Combination therapy

Abstract

The present invention relates to a combination therapy for treating KRas G12C cancer. Specifically, 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 an agent that blocks programmed death-1 receptor (PD-1) and programmed death ligand-1 (PD-L1) signaling and a KRAS G12C inhibitor of formula (I), formula I-A or formula I-B; a kit comprising the composition and a method of using the same.

Description

Technical Field

[0001] The present invention relates to combination therapies that can be used to treat cancer. Specifically, the present invention relates to a therapeutically effective combination of an agent that disrupts programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) axis signaling ("PD-1 / PD-L1 inhibitor") and a KRas G12C inhibitor, a kit comprising the composition, and methods of using the same. Background Art

[0002] Kirsten Rat Sarcoma 2 viral oncogene homolog ("KRas") is a member of the small GTPase and Ras oncogene family. KRas acts as a molecular switch cycling between an inactive (GDP-bound) state and an active (GTP-bound) state to convert upstream cellular signals received from multiple tyrosine kinases into downstream effectors that regulate a wide variety of processes including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignant diseases was observed more than three decades 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 cause constitutive activation of KRas, and downstream signaling has 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 leading to missense mutations at codons 12 and 13 of the KRas primary amino acid sequence account for approximately 40% of these KRas driver mutations in lung adenocarcinoma, with G12C transversion being the most common activating mutation (e.g., see Dogan et al. (2012) Clin Cancer Res. 18(22):6169-6177, published online on September 26, 2012. doi:10.1158 / 1078-0432.CCR-11-3265). Oncogenic KRas mutations produce 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 inhibit the expression of interferon regulatory factor 2 (IRF2), which directly inhibits the expression of CXCL3. This KRas-mediated inhibition of IRF2 leads to increased expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs), promoting the migration of these cells 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 of KRAS-expressing tumors can be overcome by enforcing IRF2 expression or by inhibiting CXCR2. (See, e.g., Liao et al., (2019) Cancer Cell 35:559–572).

[0004] Furthermore, oncogenic KRas signaling has been shown to promote tumor immune resistance to ICB therapy by inhibiting the AU-rich element binding protein tristetraprolin (TTP) stabilizing PD-L1 mRNA, which negatively regulates PD-L1 expression through AU-rich elements in the 3'UTR of PD-L1 mRNA (e.g., see Coelho et al., (2017) Immunity 47(6):1083-1099).

[0005] Oncogenic KRas has also been shown to impair antigen presentation by inhibiting MHC I expression, thereby allowing tumor cells to evade cytotoxic T lymphocytes (e.g., see El-Jawhari et al., (2014) Molecular Immunology 58(2):160-168), and KRas activating mutations upregulate IL-8 expression in NSCLC, which plays a role in cell growth and migration in KRas-associated NSCLC (e.g., see Sunaga et al., (2012) Int. J. Cancer 130(8):1733-1744).

[0006] Thus, activated KRas G12C expression modulates many aspects of the immune system and is responsible for the immunosuppressive tumor microenvironment in KRas G12C-associated tumors. Therefore, direct inhibition of KRas G12C-mediated cellular activity should reverse this reported immunosuppressive tumor microenvironment, thereby improving the clinical activity of immune checkpoint blockade therapies, including the PD-1 / PD-L1 pathway.

[0007] For all the reasons mentioned above, there is a need to develop combination therapies using KRas G12C inhibitors and ICB therapies (including anti-PD-1 and anti-PD-L1 inhibitors) to treat KRas G12C-related cancers that are resistant to ICB therapies. Summary of the invention

[0008] In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent that disrupts programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) axis signaling ("PD-1 / PD-L1 inhibitor") in combination with a KRAS G12C inhibitor of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more R 8 replace;

[0012] Y is a bond, O, S or NR 5 ;

[0013] R 1 for or

[0014] R 2is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic or heteroaromaticalkyl, wherein each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic and heteroaromaticalkyl may be optionally replaced by one or more R 9 replace;

[0015] Z is C1-C4 alkylene;

[0016] Each R 3 are independently C1-C3 alkyl, oxo or haloalkyl;

[0017] L is a bond, -C(O)- or C1-C3 alkylene;

[0018] R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaromatic, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaromatic may be optionally replaced by one or more R 6 or R 7 replace;

[0019] Each R 5 are independently hydrogen or C1-C3 alkyl;

[0020] R 6 is a cycloalkyl, a heterocyclyl, a heterocyclylalkyl, an aryl or a heteroaromatic group, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaromatic group may be optionally replaced by one or more R 7 replace;

[0021] Each R 7 are independently halogen, hydroxy, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0022] 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 the C1-C3 alkyl group may be optionally substituted with cyano, halogen, -OR 5 、-N(R 5 )2 or heteroaromatic substituted

[0023] Each R 9are independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;

[0024] Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

[0025] R 11 is a haloalkyl group;

[0026] R A does not exist, is hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2 or hydroxyalkyl;

[0027] 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, dialkylaminoalkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 replace;

[0028] m is zero or an integer between 1 and 2;

[0029] p is one or two; and wherein,

[0030] when When it is a triple bond, R A Does not exist, R B exists and p is equal to one,

[0031] or when When it is a double bond, R A Existence, R B exists and p is equal to two, or R A , R B and the carbon atom to which it is attached form a 7 Substituted 5-8 membered partially saturated cycloalkyl.

[0032] Also included for use in the methods provided herein are KRas G12C inhibitor compounds of Formula I having Formula IA:

[0033]

[0034] 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 for Formula I, and the piperazinyl ring is optionally replaced by R 8 Substitution, where R 8 As defined for Formula I.

[0035] Also included for use in the methods provided herein are KRas G12C inhibitor compounds of Formula I having Formula IB:

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , L and m are as defined for Formula I, R 2 is optionally represented by one or more R 9 Substituted heterocyclylalkyl, wherein R 9 As defined for formula I, and the piperazinyl ring is optionally replaced by R 8 Substitution, where R 8 As defined for Formula I.

[0038] In another aspect of the present invention, a drug combination for use in the method is provided, the drug combination comprising a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a combination of a KRas G12C inhibitor compound of Formula I, Formula IA or Formula 1-B 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 the PD-L1 ligand.

[0039] In one aspect of the invention, provided herein is a method for treating cancer in a subject in need thereof, the method 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 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-related cancer. In one embodiment, the KRas G12C-related 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 the signaling of the PD-L1 ligand.

[0040] Also provided is a method of treating a KRas G12C-related cancer in a subject in need thereof, wherein the KRas G12C-related cancer is resistant to treatment with a PD-1 / PD-L1 inhibitor, the method comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0041] Also provided are methods for treating a subject identified or diagnosed as having a KRas G12C-related 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 PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0042] Also provided are methods for inhibiting resistance to PD-1 / PD-L1 inhibitor treatment in a subject with a KRas G12C-related cancer, comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0043] Also provided herein are methods for 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 to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0044] Also provided herein is a method for treating a subject identified or diagnosed as having a KRAS G12C-related 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 PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0045] Also provided herein are methods of treating a subject identified or diagnosed as having a KRAS G12C-related cancer, comprising (a) administering a KRAS G12C inhibitor as a monotherapy until disease progression, and (b) after (a), administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, in combination with a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0046] In some aspects of the invention, a KRas G12C inhibitor compound and a PD-1 / PD-L1 inhibitor are the only active agents in the provided combinations and methods.

[0047] Examples of PD-1 / PD-L1 inhibitors that bind to and / or inhibit PD-1 receptor activity suitable for use in the provided combinations and methods include nivolumab Pembrolizumab Cimiprilimab Examples of PD-1 / PD-L1 inhibitors suitable for binding and / or inhibiting PD-L1 ligand activity in the provided combinations and methods include atezolizumab Avelumab Durvalumab and its biosimilars.

[0048] Also provided herein are methods of treating cancer in a subject in need thereof, the methods comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay); and (b) administering to the patient a therapeutically effective amount of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, in combination with a KRas G12C inhibitor compound of Formula I, Formula IA, Formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the combination induces a durable complete response compared to the PD-1 / PD-L1 inhibitor or KRas G12C inhibitor alone.

[0049] In one embodiment of the method, a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRasG12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are administered simultaneously. In one embodiment of the method, a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof is administered once a week for three weeks, and a KRas G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered daily for about 28 days.

[0050] Also provided herein 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. Also provided is a kit for treating KRas G12C cancer, 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.

[0051] In a related aspect, the present invention provides a kit containing 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, wherein the dose is an amount effective to inhibit the proliferation of cancer cells in a subject. In some cases, the kit includes instructions for administering 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. The instructions can provide a user with a set of instructions for using 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.

[0052] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient was treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the previous treatment was unsuccessful; and / or surgery has been administered to the patient, and optionally, the surgery was unsuccessful; and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, and optionally, the previous treatment with the kinase inhibitor was unsuccessful; and / or the patient is treated with one or more other therapeutic agents. DETAILED DESCRIPTION

[0053] The present invention relates to a combination therapy for treating KRas G12C cancer. Specifically, the present invention relates to a method for treating cancer in a subject in need thereof, the method 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 of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof; a kit comprising the composition and a method of using the same.

[0054] In one embodiment, the 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 a pharmaceutical composition thereof, induces a durable complete response in an animal having a KRas G12C-related cancer compared to a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, administered as a single agent.

[0055] definition

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0057] As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Cys.

[0058] As used herein, "KRas G12C inhibitor" refers to a compound of the present invention represented by Formula (I), Formula IA and Formula IB as described herein. These compounds are capable of negatively regulating or inhibiting 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 thereto by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, causing inhibition of the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds Nos. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Examples No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).

[0059] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0060] 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 transmits negative cellular signals to inhibit immune responses upon interaction with its two ligands, PD-L1 or PD-L2.

[0061] As used herein, "PD-1 / PD-L1 inhibitor" refers to an agent that can negatively regulate or inhibit all or part of the PD-1 / PD-L1 axis signaling activity, and includes 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.

[0062] As used herein, the term "PD-1 binding antagonist" refers to a PD-1 inhibitor, i.e., a molecule that reduces, blocks, inhibits, eliminates or interferes with the signal transduction generated by the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. In some embodiments, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its binding partner. In a specific aspect, the 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, eliminate or interfere with the signal transduction generated by the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 inhibitor reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes, which mediate signal transduction through PD-1, thereby making the non-functional 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 cemiplizumab, or a biosimilar thereof. In one embodiment, the PD-1 antibody is tislelizumab or a biosimilar thereof.

[0063] As used herein, the term "PD-L1 binding antagonist" refers to a PD-L1 inhibitor, i.e., a molecule that reduces, blocks, inhibits, eliminates or interferes with signal transduction generated by the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In some embodiments, a PD-L1 inhibitor is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, a PD-L1 inhibitor inhibits 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, eliminate or interfere with signal transduction caused by one or more interactions of PD-L1 with its binding partners, such as PD-1 and / or B7-1. In one embodiment, a PD-L1 inhibitor reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes, which mediate signal transduction through PD-L1, thereby making the non-functional T cells less dysfunctional. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one 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 (MDX-1105) or a biosimilar thereof.

[0064] "Biosimilar" refers to an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody (e.g., nivolumab or pembrolizumab) and, optionally, may have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody (e.g., a different glycoform).

[0065] As used herein, "complete response" refers to a subject with a KRas G12C-related cancer that has been treated with a combination of a PD-1 / PD-L1 inhibitor of the present invention and a KRas G12C inhibitor, wherein the treated tumor at some stage of treatment is no longer detectable by palpation, calibration, or by standard of care methods for detecting such tumors that eventually relapse. The duration of a complete response is typically measured in days.

[0066] As used herein, "durable complete response" refers to a subject with a KRas G12C-associated cancer that has been treated with a combination of a PD-1 / PD-L1 inhibitor of the present invention and a KRas G12C inhibitor, wherein the treated tumor is no longer detectable by palpation, calibration, or standard of care methods for detecting such tumors, and the tumor cannot recur due to the anti-tumor immune memory induced in the subject, remains undetectable after treatment and / or in a patient-derived animal model (PDX), and is difficult to re-challenge using the same tumor cells of the initial tumor type. The duration of a durable complete response is typically measured in weeks, months, or years.

[0067] The terms "subject", "individual" or "patient" used interchangeably as used herein refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease or condition 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., using an assay or kit approved by a regulatory agency, such as FDA approved). In some embodiments, the subject has a tumor that is positive for a KRas G12C mutation (e.g., using an assay or kit approved by a regulatory agency, such as FDA approved). The subject may be a subject having one or more tumors that are positive for a KRas G12C mutation (e.g., using an assay or kit approved by a regulatory agency, such as FDA approved). The subject may be a subject whose tumor has a KRas G12C mutation (e.g., wherein a kit or assay approved by a regulatory agency, such as FDA approved, identifies the tumor as such). In some embodiments, the subject is suspected of having a KRas G12C gene-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0068] As used herein, the term "pediatric patient" refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 years to 21 years (up to but not including the twenty-second 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. In some embodiments of any of the methods or uses described herein, an assay for determining whether a patient has a KRasG12C mutation using a sample (e.g., a biological sample or a biopsy sample, such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRasG12C-related cancer, a patient having one or more symptoms of a KRasG12C-related cancer, and / or a patient with an increased risk of developing a KRasG12C-related cancer) is used, which may 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, the assay is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0069] The term "regulatory agency" is a national agency that approves the medical use of a pharmaceutical agent in a country. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

[0070] The term "amino" refers to -NH2;

[0071] The term "acyl" refers to -C(O)CH3.

[0072] As used herein, the term "alkyl" refers to a straight chain and branched aliphatic group 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 one, two or three substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0073] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl and fluoromethyl.

[0074] The term "haloalkoxy" refers to an -O-haloalkyl group.

[0075] "Alkylene" is an alkyl group as defined above that is located between and serves to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0076] The term "alkoxy" refers to an -OC1-C6 alkyl group.

[0077] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, such as 3 to 8 carbons and further such as 3 to 6 carbons, wherein the cycloalkyl is additionally optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0078] The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S and N.

[0079] The term "hydroxyalkyl" as used herein refers to an -alkyl-OH group.

[0080] The term "dihydroxyalkyl" refers to an alkyl group as defined herein wherein two carbon atoms are each substituted with hydroxy groups.

[0081] The term "alkylamino" refers to -NR x -alkyl, where R x In one embodiment, R x For hydrogen.

[0082] The term "dialkylamino" refers to -N(R y )2, where each R y It is a C1-C3 alkyl group.

[0083] The term "alkylaminoalkyl" refers to an -alkyl-NR x -alkyl, where R x In one embodiment, Rx For hydrogen.

[0084] The term "dialkylaminoalkyl" refers to an -alkyl-N(R y )2, where each R y is a C1-C4 alkyl group, wherein --alkyl-N(R y The alkyl group of )2 may be optionally substituted with a hydroxyl group or a hydroxyalkyl group.

[0085] "Aryl" is an optionally substituted C6-C 14 As an example, the aromatic group is C6-C 10 Aryl. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0086] "Aralkyl" or "arylalkyl" comprises an aromatic group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Examples of aralkyl groups are (C1-C6)alkyl (C6-C 10 ) aryl groups, including but not limited to benzyl, phenethyl and naphthylmethyl. An example of a substituted aralkyl group is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0087] "Heterocyclyl" or "heterocyclic group" is a ring structure having about 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O and S, and the rest of the ring atoms are carbon. The heterocyclyl can be a monocyclic, bicyclic, spirocyclic or bridged ring system. The heterocyclyl is optionally substituted by R on one or more carbon or nitrogen positions. 7 Substitution, where R 7 As defined for formula I. Heterocyclic radical is also independently optionally replaced by alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkyloxycarbonyl, or replaced by oxo or low carbon alkyl on sulfur. Examples of heterocyclic radicals include but are not limited to epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolane, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane and oxazepane. Specifically excluded from the scope of this term are compounds having adjacent ring-shaped O atoms and / or S atoms.

[0088] 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.

[0089] 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 common π electrons in a cyclic array; and each ring having, in addition to carbon atoms, one to three heteroatoms selected from the group consisting of N, O and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolinyl, indolizinyl , indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazine yl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, Tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthrenyl.

[0090] " Heteroaromatic alkyl " comprises the heteroaromatic group that is covalently connected with alkyl, wherein said group is on alkyl, and any one of them is optionally substituted or unsubstituted independently.The example of heteroaromatic alkyl comprises the heteroaromatic group with 5,6,9 or 10 ring atoms of C1-C6 alkyl bonding.The example of heteroaralkyl comprises pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolylmethyl, quinolylethyl, benzofuranylmethyl, indolinylethyl isoquinolylmethyl, isoindolylmethyl, cinnolinylmethyl and benzothienylethyl.The scope of this term specifically excludes the compound with adjacent annular O atom and / or S atom.

[0091] 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. The amount may be administered in a single dose or may be administered according to a regimen such that it is effective.

[0092] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve or alleviate symptoms in some way, or to stop or reverse the progression of a condition, or to negatively regulate or inhibit the activity of PD-1 / PD-L1 or KRas G12C. The amount can be administered in a single dose or can be administered according to a regimen, whereby it is effective.

[0093] As used herein, a "combined therapeutically effective amount" of two compounds is an amount that together synergistically increases the activity of the combination compared to the therapeutically effective amount of each compound in the combination. For example, in vivo, 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, causes a complete and durable response in the subject, relative to treatment with a KRas G12C inhibitor alone. In one embodiment, 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, causes an extension of the duration of overall survival ("OS") of the subject, relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of 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, or a pharmaceutical composition thereof, causes a prolonged progression-free survival ("PFS") duration in the subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of 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, or a pharmaceutical composition thereof, causes an increase in tumor regression in the subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of 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, or a pharmaceutical composition thereof, causes an increase in tumor growth inhibition in the subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRasG12C inhibitor compound of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof causes a prolonged duration of disease stabilization in a subject, compared to treatment with a KRasG12C inhibitor alone. The amount of each compound in the combination may be the same or different from the therapeutically effective amount of each compound when administered alone as a monotherapy, as long as the combination is synergistic. The amount may be administered in a single dosage form or may be administered according to a regimen, whereby it is effective.

[0094] 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 encompasses any pharmaceutical use of the compositions herein.

[0095] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular drug combination refers to any relief, whether permanent or temporary, sustained or transient, attributable to or associated with administration of the combination.

[0096] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of a KRAS inhibitor or a PD-1 / PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, or the duration of treatment with a combination therapy described herein) means that the degree of change in the parameter may be up to 10% lower or higher than the stated value of the parameter. For example, a dose of about 5 mg / kg can vary between 4.5 mg / kg and 5.5 mg / kg. "About" is intended to modify each parameter when used at the beginning of a parameter list. 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, and about 25% or more.

[0097] Inhibitor compounds In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0098] 1. PD-1 / PD-L1 inhibitors

[0099] Programmed death protein 1 (PD-1) is an immunosuppressive receptor that is mainly expressed on activated T cells and B cells. PD-1 is a 55kDa 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, which have been shown to downregulate T cell activation after binding to PD-1 (Freeman et al. (2000) J Exp Med 192: 1027-34). PD-L1 is a ligand of PD-1 and is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8: 787-9). The interaction between PD-1 and PD-L1 leads to a decrease in tumor-infiltrating lymphocytes, reduced T cell receptor-mediated proliferation, and immune evasion of cancer cells (Dong et al. (2003) J. Mol. Med. 81:281-7).

[0100] Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effects are 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 arrest cell cycle progression.

[0101] Given that PD-L1 is upregulated in many cancers and helps evade the host immune system, blocking the interaction between PD-1 and PD-L1 has attracted the attention of the pharmaceutical industry, leading to new breakthrough types of immune checkpoint therapies for a variety of cancers. The PD-1 / PD-L1 pathway is a well-validated target for the development of antibody therapies for cancer treatment, and several anti-PD-1 and anti-PD-L1 antibodies have been tested in human clinical trials for a 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 Pembrolizumab Cimiprilimab and tislelizumab and its biosimilars. Exemplary anti-PD-L1 antibodies include atezolizumab Avelumab Durvalumab and its biosimilars.

[0102] Methods for making 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 are available from a wide variety of commercial suppliers in a form suitable for research or approved human clinical use. In addition, suitable agents that disrupt PD-1 / PD-L1 signaling for use in the compositions and methods disclosed herein and methods of preparing such agents, as well as diagnostic and efficacy markers that can be used to monitor treatment, are disclosed in the following U.S. patent application publications: 20180327848; 20180237524; 20180148790; 20180111996; 20160305947; 20160304969; 20160304606; 20150232555; 20150079109; 20140348743; 20140294852; 20140271684; 20140234296; 20130133091; 20110123550; and 20090217401.

[0103] 2. KRas G12C inhibitors

[0104] In one embodiment, the KRas G12C inhibitor used in the method is a compound of Formula (I), Formula IA, or Formula IB:

[0105]

[0106] or a pharmaceutically acceptable salt thereof, wherein:

[0107] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more R 8 replace;

[0108] Y is a bond, O, S or NR 5 ;

[0109] R 1 for or

[0110] R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic or heteroaromaticalkyl, wherein each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic and heteroaromaticalkyl may be optionally replaced by one or more R 9 replace;

[0111] Z is C1-C4 alkylene;

[0112] Each R 3 are independently C1-C3 alkyl, oxo or haloalkyl;

[0113] L is a bond, -C(O)- or C1-C3 alkylene;

[0114] R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaromatic, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaromatic may be optionally replaced by one or more R 6 or R 7 replace;

[0115] Each R 5 are independently hydrogen or C1-C3 alkyl;

[0116] R 6 is a cycloalkyl, a heterocyclyl, a heterocyclylalkyl, an aryl or a heteroaromatic group, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaromatic group may be optionally replaced by one or more R 7 replace;

[0117] Each R 7 are independently halogen, hydroxy, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0118] 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 the C1-C3 alkyl group may be optionally substituted with cyano, halogen, -OR 5 、-N(R 5 )2 or heteroaromatic substitution;

[0119] Each R 9 are independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;

[0120] Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

[0121] R 11 is a haloalkyl group;

[0122] R A does not exist, is hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2 or hydroxyalkyl;

[0123] 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, dialkylaminoalkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 replace;

[0124] m is zero or an integer between 1 and 2;

[0125] p is one or two; and wherein,

[0126] when When it is a triple bond, R A Does not exist, R B exists and p is equal to one;

[0127] or when When it is a double bond, R A Existence, R B exists and p is equal to two, or R A , R B and the carbon atom to which it is attached form a 7 Substituted 5-8 membered partially saturated cycloalkyl.

[0128] In one embodiment, the KRas G12C inhibitors used in the methods herein include compounds having Formula IA:

[0129]

[0130] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined for Formula I, R 11 is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring is optionally replaced by R8 Substitution, where R 8 As defined for Formula I.

[0131] In one embodiment, the KRas G12C inhibitors used in the methods herein include compounds having Formula IB:

[0132]

[0133] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 9 , R 11 , L and m are as defined for Formula I.

[0134] Non-limiting examples of KRas G12C inhibitor compounds of Formula (I), Formula IA, and Formula IB that can be used in the methods disclosed herein are selected from Examples 1-678 (as numbered in International Patent Publication WO2019099524) including the following structures:

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] and pharmaceutically acceptable salts thereof.

[0184] In one embodiment, the KRas G12C inhibitor is selected from:

[0185]

[0186] and pharmaceutically acceptable salts thereof.

[0187] In one embodiment, the KRas G12C inhibitor is:

[0188]

[0189] (also known as Example 234) or a pharmaceutically acceptable salt thereof.

[0190] In one embodiment, the KRas G12C inhibitor is:

[0191]

[0192] (also known as Example 359) or a pharmaceutically acceptable salt thereof.

[0193] In one embodiment, the KRas G12C inhibitor is:

[0194]

[0195] (also known as Example 478) or a pharmaceutically acceptable salt thereof.

[0196] In one embodiment, the KRas G12C inhibitor is:

[0197]

[0198] (also known as Example 507) or a pharmaceutically acceptable salt thereof.

[0199] 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, i.e., isomers of identical structure but different atomic arrangements in space. The compounds may be used as mixtures, or the individual components / isomers may be separated according to the manufacturer's instructions using commercially available reagents and conventional methods known to those skilled in the art for separation of stereoisomers and enantiomers, such as using (Sigma-Aldrich) or (Diacel Corp) chiral chromatography HPLC column for separation. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever the specification including the claims refers to the compounds of the present invention, the term "compound" is understood to cover all chiral (enantiomers and diastereoisomers) and racemic forms.

[0200] In one embodiment, the KRas G12C inhibitor compound of Formula I, Formula IA, or Formula IB used in the method comprises a trifluoroacetate salt of the above compound.

[0201] Methods for making the KRas G12C inhibitors disclosed herein are known. For example, co-owned published international PCT applications Nos. WO2017201161 and WO2019099524 describe general reaction schemes for preparing compounds of Formula I, Formula IA, or Formula IB, and also provide detailed synthetic routes for preparing each of the KRas G12C inhibitors disclosed herein.

[0202] 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 can be formulated separately into a pharmaceutical composition.

[0203] Pharmaceutical composition

[0204] In another aspect, the present invention provides a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor of the present invention and a pharmaceutical composition comprising a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical 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 well known in the art and can be prepared for administration by any route including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intravenous or rectal. In certain embodiments, a pharmaceutical composition comprising a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered intravenously. In one embodiment, the pharmaceutical composition comprising a KRas G12C inhibitor is administered orally. In one embodiment, the pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor is administered parenterally, including by subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In one embodiment, the pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor is administered intravenously.

[0205] The carrier characteristics will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, a cell culture, a tissue or a bio-compatibility and does not interfere with the biological activity effectiveness of one or more active ingredients. Therefore, in addition to the inhibitor, the composition may also contain a diluent, a filler, a salt, a buffer, a stabilizer, a solubilizing agent and other materials known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, "Remington's Pharmaceutical Sciences", the 18th edition, editor A. Gennaro, Mack Publishing Co., Easton, Pa., Easton, Pennsylvania, in 1990.

[0206] The term pharmaceutically acceptable salt as used herein refers to a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesirable toxicological effects. Examples of the salt include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid). The compounds can also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art, which specifically include quaternary ammonium salts of the formula --NR+Z-, wherein R is hydrogen, alkyl or benzyl, and Z is a counterion including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzoate and diphenylacetate).

[0207] The active compound or agent is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing severe toxic effects in the treated patient. In one embodiment, the dosage range of the active compound for the composition of all the above-mentioned KRas G12C inhibitors is about 0.01 to 300 mg / kg recipient body weight / day, for example 0.1 to 100 mg / kg recipient body weight / day, and for example 0.5 to about 25 mg / kg recipient body weight / day. The effective dosage range of a pharmaceutically acceptable carrier or diluent can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated as above using the weight of the derivative or by other means known to those skilled in the art.

[0208] Pharmaceutical compositions comprising PD-1 / PD-L1 inhibitors and pharmaceutical compositions comprising KRas G12C inhibitors can be used in any of the methods of use described herein.

[0209] Co-administration

[0210] The components of the drug combination described herein comprising a PD-1 / PD-L1 inhibitor and / or a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof for any method herein can be used simultaneously, separately or sequentially. In one embodiment, the PD-1 / PD-L1 inhibitor is administered before administering 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 its pharmaceutical composition is administered after administering 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 its pharmaceutical composition is administered approximately at the same time as 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 its pharmaceutical composition and the KRas G12C inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition thereof can be formulated into independent or separate dosage forms that can be administered simultaneously or one after another.

[0211] In some cases, it will be advantageous to administer each inhibitor separately at different times and by different routes. Thus, the components of the combination, i.e., the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the PD-1 / PD-L1 inhibitor or pharmaceutical composition thereof, need not necessarily be administered at substantially the same time or in any order.

[0212] Tumor drugs are usually administered at a maximum tolerated dose ("MTD"), which is the highest drug dose that does not cause unacceptable side effects. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition and a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof are each administered with their corresponding MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition is administered with its MTD, and a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof is administered with an amount less than its MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutical composition thereof is administered with an amount less than its MTD, and a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof is administered with its MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutical composition thereof and a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof are each administered with less than their corresponding MTD. Administration can be timed so that the peak pharmacokinetic effect of one inhibitor is consistent with the peak pharmacokinetic effect of another compound.

[0213] 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 thereof, or a pharmaceutical composition is administered daily (ie, at intervals of about 24 hours) (ie, QD). In another embodiment, two doses of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition are administered daily (ie, BID). In another embodiment, three doses of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition are administered daily (ie, TID). In any of the embodiments, the KRAS inhibitor is administered orally.

[0214] Examples of PD-1 / PD-L1 inhibitors suitable for use in the provided compositions and methods include, but are not limited to, PD-1 antibodies, including, but not limited to, nivolumab Pembrolizumab Cimiprilimab and tislelizumab and its biosimilars, and anti-PD-L1 antibodies, including but not limited to atezolizumab Avelumab Durvalumab and its biosimilars.

[0215] In one embodiment, a single dose of a PD-1 / PD-L1 inhibitor is administered. In one embodiment, a PD-1 / PD-L1 inhibitor is administered once every two weeks. In one embodiment, a PD-1 / PD-L1 inhibitor is administered once every three weeks. In one embodiment, a 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 cemiplizumab 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 of the described embodiments, the PD-1 / PD-L1 inhibitor is administered intravenously.

[0216] Combination therapy

[0217] In one aspect of the invention, provided herein is a method for treating cancer in a subject in need thereof, the method 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 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-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer. In one embodiment, the KRas G12C-related cancer is colorectal cancer.

[0218] In one embodiment, the present invention provides a method for inducing a durable complete response in a subject having cancer, comprising administering to the subject a therapeutically effective amount 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 a pharmaceutical composition thereof, wherein the subject exhibits a durable complete response.

[0219] In one embodiment, the combination therapy comprises a compound having the formula:

[0220]

[0221] (also referred to herein as Example 234) or a pharmaceutically acceptable salt thereof and a combination of 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 cemiplizumab. 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.

[0222] In one embodiment, the combination therapy comprises a compound having the formula:

[0223]

[0224] (also referred to herein as Example 359) or a pharmaceutically acceptable salt thereof and a PD-1 / PD-L1 inhibitor in combination. 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 cemiplizumab. 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.

[0225] In one embodiment, the combination therapy comprises a compound having the formula:

[0226]

[0227] (also referred to herein as Example 478) or a pharmaceutically acceptable salt thereof and a combination of 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 cemiplizumab. 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.

[0228] In one embodiment, the combination therapy comprises a compound having the formula:

[0229]

[0230] (also referred to herein as Example 507) or a pharmaceutically acceptable salt thereof and a combination of 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 cemiplizumab. 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.

[0231] By negatively regulating the activity of KRas G12C, the methods described herein are designed to inhibit the effects of KRas G12C on the immune system, which can lead to immunosuppression and PD-

[0232] Undesirable cell proliferation caused by enhanced KRas G12C activity that is resistant to 1 / PD-L1 inhibitors. The degree of covalent modification of KRas G12C can be monitored in vitro using well-known methods, including methods described in published international PCT applications No. WO2017201161 and No. WO2019099524. In addition, the inhibitory activity of the combination in the cell can be monitored, for example, by measuring the inhibition of KRas G12C activity by a certain amount of phosphorylated ERK to assess the effectiveness of the treatment, and the dosage can therefore be adjusted by the attending physician. Methods for determining the expression of PD-1 and PD-L1 are well known and can be used to monitor the PD-1 status during treatment.

[0233] The combinations and methods provided herein can be used to treat KRas G12C-related cancers in subjects 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-related cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-related cancer is lung cancer. In one embodiment, the KRAS G12C-related cancer is colorectal cancer.

[0234] In one embodiment, relative to treatment with a KRas G12C inhibitor alone, 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, or a pharmaceutical composition thereof, causes the subject's overall survival ("OS") duration to be prolonged. In one embodiment, relative to treatment with a KRas G12C inhibitor monotherapy, the increase in the subject's overall survival ("OS") duration lasts for the subject's remaining life time. In one embodiment, relative to treatment with a KRas G12C inhibitor alone, 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, or a pharmaceutical composition thereof, causes the subject's progression-free survival ("PFS") duration to be prolonged. In one embodiment, a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof and a KRasG12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, causes an increase in tumor regression in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, 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, or a pharmaceutical composition thereof, causes 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 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, or a pharmaceutical composition thereof, causes a prolonged duration of disease stabilization in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds No. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Examples No. 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 a therapeutically effective amount of Example 234 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and cemiplimab.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tislelizumab.

[0235] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and durvalumab.

[0236] In another embodiment, for KRas G12C monotherapy, once disease exacerbation has been observed, a PD-1 / PD-L1 inhibitor is administered in combination with a KRas G12C inhibitor, wherein the combination therapy causes an enhancement of the patient's clinical benefit by extending OS, extending PFS, increasing tumor regression, increasing tumor growth inhibition, or extending the duration of disease stabilization in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from No. 1-678 (numbered in WO2019099524) compounds or a pharmaceutically acceptable salt thereof (e.g., No. 234, 359, 478 or 507 examples or pharmaceutically acceptable salts thereof). In one embodiment, the PD-1 / PD-L1 inhibitor is selected from nivolumab, pembrolizumab, cimiprilimumab, tislelizumab, atezolizumab, avelumab, and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and durvalumab.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and durvalumab.

[0237] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors, such as lung tumors, colorectal tumors, pancreatic tumors, prostate tumors, breast tumors, brain tumors, skin tumors, cervical cancer, 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, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, =Urogenital tract: Kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: Hepatocellular carcinoma, bile duct carcinoma, 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 (Ewing's sarcoma). sarcoma), malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrofibroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecoma cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, 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 diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease (Hodgkin's disease), non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, 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. ;

[0238] Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay); and (b) administering to the patient a therapeutically effective amount of a PD-1 / PD-L1 inhibitor in combination with a KRas G12C inhibitor compound of Formula I, Formula IA, Formula 1-B, 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.

[0239] The combinations and methods provided herein can also be used to treat a KRas G12C-related cancer in a subject in need thereof, wherein the KRas G12C-related cancer is resistant to treatment with a PD-1 / PD-L1 inhibitor, the method comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0240] In one embodiment, the combinations and methods provided herein are used to treat cancer associated with KRas G12C and that has been determined to be previously resistant to treatment with a PD-1 / PD-L1 inhibitor, comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor, or a pharmaceutical composition thereof, in combination with a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0241] The combinations and methods provided herein can also be used to inhibit resistance to PD-1 / PD-L1 inhibitor treatment in a subject with a KRas G12C-related cancer, comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0242] In one embodiment, the present invention provides a method for treating a subject identified or diagnosed as having a KRAS G12C-related cancer, comprising (a) detecting resistance of the KRas G12C-related 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 a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0243] The combinations and compositions provided herein can also be used to treat a subject identified or diagnosed as having a KRAS G12C-related 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 PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0244] In one embodiment, the present invention provides a method of treating a subject identified or diagnosed as having a KRAS G12C-related cancer, comprising (a) administering a KRAS G12C inhibitor as a monotherapy until disease progression, and (b) after (a), administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor or a pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0245] In one embodiment, the KRasG12C inhibitor used to treat KRas G12C-related cancer in any of the aforementioned methods is a compound selected from No. 1-678 (as numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., No. 234, 359, 478 or 507 examples or pharmaceutically acceptable salts 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 a therapeutically effective amount of Example 234 and nivolumab.

[0246] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and avelumab.

[0247] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tislelizumab.

[0248] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and durvalumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and nivolumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pembrolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and cemiplizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tislelizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and atezolizumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and avelumab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and durvalumab.

[0249] In one embodiment, the compound of Formula I, Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered as a tablet or capsule. In one embodiment, a tablet or capsule formulation of a compound of Formula I contains from about 10 mg to about 100 mg (e.g., from about 10 mg to about 95 mg, from about 10 mg to about 90 mg, from about 10 mg to about 85 mg, from about 10 mg to about 80 mg, from about 10 mg to about 75 mg, from about 10 mg to about 70 mg, from about 10 mg to about 65 mg, from about 10 mg to about 60 mg, from about 10 mg to about 55 mg, from about 10 mg to about 50 mg, from about 10 mg to about 45 mg, from about 10 mg to about 40 mg, from about 10 mg to about 35 mg, from about 10 mg to about 30 mg, from about 10 mg to about 25 mg, from about 10 mg to about 20 mg, from about 10 mg to about g to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg g, about 20 mg to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, about 25 mg 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 to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, 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 95 mg, about 40 mg to about 90 mg, about 40 mg to about 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 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 95 mg about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg,about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 2 0mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg or about 100mg) a compound of formula 1-678 (as numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., 234, 359, 478 or 507 examples or pharmaceutically acceptable salts thereof). In one embodiment, the compound of formula I is orally administered once a day (QD) on a daily basis during a certain period of time. In one embodiment, the compound of formula I is orally administered twice a day (BID) on a daily basis during a certain period of time. In one embodiment, the compound of Formula I is administered at a dosage 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 to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg) over a period of time. , about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, 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 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about g to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, 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 2 80 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 1 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 500mg, about 120mg to about 480mg, 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 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg 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 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 40 0mg, 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 about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 480 mg 0mg 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 200mg to about 440mg, about 200mg to about 420mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg,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 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 30 0mg, 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 about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg 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 38 ... 0mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 500mg, about 300mg to about 480mg, about 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 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 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 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 4 40mg, about 380mg to about 420mg, about 380mg to about 400mg, about 400mg to about 500mg, about 400mg to about 480mg, about 400mg to about 460mg, about 400mg to about 440mg, about 400mg to about 420mg, about 420mg to about 500mg, about 420mg to about 480mg, about 420mg to about 460mg, about 420mg to about 440mg, about 440mg 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 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg).

[0250] In one embodiment, the combination therapy comprises administering 10 mg to about 400 mg of the drug on a daily basis (during a certain period of time), for example, at 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, about 10 mg to about about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 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 to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, 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 about 80 mg, about 40 mg to about 60 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 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 400 mg,about 80 mg to about 380 mg, 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 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 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 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 240 mg, about 140 mg to about 220 mg, about 140 mg to about 2 0mg 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, about 180mg to about 380mg,about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 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 2 40mg, 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 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, 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 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg 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 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 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg The compound of Formula I is administered orally once or twice a day in an amount of about 100 mg, about 200 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), and the PD-1 / PD-L1 inhibitor is administered iv, for example, once a week, once every two weeks, once every three weeks, depending on the dose.Or the inhibitor is administered once every four weeks. In one embodiment, the KRas G12C inhibitor is administered orally once a day. In one embodiment, the KRas G12C inhibitor is administered orally twice a day.

[0251] 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 2 weeks (Q2W) or about 10 mg / kg every 2 weeks (Q2W).

[0252] In one embodiment, avelumab or a biosimilar thereof is administered intravenously over more than 60 minutes.

[0253] 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 3 weeks (Q3W) or intravenously at a dose of 840 mg every two weeks. In one embodiment, atezolizumab or a biosimilar thereof is administered intravenously over 60 minutes.

[0254] 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 2 weeks (Q2W). In one embodiment, durvalumab or a biosimilar thereof is administered intravenously over 60 minutes.

[0255] 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 / kg once every 2 weeks (Q2W). In one embodiment, nivolumab or a biosimilar thereof is administered intravenously at a dose of 480 mg / kg once every 4 weeks (Q4W). In one embodiment, nivolumab or a biosimilar thereof is administered intravenously for more than 30 minutes.

[0256] 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 3 weeks (Q3W). In one embodiment, pembrolizumab or a biosimilar thereof is administered intravenously for more than 60 minutes.

[0257] 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 / kg once every 3 weeks (Q3W). In one embodiment, cemiplimab or a biosimilar thereof is administered intravenously over 30 minutes.

[0258] In one embodiment, the PD-1 inhibitor is tislelizumab or a biosimilar thereof. In one embodiment, tislelizumab or a biosimilar thereof is administered intravenously at a dose of 200 mg / kg once every 3 weeks (Q3W).

[0259] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of the test compound of the combination or the combination to treat or prevent a given disorder.

[0260] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose-ranging and efficacy trials, can be accomplished in healthy patients and / or patients with established conditions according to methods well known in the clinical and medical arts.

[0261] In some embodiments, the methods provided herein can be used in patients who have been treated with the combination therapy for between 1 day and 2 years (e.g., between 1 day and 22 months, between 1 day and 20 months, between 1 day and 18 months, between 1 day and 16 months, between 1 day and 14 months, between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months Between 1 week and 16 months, Between 1 week and 14 months, Between 1 week and 12 months, Between 1 week and 10 months, Between 1 week and 9 months, Between 1 week and 8 months, Between 1 week and 7 months, Between 1 week and 6 months, Between 1 week and 5 months, Between 1 week and 4 months, Between 1 week and 3 months, Between 1 week and 2 months, Between 1 week and 1 month, Between 2 weeks and 2 years, Between 2 weeks and 22 months, Between 2 weeks and 20 months, Between 2 weeks and 18 months, Between 2 weeks and 16 months, Between 2 weeks and 14 months, Between 2 weeks and 12 months, Between 2 weeks and 10 months, Between 2 weeks and 9 months, Between 2 weeks and 8 months, Between 2 weeks and 7 months , between 2 weeks and 6 months, between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 2 weeks and 1 month, between 1 month and 2 years, between 1 month and 22 months, between 1 month and 20 months, between 1 month and 18 months, between 1 month and 16 months, between 1 month and 14 months, between 1 month and 12 months, between 1 month and 10 months, between 1 month and 9 months, between 1 month and 8 months, between 1 month and 7 months, between 1 month and 6 months, between 1 month and 6 months, between 1 month and 5 months, between 1 month and 4 months, between 1 month and 3 months, between 1 month and between 2 months, between 2 months and 2 years, between 2 months and 22 months, between 2 months and 20 months, between 2 months and 18 months, between 2 months and 16 months, between 2 months and 14 months, between 2 months and 12 months, between 2 months and 10 months, between 2 months and 9 months, between 2 months and 8 months, between 2 months and 7 months, between 2 months and 6 months or between 2 months and 5 months, between 2 months and 4 months, between 3 months and 2 years, between 3 months and 22 months, between 3 months and 20 months, between 3 months and 18 months, between 3 months and 16 months, between 3 months and 14 months, between 3 months and 12 months,between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4 months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months and 10 months, between 4 months and 8 months, between 4 months and 6 months, between 6 months and 2 years, between 6 months and 22 months, between 6 months and 20 months, between 6 months and 18 months, between 6 months and 16 months, between 6 months and 14 months, between 6 months and 12 months, between 6 months and 10 months, or between 6 months and to 8 months) after a period of time (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%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 90%, 4% to 85%, 4% to 80%, 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85%, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65 ... % to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40%, 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to 99%, 8% to 95%, 8% to 90%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%,10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 99%, 15% to 95%, 15% to 90%, 15% to 8 5%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20 ... % to 99%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25% , 25% to 99%, 25% to 95%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 99%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 99%, 35% to 95%, 35% to 99% 5% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 99%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80% %, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 99%, 45% to 95%, 45% to 95%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 50% to 55%,55% to 99%, 55% to 95%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 65% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65% , 70% to 99%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 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%) (e.g., compared to the size of one or more solid tumors in the patient prior to treatment).

[0262] The phrase "survival time" means the length of time between the identification or diagnosis of a mammal's cancer (e.g., any of the cancers described herein) by medical personnel and the mammal's death (caused by the cancer). Methods of extending the survival time of a mammal having cancer are described herein.

[0263] In some embodiments, any of the methods described herein can result in an increase in the survival time of a patient (e.g., 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 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 1 % to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to 340%, 5% to 320%, 5% to 300%, 5% to 280%, 5% to 260%, 5% to 240%, 5% to 22 0%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 400%, 1 0% to 380%, 10% to 360%, 10% to 340%, 10% to 320%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%, 10% to 180%, 10% to 160%, 10% to 140%, 10% to 120% , 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 400%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 3 100%, 20% to 280%, 20% to 260%, 20% to 240%, 20% to 220%, 20% to 200%, 20% to 180%, 20% to 160%, 20% to 140%, 20% to 120%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60 %, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 400%, 30% to 380%, 30% to 360%, 30% to 340%, 30% to 320%, 30% to 300%, 30% to 280%, 30% to 260%, 30% to 240%, 30% to 220%, 30% to 200%,30% to 180%, 30% to 160%, 30% to 140%, 30% to 120%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 400%, 40% to 380%, 40% to 360%, 40% to 340%, 40% to 320%, 40% to 300%, 40% to 280%, 40% to 260%, 40% to 240%, 40% to 220%, 40% to 200%, 40% to 180%, 40% to 160%, 40% to 140%, 40% to 120%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 400%, 50% to 380%, 50% to 360%, 50% to 340%, 50% to 320%, 50% to 300%, 50% to 280%, 50% to 260%, 50% to 240%, 50% to 220%, 50% to 2 00%, 50% to 180%, 50% to 160%, 50% to 140%, 50% to 140%, 50% to 120%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 400%, 60% to 380%, 60% to 360%, 60% to 340 %, 60% to 320%, 60% to 300%, 60% to 280%, 60% to 260%, 60% to 240%, 60% to 220%, 60% to 200%, 60% to 180%, 60% to 160%, 60% to 140%, 60% to 120%, 60% to 100%, 60% to 90%, 60% to 80 %, 60% to 70%, 70% to 400%, 70% to 380%, 70% to 360%, 70% to 340%, 70% to 320%, 70% to 300%, 70% to 280%, 70% to 260%, 70% to 240%, 70% to 220%, 70% to 200%, 70% to 180%, 70% to 16 0%, 70% to 140%, 70% to 120%, to 100%, 70% to 90%, 70% to 80%, 80% to 400%, 80% to 380%, 80% to 360%, 80% to 340%, 80% to 320%, 80% to 300%, 80% to 280%, 80% to 260%, 80% to 240%, 80% to 220%, 80% to 200%, 80% to 180%, 80% to 160%, 80% to 140%, 80% to 120%, 80% to 100%, 80% to 90%, 90% to 400%, 90% to 380%, 90% to 360%, 90% to 340%, 90% to 320%, 90% to 300%,90% to 280%, 90% to 260%, 90% to 240%, 90% to 220%, 90% to 200%, 90% to 180%, 90% to 160%, 90% to 140%, 90% to 120%, 90% to 100%, 100% to 400%, 100% to 380%, 100% to 360%, 100% to 340%, 100% to 320%, 100% to 300%, 100% to 280%, 100% to 260%, 100% to 240%, 100% to 220%, 100% to 200%, 100% to 180%, 100% to 160%, 100% to 140%, 100% to 120%, 120% to 400%, 120% to 380%, 120% to 360%, 120% to 340%, 120% to 320%, 120% to 300%, 120% to 280%, 120% to 260%, 120% to 240%, 120% to 220%, 120% to 200%, 120% to 180%, 120% to 160%, 120% to 140%, 140% to 400%, 140% to 380%, 140% to 360%, 140% to 340%, 140% to 320%, 140% to 300%, 140% to 280%, 140% to 260%, 140% to 240%, 140% to 220%, 140% to 200%, 140% to 180%, 140% to 160%, 160% to 400%, 160% to 380%, 160% to 360%, 160% to 340%, 160% to 320%, 160% to 300%, 160% to 280%, 160% to 260%, 160% to 240%, 160% to 220%, 160% to 200%, 160% to 180%, 180% to 400%, 180% to 380%, 180% to 360%, 180% to 340%, 180% to 320%, 180% to 300%, 180% to 280%, 180% to 260%, 180% to 240%, 180% to 220%, 180% to 200%, 200% to 400%, 200% to 380%, 200% to 360%, 200% to 340%, 200% to 320%, 200% to 300%, 200% to 280%, 200% to 260%, 200% to 240%, 200% to 220%, 220% to 400%, 220% to 380%, 220% to 360%, 220% to 340%, 220% to 320%, 220% to 300%, 220% to 280%, 220% to 260%, 220% to 240%, 240% to 400%, 240% to 380%, 240% to 360%, 240% to 340%, 240% to 320%, 240% to 300%, 240% to 280%,or 300% to 320%) (e.g., compared to a patient with a similar cancer who is given a different treatment or who receives no treatment), or for the remaining life of the treated patient. In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient was treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the previous treatment was unsuccessful; and / or surgery has been administered to the patient, and optionally, the surgery was unsuccessful; and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has previously been determined to be nonresponsive to treatment with the platinum-based chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, and optionally, the previous treatment with the kinase inhibitor was unsuccessful; and / or the patient is treated with one or more other therapeutic agents.

[0264] Reagent test kit

[0265] 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 for treating blood cancer, 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.

[0266] In a related aspect, the present invention provides a kit containing a dose of a PD-1 / PD-L1 inhibitor or a 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, wherein the dose is an amount effective to inhibit the proliferation of cancer cells (particularly KRas G12C expressing cancer cells) in a subject. In some cases, the kit includes instructions for administering 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. The instructions can provide a user with a set of instructions for using 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.

[0267] Example A

[0268] The colon cancer cell line CT26.WT was engineered to express KRas G12C

[0269] This example demonstrates that the colon cancer cell line CT26.WT (ATCC CRL-2638) was genetically modified to express KRasG12C, thereby sensitizing these cells to targeted therapy using the KRas G12C inhibitors of the present invention.

[0270] The CT26.WT cell line is tri-allelic for the KRas gene (NCBI Ref: NM_021284), with each allele having 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 containing the 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.

[0271] Briefly, a synthetic modified guide RNA (sgRNA) was designed and synthesized to target the region around KRas codon 12 based on its high specificity and propensity to generate double-strand breaks when complexed with CAS9 DNA endonuclease. A single-stranded donor oligonucleotide (ssODN) was designed to perform homology donor repair at the sgRNA cleavage site and introduce the desired cysteine ​​codon at position 12 (GAT; D to TGT: C), while introducing silent mutations to prevent re-cleavage.

[0272] Cas9 / sgRNA riboprotein complexes 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.

[0273] One specific clone, KRas G12C CT26.WT E3 clone, was chosen for further analysis.

[0274] Example B

[0275] Inhibition of KRas G12C-dependent cell growth

[0276] This example demonstrates that exemplary compounds of the invention inhibit the growth of engineered CT26.WT KRasG12C E3 clones expressing KRas G12C more potently than the parental CT26.WT wild-type cell line.

[0277] The cellular inhibitory effect of the exemplary compounds of the present invention on KRAs G12C was determined by measuring the amount of intracellular ATP. CT26.WT wild-type cells and CT26.WT G12C E3 clones expressing KRas G12C were cultured in RPMI medium supplemented with 10% fetal bovine serum and 1% penicillin / 1% streptomycin and plated in 96-well white detection plates at a density of 1000 cells / 90 μl / well. The dose-response curve of the compounds of the present invention was determined by adding 10 μl aliquots of the stock solution of the compounds at different concentrations to the same medium in each well, with a concentration range of 10 μM using 3-fold dilutions to a final concentration of 1.5 nM. The plates were incubated at 37° C. for 3 days, and the viability of the cells was measured on day 3 using a CTG assay kit (Cell Titre Glo; Promega cat. no G7573) according to the manufacturer's instructions.

[0278] The IC of each cell line on day 3 was calculated using Graph Pad PRISM software. 50 The results are shown in Table 1.

[0279] Table 1

[0280]

[0281] 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 parental wild-type KRas cell line, demonstrating the enhanced sensitivity and specificity of this cell line to the KRas G12C inhibitors of the present invention.

[0282] Example C

[0283] In vivo model for testing KRas G12C inhibitor-immune cell modulation

[0284] This example demonstrates that in vivo administration of a KRasG12C inhibitor alone or in combination with an anti-PD-1 antibody to animals carrying the CT26.WTK RasG12C E3 clone results in intratumoral modulation of key immune cell populations.

[0285] BALBc mice were inoculated in the right flank with 1x10 6 CT26.WT KRas G12C E3 cells, which have the KRas G12C mutation. When the tumor volume reached 200–400 mm 3 At the age of 15 years (day 0), the mice were divided into two groups, each with three groups of 5 mice. The first group was given vehicle (10% Captisol in 50 mM citrate buffer pH 5.0) every day, the second group was given 100 mg / kg oral dose of KRas G12C inhibitor Example 478 every day for four days (day 4), the third group was given 10 mg / kg murine anti-PD-1 antibody IP on days 1, 4 and 7, and the fourth group was given 100 mg / kg oral dose of KRas G12C inhibitor Example 478 every day for four days and 10 mg / kg murine anti-PD-1 antibody IP on days 1, 4 and 7.

[0286] Approximately three hours after the last dose on day 4, mice were euthanized and tumors were harvested for FACS analysis (MIBioresearch, 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 cell debris by centrifugation, washed, and resuspended in ice-cold DPBS medium. 1x10 6 Aliquots of 10 cells are transferred to predetermined wells of a deep-well 96-well plate containing specific fluorescein-labeled antibodies against extracellular and intracellular markers of specific immune cells.

[0287] A plate design is used to quantify the percentage of CD45+CD3+T cells including CD4+ and CD8+T cells, CD69 and PD-1 expressing CD8+T cells, KI-67+CD8+T cells, natural killer (NK) T cells and regulatory T cells (T-regs). The percentage of cells is determined using the Attune NxT acoustic focusing cytometer. The results are shown in Table 2.

[0288] Table 2

[0289] Immune cell populations were post-treated with KRas G12C inhibitors or a combination of KRas G12C inhibitors + PD-1 / PD-L1 inhibitors

[0290]

[0291] #-Percentage of live cells

[0292] *Remaining percentage of CD45+ cells

[0293] Percentage of CD8+T cells

[0294] The second plate involves the percentage of CD45+CD11+ cells for quantification, which includes suppressor cells of myeloid origin (G-MDSC and M-MDSC), M1 and M2 macrophages and dendritic cells (DC). The percentage of cells is determined using the Attune NxT acoustic focusing cytometer. Positive and negative control samples are processed in parallel. The results are shown in Table 3.

[0295] Table 3

[0296] Immune cell populations were post-treated with KRas G12C inhibitor or KRas G12C inhibitor + anti-PD-1 / anti-PD-L1 combination

[0297]

[0298] #-Percentage of live cells

[0299] *Remaining percentage of CD45+ cells

[0300] After four days of administration of Example 478 at 100 mg / kg, many differences in immune cell populations in the tumor microenvironment were observed. For example, the percentage of CD45+ cells in the tumor's living cells increased. This increase indicates the presence of an active immune tumor microenvironment (TME), because it is not only a marker of hematopoietic cells, but also an important regulator of T and B cell antigen receptor-mediated activation (e.g., see Perrick N.CD45.PathologyOutlines.com website http: / / www.pathologyoutlines.com / topic / cdmarkerscd45.html). Additional increases were observed in CD4 and CD4 helper T cell populations. These immune cell types are essential for stimulating killer T cells, macrophages, and B cells to produce immune responses. The observed increase in CD8 positive immune cells and cytotoxic T cells leads to effective killing of target cells. In the presence of antigens, CD8+T cells undergo 3 stages triggered by proliferation, followed by contraction and eventual differentiation into long-lived memory T cells. This increase in CD8 positive immune cells may also represent an early marker of CD8 positive immune cell clonal expansion, thus providing a mechanism for effectively identifying and killing cancer cells now and in the future (e.g., see Clambey et al., (2005) Immun Rev 205: 170-189). Consistent with the increase in T cells, Example 478 treatment in tumors leads to an increase in CD19 positive cells. This marker is a common B cell marker, representing a cell type that regulates B cell development, activation and differentiation (e.g., see Otero & Ricket (2003) J. Immunol. 171: 5921-5930). Therefore, this increase in B cells can trigger a high affinity response to pathogens and can provide protective long-lived humoral immunity to the host.

[0301] In addition, M1 macrophages represent the first responders of intracellular pathogens and show high levels of phagocytic activity. The observed increase in M1 provides a basis for the increase in proinflammatory cytokine signaling and provides a marker for acute inflammatory response (Atri et al., (2018) Int J Mol Sci 19: 1801). MDSCs accumulate significantly under pathological conditions and have been detected in almost all studied tumor models and tested cancer patients (for example, see Youn & Gabrilovich (2010) Euro J Immunol 40: 2969-2975). These conditions not only lead to the expansion of MDSC cells, but also can lead to their activation, thereby upregulating many intermediates with potential immunosuppressive activity, such as ROS, iNOS, COX2 and arginase (Youn & Gabrilovich (2010) Euro J Immunol 40: 2969-2975).

[0302] The majority of the increased CD8+ T cell population after treatment with Example 478 monotherapy expressed PD-1 (83%) and remained susceptible to inhibition by PD-L1, thereby blocking the activation of these T cells; however, after four days of combined treatment, the expression of PD-1 surface protein in CD8+ T cells had been blocked by the binding of the PD-1 inhibitor (only 1.2% expressed PD-1), thereby preventing these T cells from being inhibited by PD-L1 and allowing these cells to be activated and produce an adaptive anti-tumor response, resulting in a durable complete response in the animal model.

[0303] In summary, treatment with the KRas G12C inhibitor of the present invention resulted 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 of treatment with the PD-1 inhibitor was the significant reduction in PD-1 positive CD8 immune cells in the tumor. This modulation suggests that in the already immunothermal tumor microenvironment described by treatment with the KRas G12C inhibitor alone, reduction of this immune cell population will result in additional anti-tumor activity by eliminating the existing inhibitory effects dictated by PD-1 / PD-L1 axis signaling.

[0304] Example D

[0305] In vivo model for testing KRas G12C inhibitor + PD-1 / PD-L1 inhibitor combination

[0306] BALBc mice were inoculated with 1x10 6 Tumor volumes were measured every two to three days using a caliper and calculated by the following formula: 0.5 × (length × width)2 .

[0307] When the tumor volume reaches 200-400mm 3 At the time of the study (study day 0), the mice were divided into four groups of 5 mice each. The first group was given vehicle (10% Captisol in 50mM citrate buffer pH 5.0) daily on study day 15, and also given vehicle (BioXcel diluent) intraperitoneally on study days 1, 4 and 7. The second group was given a 10 mg / kg dose of murine anti-PD-1 antibody (F26, BioXcel) intraperitoneally daily on days 1, 4 and 7. The third group was given a 100 mg / kg dose of KRas G12C inhibitor Example 478 through study day 29. The fourth group was given a 100 mg / kg dose of KRas G12C inhibitor Example 478 daily on study day 29, combined with a 10 mg / kg intraperitoneal dose of F26 murine anti-PD-1 antibody on study days 1, 4 and 7.

[0308] On study day 29, administration of the KRas G12C inhibitor Example 478 at a dose of 100 mg / kg was discontinued in both the monotherapy and combination groups.

[0309] On study day 39, four tumor-free mice from the combination group received 1x10 6 The mice were then re-challenged with CT26.WTKRas G12C E3 cells and tumor growth was monitored for twenty-four days to determine whether a durable, adaptive immune response was observed.

[0310] Table 4

[0311] Mean tumor volume (mm) of mice bearing CT26.WT KRas G12C E3 clone tumors treated with single agents and combinations 3 )

[0312] Table 4A

[0313] Group 1: Vehicle

[0314] Study Days M1 M2 M3 M4 M5 0 132 251 157 339 261 3 306 644 357 520 319 7 713 1164 943 829 630 9 885 1583 1269 1024 591 11 1389 1936 1723 1178 892 14 2034 2633 2394 1541 1501

[0315] Table 4B

[0316] Group 2: 10mg / kg ipF26 mouse anti-PD-1 antibody

[0317] Study Days M1 M2 M3 M4 M5 0 229 312 104 232 273 3 403 484 183 367 469 7 529 522 568 728 779 9 805 840 725 875 1164 11 1073 968 1206 1254 1518 14 1760 1091 1604 1784 2088

[0318] Table 4C

[0319] Group 3: 100 mg / kg KRas G12C inhibitor Example 478

[0320]

[0321]

[0322] Table 4D

[0323] Group 4: 100 mg / kg KRas G12C inhibitor Example 478 + 10 mg / kg ipF26 mouse anti-PD-1

[0324]

[0325]

[0326] "R" refers to the original implantation site on the right limb, and "L" refers to the re-attack site on the left limb

[0327] As shown in Table 4B, administration of anti-PD-1F26 antibody as a single agent exhibited only a minimum of 19.8% tumor growth inhibition on day 14 compared to vehicle-treated mice.

[0328] As shown in Table 4C, administration of the KRas G12C inhibitor Example 478 as a single agent exhibited a strong anti-tumor response, with all five treated mice achieving a complete response after nine days of administration (study day 9). All five mice were free of detectable tumors for at least five days; however, tumor growth was eventually detected at the original implant site in all five mice that were still receiving Example 478 daily (three mice, study days 17, 21, and 25) or after administration was stopped on study day 29 (two mice, study days 44 and 46).

[0329] As shown in Table 4D, the co-administration of the combination of anti-PD-1F26 antibody and KRas G12C inhibitor Example 478 similarly exhibited a strong anti-tumor response, with all five treated mice (M1-M5) reaching complete responses after fourteen days of administration (study day 14). After the administration of Example 478 was stopped (study day 120), four of the five mice (M1 and M3-M5) remained without detectable tumors for at least ninety-one days. Starting from the 44th day of the study, tumor growth was detected in one mouse (M2) after fifteen days of stopping the administration of Example 478.

[0330] Four of the five mice (M1 and M3-M5) remained free of detectable tumors on study day 39 and were re-challenged with CT26.WT KRas G12C E3 cells on the contralateral left side. No detectable tumor growth was observed at the original implantation site (R) or the second re-implantation site (L), while, in comparison, implantation of the same cells into naive mice resulted in tumor formation (data not shown). These results indicate that animals treated with the combination exhibit anti-tumor immune memory that results in a durable complete response for at least forty-nine days, demonstrating the superiority of the combination therapy in the treatment and potential prevention of recurrence of KRas G12C-associated cancers. Tables 5A-5D represent a repeat of the studies shown in 4A-4D. In the second study, the number of treated mice was increased from 5 animals per group to 10 animals per group.

[0331] When the tumor volume reaches 200-400mm 3 At the time of the study (study day 0), the mice were divided into four groups of 10 mice each. The first group was given vehicle (10% Captisol in 50mM citrate buffer pH 5.0) daily on study day 10, and also given vehicle (BioXcel diluent) intraperitoneally on study days 1, 4 and 7. The second group was administered a 10 mg / kg dose of murine anti-PD-1 antibody (F26, BioXcel) intraperitoneally daily on days 1, 4 and 7. The third group was administered a 100 mg / kg dose of KRas G12C inhibitor Example 478 through study day 25. The fourth group was administered a 100 mg / kg dose of KRas G12C inhibitor Example 478 daily on study day 25, combined with a 10 mg / kg intraperitoneal dose of F26 murine anti-PD-1 antibody on study days 1, 4 and 7.

[0332] On study day 25, the KRas G12C inhibitor Example 478 at a dose of 100 mg / kg was discontinued in both the monotherapy and combination groups.

[0333] On study day 32, seven tumor-free mice from the combination group received 1x10 6 The mice were then re-challenged with CT26.WTKRas G12C E3 cells and tumor growth was monitored for fifty days to determine whether a durable, adaptive immune response was observed.

[0334] Table 5

[0335] Mean tumor volumes (mm) of replicates of mice bearing CT26.WT KRas G12C E3 clone tumors treated with single agents and combinations 3 )

[0336] Table 5A

[0337] Group 1: Vehicle

[0338] Study Days M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 0 203 182 257 200 181 255 222 157 225 332 3 519 355 634 416 486 754 426 310 571 1024 5 780 632 747 953 643 1311 571 516 916 1256 7 1096 981 1172 1303 981 1678 841 857 1452 1617 10 1967 1690 2192 2286 1848 2658 1582 1740 2453 2552

[0339] Table 5B

[0340] Group 2: 10mg / kg ipF26 mouse anti-PD-1 antibody

[0341] Study Days M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 0 198 171 304 206 270 213 186 230 252 165 3 450 224 735 547 515 250 503 618 420 5 545 391 1058 795 929 470 584 778 606 7 796 617 1755 1175 1549 915 937 1033 1304 10 1132 1023 2258 1695 2150 1509 1554 1576 1626

[0342] Table 5C

[0343] Group 3: 100 mg / kg KRas G12C inhibitor example

[0344]

[0345]

[0346] "R" refers to the right original implant site and "L" refers to the left re-implant site

[0347] Table 5D

[0348] Group 4: 100 mg / kg KRas G12C inhibitor Example 478 + 10 mg / kg ipF26 mouse anti-PD-1

[0349]

[0350]

[0351] "R" refers to the right original implantation site, and "L" refers to the left re-challenge site. As shown in Table 5B, administration of anti-PD-1F26 antibody as a single agent showed only a minimum of 25.6% tumor growth inhibition on day 10 compared with vehicle-treated mice.

[0352] As shown in Table 5C, the administration of KRas G12C inhibitor Example 478 as a single agent exhibited a strong anti-tumor response, with all ten treated mice achieving complete responses in all mice after ten days of administration (study day 10). Nine of the ten mice had no detectable tumors for at least four days after achieving a complete response; however, while still receiving Example 478 daily (five mice, study day 14 (M2), day 17 (M4) and day 19 (M1, M3 and M6)) or after stopping administration on study day 25 (one mouse (M6), study day 26), tumor growth was eventually detected in six of the nine mice at the initial implantation site. Three mice (M7-M9) remained tumor-free for six days after daily administration of Example 478 was stopped (day 31), and one mouse (M10) remained tumor-free for at least forty-nine days.

[0353] As shown in Table 5D, the co-administration of the combination of anti-PD-1F26 antibody and KRas G12C inhibitor Example 478 similarly exhibited a strong anti-tumor response, with nine treated mice in ten reaching complete responses after ten days of administration (study day 10). After stopping the administration of Example 478 (study day 49), eight mice remained without detectable tumors for at least twenty-four days. From the study day 52, tumor growth was detected in one (M3) of eight mice.

[0354] Seven of the ten mice (M1, M4, M5, M6, M8, M9, and M10) still had no detectable tumors on study day 32 and were re-challenged with CT26.WT KRas G12C E3 cells on the contralateral left side. In six of the seven mice, no detectable tumor growth was observed at the original implantation site (R) or the second re-implantation site (L), while, in comparison, implantation of the same cells into naive mice resulted in tumor formation (data not shown). Tumor formation (M3) was detected in one mouse at the original implantation site on study day 52; however, no tumor formation was detected at the re-challenge site. These results indicate that animals treated with the combination exhibit anti-tumor immune memory that results in a lasting complete response for at least fifty days, demonstrating the superiority of the combination therapy in treating and potentially preventing recurrence of KRas G12C-associated cancers.

[0355] Although the invention has been described in conjunction with particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention, generally following the principles of the invention and including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains and as may be applied to the basic features set forth above and as fall within the scope of the appended claims.

Claims

1. Use of a) a PD-1 / PD-L1 inhibitor selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab and durvalumab in combination with b) a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating colorectal cancer in a subject in need thereof:

2. The use according to claim 1, wherein the PD-1 / PD-L1 inhibitor is a PD-1 inhibitor.

3. The use according to claim 2, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplizumab and tislelizumab.

4. The use according to claim 3, wherein the PD-1 inhibitor is nivolumab.

5. The use according to claim 3, wherein the PD-1 inhibitor is pembrolizumab. The use according to claim 3, wherein the PD-1 inhibitor is cemiplimab.

7. The use according to claim 3, wherein the PD-1 inhibitor is tislelizumab.

8. The use according to claim 1, wherein the PD-1 / PD-L1 inhibitor is a PD-L1 inhibitor.

9. The use according to claim 8, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab and durvalumab.

10. The use according to claim 9, wherein the PD-L1 inhibitor is atezolizumab.

11. The use according to claim 9, wherein the PD-L1 inhibitor is avelumab.

12. The use according to claim 9, wherein the PD-L1 inhibitor is durvalumab.

13. Use of a) a PD-1 / PD-L1 inhibitor selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab and durvalumab in combination with b) a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating colorectal cancer in a subject in need thereof: wherein the cancer is resistant to treatment with a PD-1 / PD-L1 inhibitor.

14. Use of a) a PD-1 / PD-L1 inhibitor selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab and durvalumab in combination with b) a compound of the following formula or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating colorectal cancer and determining resistance to previous PD-1 / PD-L1 inhibitor treatment:

15. Use of a) a PD-1 / PD-L1 inhibitor selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab and durvalumab in combination with b) a compound of the following formula or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting resistance to PD-1 / PD-L1 inhibitor treatment in a subject with colorectal cancer:

16. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab and durvalumab and b) a pharmaceutical composition comprising a compound of the following formula or a pharmaceutically acceptable salt thereof: The kit is used to treat colorectal cancer in a subject.

17. The kit of claim 16, further comprising instructions for administering the pharmaceutical composition.

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