formula I.

[0079] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula IB [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 9 , R 11 , L, and m are as defined in Formula I.

[0080] Non-limiting examples of KRas G12C inhibitor compounds of Formula (I), Formula IA, and Formula IB useful in the methods disclosed herein have the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0081] In one embodiment, the KRas G12C inhibitor is [ka] and pharmaceutically acceptable salts thereof.

[0082] In one embodiment, the KRas G12C inhibitor is [ka] (also referred to as Example 234) or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the KRas G12C inhibitor is [ka] (also referred to as Example 359) or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment, the KRas G12C inhibitor is [ka] (also referred to as Example 478) or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the KRas G12C inhibitor is [ka] (also referred to as Example 507) or a pharmaceutically acceptable salt thereof.

[0086] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or individual components / isomers may be prepared using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0087] In one embodiment, the KRas G12C inhibitor compound of Formula I, Formula IA, or Formula IB used in the method comprises the trifluoroacetate salt of the compound.

[0088] The method for producing the KRas G12C inhibitor disclosed herein is known.For example, commonly owned and published International PCT Application Nos. 2017 / 201161 and 2019 / 099524 describe the general reaction scheme for preparing the compound of Formula I, Formula IA or Formula IB, and also provide the detailed synthetic route for preparing each KRas G12C inhibitor disclosed herein.

[0089] The PD-1 / PD-L1 inhibitor and the KRas G12C compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, may be formulated separately into pharmaceutical compositions.

[0090] Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor according to the present invention and a pharmaceutical composition comprising a KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The KRas G12C inhibitor can be independently formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intravenous, or rectal. In certain embodiments, the pharmaceutical composition comprising a KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered intravenously. In one embodiment, the pharmaceutical composition comprising a KRas G12C inhibitor is administered orally. In one embodiment, a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor is administered parenterally, including via subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In one embodiment, a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor is administered intravenously.

[0091] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with biological systems such as cells, cell cultures, tissues, or organisms, and does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, in addition to inhibitors, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0092] As used herein, the term pharmaceutically acceptable salt refers to the salt that maintains the desired biological activity of the compound identified above and exhibits minimal or no undesired toxicological effects.Examples of such salt include but are not limited to the acid addition salt formed with inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid etc.), and the salt formed with organic acid such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known to those of skill in the art, specifically including quaternary ammonium salts of the formula --NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion that includes chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0093] The active compound or agent is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all of the above-described compositions of KRas G12C inhibitors ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and as a further example, from 0.5 to about 25 mg per 0.1 kilogram of recipient body weight per day. The effective dosage range of the pharmaceutically acceptable carrier or diluent can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as described above using the weight of the derivative or by other means known to those skilled in the art.

[0094] The pharmaceutical composition comprising the PD-1 / PD-L1 inhibitor and the pharmaceutical composition comprising the KRas G12C inhibitor may be used in any of the methods of use described herein.

[0095] Simultaneous administration The components of the pharmaceutical combinations described herein, including a PD-1 / PD-L1 inhibitor and / or a KRasG12C inhibitor, or a pharmaceutically acceptable salt thereof, for use in any of the methods herein, can be for simultaneous, separate, or sequential use. In one embodiment, the PD-1 / PD-L1 inhibitor is administered prior to the administration of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another embodiment, the PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof is administered after the administration of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another embodiment, the PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof is administered approximately simultaneously with the administration of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and the KRas G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, may be formulated into separate or individual dosage forms that can be co-administered simultaneously or sequentially.

[0096] Separate administration of each inhibitor at different times and by different routes may be advantageous in some cases. Thus, the components of a combination, i.e., a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, do not necessarily need to be administered at essentially the same time or in any order.

[0097] Oncology drugs are typically administered at a maximum tolerated dose ("MTD"), which is the highest dose of drug that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, and the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, are each administered at their respective MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered at its MTD, and the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, is each administered at an amount less than its MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered at an amount less than its MTD, and the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, is each administered at its MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, and the PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, are each administered at an amount less than their respective MTD. The administration can also be timed so that the peak pharmacokinetic effect of one inhibitor coincides with the peak pharmacokinetic effect of the other.

[0098] In one embodiment, a single dose of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered daily (i.e., approximately 24 hours apart) (i.e., once a day). In another embodiment, two doses of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., twice a day). In another embodiment, three doses of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., three times a day). In any one of these embodiments, the KRAS inhibitor is administered orally.

[0099] Examples of PD-1 / PD-L1 inhibitors suitable for the provided compositions and methods include PD-1 antibodies, including but not limited to, nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), and tislelizumab, and biosimilars thereof; and anti-PD-L1 antibodies, including but not limited to, atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and biosimilars thereof.

[0100] In one embodiment, a single dose of the PD-1 / PD-L1 inhibitor is administered. In one embodiment, the PD-1 / PD-L1 inhibitor is administered once every two weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is administered once every three weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is administered once every four weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is nivolumab and is administered once every two weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is nivolumab and is administered once every four weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is pembrolizumab and is administered once every three weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is atezolizumab and is administered once every three weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is cemiplimab and is administered once every three weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is tislelizumab and is administered once every three weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is avelumab and is administered once every two weeks. In one embodiment, the PD-1 / PD-L1 inhibitor is durvalumab and is administered once every two weeks. In any one of the foregoing embodiments, the PD-1 / PD-L1 inhibitor is administered intravenously.

[0101] Combination therapy In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer. In one embodiment, the KRas G12C-associated cancer is colorectal cancer.

[0102] In one embodiment, the invention provides a method for inducing a durable complete response in a subject having cancer, comprising administering to the subject therapeutically effective amounts of a combination of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof, wherein the subject experiences a durable complete response.

[0103] In one embodiment, the combination therapy comprises a compound having the formula [ka] (also referred to herein as Example No. 234), or a pharmaceutically acceptable salt thereof, and a PD-1 / PD-L1 inhibitor. In one embodiment, the PD-1 / PD-L1 inhibitor is nivolumab. In one embodiment, the PD-1 / PD-L1 inhibitor is pembrolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is cemiplimab. In one embodiment, the PD-1 / PD-L1 inhibitor is tislelizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is avelumab. In one embodiment, the PD-1 / PD-L1 inhibitor is durvalumab.

[0104] In one embodiment, the combination therapy comprises a compound having the formula [ka] (also referred to herein as Example No. 359), or a pharmaceutically acceptable salt thereof, and a PD-1 / PD-L1 inhibitor. In one embodiment, the PD-1 / PD-L1 inhibitor is nivolumab. In one embodiment, the PD-1 / PD-L1 inhibitor is pembrolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is cemiplimab. In one embodiment, the PD-1 / PD-L1 inhibitor is tislelizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is avelumab. In one embodiment, the PD-1 / PD-L1 inhibitor is durvalumab.

[0105] In one embodiment, the combination therapy comprises a compound having the formula [ka] (also referred to herein as Example No. 478), or a pharmaceutically acceptable salt thereof, and a PD-1 / PD-L1 inhibitor. In one embodiment, the PD-1 / PD-L1 inhibitor is nivolumab. In one embodiment, the PD-1 / PD-L1 inhibitor is pembrolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is cemiplimab. In one embodiment, the PD-1 / PD-L1 inhibitor is tislelizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is avelumab. In one embodiment, the PD-1 / PD-L1 inhibitor is durvalumab.

[0106] In one embodiment, the combination therapy comprises a compound having the formula [ka] (also referred to herein as Example No. 507), or a pharmaceutically acceptable salt thereof, and a PD-1 / PD-L1 inhibitor. In one embodiment, the PD-1 / PD-L1 inhibitor is nivolumab. In one embodiment, the PD-1 / PD-L1 inhibitor is pembrolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is cemiplimab. In one embodiment, the PD-1 / PD-L1 inhibitor is tislelizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-1 / PD-L1 inhibitor is avelumab. In one embodiment, the PD-1 / PD-L1 inhibitor is durvalumab.

[0107] By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced KRas G12C activity, which can lead to immune suppression and resistance to PD-1 / PD-L1 inhibitors. The degree of covalent modification of KRas G12C can be monitored in vitro using well-known methods, including those described in published International PCT Applications Nos. 2017 / 201161 and 2019 / 099524. Furthermore, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the amount of phosphorylated ERK to assess the effectiveness of treatment, and the dosage can be adjusted accordingly by the attending physician. Methods for measuring PD-1 and PD-L1 expression are well-known and can be used to monitor PD-1 status during treatment.

[0108] The combinations and methods provided herein can be used to treat KRas G12C-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the PD-1 / PD-L1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-associated cancer is lung cancer. In one embodiment, the KRAS G12C-associated cancer is colorectal cancer.

[0109] In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in overall survival ("OS") in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the increase in overall survival ("OS") in a subject relative to treatment with a KRas G12C inhibitor monotherapy is for the remaining lifespan of the subject. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in progression-free survival ("PFS") in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth regression in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof).In one embodiment, the PD-1 / PD-L1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and avelumab.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and durvalumab.

[0110] In another embodiment, a PD-1 / PD-L1 inhibitor is administered in combination with a KRas G12C inhibitor once disease progression has been observed with KRas G12C monotherapy, and the combination therapy provides improved clinical benefit to the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or stable disease duration in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO 2019 / 099524) or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the PD-1 / PD-L1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and avelumab.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and durvalumab.

[0111] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as lung, colon, pancreatic, prostate, breast, brain, skin, cervical, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds are effective against cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal carcinoma), and esophageal: ... adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-secreting tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampullary carcinoma, bile duct carcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant Giant cell tumors: chordoma, osteochondroma (osteochondroma), benign chordoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningiomas (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma)), fallopian tubes (carcinoma); hematology: blood It can be used to treat lymphomas (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentil dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer. In one embodiment, the KRas G12C-associated cancer is colorectal cancer.

[0112] Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising: (a) determining (e.g., using a regulatory agency-approved, e.g., FDA-approved, assay or kit) that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor and a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the PD-1 / PD-L1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.

[0113] The combinations and methods provided herein may also be used to treat a KRas G12C-associated cancer in a subject in need thereof, wherein the KRas G12C-associated cancer is resistant to treatment with a PD-1 / PD-L1 inhibitor, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0114] In one embodiment, the combinations and methods provided herein are used for the treatment of KRas G12C-associated cancers and when a patient has previously been determined to have developed resistance to treatment with a PD-1 / PD-L1 inhibitor, and comprise administering to a subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0115] In addition, the combinations and methods provided herein may also be used to suppress resistance to treatment with a PD-1 / PD-L1 inhibitor in a subject with a KRas G12C-associated cancer, comprising administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0116] In one embodiment, the invention provides a method of treating a subject identified or diagnosed with a KRAS G12C-associated cancer, comprising: (a) detecting resistance of the KRas G12C-associated cancer in the subject to treatment with a PD-1 / PD-L1 inhibitor previously administered to the patient; and (b) after (a), administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0117] The combinations and methods provided herein may also be used for treating a subject who has been identified or diagnosed with a KRas G12C-associated cancer and who has been determined to have previously developed resistance to treatment with a KRAS G12C inhibitor, comprising administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0118] In one embodiment, the invention provides a method of treating a subject identified or diagnosed with a KRas G12C-associated cancer, comprising: (a) administering a KRAS G12C inhibitor as monotherapy until disease progression; and (b) following (a), administering to the subject therapeutically effective amounts of a combination of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0119] In one embodiment, the KRas G12C inhibitor used to treat a KRas G12C-associated cancer in any of the aforementioned methods is a compound selected from Compound Nos. 1-678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the PD-1 / PD-L1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and pembrolizumab.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and durvalumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and nivolumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and pembrolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and cemiplimab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and tislelizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and atezolizumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and avelumab. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and durvalumab.

[0120] In one embodiment, the compound of Formula I, Formula IA, Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as a tablet or capsule. In one embodiment, a tablet or capsule formulation of the compound of Formula I is administered in a dose range of about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 ...0 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 30 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 30 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 1 About 20mg, about 10mg to about 15mg, about 15mg to about 100mg, about 15mg to about 95mg, about 15mg to about 90mg, about 15mg to about 85mg, about 15mg to about 80mg, about 15mg to about 75mg, about 15mg to about 70mg, about 15mg to about 65mg, Approx. 15mg to approx. 60mg, approx. 15mg to approx. 55mg, approx. 15mg to approx. 50mg, approx. 15mg to approx. 45mg, approx. 15mg to approx. 40mg, approx. 15mg to approx. 35mg, approx. 00mg, about 20mg to about 95mg, about 20mg to about 90mg, about 20mg to about 85mg, about 20mg to about 80mg, about 20mg to about 75mg, about 20mg to about 70mg, about 20mg to about 65mg, about 20mg to about 60mg, about 20mg to about 55mg, about 2 0mg to about 50mg, about 20mg to about 45mg, about 20mg to about 40mg, about 20mg to about 35mg, about 20mg to about 30mg, about 20mg to about 25mg, about 25mg to about 100mg, about 25mg to about 95mg, about 25mg to about 90mg, about 25mg to about 85 mg, about 25 mg to about 80 mg, about 25 mg to about 75 mg, about 25 mg to about 70 mg, about 25 mg to about 65 mg, about 25 mg to about 60 mg, about 25 mg to about 55 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg ~35mg, 25mg~30mg, 30mg~100mg, 30mg~95mg, 30mg~90mg, 30mg~85mg, 30mg~80mg, 30mg~75mg, 30mg~70mg, 30mg~65mg,about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45mg to about 50mg, about 50mg to about 100mg, about 50mg to about 95mg, about 50mg to about 90mg, about 50mg to about 85mg, about 50mg to about 80mg, about 50mg to about 75mg, about 50mg to about 70mg, about 50mg to about 65mg, about 50mg to about 60mg, about 50mg to about 55mg, about 55mg to about 100mg, about 55mg to about 95mg, about 55mg to about 90mg, about 55mg to about 85mg, about 55mg to about 80mg, about 55mg to about 75mg, about 55mg to about 70mg, about 55mg to about 65mg, about 55mg to about 60mg, about 60mg to about 100mg, about 60mg to about 95mg, about 60mg to about 90mg, about 60mg to about 85mg, about 60mg to about 80mg, about 60mg to about 75mg, about 60mg to about 70mg, about 60mg to about 65mg, about 65mg to about 100mg, about 65mg to about 95mg, about 65mg to about 90mg, about 65mg to about 85mg, about 65mg to about 80mg, about 65mg to about 75mg, about 65mg to about 70mg, about 70mg to about 100mg, about 70mg to about 95mg, about 70mg to about 90mg, about 70mg to about 85mg, about 70mg to about 80mg, about 70mg to about 75mg,Approximately 75mg to approximately 100mg, approximately 75mg to approximately 95mg, approximately 75mg to approximately 90mg, approximately 75mg to approximately 85mg, approximately 75mg to approximately 80mg, approximately 80mg to approximately 100mg, approximately 80mg to approximately 95mg, approximately 80mg to approximately 90mg, approximately 80m g ~ 85mg, 85mg ~ 100mg, 85mg ~ 95mg, 85mg ~ 90mg, 90mg ~ 100mg, 90mg ~ 95mg, 95mg ~ 100mg, 10mg, 15mg, 20mg, 2 The compound of formula I comprises a compound of formula I-678 (as numbered in WO2019 / 099524) or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof) in an amount of about 5 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In one embodiment, the compound of formula I is orally administered once daily (QD) for a period of time. In one embodiment, the compound of formula I is orally administered twice daily (BID) for a period of time. In one embodiment, the compound of formula I is administered at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg ~160mg, 20mg~140mg, 20mg~120mg, 20mg~100mg, 20mg~80mg, 20mg~60mg, 20mg~40mg, 40mg~500mg, 40mg~480mg, 40mg~460mg, 40m g ~ about 440mg, about 40mg - about 420mg, about 40mg - about 400mg, about 40mg - about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, about 40mg - about 300mg, about 40mg - about 280mg, about 40mg - about 260mg,about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 60mg to about 180mg, about 60mg to about 160mg, about 60mg to about 140mg, about 60mg to about 120mg, about 60mg to about 100mg, about 60mg to about 80mg, about 80mg to about 500mg, about 80mg to about 480mg, about 80mg to about 460mg, about 80mg to about 440mg, about 80mg to about 420mg, about 80mg to about 400mg, about 80mg to about 380mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg,about 120mg to about 460mg, about 120mg to about 440mg, about 120mg to about 420mg, about 120mg to about 400mg, about 120mg to about 380mg, about 120mg to about 360mg, about 120mg to about 340mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 50 0mg, about 140mg to about 480mg, about 140mg to about 460mg, about 140mg to about 440mg, about 140mg to about 420mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 500mg, about 160mg to about 480mg, about 160mg to about 460mg, about 160mg to about 440mg, about 160mg to about 420mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 500mg, about 18 0mg to about 480mg, about 180mg to about 460mg, about 180mg to about 440mg, about 180mg to about 420mg, about 180mg to about 400mg, about 180mg to about 380mg, about 180mg to about 360mg, about 180mg to about 340mg, about 180mg to about 320mg, about 180mg to about 300mg, about 180mg to about 280mg, about 180mg to about 260mg, about 180mg to about 240mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 500mg, about 200mg to about 480mg, about 200mg to about 460mg,about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 24, 0mg, about 200mg to about 220mg, about 220mg to about 500mg, about 220mg to about 480mg, about 220mg to about 460mg, about 220mg to about 440mg, about 220mg to about 420mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 500mg, about 240mg to about 480mg, about 240mg to about 460mg, about 240mg to about 440mg, about 240mg to about 420mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 500mg, about 260mg to about 480mg, about 260mg to about 460mg, about 260mg to about 440mg, about 260mg to about 420mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg g to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 3 300mg to about 460mg, about 300mg to about 440mg, about 300mg to about 420mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 500mg, about 320mg to about 480mg, about 320mg to about 460mg, about 320mg to about 440mg, about 320mg to about 420mg, about 320mg to about 400mg, about 320mg to about 380mg, about 320mg to about 360mg, about 320mg to about 340mg, about 340mg to about 500mg,Approximately 340mg to approximately 480mg, approximately 340mg to approximately 460mg, approximately 340mg to approximately 440mg, approximately 340mg to approximately 420mg, approximately 340mg to approximately 400mg, Approximately 340mg to approximately 380mg, approximately 340mg to approximately 360mg, approximately 360mg to approximately 500mg, approximately 360mg to approximately 480mg, approximately 360mg to approximately 460mg, Approximately 360mg to approximately 440mg, approximately 360mg to approximately 420mg, approximately 360mg to approximately 400mg, approximately 360mg to approximately 380mg, approximately 380mg to approximately 500mg, Approximately 380mg to approximately 480mg, approximately 380mg to approximately 460mg, approximately 380mg to approximately 440mg, approximately 380mg to approximately 420mg, approximately 380mg to approximately 400mg, approximately It is orally administered in an amount of 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg. ,

[0121] In one embodiment, the combination therapy is administered daily (over a period of time) once or twice daily, for example, at a dose of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, approx. 10 mg to approx. 80 mg, approx. 10 mg to approx. 60 mg, approx. 10 mg to approx. 40 mg, approx. 10 mg to approx. 20 mg, approx. 20 mg to approx. 400 mg, approx. 20 mg to approx. 380 mg, approx. 00mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20 mg ~ about 100mg, about 20mg - about 80mg, about 20mg - about 60mg, about 20mg - about 40mg, about 40mg - about 400mg, about 40mg - about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, about 40mg - about 300mg, About 40mg to about 280mg, about 40mg to about 260mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 120mg, about 40mg to about 1 00mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60m g ~ about 260mg, about 60mg - about 240mg, about 60mg - about 220mg, about 60mg - about 200mg, about 60mg - about 180mg, about 60mg - about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg,About 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg to about 260mg, about 80mg to about 240mg, about 80mg to about 220mg, about 80mg to about 200mg, about 80mg to about 180mg, about 80mg to about 160mg, about 80mg to about 140mg, about 80mg to about 120mg, about 80mg to about 100mg, about 100mg to about 400mg, about 10 0mg to about 380mg, about 100mg to about 360mg, about 100mg to about 340mg, about 100mg to about 320mg, about 100mg to about 300mg, about 100mg to about 280mg, about 100mg to about 260mg, about 100mg to about 240mg, about 100mg to about 220mg, about 100mg to about 200mg, about 100mg to about 180mg, about 100mg to about 160mg, about 100mg to about 140mg, about 100mg to about 120mg, about 120mg to about 400mg, about 120mg to about 380mg, about 120mg to about 360mg, about 120mg to about 340mg, about 120mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 24 0mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 400mg,Approximately 180mg to approximately 380mg, approximately 180mg to approximately 360mg, approximately 180mg to approximately 340mg, approximately 180mg to approximately 320mg, approximately 180mg to approximately 300mg, approximately 180mg to approximately 280mg, approximately 180mg to approximately 260mg, approximately 180mg to approximately 240mg, approximately 180mg to approximately 220 mg, approx. 180 mg ~ approx. 200 mg, approx. 200 mg ~ approx. 400 mg, approx. 200 mg ~ approx. 380 mg, approx. 200 mg ~ approx. 360 mg, approx. 200 mg ~ approx. 340 mg, approx. 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220m g ~ approx. 280 mg, approx. 220 mg ~ approx. 260 mg, approx. 220 mg ~ approx. 240 mg, approx. 240 mg ~ approx. 400 mg, approx. 240 mg ~ approx. 380 mg, approx. 0mg to about 280mg, about 240mg to about 260mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, about 260mg to about 280mg, Approximately 280mg to approximately 400mg, approximately 280mg to approximately 380mg, approximately 280mg to approximately 360mg, approximately 280mg to approximately 340mg, approximately 280mg to approximately 320mg, approximately 280mg to approximately 300mg, approximately 300mg to approximately 400mg, approximately 300mg to approximately 380mg, approximately 300mg to approximately 360m g, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg), as well as oral administration of a compound of Formula I in an amount of, for example, once a week, once every two weeks, once every three weeks,or intravenous administration of a PD-1 / PD-L1 inhibitor administered once every four weeks. In one embodiment, the KRas G12C inhibitor is administered orally once daily. In one embodiment, the KRas G12C inhibitor is administered orally twice daily.

[0122] In one embodiment, the PD-L1 inhibitor is avelumab or a biosimilar thereof. In one embodiment, avelumab or a biosimilar thereof is administered intravenously in an amount of about 800 mg every two weeks (Q2W) or about 10 mg / kg every two weeks (Q2W). In one embodiment, avelumab or a biosimilar thereof is administered intravenously over 60 minutes.

[0123] In one embodiment, the PD-L1 inhibitor is atezolizumab or a biosimilar thereof. In one embodiment, atezolizumab or a biosimilar thereof is administered intravenously at a dose of 1200 mg once every three weeks (Q3W) or at a dose of 840 mg every two weeks. In one embodiment, atezolizumab or a biosimilar thereof is administered intravenously over 60 minutes.

[0124] In one embodiment, the PD-L1 inhibitor is durvalumab or a biosimilar thereof. In one embodiment, durvalumab or a biosimilar thereof is administered intravenously at a dose of 10 mg / kg once every two weeks (Q2W). In one embodiment, durvalumab or a biosimilar thereof is administered intravenously over 60 minutes.

[0125] In one embodiment, the PD-1 inhibitor is nivolumab or a biosimilar thereof. In one embodiment, nivolumab or a biosimilar thereof is administered intravenously at a dose of 240 mg once every two weeks (Q2W). In one embodiment, nivolumab or a biosimilar thereof is administered intravenously at a dose of 480 mg once every four weeks (Q4W). In one embodiment, nivolumab or a biosimilar thereof is administered intravenously over 30 minutes.

[0126] In one embodiment, the PD-1 inhibitor is pembrolizumab or a biosimilar thereof. In one embodiment, pembrolizumab is administered intravenously at a dose of 200 mg once every three weeks (Q3W). In one embodiment, pembrolizumab or a biosimilar thereof is administered intravenously over 60 minutes.

[0127] In one embodiment, the PD-1 inhibitor is cemiplimab or a biosimilar thereof. In one embodiment, cemiplimab or a biosimilar thereof is administered intravenously at a dose of 350 mg once every three weeks (Q3W). In one embodiment, cemiplimab or a biosimilar thereof is administered intravenously over 30 minutes.

[0128] In one embodiment, the PD-1 inhibitor is tislelizumab or a biosimilar thereof. In one embodiment, the tislelizumab or a biosimilar thereof is administered intravenously at a dose of 200 mg once every three weeks (Q3W).

[0129] Those skilled in the art will recognize that both in vivo and in vitro testing using suitable, known, and generally accepted cellular and / or animal models are predictive of the ability of a test compound or combination to treat or prevent a given disorder.

[0130] Those skilled in the art will further recognize that human clinical trials, including first-in-human dose ranging and efficacy studies in healthy patients and / or patients afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0131] In some embodiments, the methods provided herein provide for a method of administering a medicament for a period of 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months , 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months Months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months, 1 month to 6 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, or 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months).1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%) of the volume of one or more solid tumors in a patient after treatment with the combination therapy , 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70%, 4%~65%, 4%~60% , 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75%, 6%~70%, 6%~65 %, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~80%, 8%~75%, 8%~7 0%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85%, 10%~80%, 10%~7 5%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15%~95%, 15%~90%, 15 %~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%, 15%~25%, 15%~20%,20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、70%~75%、The treatment may result in a 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100% reduction (e.g., compared to the size of one or more solid tumors in the patient before treatment).

[0132] The phrase "survival time" refers to the length of time from identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional to the time of death (caused by the cancer) of the mammal. Methods for increasing survival time in a mammal with cancer are described herein.

[0133] In some embodiments, any of the methods described herein results in an increase in patient survival time (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%, between 1% and 75%, between 1% and 70%, between 1% and 65%, between 1% and 60%, between 1% and 55%, between 1% and 50 ... ~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~360%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~400% %~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10% , 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~240%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~14 0%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~ 320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20%~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~7 0%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%, 30%~300%, 30%~280%, 30%~260%, 30%~240%, 30%~220%,30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、70%~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%、240%~360%、240%~340%、240%~320%、240%~300%、240% to 280%, 240% to 260%, 260% to 400%, 260% to 380%, 260% to 360%, 260% to 340%, 260% to 320%, 260% to 300%, 260% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%) (e.g., compared to a patient with a similar cancer who has received a different treatment or no treatment), or an increase in the remaining lifespan of the treated patient.

[0134] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally where the previous treatment was unsuccessful, and / or the patient has undergone surgery, optionally where the surgery was unsuccessful, and / or the patient has been treated with a platinum-based chemotherapy agent, optionally where the patient has previously been determined to be non-responsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, optionally where the previous treatment with the kinase inhibitor was unsuccessful, and / or the patient has been treated with one or more other therapeutic agent(s).

[0135] kit The present invention also relates to a kit comprising a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Also provided is a kit comprising a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating hematological cancers.

[0136] In a related aspect, the present invention provides a kit comprising a dose of a PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and a dose of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in amounts effective to inhibit the proliferation of cancer cells, particularly KRas G12C-expressing cancer cells, in a subject. The kit, in some cases, includes an insert containing instructions for administering the PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof and the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The insert may provide the user with a set of instructions for using the PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0137] Example A Engineering the colon cancer cell line CT26.WT to express KRas G12C This example demonstrates that the colon cancer cell line CT26.WT (ATCC CRL-2638) was genetically modified to express KRas G12C, rendering these cells sensitive to targeted therapy using KRas G12C inhibitors of the present invention.

[0138] The CT26.WT cell line is triallelic for the KRas gene (NCBI reference: NM_021284), with each allele carrying a mutation at codon 12 that changes a glycine residue (G) to an aspartic acid residue (D). To generate a CT26.WT cell line derivative carrying a KRas G12C mutation, the G12D codon was changed to a G12C codon using the CRISPR / CAS9 system (Synthego, Redwood City, CA) in the following manner.

[0139] Briefly, a synthetic modified guide RNA (sgRNA) targeting the region near the KRas 12 codon was designed and synthesized based on its high specificity and propensity to create a double-stranded break when complexed with the CAS9 DNA endonuclease. A single-stranded donor oligonucleotide (ssODN) was designed to enable homologous donor repair at the sgRNA cleavage site, introducing the desired cysteine ​​codon (GAT;D to TGT;C) at position 12 while also introducing a silent mutation to prevent re-cleavage.

[0140] The Cas9 / sgRNA riboprotein complex and ssODN were transfected into CT26.WT cells. Single-cell CT26.WT clones were isolated and their genotypes were screened by Sanger DNA sequencing to identify homozygous G12C-targeted clones.

[0141] One particular clone, the KRas G12C CT26.WT E3 clone, was selected for further analysis.

[0142] Example B Inhibition of KRas G12C-dependent cell proliferation This example demonstrates that exemplary compounds of the invention inhibit the growth of an engineered CT26.WT KRas G12C E3 clone that expresses KRas G12C with greater potency than the parental CT26.WT wild-type cell line.

[0143] Cellular inhibition of KRAs G12C by exemplary compounds of the present invention was determined by measuring the amount of intracellular ATP.

[0144] CT26.WT wild-type cells and the CT26.WT G12C E3 clone expressing KRas G12C were cultured in RPMI medium supplemented with 10% fetal bovine serum and 1% penicillin / 1% streptomycin and seeded at a density of 1,000 cells / 90 μl / well into 96-well white assay plates. Dose-response curves for compounds of the present invention were determined by adding 10 μl aliquots of various concentrations of compound stock solutions to each well in the same medium over a 10 μM concentration range, using 3-fold dilutions to a final concentration of 1.5 nM. Plates were incubated at 37°C for 3 days, and cell viability was measured on the third day using a CTG assay kit (Cell Titre Glo; Promega catalog number G7573) according to the manufacturer's instructions.

[0145] IC of each cell line on day 3 50 The values ​​were calculated using Graph pad PRISM software and the results are shown in Table 1. [Table 1]

[0146] As shown in Table 1, the CT26.WT cell line expressing KRas G12C was approximately 7-fold more sensitive to inhibition by Example 478 than the isogenic parent wild-type KRas cell line, thereby demonstrating the enhanced sensitivity and specificity of this cell line to the KRas G12C inhibitors of the present invention.

[0147] Example C In vivo model for investigating KRas G12C inhibitors - immune cell regulation This example demonstrates that in vivo administration of a KRas G12C inhibitor, alone or in combination with an anti-PD-1 antibody to CT26.WT KRas G12C E3 clone-bearing animals, results in intratumoral modulation of key immune cell populations.

[0148] BALBc mice were treated with 1 × 10 6CT26.WT KRas G12C E3 cells were inoculated into the right hind flank. Tumor volumes were 200–400 mm 3 When mice reached a size of 0.02 mm (day 0), they were divided into two sets of three groups of 5 mice each. The first group received vehicle (10% Captisol in 50 mM citrate buffer pH 5.0) daily, the second group received a 100 mg / kg oral dose of the KRas G12C inhibitor Example 478 daily for 4 days (day 4), the third group received a 10 mg / kg intraperitoneal dose of a murine anti-PD-1 antibody on days 1, 4, and 7, and the fourth group received a combination of a 100 mg / kg oral dose of the KRas G12C inhibitor Example 478 daily for 4 days and a 10 mg / kg intraperitoneal dose of a murine anti-PD-1 antibody on days 1, 4, and 7.

[0149] Approximately 3 hours after the final dose on day 4, mice were euthanized and tumors were harvested for FACS analysis (MI Bioresearch, Ann Arbor, MI). Individual tumors were homogenized, and viable tumor cells were isolated from the homogenized tumors using 7-AAD Viability dye. Isolated viable cells were separated from cellular debris by centrifugation, washed, and resuspended in ice-cold DPBS medium. 1 × 10 6 Aliquots of cells were transferred to predefined wells in deep-well 96-well plates containing specific fluorescein-tagged antibodies against extracellular and intracellular markers of specific immune cells.

[0150] One plate was designed to quantify the percentage of CD4+ and CD8+ T cells, CD69- and PD-1-expressing CD8+ T cells, KI-67+ CD8+ T cells, natural killer (NK) T cells, and CD45+ CD3+ T cells, including regulatory T cells (T-regs). Cell percentages were determined using an Attune NxT Acoustic Focusing Cytometer. The results are shown in Table 2. [Table 2]

[0151] A second plate was designed to quantify the percentage of CD45+CD11+ cells, including myeloid-derived suppressor cells (G-MDSC and M-MDSC), M1 and M2 macrophages, and dendritic cells (DCs). Cell percentages were determined using an Attune NxT Acoustic Focusing Cytometer. Positive and negative control samples were processed in parallel. The results are shown in Table 3. [Table 3]

[0152] After administration of Example 478 at 100 mg / kg for 4 days, numerous differences in immune cell populations in the tumor microenvironment were observed. For example, intratumoral CD45+ cells increased as a percentage of live cells. This increase indicates an active immune tumor microenvironment (TME), as CD45+ cells are not only a marker of hematopoietic cells but also an essential regulator of T cell and B cell antigen receptor-mediated activation (see, e.g., Perrick N. CD45. PathologyOutlines.com website. http: / / www.pathologyoutlines.com / topic / cdmarkerscd45.html). Further increases were observed in CD4 and CD4 helper T cell populations. These immune cell types are most important in stimulating killer T cells, macrophages, and B cells to initiate immune responses. The observed increase in CD8+ immune cells, cytotoxic T cells, leads to effective killing of target cells. In the presence of antigen, CD8+ T cells progress through three stages, initiated by proliferation, then contraction, and finally differentiation into long-lived memory T cells. This increase in CD8-positive immune cells may also represent an early sign of clonal expansion of CD8-positive immune cells, thus providing a mechanism for efficient recognition and killing of current and future cancer cells (e.g., Clambey et al., (2005) Immun Rev 205:170-189). Consistent with the increase in T cells, treatment of tumors with Example 478 caused an increase in CD19-positive cells. This marker, a common B-cell marker, represents a cell type that regulates the development, activation, and differentiation of B cells (e.g., see Otero & Ricket (2003) J. Immunol. 171:5921-5930). Therefore, this increase in B cells can induce high-affinity responses against pathogens and provide the host with protective, long-lived humoral immunity.

[0153] Furthermore, M1 macrophages are first responders to intracellular pathogens and exhibit high levels of phagocytic activity. The observed increase in M1 provides a rationale for increased proinflammatory cytokine signaling, a hallmark of acute inflammatory responses (Atri et al., (2018) Int J Mol Sci 19:1801). MDSCs significantly accumulate during pathological conditions and have been detected in almost all tumor models studied and cancer patients examined (see, for example, Youn & Gabrilovich (2010) Euro J Immunol 40:2969-2975). These conditions not only cause the expansion of MDSC cells but can also lead to their activation, which in turn upregulates many intermediates with potential immunosuppressive activity, such as ROS, iNOS, COX2, and arginase (Youn & Gabrilovich (2010) Euro J Immunol 40:2969-2975).

[0154] The majority of the expanded CD8+ T cell population after treatment with single-agent Example 478 expressed PD-1 (83%) and remained sensitive to inhibition by PD-L1, thereby blocking activation of these T cells; however, after 4 days of combination therapy, PD-1 surface protein expression on CD8+ T cells was blocked by binding of the PD-1 inhibitor (only 1.2% expressed PD-1), thereby preventing these T cells from being suppressed by PD-L1 and allowing these cells to become activated and mount an adaptive anti-tumor response, resulting in durable complete responses in animal models.

[0155] In summary, treatment with the KRas G12C inhibitor of the present invention results in modulation of key immune cell subtypes in the tumor, which may contribute to the overall mechanism of tumor reduction in this model. A notable contribution from treatment with a PD-1 inhibitor was the dramatic reduction in intratumoral PD-1-positive CD8 immune cells. This modulation, as documented with KRas G12C inhibitor treatment alone, suggests that reducing this immune cell population in an already immunologically hot tumor microenvironment may lead to further antitumor activity by removing existing inhibition dictated by the PD-1 / PD-L1 axis signaling pathway.

[0156] Example D In vivo model to investigate the combination of KRas G12C inhibitors plus PD-1 / PD-L1 inhibitors BALBc mice were treated with 1 × 10 6 CT26.WT KRas G12C E3 cells were inoculated into the right hind flank, and tumor volume was measured every 2–3 days using a caliper. Tumor volume was calculated using the formula: 0.5 × (length × width). 2 was calculated by

[0157] Tumor volume 200-400mm 3 When mice reached a size of 100 mg / kg (Study Day 0), they were divided into four groups of 5 mice each. The first group received vehicle (10% Captisol in 50 mM citrate buffer pH 5.0) daily until Study Day 15 and also received vehicle (BioXcel diluent) intraperitoneally on Study Days 1, 4, and 7. The second group received a 10 mg / kg intraperitoneal dose of murine anti-PD-1 antibody (F26, BioXcel) daily on Study Days 1, 4, and 7. The third group received a 100 mg / kg dose of the KRas G12C inhibitor Example 478 until Study Day 29. The fourth group received a 100 mg / kg dose of the KRas G12C inhibitor Example 478 daily until Study Day 29, in combination with a 10 mg / kg intraperitoneal dose of the F26 murine anti-PD-1 antibody on Study Days 1, 4, and 7.

[0158] On study day 29, administration of the 100 mg / kg dose of the KRas G12C inhibitor Example 478 was stopped in the single agent and combination groups.

[0159] On study day 39, four tumor-free mice in the combination group received 1 × 10 6 CT26.WT KRas G12C E3 cells were re-challenged into the contralateral left flank and mice were monitored for tumor growth over a 24 day period to determine whether a sustained adaptive immune response was observed.

[0160] Table 4 Tumor volume (mm ) of CT26.WT KRas G12C E3 clone tumor-bearing mice treated with single agents and combinations 3 ) [Table 4] [Table 5] [Table 6] [Table 7]

[0161] As shown in Table 4B, administration of anti-PD-1F26 antibody as a single agent only resulted in a minimum of 19.8% tumor growth inhibition at day 14 compared to vehicle-treated mice.

[0162] As shown in Table 4C, administration of the KRas G12C inhibitor Example 478 as a single agent produced a strong antitumor response, with all five treated mice achieving a complete response after nine days of dosing (study day 9). All five mice remained free of detectable tumors for at least five days; however, tumor growth was eventually detected at the original site of implantation in all five mice, either while still receiving Example 478 daily (three mice, study days 17, 21, and 25) or after dosing was stopped on study day 29 (two mice, study days 44 and 46).

[0163] As shown in Table 4D, coadministration of the anti-PD-1 F26 antibody and the KRas G12C inhibitor Example 478 in combination produced similarly potent anti-tumor responses, with all five treated mice (M1-M5) achieving a complete response after 14 days of dosing (study day 14). Four of the five mice (M1 and M3-M5) remained free of detectable tumors for at least 91 days after dosing with Example 478 was stopped (study day 120). Tumor growth was detected in a single mouse (M2) starting on study day 44, 15 days after dosing with Example 478 was stopped.

[0164] Four of the five mice (M1 and M3–M5) remained tumor-free on study day 39 and were re-challenged with CT26.WT KRas G12C E3 cells in the contralateral left flank. No detectable tumor growth was observed at the original implantation site (R) or the second reimplantation site (L). In contrast, implantation of the same cells into naive mice resulted in tumor formation (data not shown). These results indicated that the combination-treated animals exhibited antitumor immune memory that resulted in a sustained complete response for at least 49 days, demonstrating the superiority of combination therapy in treating KRas G12C-associated cancers and potentially preventing recurrence.

[0165] Tables 5A-5D represent repeats of the studies shown in 4A-4D. In the second study, the number of treated mice was increased from 5 per group to 10 per group.

[0166] Tumor volume 200-400mm 3 When mice reached a size of 100 mg / kg (Study Day 0), they were divided into four groups of 10 mice each. The first group received vehicle (10% Captisol in 50 mM citrate buffer pH 5.0) daily through Study Day 10 and also received vehicle (BioXcel diluent) intraperitoneally on Study Days 1, 4, and 7. The second group received a 10 mg / kg intraperitoneal dose of murine anti-PD-1 antibody (F26, BioXcel) daily on Study Days 1, 4, and 7. The third group received a 100 mg / kg dose of the KRas G12C inhibitor Example 478 through Study Day 25. The fourth group received a 100 mg / kg dose of the KRas G12C inhibitor Example 478 daily through Study Day 25, in combination with a 10 mg / kg intraperitoneal dose of the F26 murine anti-PD-1 antibody on Study Days 1, 4, and 7.

[0167] On study day 25, administration of the 100 mg / kg dose of the KRas G12C inhibitor Example 478 was stopped in the single agent and combination groups.

[0168] On study day 32, seven tumor-free mice in the combination group received 1 × 10 6 The mice were re-challenged with CT26.WT KRas G12C E3 cells in the contralateral left flank and tumor growth in the mice was monitored over a 50-day period to determine whether a sustained adaptive immune response was observed.

[0169] Table 5 Replicate tumor volumes (mm ) of CT26.WT KRas G12C E3 clone tumor-bearing mice treated with single agents and combinations 3 ) [Table 8] [Table 9] [Table 10] [Table 11]

[0170] As shown in Table 5C, administration of the KRas G12C inhibitor Example 478 as a single agent produced a strong antitumor response, with all 10 treated mice achieving a complete response after 10 days of dosing (Study Day 10). Nine of the 10 mice remained free of detectable tumors for at least four days after achieving a complete response; however, tumor growth was eventually detected in six of the nine mice at the original site of implantation while receiving Example 478 daily (five mice, Study Days 14 (M2), 17 (M4), and 19 (M1, M3, and M6)) or after dosing was stopped on Study Day 25 (one mouse (M6), Study Day 26). Three mice (M7-M9) remained tumor-free for 6 days after daily administration of Example 478 was stopped (day 31), and one mouse (M10) remained tumor-free for at least 49 days.

[0171] As shown in Table 5D, co-administration of the anti-PD-1 F26 antibody and the KRas G12C inhibitor Example 478 in combination produced a similarly potent anti-tumor response, with 9 of 10 treated mice achieving a complete response after 10 days of dosing (study day 10). Eight mice remained free of detectable tumors for at least 24 days after dosing with Example 478 was stopped (study day 49). Tumor growth was detected in 1 of 8 mice (M3) starting on study day 52.

[0172] Seven of the 10 mice (M1, M4, M5, M6, M8, M9, and M10) remained tumor-free on study day 32 and were re-challenged with CT26.WT KRas G12C E3 cells in the contralateral left flank. No detectable tumor growth was observed at the original implantation site (R) or the second re-implantation site (L) in six of the seven mice. In contrast, transplantation of the same cells into naive mice resulted in tumor formation (data not shown). Tumor formation was detected in a single mouse (M3) at the original implantation site on study day 52; however, no tumor formation was detected at the re-challenge site. These results indicated that the combination-treated animals exhibited antitumor immune memory that resulted in a sustained complete response for at least 50 days, demonstrating the superiority of combination therapy in treating KRas G12C-associated cancers and potentially preventing recurrence.

[0173] While the invention has been described in relation to particular embodiments thereof, which embodiments are capable of further modification, it will be understood that this application is generally intended to cover any variation, use, or alteration of the invention in accordance with the principles of the invention, including departures from the present disclosure that come within known or customary practice within the art to which this invention pertains and that may apply to the essential features set forth above and that fall within the scope of the following appended claims.

Claims

1. 1. A method of treating a KRas G12C-associated cancer in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor and a compound of the formula: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the PD-1 / PD-L1 inhibitor is a PD-1 inhibitor.

3. 3. The method of claim 2, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and biosimilars thereof.

4. 4. The method of claim 3, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.

5. 5. The method of claim 4, wherein the therapeutically effective amount of nivolumab or a biosimilar thereof in the combination is about 240 mg administered every two weeks.

6. 5. The method of claim 4, wherein the therapeutically effective amount of nivolumab or a biosimilar thereof in the combination is about 480 mg administered every four weeks.

7. 4. The method of claim 3, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.

8. 8. The method of claim 7, wherein the therapeutically effective amount of pembrolizumab or a biosimilar thereof in the combination is about 200 mg administered every three weeks.

9. The method of claim 7, wherein the KRas G12C-associated cancer is non-small cell lung cancer.

10. 4. The method of claim 3, wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof.

11. 11. The method of claim 10, wherein the therapeutically effective amount of pembrolizumab or a biosimilar thereof in the combination is about 350 mg administered every three weeks.

12. 4. The method of claim 3, wherein the PD-1 inhibitor is tislelizumab or a biosimilar thereof.

13. 13. The method of claim 12, wherein the therapeutically effective amount of tislelizumab or a biosimilar thereof in the combination is about 200 mg administered every three weeks.

14. 2. The method of claim 1, wherein the PD-1 / PD-L1 inhibitor is a PD-L1 inhibitor.

15. 15. The method of claim 14, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof.

16. The method of claim 15, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.

17. 17. The method of claim 16, wherein the therapeutically effective amount of atezolizumab or a biosimilar thereof in the combination is about 1200 mg administered every three weeks.

18. 16. The method of claim 15, wherein the PD-L1 inhibitor is avelumab or a biosimilar thereof.

19. 19. The method of claim 18, wherein the therapeutically effective amount of avelumab or a biosimilar thereof in the combination is about 10 mg / kg administered every two weeks or 800 mg every two weeks.

20. 16. The method of claim 15, wherein the PD-L1 inhibitor is durvalumab or a biosimilar thereof.

21. 21. The method of claim 20, wherein the therapeutically effective amount of durvalumab or a biosimilar thereof in the combination is about 10 mg / kg administered every two weeks.

22. The PD-1 / PD-L1 inhibitor and the compound of the formula 【Chemistry 2】 10. The method of claim 1, wherein the medicament for treating rheumatoid arthritis, or a pharmaceutically acceptable salt thereof, is administered on the same day.

23. The PD-1 / PD-L1 inhibitor and the compound of the formula 【Chemistry 3】 10. The method of claim 1, wherein said agonist, agonist, or a pharmaceutically acceptable salt thereof is administered on different days.

24. The compound of the formula: 【Chemistry 4】 10. The method of claim 1, wherein said compound is administered at a maximum tolerated dose, or a pharmaceutically acceptable salt thereof.

25. The PD-1 / PD-L1 inhibitor and the compound of the formula 【Chemistry 5】 The method of claim 1, wherein each of the pharmaceutically acceptable salts thereof is administered at a maximum tolerated dose.

26. The PD-1 / PD-L1 inhibitor and the compound of the formula 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, wherein a therapeutically effective amount of said combination of said compound of the formula: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, resulting in increased overall survival, increased progression-free survival, increased tumor growth regression, increased tumor growth inhibition, or increased duration of stable disease in the subject compared to treatment with ribozyme Q10 or a pharmaceutically acceptable salt thereof alone.

27. The PD-1 / PD-L1 inhibitor and the compound of the formula 【Chemistry 8】 10. The method of claim 1, wherein said medicament is a medicament for treating atopic dermatitis, or a pharmaceutically acceptable salt thereof, that results in a durable complete response.

28. a therapeutically effective amount of a PD-1 / PD-L1 inhibitor and a compound of the formula 【Chemistry 9】 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

29. 10. The method of claim 1, wherein the method comprises a durable complete response in the subject with a KRas G12C-associated cancer.

30. 1. A method of treating a KRas G12C-associated cancer in a subject in need thereof, wherein the KRas G12C-associated cancer is resistant to treatment with a PD-1 / PD-L1 inhibitor, the method comprising administering a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a compound of the formula: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

31. 1. A method for treating a KRas G12C-associated cancer that has previously been determined to have acquired resistance to treatment with a PD-1 / PD-L1 inhibitor, comprising administering to a patient a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a compound of the formula: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

32. 1. A method for suppressing resistance to treatment with a PD-1 / PD-L1 inhibitor in a subject having a KRas G12C-associated cancer, comprising administering to a subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a compound of the formula: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

33. 1. A method of treating a subject identified or diagnosed as having a KRAS G12C-associated cancer, comprising: (a) detecting resistance of the KRas G12C-associated cancer in the subject to treatment with a PD-1 / PD-L1 inhibitor previously administered to the patient; and (b) after (a), administering a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a compound of the formula: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

34. 1. A method of treating a subject identified or diagnosed with a KRas G12C-associated cancer and determined to have previously developed resistance to treatment with a KRAS G12C inhibitor, comprising administering to a subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a compound of the formula: 【Chemistry 14】 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

35. 1. A method of treating a subject identified or diagnosed with a KRas G12C-associated cancer, comprising: (a) administering a KRAS G12C inhibitor as monotherapy until disease progression; and (b) following (a), administering a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof, and a compound of the formula: 【Chemistry 15】 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

36. 2. The method of claim 1, wherein the therapeutically effective amount of the KRas G12C inhibitor is about 0.01 to 100 mg / kg per day.

37. 37. The method of claim 36, wherein the therapeutically effective amount of the KRas G12C inhibitor is about 0.1 to 50 mg / kg per day.

38. The KRas G12C-associated cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-secreting tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenoma) Cancer, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chordoma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningiomas (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor) tumors (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) )), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentil dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

39. 39. The method of claim 38, wherein the cancer is non-small cell lung cancer.

40. 39. The method of claim 38, wherein the cancer is colon cancer.

41. 39. The method of claim 38, wherein the cancer is pancreatic cancer.

42. 30. A kit comprising the pharmaceutical composition of claim 27 for treating KRas G12C cancer in a subject.

43. 1. A kit for treating KRas G12C cancer in a subject, comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor; and b) a compound of the formula: 【Chemistry 16】 、 or a pharmaceutically acceptable salt thereof; kit.

44. 43. The kit of claim 42, further comprising an insert containing instructions for administration of the pharmaceutical composition.

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