Treatment methods with krasg12c inhibition

Abstract

Provided herein are methods of treating diseases including cancers, where the methods comprise administration of Compound 1, or a pharmaceutically acceptable salt thereof, as described herein. Such methods include the treatment of lung cancer comprising a KRASG12C mutation.

Description

PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1TREATMENT METHODS WITH KRASG12C INHIBITIONCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 704,462, filed October 7, 2024, which is incorporated herein in its entirety for all purposes.BACKGROUND

[0002] RAS mutations occur in approximately 20-30% of human cancers, including the majority of pancreatic ductal adenocarcinoma (PDAC), half of colorectal cancers, and a third of all lung cancers. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority and a major challenge for cancer research. RAS proteins did not appear to present suitable pockets to which drugs could bind, except for the GDP / GTP binding site. Unfortunately, RAS proteins bind to these nucleotides with very high (picomolar) affinities, making the development of effective nucleotide analogs virtually impossible. Attempts to block pathways downstream of RAS with a hope to provide clinical benefit for patients suffering from RAS-driven cancers have been generally disappointing.

[0003] The three RAS genes (HR AS, NRAS, and KRAS) encode four 188-189 amino acid proteins that share 82%-90% amino acid sequence identity and near-identical structural and biochemical properties. However, they are differentially expressed, and mutated with different frequencies in cancer. KRAS is the most frequently mutated oncogene in cancer, and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Significant cancer type preferences exist among the RAS genes. KRAS mutations predominate in lung, colorectal, and pancreatic cancer, whereas NRAS mutations predominate in cutaneous melanomas and acute myelogenous leukemia, and HRAS mutations are found in bladder and head and neck squamous cell carcinomas.

[0004] An estimated over 600,000 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day (Cancer Facts and Figures 2021). The greatest number of deaths are from cancers of the lung, prostate, and colorectum in men, and cancers of the lung, breast, and colorectum in women. Almost one-quarter of all cancer deaths are due to lungPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 cancer, 82% of which is directly caused by cigarette smoking. The 5-year survival rate for lung cancer patients is only about 20%.

[0005] KRAS is mutationally activated in lung cancer, and Glycine-to-Cysteine (G12C) mutations account for the majority of codon 12 mutations associated with cigarette smoking. A significant percentage of colorectal cancers are also driven by KRAS G12C mutations.

[0006] To date, two KRAS G12C inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain lung cancers. Those KRAS G12C inhibitors (e.g., Amgen Inc.’s sotorasib and Mirati Therapeutics. Inc.’s adagrasib) target inactive (GDP)-bound protein, and their effectiveness is enabled by high (comparable to wild type (WT) KRAS) intrinsic GTP hydrolysis rate of KRAS G12C mutant. Clinical data for these agents have shown that though most patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS G12C inhibition, patients with colorectal cancer bearing the same mutation rarely respond. Agents such as sotorasib and adagrasib bind to the GDP-bound (OFF) form of KRASG12Cbut do not covalently bind to the active GTP-bound (ON) form. The cause of limited efficacy of KRAS G12C (GDP) inhibitors in colorectal cancers has been investigated. Unlike non-small cell lung cancer (NSCLC) cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRAS G12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Also, it has been reported that KRAS G12C-GDP inhibitors induce transcription of new KRAS G12C that is in GTP-bound conformation, and insensitive to KRAS G12C inactive state inhibitors. Further, heterogenous adaptive resistance mechanisms to these agents have been identified. Many patients do not respond to the approved KRASG12Cinhibitors altogether, and complete responses (CRs) are infrequent. Accordingly, agents that inhibit only the GDP-bound (OFF) form of KRASG12Cmay have intrinsically limited therapeutic effects. Therefore, there is a need for improved KRAS G12C inhibitors.

[0007] The present disclosure encompasses a recognition that current treatments available for treating KRAS G12C mutated cancers have limited efficacy.SUMMARY

[0008] The present disclosure provides methods of treating diseases and disorders such as cancers with KRAS G12C inhibitors capable of targeting both active GTP-bound protein andPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 inactive GDP-bound protein. The method comprises administering a compound (e.g., Compound 1, also known as BBO-8520), or a pharmaceutically acceptable salt thereof (e.g., as described herein) to a subject in need thereof. The present disclosure may provide therapeutic advantages over KRAS G12C-GDP inhibitors such as sotorasib and adagrasib. In some embodiments, compounds provided herein have inhibitory activity against a KRAS protein comprising a glycine-to-cysteine mutation at codon 12 (i.e., a G12C mutation) in both its active and inactive conformations. In some embodiments, compounds provided herein are useful in the treatment of cancers, such as cancers characterized by a KRAS G12C mutation.

[0009] In a first aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of the compound, and the cancer is described herein.

[0010] In some embodiments, the compound is Compound 1:or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound is Compound 1:PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1(Compound 1).

[0012] In a second aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, method comprising administering to the subject a therapeutically effective amount of Compound 1:(Compound 1), or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0013] In some embodiments of the second aspect, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered in combination with pembrolizumab.

[0014] In a third aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, method comprising administering i) a therapeutically effective amount of Compound 1 :or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of pembrolizumab.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0015] In some embodiments of the third aspect, the therapeutically effective amounts of Compound 1 , or a pharmaceutically acceptable salt thereof, and pembrolizumab are each described herein.

[0016] In some embodiments of any one of the first to third aspects, the method comprises administering a therapeutically effective amount of Compound 1 to the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows the disruption of active GTP -bound KRASG12C and RAFI binding by Compound 1, as described in Example 4.

[0018] FIGs. 2A-2B show the kmact / Ki values for Compound 1 of GTP-bound KRASG12Cand GDP-bound KRASG12C, as described in Example 6.

[0019] FIGs. 3A-3B show the pERK and 3D viability of Compound 1 in various cell line panels, as described in Example 7.

[0020] FIG. 4 shows the fraction of RAS bound to RAF across early compound treatment time points in pancreatic carcinoma MIA PaCa-2 cells, which bear a KRASG12Cmutation, as described in Example 8.

[0021] FIGs. 5A-5C show the measurement of potency of Compound 1 and other agents when there is more GTP-bound KRASG12C in an NCI-H358 model, as described in Example 8.

[0022] FIGs. 6 -6C show the effect of Compound 1 on viability of NCI-H358 cells after treatment with hepatocyte growth factor, as described in Example 8.

[0023] FIGs. 7A-7B show dose response (FIG. 7A) and time response (FIG. 7B) effects of Compound 1 on pERK levels in MIA PaCa-2 cell line-derived subcutaneous Matrigel plugs, as described in Example 10.

[0024] FIG. 8 shows efficacy of Compound 1 in a MIA PaCa-2 (KRASG12C) PDAC CDX model, as described in Example 11.

[0025] FIG. 9 shows efficacy of Compound 1 in NCI-H358 (KRASG12C) NSCLC CDX model, as described in Example 12.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0026] FIG. 10 shows anti-tumor efficacy of Compound 1 in BALB / c nude mice bearing LUNM055 patient-derived xenograft subcutaneous tumors, as described in Example 13.

[0027] FIGs. 11A-11C show anti-tumor efficacy of Compound 1 and sotorasib in BALB / c nude mice bearing sotorasib-resistant MIA PaCa-2 cell line-derived xenograft subcutaneous tumors, as described in Example 14.

[0028] FIG. 12 shows efficacy of Compound 1 and anti-PD- 1 in a syngeneic liver model, as described in Example 15.

[0029] FIG. 13 shows anti-tumor activity in efficacy evaluable patients (n = 10) with NSCLC in Phase la clinical study, as described in Example 2.DETAILED DESCRIPTIONDefinitions

[0030] Unless specifically indicated otherwise, the group “X^” as used herein in any one of formulae of compounds as disclosed herein, refers to methyl.

[0031] Unless specifically indicated otherwise, a dosage amount (e.g., a total daily dosage of from about 10 mg to about 2000 mg, etc.) refers to an amount of the compound (e.g., Compound 1) in its free base form. By way of example, when a mono hydrochloric acid (HC1) salt of Compound 1 is dosed, the amount of the mono HC1 salt of Compound 1 required to provide a 1000 mg dose of Compound 1 is 1049.9 mg. One skilled in the art understands the necessary conversion when a pharmaceutically acceptable salt of the compound (e.g., Compound 1) is administered in any one of embodiments as described herein.

[0032] When ranges of values are disclosed, and the notation “from m . . . to m” or “between m . . . and m” is used, where m and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 p M (micromolar),” which is intended to include 1 p M, 3 p M, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0033] “About,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures. In some embodiments, “about” means a range extending to + / - 10% of the specified value. Tn some embodiments, “about” means a range of + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1% of the specified value. In some embodiments, “about” means a range of + / - 10% of the specified value. In some embodiments, “about” means a range of + / - 5% of the specified value. In some embodiments, “about” means the specified value.

[0034] “Tautomer”, as use herein, alone or in combination, refers to one of two or more isomers that rapidly interconvert. Generally, this interconversion is sufficiently fast so that an individual tautomer is not isolated in the absence of another tautomer. The ratio of the amount of tautomers can be dependent on solvent composition, ionic strength, and pH, as well as other solution parameters. The ratio of the amount of tautomers can be different in a particular solution and in the microenvironment of a biomolecular binding site in said solution. Examples of tautomers that are well known in the art include keto I enol, enamine I imine, and lactam / lactim tautomers. Examples of tautomers that are well known in the art also include 2-hydroxypyridine / 2(lH)-pyridone and 2-aminopyridine 1 2( l H)-iminopyridone tautomers.

[0035] Asymmetric centers may exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially availablePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this disclosure. Additionally, the compounds provided herein may comprise conformational isomers, which compounds comprise groups that can orient in different conformations in relation to another moiety. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0036] “KRAS inhibitor” is used herein to refer to a compound that exhibits an IC50 with respect to KRAS activity of no more than about 100 pM and more typically not more than about 50 pM, as measured in the assays described generally herein, such as level of covalent modification to Cysl2 in KRAS G12C as measured using a matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) assay, and / or a KRAS G12C protein-effector protein interaction disruption assay. “ICso” is that concentration of inhibitor which reduces the activity of an enzyme (e.g., KRAS) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against KRAS. In certain embodiments, compounds exhibit an ICso with respect to KRAS (e.g., KRAS having a G12C mutation) of no more than about 50 pM; in further embodiments, compounds exhibit an IC50 with respect to KRAS (e.g. , KRAS having a G12C mutation) of no more than about 10 pM; in yet further embodiments, compounds exhibit an IC50 with respect to KRAS (e.g. , KRAS having a G12C mutation) of not more than about 1 pM; in yet further embodiments, compounds exhibit an IC50 with respect to KRAS (e.g. , KRAS having a G12C mutation) of not more than about 200 nanomolar (nM), as measured in the KRAS assay described herein. In some embodiments, compounds exhibit an IC50 with respect to KRAS (e.g., KRAS having a G12C mutation) of less than about 50 pM, such as less than about 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or less. In certain embodiments, compounds exhibit an IC50 with respect to KRAS (e.g., KRAS having a G12C mutation) of less than about 1 pM, such as less than about 900 nM,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or less. In some embodiments, a KRAS inhibitor has inhibitory activity against KRAS having a G12C mutation that exceeds its inhibitory activity against KRAS having another mutation, such as a G12D, G12R, G12S, G12A, or G12V mutation. For example, in some embodiments, a KRAS inhibitor provided herein has at least two-fold, fivefold, ten-fold, twenty-fold, thirty-fold, forty-fold, fifty-fold, one hundred-fold, or higher inhibitory activity against KRAS having a G12C mutation relative to KRAS having another mutation such as a G12D, G12R, G12S, G12A, or G12V mutation. In some embodiments, a KRAS inhibitor provided herein has greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12D mutation. In some embodiments, a KRAS inhibitor provided herein has greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12R mutation. In some embodiments, a KRAS inhibitor provided herein has greater inhibitory activity against KRAS having a G12C mutation than against an KRAS having a G12S mutation. In some embodiments, a KRAS inhibitor provided herein has greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12A mutation. In some embodiments, a KRAS inhibitor provided herein has greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12V mutation. In some embodiments, a KRAS inhibitor provided herein has greater inhibitory activity against active (“GTP-bound”) KRAS having a G12C mutation than against an inactive (“GDP-bound”) KRAS having a G12C mutation. In some embodiments, a KRAS inhibitor provided herein has lower inhibitory activity against active (“GTP-bound”) KRAS having a G12C mutation than against an inactive (“GDP-bound”) KRAS having a G12C mutation. In some embodiments, a KRAS inhibitor provided herein has inhibitory activity against both active (“GTP-bound”) and inactive (“GDP-bound”) KRAS having a G12C mutation. In some embodiments, a KRAS inhibitor provided herein has similar inhibitory activity against active (“GTP-bound”) and inactive (“GDP-bound”) KRAS having a G12C mutation. In some embodiments, a KRAS inhibitor provided herein has inhibitory activity against a K-RAS4a splice variant. In some embodiments, a KRAS inhibitor provided herein has inhibitory activity against a K-RAS4b splice variant. In some embodiments, a KRAS inhibitor provided herein has inhibitory activity against both K-RAS4a and K-RAS4b splice variants.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0037] “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease, disorder, or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amounts will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0038] The term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0039] “Treat,” “treating,” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology, disease, disorder, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, disease, disorder, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; and / or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. Treatment may also be preemptive in nature; i.e., it may include prevention of a disease, disorder, or condition, prevention of onset of one or more symptoms of a disease, disorder, or condition, and / or prevention of escalation of a disease, disorder, or condition. Prevention of a disease, disorder, or condition may involve complete protection from disease, and / or prevention of disease progression (e.g., to a later stage of the disease, disorder, or condition). For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease, disorder, or condition to a clinically significant or detectable level.

[0040] “Patient” or “subject” refers to a living organism suffering from or prone to a disease, disorder, or condition that can be treated by administration of a compound or pharmaceutical composition as provided herein. Non-limiting examples include humans,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 rats, mice, rabbits, hamsters, guinea pigs, hamsters, cats, dogs, non-human primates (e.g., monkeys), goats, pigs, sheep, cows, deer, horses, and other non-mammalian animals. Examples of mammals that can be treated by administration of a compound or pharmaceutical composition provided herein include, for example, rodents (e.g., rats, mice, squirrels, guinea pigs, hamsters, etc.), lagomorphs (e.g., rabbits, hares, etc.), primates (e.g., monkeys, apes, etc.), bovines (e.g., cattle), odd-toed ungulates (e.g., horses), even-toed ungulates (e.g., bovines such as cattle, ovine such as sheep, caprine such as goats, porcine such as pigs, etc.), and marsupials (e.g., kangaroo, wallaby, wallaroo, sugar glider, etc.). In some embodiments, the patient or subject is human. In some embodiments, the patient or subject is a companion animal such as a cat or dog. In some embodiments, the patient or subject is a farm animal such as a goat, sheep, cow, pig, or horse. In some embodiments, the patient or subject is an exotic animal such as a primate (e.g., monkey), marsupial (e.g., kangaroo, wallaby, wallaroo, sugar glider, etc.), or a non-domesticated or hybrid cat or dog.

[0041] “Composition,” as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0042] “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0043] “Treatment cycle” refers to the period of time in which a subject receives the treatment at a prescribed dose level (e.g., 100 milligrams (mg), 200 mg, 400 mg, 800 mg, etc.) and dosing interval (e.g., once a day, twice a day, etc.).

[0044] “Adverse event,” as used herein, is any untoward medical occurrence in a subject, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Examples of adverse events include, but are not limited to, nausea or vomiting; diarrhea lasting longer than 3 days; adrenal insufficiency; interstitial lung disease; pneumonitis; photosensitivity; higher than normal alkaline phosphatase, aspartatePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 aminotransferase (AST), or alanine aminotransferase (ALT) levels; anemia; febrile neutropenia; thrombocytopenia; or hematologic reactions.

[0045] “Initial dose” refers to a dose level (e.g., 100 mg, 200 mg, 400 mg, 800 mg, etc.) prescribed for a treatment cycle to be given to the subject at the prescribed interval (e.g., once a day, twice a day, etc.). As used herein, “initial dose level” is intended to encompass the dosing standard for the duration of the treatment cycle in the absence of an adverse event.

[0046] “Reduced dose,” as used herein, is intended to encompass a dose level (e.g., 25 mg, 50 mg, 100 mg, 200 mg, etc.) prescribed for the duration of an adverse event in the place of the initial dose level unless and until the adverse event is resolved. A subject may revert to the initial dose level from a reduced dose once the adverse event is resolved.

[0047] “Mediated by KRASG12C” refers to any disease, disorder, or condition whose severity, symptoms, or existence can be altered due to contact, interference, or other interaction with KRAS having a G12C mutation. As used herein, “mediated by KRASG12C” is intended to encompass an effect on a disease, disorder, or condition caused by an interaction with KRASG12C.

[0048] The compounds disclosed herein can exist as therapeutically acceptable salts (also referred to herein as “pharmaceutically acceptable salts”). The present disclosure includes compounds provided herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.

[0049] The terms “therapeutically acceptable salt” and “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,PATENTAttorney Docket No. 2014229-0161 Thera-23.WO 1 hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0050] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, MN-dimethylaniline, A-methylpiperidine, / V-melhyhnorpholine, dicyclohexylamine, procaine, dibenzylamine, A'-dibenzylphenethylamine, 1-ephenamine, and N, TV’-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0051] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

[0052] “KRAS G12C-positive cancer” refers to a cancer characterized by a KRAS G12C mutation.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0053] “A cancer resistant to a KRAS inhibitor," and / or “a cancer that is a KRAS-positive cancer resistant to a KRAS inhibitor” refer to a cancer or tumor that either fail to respond sufficiently favorably to treatment with a prior KRAS inhibitor, such as a prior KRAS G12C inhibitor, or alternatively, recurs or relapses after responding favorably to a KRAS inhibitor.

[0054] As used herein, “disease control rate (DCR)” is the proportion of patients (in percentage) in the respective analysis population who have complete response (CR), partial response (PR), or stable disease (SD) lasting greater than or equal to approximately 2 months. The DCR is the sum of the CR, PR, and SD rates.

[0055] As used herein, “complete response (CR)” in a patient is defined as the disappearance of all target lesions.

[0056] As used herein, “partial response (PR)” in a patient is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0057] As used herein, “stable disease (SD)” in a patient is defined as neither sufficient shrinkage to qualify for a partial response (PR) nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.

[0058] As used herein, “overall response rate (ORR)” is the proportion of patients in the analysis population who have complete response (CR) or partial response (PR).

[0059] “A,” “an,” or “a(n)”, when used in reference to a group of substituents or “substituent group” herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is unsubstituted or substituted with at least one alkyl and / or at least one aryl, wherein each alkyl and / or aryl is optionally different. In another example, where a compound is substituted with “a” substituent group, the compound is substituted with at least one substituent group, wherein each substituent group is optionally different.Compounds

[0060] The present disclosure provides methods and uses of a compound according to Formula (I) (e.g., Compound 1). Compound 1 is described in International Patent Application No. PCT / US2022 / 037992, filed July 22, 2022, and published as WOPATENTAttorney Docket No. 2014229-0161Thera-23.WO 12023004012 on January 26, 2023, which is herein incorporated by reference in its entirety. The synthesis of Compound 1 is described in Example 33 of WO 2023004012. Compound 1 may be referred to as 4-((S)-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. Compound 1 is also known as BBO-8520.

[0061] In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0062] In some embodiments, the compound of Formula (I) is Compound 1:(Compound 1) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, atropisomer, tautomer, or combination thereof. In some embodiments, the compound of Formula (I) is Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is Compound 1. In some embodiments, the compound of Formula (I) is a pharmaceutically acceptable salt of Compound 1 (e.g., as described herein).

[0063] In some embodiments, Compound 1 is in a neutral form (i.e., in its free base form).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0064] In some embodiments, Compound 1 has a purity of at least about 95% by ultraperformance liquid chromatograph (UPLC), such as at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%. In some embodiments, Compound 1 has a purity of from about 95% to about 99%, from about 96% to about 99%, from about 97% to about 99%, or from about 98% to about 99%, as determined by UPLC. In some embodiments, Compound 1 has a purity of from about 95% to about 100%, from about 96% to about 100%, from about 97 % to about 100%, from about 98% to about 100%, or from about 99% to about 100%, as determined by UPLC.

[0065] In some embodiments, a compound of Formula (I) is selected from Compound 1, Compound 2, or a combination thereof, wherein Compound 2 is represented by:(Compound 2).Without wishing to be bound by theory, Compound 1 and Compound 2 are considered atropisomers. The atropisomerism of these compounds may be described herein as the 7- position atropisomerism.

[0066] In some embodiments, Compound 1 has at least 95% chiral purity of the 7-position atropisomer, such as at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%. In some embodiments, Compound 1 has a chiral purity of the 7-position atropisomer of from about 95% to about 99%, from about 96% to about 99%, from about 97% to about 99%, or from about 98% to about 99%. In some embodiments, Compound 1 has a chiral purity of the 7-position atropisomer of from about 95% to about 100%, from about 96% to about 100%, from about 97% to about 100%, from about 98% to about 100%, or from about 99% to about 100%. In some embodiments, chiral purity is assessed using high-performance liquid chromatography (HPLC) or ultra-performance liquid chromatography (UPLC).

[0067] Without wishing to be bound by theory, Compound 1, or a form thereof, such as any pharmaceutically acceptable salt thereof, may be capable of interacting covalently with aPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 cysteine (C) at the 12 position of the KRAS protein (e.g., a G12C mutation) (e.g., via the acrylamide moiety therein). Moreover, Compound 1, or a form thereof, such as any pharmaceutically acceptable salt thereof, may be capable of selectively binding a KRAS protein in both active (G TP -bound) and inactive (GDP-bound) conformations.

[0068] Selected features of Compound 1 are described in the Examples.Subject

[0069] In some embodiments, the subject is under the care of a medical practitioner. In some embodiments, the subject has been diagnosed with a cancer (e.g., as described herein).

[0070] In some embodiments, the subject has a disease, disorder, or condition mediated by KRASG12C. In some embodiments, the disease, disorder, or condition mediated by KRASG12Cis a KRAS G12C-positive cancer. In some embodiments, the disease, disorder, or condition is ameliorated by the inhibition of KRAS having a G12C mutation.

[0071] In some embodiments, the disease, disorder, or condition of the subject is assessed by a molecular diagnostic using an appropriate clinically validated and / or FDA approved test. In some embodiments, the disease, disorder, or condition, such as a cancer, has no available standard of care and / or no curative therapy.

[0072] In some embodiments, the subject has a cancer.

[0073] In some embodiments, the subject was previously diagnosed with the cancer. In some embodiments, the subject has previously undergone a treatment regimen for the cancer. In some embodiments, the subject has progressed on or within 2 years of the end of a prior multimodal therapy with a curative intent, such as within 12 months or within 6 months of the end of a prior multimodal therapy with a curative intent. In some embodiments, the subject has previously entered remission from the cancer.

[0074] In some embodiments, the subject previously undergone treatment with a KRAS inhibitor therapy. In some embodiments, the subject was previously treated with a KRAS inhibitor selected from MRTX-EX185, MRTX1133, ARS-853, ARS-1620, JNI-74699157 (ARS-3248), ASP2453, LY3499446, LY3537982, D-1553, JDQ443, BI 1823911, RMC- 6236, RMC-6291, RMC-9805, RMC-5127, RMC-0708, RMC-8839, RMC-036, RMC-037, ERAS-3490, glecirasib (JAB-21822), sotorasib (AMG510), adagrasib (MRTX849), divarasibPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1(GDC-6036), BPI-421286, GFH925, D3S-001, GH35, HBI-2438, BI3706674, LY3962673, LY4066434, QTX3046, QTX3034, JAB23425, HRS-4642 and a combination thereof. In some embodiments, the subject was previously treated with a KRAS G12C-selective inhibitor. In some embodiments, the subject was previously treated with a KRAS G12C (OFF) inhibitor (e.g., a KRAS G12C (GDP) inhibitor). In some embodiments, the subject was previously treated with a KRAS G12C-selective inhibitor that does not bind covalently to the active GTP-bound (ON) form of KRAS G12C. In some embodiments, the subject was previously treated with sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), JDQ443, LY3537892, or a combination thereof.

[0075] In some embodiments, the subject has not previously undergone treatment with a KRAS inhibitor therapy.

[0076] In some embodiments, the cancer is characterized by a solid tumor. In some embodiments, the cancer includes a solid tumor. In some embodiments, the cancer includes a liquid tumor.

[0077] In some embodiments, the cancer or solid tumor responds to treatment with a KRAS inhibitor, such as a KRAS G12C inhibitor, such as an inhibitor capable of interacting with one or both of the ON and OFF states of KRAS, as described herein. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, esophageal / gastroesophageal cancer, small bowel cancer, breast cancer, glioblastoma, biliary tract cancer, appendiceal cancer, ovarian cancer, endometrial cancer, and lung cancer. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is KRASG12C-positive CRC, such as KRASG12C-positive locally advanced and unresectable or metastatic CRC. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is locally advanced and unresectable or metastatic NSCLC. In some embodiments, the cancer is advanced NSCLC. In some embodiments, the cancer is KRASG12C -positive NSCLC, such as KRASG12C-positive locally advanced and unresectable or metastatic NSCLC.

[0078] In some embodiments, the subject has a cancer characterized by a mutant KRAS.

[0079] In some embodiments, the cancer is a KRASG12C-positive cancer.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0080] In some embodiments, the subject does not have a KRAS mutation selected from G12D, G12V, M72K, Q61H, R164Q, R68S, or T2S.

[0081] In some embodiments, the cancer or solid tumor is resistant to treatment with a chemotherapeutic drug and / or ionizing radiation. In some embodiments, the cancer or solid tumor has acquired resistance to a chemotherapeutic drug and / or ionizing radiation. In some embodiments, the cancer or solid tumor is resistant to treatment with a KRAS inhibitor. In some embodiments, the cancer or solid tumor is resistant to treatment with a KRAS G12C inhibitor other than Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer or solid tumor is resistant to treatment with a KRAS G12C (OFF) inhibitor (e.g., a KRAS G12C (GDP) inhibitor). In some embodiments, the cancer or solid tumor is resistant to treatment with a KRAS G12C-selective inhibitor that does not bind covalently to the active GTP-bound (ON) form of KRAS G12C. In some embodiments, the cancer or solid tumor is resistant to treatment with sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), JDQ443, LY3537892, or a combination thereof.

[0082] In some embodiments, the subject does not have a targetable driver mutation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, NTRK, or HER2.

[0083] In some embodiments, the subject has measurable disease by RECIST vl.l.

[0084] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

[0085] In some embodiments, the subject is a human.

[0086] In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject is between 18 and 65 years of age. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is between 2 and 18 years of age. In some embodiments, the subject is between 5 and 18 years of age. In some embodiments, the subject is between 8 and 18 years of age. In some embodiments, the subject is between 10 and 18 years of age. In some embodiments, the subject is between 12 and 18 years of age.

[0087] In some embodiments, the subject has progression on or disease recurrence after available standard of care treatments including an immune checkpoint inhibitor, a platinumbased doublet chemotherapy, or both.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0088] In some embodiments, the subject has adequate organ functions including adequate hematological, renal, hepatic, and coagulating functions.

[0089] In some embodiments, the subject has an absolute neutrophil count (ANC) >1500 / pL.

[0090] In some embodiments, the subject has a platelet count of > 100,000 / pL.

[0091] In some embodiments, the subject has hemoglobin of >9 g / dL without transfusion for at least 2 weeks or without erthyropoiesis-stimulating agents for at least 6 weeks.Methods and uses

[0092] The present disclosure provides methods of treating diseases, disorders, and conditions with a compound according to Formula (I) (e.g., Compound 1), or a form thereof. In some embodiments, the method of treating a disease, disorder, or condition (e.g., in a subject in need thereof) comprises providing (e.g., administering) Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a disease, disorder, or condition (e.g., in a subject in need thereof) comprises administering Compound 1. In some embodiments, the method of treating a disease, disorder, or condition (e.g., in a subject in need thereof) comprises providing (e.g., administering) a therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a disease, disorder, or condition (e.g., in a subject in need thereof) comprises providing (e.g., administering) a therapeutically effective amount of Compound 1. In some embodiments, the method of treating a disease, disorder, or condition (e.g., in a subject in need thereof) comprises providing (e.g., administering) a pharmaceutical composition (e.g., as described herein) comprising a therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable thereof.

[0093] The present disclosure also provides a compound of Formula (I) (e.g. Compound 1), or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, for use as a medicament for treating a disease, disorder, or condition (e.g., a cancer) (e.g., in a subject in need thereof).

[0094] The present disclosure also provides the use of a compound of Formula (I) (e.g. Compound 1), or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, for treating a disease, disorder, or condition (e.g., a cancer, as described herein, such as a cancer characterized by a KRAS protein having a G12C mutation) (e.g., in a subject in need thereof).

[0095] The present disclosure also provides the use of a compound provided herein of Formula (I) (e.g., Compound 1), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating a disease, disorder, or condition (e.g., a cancer, as described herein, such as a cancer characterized by a KRAS protein having a G12C mutation) (e.g., in a subject in need thereof).

[0096] The present disclosure also provides methods of modulating (e.g. inhibiting) a KRAS protein (e.g., in a subject in need thereof) with a compound according to Formula (I) (e.g., Compound 1), or a form thereof. In some embodiments, the method of modulating (e.g., inhibiting) a KRAS protein (e.g., in a subject in need thereof) comprises administering Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS protein is in the active (GTP -bound) conformation. In some embodiments, the KRAS protein is in the inactive (GDP-bound) conformation. In some embodiments, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered to a subject that is a human having a disease, disorder, or condition such as a cancer, such as a cancer characterized by a KRAS protein having a G12C mutation.

[0097] The present disclosure also provides a compound of Formula (I) (e.g. Compound 1), or a salt (e.g. pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, for use in inhibiting KRAS (e.g., KRAS having a G12C mutation) (e.g., in a subject in need thereof). The present disclosure also provides a compound of Formula (I) (e.g. Compound 1), or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and aPATENTAttorney Docket No. 2014229-0161 Thera-23.WO 1 pharmaceutically acceptable excipient, for use in the manufacture of a medicament for inhibiting KRAS (e.g., KRAS having a G12C mutation) in a subject in need thereof.

[0098] The present disclosure also provides the use of a compound of Formula (I) (e.g. Compound 1), or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, for inhibiting KRAS (e.g., KRAS having a G12C mutation) in a subject in need thereof.

[0099] The present disclosure also provides the use of a compound of Formula (I) (e.g. Compound 1), or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient, in the manufacture of a medicament for inhibiting KRAS (e.g., KRAS having a G12C mutation) in a subject in need thereof.

[0100] The present disclosure also provides a method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g. Compound 1), or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof to a subject (e.g., patient) (e.g., a subject in need thereof), thereby ameliorating, reducing, eliminating, ceasing, delaying the progression of, or improving one or more symptoms of the subject, such as one or more symptoms of a disease, disorder, or condition (e.g., a cancer). In some embodiments, the subject has a cancer characterized by a mutant KRAS (e.g., KRAS having a G12C mutation).

[0101] In some embodiments of any of the methods, uses, and medicaments provided herein, the disease, disorder, or condition is a cancer (e.g., as described herein). In some embodiments of any of the methods, uses, and medicaments provided herein, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), colorectal cancer (CRC), endometrial cancer, uterine carcinosarcoma, Ewing sarcoma, osteosarcoma, Rhabdomyosarcoma, adrenocortical carcinoma, neuroblastoma, Wilm tumor, retinoblastoma, skin cancer, breast cancer, prostate cancer, head and neck cancer, or ovarian cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small cell lung cancer adenocarcinoma), or colorectal cancer (CRC). In some embodiments, the cancer isPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 pancreatic cancer (e.g., pancreatic ductal adenocarcinoma). In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer adenocarcinoma). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is or comprises a solid tumor.

[0102] In some embodiments of any of the methods, uses, and medicaments provided herein, the disease, disorder, or condition is related to KRAS, such as a disorder associated with a mutation of KRAS or dysregulation of KRAS. In some embodiments, the disease, disorder, or condition is related to the KRAS gene, such as a disease, disorder, or condition associated with a mutation of the KRAS gene or dysregulation of the KRAS gene. Mutation or dysregulation of KRAS or KRAS may include mutation or dysregulation of human K-Ras4a and / or human K-Ras4b. In some embodiments, the disease, disorder, or condition is related to the KRAS (e.g., human K-Ras4a or K-Ras4b) signaling pathway activity, such as a disease, disorder, or condition related to aberrant KRAS signaling pathway activity. In some embodiments, the disease, disorder, or condition is related to mutation or dysregulation of human K-Ras4b. In some embodiments, the disease, disorder, or condition is related to aberrant K-Ras4b signaling pathway activity. In some embodiments, the disease, disorder, or condition is related to mutation or dysregulation of human K-Ras4a. In some embodiments, the disease, disorder, or condition is related to aberrant K-Ras4a signaling pathway activity.

[0103] In some embodiments, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered in a unit dosage form. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a capsule comprising about 25 milligrams (mg), about 50 mg, about 100 mg, or about 200 mg of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form is a capsule comprising about 25 mg or about 50 mg of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof).

[0104] In some embodiments, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered once, twice, three times, or four times per day. In some embodiments, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered once a day (e.g., daily or “QD”). In some embodiments, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered twice a day (e.g., “BID”).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0105] In some embodiments, the administration of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) occurs according to a treatment cycle. In some embodiments, the treatment cycle is 21 days. In some embodiments, the treatment cycle is 28 days. In some embodiments, treatment with the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) comprises administration of the compound for multiple treatment cycles, such as multiple treatment cycles of 21 or 28 days. In some embodiments, treatment with the compound (e.g., Compound 1 , or a pharmaceutically acceptable salt thereof) comprises administration of the compound for at least 2, 3, 4, 5, 6, or more treatment cycles, such as at least 1, 2, 3, 4, 5, or 6 treatment cycles of 21 or 28 days. In some embodiments, treatment with the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) comprises administration of the compound for 1, 2, 3, 4, 5, or 6 treatment cycles, such as 1, 2, 3, 4, 5, or 6 treatment cycles of 21 or 28 days. In some embodiments, the methods and / or uses comprise chronic administration. In yet other embodiments, the methods and / or uses comprise administration over the course of several weeks, months, years, or decades. In still other embodiments, the methods and / or uses comprise administration over the course of several weeks. In still other embodiments, the methods and / or uses comprise administration over the course of several months. In still other embodiments, the methods and / or uses comprise administration over the course of several years. In still other embodiments, the methods and / or uses comprise administration over the course of several decades.

[0106] In some embodiments, the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) is administered to the subject at an initial dose level of about 10 mg / day, about 25 mg / day, about 50 mg / day, about 100 mg / day, about 200 mg / day, about 400 mg / day, about 800 mg / day, about 1200 mg / day, about 1500 mg / day, about 1800 mg / day, or about 2000 mg / day. In some embodiments, the initial dose level is about 100 mg / day. In some embodiments, the initial dose level is about 200 mg / day. In some embodiments, the initial dose level is about 400 mg / day. In some embodiments, the initial dose level is about 800 mg / day.

[0107] In some embodiments, the total daily dosage of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) administered to the subject is at least about 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575, mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, or 2000 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 100 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 200 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 400 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at least about 800 mg.

[0108] In some embodiments, the total daily dosage of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) administered to the subject is at most about 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg,950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575, mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, or 2000 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is at most about 2000 mg.

[0109] In some embodiments, the total daily dosage of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof), is between about 1-2000 milligrams (mg), about 1-1500 mg, about 10-1500 mg, about 20-1500 mg, about 30-1500 mg, about 40-1500 mg, about 50-1500 mg, about 60-1500 mg, about 70-1500 mg, about 80-1500 mg, about 90- 1500 mg, about 100-1500 mg, about 125-1500 mg, about 150-1500 mg, about 175-1500 mg, about 200-1500 mg, about 225-1500 mg, about 250-1500 mg, about 275-1500 mg, aboutPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1300-1500 mg, about 325-1500 mg, about 350-1500 mg, about 375-1500 mg, about 400-1500 mg, about 425-1500 mg, about 450-1500 mg, about 475-1500 mg, about 500-1500 mg, about 525-1500 mg, about 550-1500 mg, about 575-1500 mg, about 600-1500 mg, about 625-1500 mg, about 650-1500 mg, about 675-1500 mg, about 700-1500 mg, about 725-1500 mg, about 750-1500 mg, about 775-1500 mg, about 800-1500 mg, about 825-1500 mg, about 850-1500 mg, about 875-1500 mg, about 900-1500 mg, about 925-1500 mg, about 950-1500 mg, about 975-1500 mg, about 1000- 1500 mg, about 1025-1500 mg, about 1050-1500 mg, about 1075- 1500 mg, 1100-1500 mg, about 1125-1500 mg, about 1150-1500 mg, about 1175-1500 mg, about 1200-1500 mg, about 1225-1500 mg, about 1250-1500 mg, about 1275-1500 mg, about 1300-1500 mg, about 1325-1500 mg, about 1350-1500 mg, about 1375-1500 mg, about 1400-1500 mg, about 1425-1500 mg, about 1450-1500 mg, about 1475-1500 mg, about 1- 1200 mg, about 10-1200 mg, about 20-1200 mg, about 30-1200 mg, about 40-1200 mg, about 50-1200 mg, about 60-1200 mg, about 70-1200 mg, about 80-1200 mg, about 90-1200 mg, about 100-1200 mg, about 125-1200 mg, about 150-1200 mg, about 175-1200 mg, about 200-1200 mg, about 225-1200 mg, about 250-1200 mg, about 275-1200 mg, about 300-1200 mg, about 325-1200 mg, about 350-1200 mg, about 375-1200 mg, about 400-1200 mg, about 425-1200 mg, about 450-1200 mg, about 475-1200 mg, about 500-1200 mg, about 525-1200 mg, about 550-1200 mg, about 575-1200 mg, about 600-1200 mg, about 625-1200 mg, about 650-1200 mg, about 675-1200 mg, about 700-1200 mg, about 725-1200 mg, about 750-1200 mg, about 775-1200 mg, about 800-1200 mg, about 825-1200 mg, about 850-1200 mg, about 875-1200 mg, about 900-1200 mg, about 925-1200 mg, about 950-1200 mg, about 975-1200 mg, about 1000-1200 mg, about 1025-1200 mg, about 1050-1200 mg, about 1075-1200 mg, 1100-1200 mg, about 1125-1200 mg, about 1150-1200 mg, about 1175-1200 mg, about 1- 1000 mg, about 10-1000 mg, about 20-1000 mg, about 30-1000 mg, about 40-1000 mg, about 50-1000 mg, about 60-1000 mg, about 70-1000 mg, about 80-1000 mg, about 90-1000 mg, about 100-1000 mg, about 125-1000 mg, about 150-1000 mg, about 175-1000 mg, about 200-1000 mg, about 225-1000 mg, about 250-1000 mg, about 275-1000 mg, about 300-1000 mg, about 325-1000 mg, about 350-1000 mg, about 375-1000 mg, about 400-1000 mg, about 425-1000 mg, about 450-1000 mg, about 475-1000 mg, about 500-1000 mg, about 525-1000 mg, about 550-1000 mg, about 575-1000 mg, about 600-1000 mg, about 625-1000 mg, about 650-1000 mg, about 675-1000 mg, about 700-1000 mg, about 725-1000 mg, about 750-1000 mg, about 775-1000 mg, about 800-1000 mg, about 825-1000 mg, about 850-1000 mg, about 875-1000 mg, about 900-1000 mg, about 925-1000 mg, about 950-1000 mg, about 975-1000PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 mg, about 1-750 mg, about 10-750 mg, about 20-750 mg, about 30-750 mg, about 40-750 mg, about 50-750 mg, about 60-750 mg, about 70-750 mg, about 80-750 mg, about 90-750 mg, about 100-750 mg, about 125-750 mg, about 150-750 mg, about 175-750 mg, about 200- 750 mg, about 225-750 mg, about 250-750 mg, about 275-750 mg, about 300-750 mg, about 325-750 mg, about 350-750 mg, about 375-750 mg, about 400-750 mg, about 425-750 mg, about 450-750 mg, about 475-750 mg, about 500-750 mg, about 525-750 mg, about 550-750 mg, about 575-750 mg, about 600-750 mg, about 625-750 mg, about 650-750 mg, about 675- 750 mg, about 700-750 mg, about 725-750 mg, about 1-500 mg, about 10-500 mg, about 20- 500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 70- 500 mg, about 80-500 mg, about 90-500 mg, about 100-500 mg, about 125-500 mg, about 150-500 mg, about 175-500 mg, about 200-500 mg, about 225-500 mg, about 250-500 mg, about 275-500 mg, about 300-500 mg, about 325-500 mg, about 350-500 mg, about 375-500 mg, about 400-500 mg, about 425-500 mg, about 450-500 mg, about 475-500 mg, about 1- 300 mg, about 10-300 mg, about 20-300 mg, about 30-300 mg, about 40-300 mg, about SO- SOO mg, about 60-300 mg, about 70-300 mg, about 80-300 mg, about 90-300 mg, about 100- 300 mg, about 125-300 mg, about 150-300 mg, about 175-300 mg, about 200-300 mg, about 225-300 mg, about 250-300 mg, about 275-300 mg, about 1-150 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40-150 mg, about 50-150 mg, about 60-150 mg, about 70-150 mg, about 80-150 mg, about 90-150 mg, about 100-150 mg, about 125-150 mg, about 100-200 mg, about 125-175 mg, about 200-400 mg, about 275-325 mg, about 400-600 mg, about 475-525 mg, about 500-900 mg, about 650-850 mg, about 725-775 mg, about 900- 1100 mg, about 975-1025 mg, about 1100-1300 mg, or about 1175-1225 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is between about 50-150 mg, about 150-250 mg, about 250-350 mg, about 350-450 mg, about 450-550 mg, about 550-650 mg, about 650-750 mg, about 750-850 mg, about 850- 950 mg, about 950-1050 mg, or about 1150-1250 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is between about 50-150 mg, about 150-250 mg, about 350-450 mg, or about 750-850 mg.

[0110] In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 50-150 mg, about 150-250 mg, about 250- 350 mg, about 350-450 mg, about 450-550 mg, about 550-650 mg, about 650-750 mg, or about 750-850 mg. In some embodiments, the total daily dosage of the compound, or thePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 pharmaceutically acceptable salt thereof, is about 150-250 mg, about 250-350 mg, about 350- 450 mg, about 450-550 mg, about 550-650 mg, or about 650-750 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 50-150 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 150-250 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 250-350 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 350-450 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 450-550 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 550-650 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 650-750 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 750-850 mg.

[0111] In some embodiments, the total daily dosage of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) administered to the subject is about 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg,700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg,1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg,1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575, mg, 1600 mg, 1625 mg,1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg,1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, or 2000 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg, about 200 mg, about 300 mg, about 500 mb, about 650 mg, or about 900 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 300 mg. In some embodiments, the total daily dosage of the compound, orPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 the pharmaceutically acceptable salt thereof, is about 400 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 500 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 650 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 700 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 800 mg. In some embodiments, the total daily dosage of the compound, or the pharmaceutically acceptable salt thereof, is about 900 mg.

[0112] In some embodiments, the compound is formulated as a unit dosage form. In some embodiments, the unit dosage form is a capsule or tablet. In some embodiments, the capsule or tablet comprises about 25 mg, about 50 mg, about 100 mg, or about 200 mg of the compound (e.g., Compound 1). In some embodiments, the capsule or tablet comprises about 25 mg or about 50 mg of the compound (e.g., Compound 1).

[0113] In some embodiments, when the subject experiences an adverse event, the compound is administered to the subject at a reduced dose comprising 50% of the initial dose level. In some embodiments, dose adjustment (e.g., dose de-escalation) may be done at the end of a treatment cycle, such as the end of a 21- or 28-day treatment cycle. In some embodiments, dose adjustment (e.g., dose de-escalation) may be done during a treatment cycle, such as during a 21- or 28-day treatment cycle.

[0114] In some embodiments, when the subject experiences an adverse event, the compound is administered to the subject at a reduced dose according to the schedule included in Table 1 below.Table 1. Schedule of dose reductions

[0115] In some embodiments, when the subject experiences an adverse event, the subject is treated with the reduced dose until the adverse event is resolved. In some embodiments, the subject is treated with the reduced dose for the remainder of the treatment.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0116] In some embodiments, the adverse event is nausea; vomiting; diarrhea (e.g., diarrhea lasting longer than 3 days); adrenal insufficiency; interstitial lung disease; pneumonitis; photosensitivity; higher than normal alkaline phosphatase, aspartate aminotransferase (AST), and / or alanine aminotransferase (ALT) levels; anemia; febrile neutropenia; thrombocytopenia; a hematologic reaction; or a combination thereof.

[0117] In some embodiments, the administration of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) comprises one or more dose de-escalations. In some embodiments, the administration of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) comprises only one dose de-escalation. In some embodiments, the administration of the compound (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) comprises 2, 3, or more dose de-escalations.

[0118] In some embodiments, the disease, disorder, or condition is mediated by KRASG12C.

[0119] In some embodiments, the disease, disorder, or condition is ameliorated by the inhibition of KRASG12C.

[0120] In some embodiments, the disease, disorder, or condition is a cancer. In some embodiments, the cancer is a solid tumor. Cancers that may be treated by the methods disclosed herein include, but are not limited to, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, and prostate cancer; cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, liver and biliary passages; pancreas, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testis, bladder, kidney and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components of the central and peripheral nervous systems, as well as associated structures such as the meninges; and thyroid and other endocrine glands. The term “cancer” also encompasses cancers that do not necessarily form solid tumors, including Hodgkin’s disease, non-Hodgkin’ s lymphomas, multiple myeloma, and hematopoietic malignancies including leukemias (Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomas including lymphocytic, granulocytic and monocytic lymphomas. Additional types of cancers which may be treated using thePATENTAttorney Docket No. 2014229-0161 Thera-23.WO 1 compounds and methods provided herein include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing’s tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphatic system cancer, lymphomas, lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myelomas, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinomas, paraganglioma, parathyroid tumors, pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers, melanoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm’s tumor. Additional diseases and disorders that may be treated by the methods disclosed herein include, but are not limited to, diseases or disorders related to KRAS, such as diseases or disorders associated with a mutation of KRAS (e.g., KRAS G12C mutation) or dysregulation of KRAS, and diseases or disorders related to the KRAS gene, such as diseases or disorders associated with a mutation of the KRAS gene or dysregulation of the KRAS gene.

[0121] In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, esophageal / gastroesophageal cancer, small bowel cancer, breast cancer, glioblastoma, biliary tract cancer, appendiceal cancer, ovarian cancer, endometrial cancer, and lung cancer. In some embodiments, the cancer is characterized by a mutant KRAS. In some embodiments, the cancer is a KRASG12C-positive cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is locally advanced and unresectable or metastatic NSCLC. In some embodiments, the cancer is advanced NSCLC. In some embodiments, the NSCLC is KRAS mutant NSCLC. In some embodiments, the NSCLC is characterized by a G12C, G12D, G12V, G12A, G12S, G12R, or Q61 mutation in KRAS. InPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 some embodiments, the NSCLC is KRAS G12C mutant NSCLC. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is breast cancer.

[0122] In some embodiments, the cancer has resistance (e.g., an inherent or acquired resistance) to a KRAS inhibitor (e.g., as described herein). In some embodiments, the cancer has resistance to one or more chemotherapeutic drugs and / or ionizing radiation.

[0123] In some embodiments, the subject has previously undergone a treatment regimen for the cancer.

[0124] In some embodiments, the subject has progressed on or within 6 months of the end of a prior multimodal therapy with a curative intent.

[0125] In some embodiments, the subject has previously undergone treatment with a KRAS inhibitor therapy. In some embodiments, the subject was previously treated with a KRAS inhibitor selected from MRTX-EX185, MRTX1133, ARS-853, ARS-1620, JNJ-74699157 (ARS-3248), ASP2453, LY3499446, LY3537982, D-1553, JDQ443, BI 1823911, RMC- 6236, RMC-6291, RMC-9805, RMC-5127, RMC-0708, RMC-8839, RMC-036, RMC-037, ERAS-3490, glecirasib (JAB-21822), sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), BPI-421286, GFH925, D3S-001, GH35, HBI-2438, BI3706674, LY3962673, LY4066434, QTX3046, QTX3034, JAB23425, HRS-4642 and a combination thereof. In some embodiments, the subject was previously treated with a KRASG12C-selective inhibitor. In some embodiments, the subject was previously treated with a KRASG12C(off) inhibitor. In some embodiments, the subject was previously treated with sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), JDQ443, LY3537892, or a combination thereof.

[0126] In some embodiments, the subject has not previously undergone treatment with a KRAS inhibitor therapy.

[0127] In some embodiments, the subject has previously entered remission from the cancer.

[0128] In some embodiments, the subject does not have a KRAS mutation selected from G12D, G12V, M72K, Q61H, R164Q, R68S, or T2S.

[0129] In some embodiments, the subject has no other targetable driver mutations. In some embodiments, the subject does not have a targetable driver mutation in epidermal growthPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS 1, BRAF, RET, MET, NTRK, or HER2.

[0130] In some embodiments, the subject has measurable disease by RECIST vl.l. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

[0131] In some embodiments, the subject is a human. In some embodiments, the subject is at least 18 years of age.

[0132] In some embodiments, the subject has progression on or disease recurrence after available standard of care treatments including an immune checkpoint inhibitor, a platinumbased doublet chemotherapy, or both. In certain embodiments, the standard of care treatments include an immune checkpoint inhibitor (ICI). In some embodiments, the prior treatment includes a KRASG12C (OFF) inhibitor. In some embodiments, the progression or disease recurrence occurs after at least 1 prior line of systemic therapy. In certain embodiments, the at least one prior line of systemic therapy includes platinum-based doublet therapy, ICI, or both.

[0133] In some embodiments, the subject has an absolute neutrophil count (ANC) >1500 / pL. In some embodiments, the subject has a platelet count of >100,000 / pL. In some embodiments, the subject has hemoglobin of >9 g / dL without transfusion for at least 2 weeks or without erthyropoiesis-stimulating agents for at least 6 weeks.

[0134] In some embodiments, provided methods and / or uses contemplate administration of the compound to a subject that does not have inadequate organ function as defined below: a. Absolute neutrophil count (ANC) <l,500 / |tL b. Platelets <100,000 / pL c. Hemoglobin <9 g / dL without transfusion for at least 2 weeks prior to enrollment d. Hemoglobin <9 g / dL without erythropoiesis-stimulating agents (e.g., Epo, Procrit®) for at least <6 weeks prior to enrollment e. Serum creatinine >1.5 x upper limit of normal (ULN), unless creatinine clearance >60 mL / min (measured or calculated using the Cockcroft- Gault formula: (140 - age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg / dL) f. Serum total bilirubin >1.5 x institutional ULN or >2.0 x ULN if the subject has a diagnosis of Gilbert syndrome.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 g. AST / serum glutamic-oxaloacetic transaminase (SGOT) and / or ALT / serum glutamic-pyruvic transaminase (SGPT) >2.5 x ULN or AST and / or ALT >5.0 x ULN with documented liver metastases. h. International normalized ratio (INR) or prothrombin time (PT) >1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants. i. aPTT > 1 .5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.

[0135] In certain embodiments, the subject does not have any other life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating subject’s safety, or interfere with or compromise the integrity of the study outcomes.

[0136] In some embodiments, the subject does not have any of the following cardiac- related issues or findings: a. History of significant cardiovascular disease, such as cerebrovascular accident, myocardial infarction or unstable angina, within the last 6 months before starting study treatment. b. Clinically significant cardiac disease, including New York Heart Association Class II or higher heart failure. c. History of left ventricular ejection fraction (LVEF) <50% within the previous 12 months before starting study treatment. d. Resting QT interval corrected for heart rate (QTc) >470 msec, derived as the average from 3 ECGs at screening. e. Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., third degree heart block, Mobitz Type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation). f. Subjects with a pacemaker may be allowed on study following review and agreement between the treating physician and medical monitor.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0137] In certain embodiments, the subject does not have a diagnosis of another invasive malignancy within the previous 2 years from time of informed consent other than curatively treated non-melanomatous skin cancer, superficial urothelial carcinoma, in situ cervical cancer, or any other curatively treated or closely monitored malignancy that is not expected to require treatment for recurrence or progress during the course of the study. In some embodiments, the subject does not have untreated brain metastases (subjects with stable brain metastases are allowed). In certain embodiments, the subject is not on dialysis. In still other embodiments, the subject does not have a history of allogeneic bone marrow transplant.

[0138] In some embodiments, the compounds, compositions, and methods provided herein are useful in the prevention and / or reduction of tumor invasion, growth, and / or metastasis.

[0139] In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) (e.g. Compound 1), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, slows or prevents growth of a tumor. In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) (e.g.Compound 1), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, results in shrinkage of a tumor (e.g., tumor regression). In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) (e.g. Compound 1), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, results in at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% regression of a tumor, such as for a period of one or more weeks (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks), a period of one or more months (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months), or a period of one or more years (e.g., at least about 1, 2, 3, or more years). In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) (e.g., Compound 1), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, stabilizes a tumor. In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) (e.g., Compound 1), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, stabilizes a tumor for a period of one or more weeks (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks), a period of one or more months (e.g., at least about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or more months), or a period of one or more years (e.g., at least about 1, 2, 3, or more years). In somePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 embodiments, the subject has a cancer characterized by a mutant KRAS (e.g., KRAS having a G12C mutation).

[0140] In some embodiments, the compound (e.g., Compound 1), or pharmaceutically acceptable salt thereof, is administered in combination with another therapeutic agent, such as another agent suitable for treating a cancer.Compositions

[0141] In some embodiments, methods and uses provided herein comprise administering a compound of Formula (1) (e.g., Compound 1) a pharmaceutical composition comprising the compound. In some such embodiments, methods and uses provided herein comprise administering Compound 1, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

[0142] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the oral pharmaceutical formulation is selected from a tablet and a capsule.

[0143] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration.

[0144] In some embodiments, a pharmaceutically acceptable carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration selected. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any suitable manner known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0145] In some embodiments, a pharmaceutical formulation can be suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration. The most suitable route mayPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 depend on, for example, the condition and disorder of the subject to which the pharmaceutical formulation will be administered. A pharmaceutical formulation can be provided in a unit dosage form. A pharmaceutical formulation can be prepared by any suitable method. A method of preparing a pharmaceutical formulation may comprise bringing Compound 1 , or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (“active ingredient”) in contact with one or more pharmaceutically acceptable carriers (e.g., accessory ingredients). Tn general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0146] Pharmaceutical formulations of Compound 1, in any available form (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer etc.) may be provided as discrete units. For example, a formulation suitable for oral administration may be provided as capsules, cachets, and / or tablets containing a predetermined amount of the compound in any suitable form (e.g., the active ingredient); as a solution or suspension in a solvent (e.g., aqueous or non-aqueous solvent); as an emulsion (e.g., an oil-in-water liquid emulsion or water-in-oil liquid emulsion); or as a powder or granules. The active ingredient may additionally or alternatively be provided as a bolus, electuary, or paste.

[0147] Pharmaceutical preparations suitable for oral administration include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by, for example, compression or molding, optionally with one or more accessory ingredients, such as one or more pharmaceutically acceptable excipients. Compressed tablets may be prepared by, for example, compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by, for example, molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with, for example, one or more fillers such as lactose, one or more binders such as one or more starches, and / or one or more lubricants such as talc or magnesium stearate and, optionally, one or more stabilizers. In soft capsules, the active compounds may be dissolvedPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers and other elements may also be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain a gum, gelling agent, polymer, solvent, or combination thereof. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0148] A pharmaceutical composition comprising Compound 1, or a form thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.), may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules, vials, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, prior (e.g., immediately prior) to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0149] A pharmaceutical composition comprising Compound 1, or a form thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer etc.), may be formulated as a solution for injection, which solution may be an aqueous or non-aqueous (oily) sterile solution and may comprise one or more antioxidants, thickening agents, suspending agents, buffers, solutes, and / or bacteriostats. The addition of one or more such additives may render the formulation isotonic with the blood of the intended recipient (e.g., subject or patient). Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0150] In addition to the formulations described elsewhere herein, Compound 1 in any suitable form (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.)) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0151] A pharmaceutical composition comprising Compound 1 or a form thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) that is suitable for buccal or sublingual administration may take the form of tablets, lozenges, pastilles, or gels. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. A pharmaceutical composition comprising a compound provided herein or a form thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) that is suitable for rectal administration may be formulated as a suppository or retention enema and may comprise a medium such as, for example, cocoa butter, polyethylene glycol, or other glycerides.

[0152] Compound 1 or a form thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) may be formulated for non-systemic administration, such as topical administration. This includes the application of a compound disclosed herein, or a form thereof, externally to the epidermis or the buccal cavity and the instillation of such a compound, or a form thereof, into the ear, eye and nose, such that the compound, or a form thereof, does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0153] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0154] For administration by inhalation, Compound 1 or forms thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) may be conveniently delivered from an insufflator, nebulizer pressurized packs, or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds provided herein may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0155] Preferred unit dosage formulations are those containing an effective dose, as described herein, or an appropriate fraction thereof, of the active ingredient (e.g., Compound 1, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof).

[0156] It should be understood that in addition to the ingredients particularly described elsewhere herein, the formulations described herein may include other useful agents having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0157] Compound 1 or forms thereof (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) may be administered orally or via injection at a dose of from 0.1 to 500 mg / kg per day. The dose range for adult humans is generally from 5 mg to 2 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg.

[0158] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1BBO-8520 Monotherapy and Combination Therapy

[0159] In a first aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of the compound.

[0160] In some embodiments, the compound is Compound 1:or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound is Compound 1:(Compound 1).

[0162] In some embodiments, the cancer is described according to any one of embodiments herein in Section - Uses and Methods of Treatment.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0163] In some embodiments, the cancer is a solid tumor.

[0164] In some embodiments, the cancer is pancreatic cancer, colorectal cancer, esophageal / gastroesophageal cancer, small bowel cancer, breast cancer, glioblastoma, biliary tract cancer, appendiceal cancer, ovarian cancer, endometrial cancer, or lung cancer.

[0165] In some embodiments, the cancer is pancreatic cancer, colorectal cancer, or lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, or non-small cell lung cancer (NSCLC). In some embodiments, the cancer is PDAC. In some embodiments, the cancer is NSCLC.

[0166] In some embodiments, the cancer is characterized by a mutation in a KRAS protein.

[0167] In some embodiments, the cancer is characterized by KRAS G12C mutation. In some embodiments, the cancer is a KRAS G12C positive cancer.

[0168] In some embodiments, the cancer is resistant to a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is resistant to a KRAS G12C inhibitor that only binds to an inactive GDP-bound state of KRAS G12C. In some embodiments, the cancer is resistant to sotorasib, adagrasib, or divarasib.Non-small Cell Lung Cancer (NSCLC)

[0169] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0170] In a second aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, method comprising administering to the subject a therapeutically effective amount of Compound 1:(Compound 1),PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0171] In some embodiments, the NSCLC is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the NSCLC is described in Example 2.

[0172] In some embodiments, the NSCLC is characterized by a mutation in a KRAS protein.

[0173] In some embodiments, the NSCLC is characterized by KRAS G12C mutation. In some embodiments, the NSCLC is a KRAS G12C positive cancer.

[0174] In some embodiments, the NSCLC is resistant to a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the NSCLC is resistant to a KRAS G12C inhibitor that only binds to an inactive GDP-bound state of KRAS G12C. In some embodiments, the NSCLC is resistant to sotorasib, adagrasib, or divarasib.

[0175] In some embodiments, the NSCLC is an advanced or metastatic NSCLC.

[0176] In some embodiments, the subject is described according to any one of embodiments herein in Sections - Subject and Uses and Methods of Treatment. In some embodiments, the subject is described in Example 2. In some embodiments, the subject meets inclusion criteria, as described in Example 2. In some embodiments, the subject meets both inclusion and exclusive criteria, as described in Example 2.

[0177] In some embodiments, the subject does not have a KRAS mutation selected from G12D, G12V, M72K, Q61H, R164Q, R68S, and T2S.

[0178] In some embodiments, the subject does not have a targetable driver mutation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, NTRK, or HER2.

[0179] In some embodiments, the subject has progression on or disease recurrence after available standard of care (SoC) treatments comprising an immune checkpoint inhibitor, a platinum-based doublet chemotherapy, or both. In some embodiments, the immunePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 checkpoint inhibitor (ICI) is pembrolizumab, atezolizumab, nivolumab, ipilimumab, durvalumab, tremelimumab, cemiplimab-rwlc, or a combination thereof.

[0180] In some embodiments, the subject has progression on or disease recurrence after available standard of care (SoC) treatments comprising a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS G12C inhibitor only binds to an inactive GDP-bound state of KRAS G12C. In some embodiments, the KRAS G12C inhibitor is sotorasib, adagrasib, divarasib, JDQ443, LY3537892, or a combination thereof. In some embodiments, the KRAS G12C inhibitor is sotorasib, adagrasib, or divarasib.

[0181] In some embodiments, the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2). In some embodiments, the subject does not have tumors with a targetable driver mutation in epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, NTRK, or HER2.

[0182] For treating all types of cancer (e.g., pancreatic cancer, colorectal cancer, and NSCLC), in some embodiments, the subject has not previously undergone treatment with a KRAS inhibitor therapy. In some embodiments, the subject has not previously treated with a KRAS inhibitor selected from MRTX-EX185, MRTX1133, ARS-853, ARS-1620, JNJ- 74699157 (ARS-3248), ASP2453, LY3499446, LY3537982, D-1553, JDQ443, Bl 1823911, RMC-6236, RMC-6291, RMC-9805, RMC-5127, RMC-0708, RMC-8839, RMC-036, RMC- 037, ERAS-3490, glecirasib (JAB-21822), sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), BPI-421286, GFH925, D3S-001, GH35, HBI-2438, BI3706674, LY3962673, LY4066434, QTX3046, QTX3034, JAB23425, HRS-4642 and a combination thereof.

[0183] For treating all types of cancer (e.g., pancreatic cancer, colorectal cancer, and NSCLC), in some embodiments, the subject has not previously been treated with the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof.

[0184] For treating all types of cancer (e.g., pancreatic cancer, colorectal cancer, andNSCLC), in some embodiments, the subject was previously treated with a KRAS G12CPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the subject was previously treated with a KRAS inhibitor selected from MRTX-EX185, MRTX1133, ARS-853, ARS-1620, JNJ-74699157 (ARS-3248), ASP2453, LY3499446, LY3537982, D-1553, JDQ443, BI 1823911, RMC-6236, RMC-6291, RMC-9805, RMC- 5127, RMC-0708, RMC-8839, RMC-036, RMC-037, ERAS-3490, glecirasib (JAB-21822), sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), BPI-421286, GFH925, D3S-001, GH35, HB 1-2438, BI3706674, LY3962673, LY4066434, QTX3046, QTX3034, JAB23425, HRS-4642 and a combination thereof.

[0185] For treating all types of cancer (e.g., pancreatic cancer, colorectal cancer, and NSCLC), in some embodiments, the subject was previously treated with a KRAS G12C inhibitor, wherein the KRAS inhibitor only binds to an inactive GDP-bound state of KRAS G12C.

[0186] For treating all types of cancer (e.g., pancreatic cancer, colorectal cancer, and NSCLC), in some embodiments, the subject was previously treated with sotorasib, adagrasib, divarasib, JDQ443, LY3537892, or a combination thereof. In some embodiments, the subject was previously treated with sotorasib, adagrasib, or divarasib.

[0187] For treating all types of cancer (e.g., pancreatic cancer, colorectal cancer, and NSCLC), in some embodiments, the subject is a human. In some embodiments, the subject is an adult of at least 18 years old.Administration

[0188] In some embodiments, the administration of the compound of Formula (I), Compound 1, or a or a pharmaceutically acceptable salt thereof is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the administration of Compound 1 (or a pharmaceutically acceptable salt thereof) is described in Example 2.

[0189] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount, with a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0190] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount, with a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

[0191] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 50 mg to about 2000 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 1500 mg, from about 50 mg to about 1200 mg, from about 100 mg to about 1200 mg, from about 200 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 400 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 600 mg to about 1200 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 100 mg to about 900 mg, from about 200 mg to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, from about 500 mg to about 900 mg, from about 50 mg to about 800 mg, from about 100 mg to about 800 mg, from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, from about 500 mg to about 800 mg, from about 50 mg to about 700 mg, from about 100 mg to about 700 mg, from about 200 mg to about 700 mg, from about 300 mg to about 700 mg, from about 400 mg to about 700 mg, from about 500 mg to about 700 mg, from about 50 mg to about 600 mg, from about 100 mg to about 600 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 400 mg to about 600 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 400 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 200 mg, or from about 100 mg to about 200 mg of the compound of Formula (I) or Compound 1.

[0192] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 100 mg to about 900 mg, from about 200 mg to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, or from about 500 mg to about 900 mg of the compound of Formula (I) or Compound 1 .PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0193] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, or from about 500 mg to about 800 mg of the compound of Formula (I) or Compound 1.

[0194] In some embodiments, the therapeutically effective amount is a total daily dosage of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 700 mg, or about 800 mg of the compound of Formula (I) or Compound 1.

[0195] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 50 mg to about 2000 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 1500 mg, from about 50 mg to about 1200 mg, from about 100 mg to about 1200 mg, from about 200 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 400 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 600 mg to about 1200 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 100 mg to about 900 mg, from about 200 mg to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, from about 500 mg to about 900 mg, from about 50 mg to about 800 mg, from about 100 mg to about 800 mg, from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, from about 500 mg to about 800 mg, from about 50 mg to about 700 mg, from about 100 mg to about 700 mg, from about 200 mg to about 700 mg, from about 300 mg to about 700 mg, from about 400 mg to about 700 mg, from about 500 mg to about 700 mg, from about 50 mg to about 600 mg, from about 100 mg to about 600 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 400 mg to about 600 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 400 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 200 mg, or from about 100 mg to about 200 mg of Compound 1.

[0196] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 50 mg to about 900 mg, from about 100 mg to about 900 mg, from about 200 mgPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, from about 500 mg to about 900 mg, from about 50 mg to about 800 mg, from about 100 mg to about 800 mg, from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, from about 500 mg to about 800 mg, from about 50 mg to about 700 mg, from about 100 mg to about 700 mg, from about 200 mg to about 700 mg, from about 300 mg to about 700 mg, from about 400 mg to about 700 mg, from about 500 mg to about 700 mg, from about 50 mg to about 600 mg, from about 100 mg to about 600 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 400 mg to about 600 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 400 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 200 mg, or from about 100 mg to about 200 mg of Compound 1.

[0197] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 200 mg to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, from about 500 mg to about 900 mg, from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, from about 500 mg to about 800 mg, from about 200 mg to about 700 mg, from about 300 mg to about 700 mg, from about 400 mg to about 700 mg, from about 500 mg to about 700 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 400 mg to about 600 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 200 mg to about 400 mg of Compound 1.

[0198] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 100 mg to about 900 mg, from about 200 mg to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, from about 500 mg to about 900 mg, from about 600 mg to about 900 mg, or from about 700 mg to about 900 mg of the compound of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 100 mg to about 900 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 200 mg to about 900 mg of Compound 1 . In some embodiments, the therapeutically effective amount is a total daily dosage of from about 300 mg to about 900 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from aboutPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1400 mg to about 900 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 500 mg to about 900 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 600 mg to about 900 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 700 mg to about 900 mg of Compound 1.

[0199] In some embodiments, the therapeutically effective amount is a total daily dosage of from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, or from about 500 mg to about 800 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 100 mg to about 800 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 200 mg to about 800 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 300 mg to about 800 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 400 mg to about 800 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of from about 500 mg to about 800 mg of Compound 1.

[0200] In some embodiments, the therapeutically effective amount is a total daily dosage of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 700 mg, or about 800 mg of Compound 1.

[0201] In some embodiments, the therapeutically effective amount is a total daily dosage of about 100 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 200 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 300 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 400 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 500 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 600 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 700 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total dailyPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 dosage of about 800 mg of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 900 mg of Compound 1.

[0202] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0203] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0204] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

[0205] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.Treatment

[0206] In some embodiments, the treatment (e.g., treatment cycle, duration, dose escalation or de-escalation) is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the treatment is described in Example 2.

[0207] In some embodiments, the treatment comprises one or more treatment cycles; and the administration of the compound of Formula (I) or Compound 1 comprises a dose escalation or de-escalation after a previous treatment cycle, wherein the dose escalation or de- escalation is determined by a dose-limiting toxicity (DLT) assessment.

[0208] In some embodiments, the treatment comprises one or more treatment cycles; and the administration of Compound 1 comprises a dose escalation or de-escalation after a previous treatment cycle, wherein the dose escalation or de-escalation is determined by a dose-limiting toxicity (DLT) assessment (as described herein).

[0209] In some embodiments of any one of the first and second aspects and the embodiments thereof, the method comprises administering a therapeutically effective amount of Compound 1 to the subject, wherein the therapeutically effective amount is described herein.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Combination Therapy

[0210] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0211] In some embodiments of the second aspect, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in combination with pembrolizumab.

[0212] In some embodiments, pembrolizumab is administered by an intravenous injection. In some embodiments, pembrolizumab is administered by intravenous infusion.

[0213] Pembrolizumab can be administered in a recommended dosage according to the product’s dosing information when used alone. In some embodiments, pembrolizumab is administered in a dosage of 200 mg every three weeks (q3week) or 400 mg every six weeks (q6week) by intravenous (IV) administration. In some embodiments, pembrolizumab is administered in a dosage of 200 mg every three weeks by intravenous (IV) administration. In some embodiments, pembrolizumab is administered in a dosage of 400 mg every six weeks by intravenous (IV) administration.

[0214] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered concomitantly.

[0215] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered sequentially. In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, is administered prior to administration of pembrolizumab. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered after administration of pembrolizumab.

[0216] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are provided in jointly therapeutically effective amounts.

[0217] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are provided in synergistically effective amounts.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0218] In some embodiments, the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof, and / or pembrolizumab are each used at a dose lower than when each is used alone.

[0219] In a third aspect, the present disclosure provides a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, method comprising administering i) a therapeutically effective amount of Compound 1 :or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of pembrolizumab.

[0220] In some embodiments of the third aspect, the NSCLC is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the NSCLC is described in Example 2. In some embodiments, the NSCLC is described according to any one of embodiments herein in the second aspect.

[0221] In some embodiments, the subject is described according to any one of embodiments herein in Sections - Subject and Uses and Methods of Treatment. In some embodiments, the subject is described in Example 2. In some embodiments, the subject meets inclusion criteria, as described in Example 2. In some embodiments, the subject meets both inclusion and exclusive criteria, as described in Example 2. In some embodiments, the subject is described according to any one of embodiments herein in the second aspect.

[0222] In some embodiments, the therapeutically effective amount and administration of Compound 1 , or a pharmaceutically acceptable salt thereof, is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the therapeutically effective amount and administration of Compound 1 (or a pharmaceutically acceptable salt thereof) is described in Example 2. In some embodiments, the therapeutically effective amount and administration of Compound 1 (or aPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 pharmaceutically acceptable salt thereof) is described according to any one of embodiments herein in the second aspect.

[0223] In some embodiments, the treatment (e.g., treatment cycle, duration, dose escalation or de-escalation) is described according to any one of embodiments herein in Section - Uses and Methods of Treatment. In some embodiments, the treatment is described in Example 2. In some embodiments, the treatment is described according to any one of embodiments herein in the second aspect.

[0224] In some embodiments of the third aspects, the method comprises administering a therapeutically effective amount of Compound 1 to the subject, wherein the therapeutically effective amount of Compound 1 is described herein.

[0225] In some embodiments of the third aspects, the therapeutically effective amount of pembrolizumab is described herein.

[0226] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered concomitantly.

[0227] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered sequentially. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered prior to administration of pembrolizumab. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered after administration of pembrolizumab.

[0228] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are provided in jointly therapeutically effective amounts. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are provided in synergistically effective amounts.

[0229] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and / or pembrolizumab are each used at a dose lower than when each is used alone. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used at a dose lower than when it is used alone. In some embodiments, pembrolizumab is used at a dose lower than when it is used alone. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, and pembrolizumab are each used at a dose lower than when each is used alone.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Embodiments

[0230] Embodiment 1. A method, comprising administering a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0231] Embodiment 2. The method of embodiment 1 , wherein the compound isCompound 1:or a pharmaceutically acceptable salt thereof.

[0232] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the subject has a disease, disorder, or condition mediated by KRASG12C.

[0233] Embodiment 4. The method of embodiment 3, wherein the disease, disorder, or condition is ameliorated by the inhibition of KRAS having a G12C mutation.

[0234] Embodiment 5. The method of any one of embodiments 1-4, wherein the subject has a cancer.

[0235] Embodiment 6. The method of embodiment 5, wherein the subject was previously diagnosed with the cancer.

[0236] Embodiment 7. The method of embodiment 5 or 6, wherein the subject has previously undergone a treatment regimen for the cancer.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0237] Embodiment 8. The method of embodiment 7, wherein the subject has progressed on or within 6 months of the end of a prior multimodal therapy with a curative intent.

[0238] Embodiment 9. The method of embodiment 7 or 8, wherein the subject previously undergone treatment with a KRAS inhibitor therapy.

[0239] Embodiment 10. The method of embodiment 9, wherein the subject was previously treated with a KRAS inhibitor selected from MRTX-EX185, MRTX1133, ARS- 853, ARS-1620, JNJ-74699157 (ARS-3248), ASP2453, LY3499446, LY3537982, D-1553, JDQ443, BI 1823911, RMC-6236, RMC-6291, RMC-9805, RMC-5127, RMC-0708, RMC- 8839, RMC-036, RMC-037, ERAS-3490, glecirasib (JAB-21822), sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), BPI-421286, GFH925, D3S-001, GH35, HBI-2438, BI3706674, LY3962673, LY4066434, QTX3046, QTX3034, JAB23425, HRS- 4642 and a combination thereof.

[0240] Embodiment 11. The method of embodiment 9, wherein the subject was previously treated with a KRAS G12C- selective inhibitor.

[0241] Embodiment 12. The method of embodiment 11, wherein the subject was previously treated with a KRASG12C(off) inhibitor.

[0242] Embodiment 13. The method of embodiment 12, wherein the subject was previously treated with sotorasib (AMG510), adagrasib (MRTX849), divarasib (GDC-6036), JDQ443, LY3537892, or a combination thereof.

[0243] Embodiment 14. The method of embodiment 7 or 8, wherein the subject has not previously undergone treatment with a KRAS inhibitor therapy.

[0244] Embodiment 15. The method of any one of embodiments 5-14, wherein the subject has previously entered remission from the cancer.

[0245] Embodiment 16. The method of any one of embodiments 5-15, wherein the cancer is a solid tumor.

[0246] Embodiment 17. The method of any one of embodiments 5-16, wherein the cancer is selected from the group consisting of pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, esophageal / gastroesophageal cancer, small bowel cancer,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 breast cancer, glioblastoma, biliary tract cancer, appendiceal cancer, ovarian cancer, endometrial cancer, and lung cancer.

[0247] Embodiment 18. The method of any one of embodiments 5-17, wherein the subject has a cancer characterized by a mutant KRAS.

[0248] Embodiment 19. The method of embodiment 18, wherein the cancer is a KRASG12C-positive cancer.

[0249] Embodiment 20. The method of any one of embodiments 5-19, wherein the cancer is non-small cell lung cancer (NSCLC).

[0250] Embodiment 21. The method of embodiment 20, wherein the cancer is locally advanced and unresectable or metastatic NSCLC.

[0251] Embodiment 22. The method of embodiment 21, wherein the cancer is advanced NSCLC.

[0252] Embodiment 23. The method of any one of embodiments 5-22, wherein the subject does not have a KRAS mutation selected from G12D, G12V, M72K, Q61H, R164Q, R68S, or T2S.

[0253] Embodiment 24. The method of any one of embodiments 5-23, wherein the subject does not have a targetable driver mutation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, NTRK, or HER2.

[0254] Embodiment 25. The method of any one of embodiments 5-24, wherein the subject has measurable disease by RECIST vl.l.

[0255] Embodiment 26. The method of any one of embodiments 5-25, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

[0256] Embodiment 27. The method of any one of embodiments 5-26, wherein the subject is a human.

[0257] Embodiment 28. The method of embodiment 27, wherein the subject is at least18 years of age.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0258] Embodiment 29. The method of any one of embodiments 5-28, wherein the subject has progression on or disease recurrence after available standard of care treatments including an immune checkpoint inhibitor, a platinum-based doublet chemotherapy, or both.

[0259] Embodiment 30. The method of any one of embodiments 1-29, wherein the subject has an absolute neutrophil count (ANC) >1500 / |iL.

[0260] Embodiment 31. The method of any one of embodiments 1-30, wherein the subject has a platelet count of >100,000 / pL.

[0261] Embodiment 32. The method of any one of embodiments 1-31, wherein the subject has hemoglobin of >9 g / dL without transfusion for at least 2 weeks or without erthyropoiesis-stimulating agents for at least 6 weeks.

[0262] Embodiment 33. The method of any one of embodiments 1-32, wherein the compound is administered in a unit dosage form.

[0263] Embodiment 34. The method of embodiment 33, wherein the unit dosage form is a capsule.

[0264] Embodiment 35. The method of embodiment 34, wherein the capsule comprises about 25 mg, about 50 mg, about 100 mg, or about 200 mg of the compound.

[0265] Embodiment 36. The method of embodiment 35, wherein the capsule comprises about 25 mg or about 50 mg of the compound.

[0266] Embodiment 37. The method of any one of embodiments 33-36, wherein the compound is administered once a day.

[0267] Embodiment 38. The method of any one of embodiments 33-36, wherein the compound is administered twice a day.

[0268] Embodiment 39. The method of any one of embodiments 33-38, wherein the administration occurs according to a treatment cycle.

[0269] Embodiment 40. The method of embodiment 39, wherein the treatment cycle is 21 days.

[0270] Embodiment 41. The method of embodiment 39, wherein the treatment cycle is 28 days.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0271] Embodiment 42. The method of any one of embodiments 33-41, wherein the compound is administered to the subject at a total daily dosage of 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1 100 mg, 1 125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575, mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, or 2000 mg.

[0272] Embodiment 43. The method of embodiment 42, wherein the total daily dosage is about 100 mg, 200 mg, 300 mg, 500 mg, 650 mg, or 900 mg.

[0273] Embodiment 44. The method of embodiment 42, wherein the total daily dosage is about 100 mg or 200 mg.

[0274] Embodiment 45. The method of embodiment 42, wherein the total daily dosage is about 300 mg or 500 mg.

[0275] Embodiment 46. The method of embodiment 42, wherein the total daily dosage is about 650 mg or 900 mg.

[0276] Embodiment 47. The method of any one of embodiments 42-46, wherein, when the subject experiences an adverse event, the compound is administered to the subject at a reduced dose comprising 50% of the initial dose level.

[0277] Embodiment 48. The method of any one of embodiments 42-46, wherein, when the subject experiences an adverse event, the compound is administered to the subject at a reduced dose according to the following schedule:PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0278] Embodiment 49. The method of embodiment 47 or 48, wherein the subject is treated with the reduced dose until the adverse event is resolved.

[0279] Embodiment 50. The method of embodiment 49, wherein the subject resumes the initial dose level after the adverse event is resolved.

[0280] Embodiment 51. The method of any one of embodiments 47-50, wherein the adverse event is nausea; vomiting; diarrhea lasting longer than 3 days; adrenal insufficiency; interstitial lung disease; pneumonitis; photosensitivity; higher than normal alkaline phosphatase, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) levels; anemia; febrile neutropenia; thrombocytopenia; or a hematologic reaction.

[0281] Embodiment 52. Use of a compound of Formula (I):or a pharmaceutically acceptable salt thereof, in the treatment of a disease, disorder, or condition.

[0282] Embodiment 53. The use of embodiment 52, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0283] Embodiments 54 to 67. The use of embodiment 52 or 53, wherein the disease, disorder, or condition (e.g., cancer) is defined according to any one of respective embodiments 3 to 4 and 16 to 22; and the compound is defined according to any one of respective embodiments 33 to 36.

[0284] Embodiment 68. A compound of Formula (I)PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease, disorder, or condition, wherein the method comprises a step of administering the compound to a subject in need thereof.

[0285] Embodiment 69. The compound of embodiment 68, wherein the compound isCompound 1 or a pharmaceutically acceptable salt thereof.

[0286] Embodiments 70 to 117. The compound of embodiment 68 or 69, wherein the disease, disorder, or condition (e.g., cancer), the subject, the compound, and administration are each defined according to any one of respective embodiments 3 to 51.

[0287] Embodiment 118. Use of a compound of Formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease, disorder, or condition.

[0288] Embodiment 119. The use of embodiment 118, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0289] Embodiments 120 to 133. The use of embodiment 118 or 119, wherein the disease, disorder, or condition (e.g., cancer) is defined according to any one of respective embodiments 3 to 4 and 16 to 22; and the compound is defined according to any one of respective embodiments 33 to 36.EXAMPLES

[0290] Selected abbreviations used in the preceding sections and the Examples are summarized in Table 2.Table 2. AbbreviationsPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Example 1: Synthesis of Compound D, Compound 1, and Compound 2:4-(4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yI)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7- yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound D, i.e., the compound of Formula (I)),4-((S)-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifhioromethyl)quinazolin-7- yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound 1), and4-((R)-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7- yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound 2)PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0291] Step A: Preparation of tert-butyl (2R,5S)-4-(7-(2-((tert-butoxycarbonyl)amino)-3- cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-dimethylpiperazine- 1 -carboxylate: To a mixture of tert-butyl (2R,5S)-4-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]-2,5- dimethyl-piperazine-1 -carboxylate (100 mg, 0.15 mmol), tert-butyl N-[3-cyano-4-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (91 mg, 0.23 mmol), and CS2CO3 (147 mg, 0.45 mmol) in toluene (2 mL) was added DPEPhosPdCh (16 mg, 0.023 mmol) at ambient temperature. After bubbling with nitrogen for 2 minutes, the reaction mixture was stirred at 95 °C for 6 hours. After cooling to ambient temperature, reaction mixture was diluted with ethyl acetate and the organic layers washed with water, then with saturated brine solution. The organic layers were then separated, dried (Na2SO4) and concentrated under reduced pressure. The crude was then purified by preparative-TLC (20% MeOH in DCM) to afford tert-butyl (3R)-3-((7-(2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)(methyl)amino)pyrrolidine-l-carboxylate (33 mg, 20%). LCMS ESI (+) m / z 876.3 (M+H).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0292] Step B: Preparation of 2-amino-4-(4-((2S,5R)-2,5-dimethylpiperazin-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile: To a solution of tert-butyl (3R)-3-((7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro- 2-(((2R,7aS)-2-Huorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-4-yl)(methyl)amino)pyrrolidine-l-carboxylate (33.0 mg, 0.038 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.5 mL) at ambient temperature. The reaction was stirred at ambient temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford 7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methyl((R)-pyrrolidin-3-yl)amino)-6- (trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine, which was used directly in the next step. LCMS ESI (+) m / z 675.22 (M+H).

[0293] Step C: Preparation of 4-(4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8- Huoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound D), 4-((S)-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound 1) and 4-((R)-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile(Compound 2): To a solution of 2-amino-4-[4-[(2S,5R)-2,5-dimethylpiperazin-l-yl]-8- fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6- (trifhioromethyl)quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (30 mg, 0.044 mmol) and TEA (0.019 mL, 0.13 mmol) in DCM (3 mL) was added prop-2-enoyl prop-2- enoate (4.4 mg, 0.0399 mmol) at -78 °C. The mixture was stirred at -78 °C for 40 minutes. The reaction was quenched with HrO (10 mL) and extracted with EtOAc. The organic layers were washed with brine, dried (MgSCL), filtered and concentrated to dryness. The crude was purified by preparative RP-HPLC to give 4-(4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile(Compound D) (2.2 mg, 6%) as a white solid. LCMS ESI (+) m / z 730.4 (M+H).]HNMRPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1(400 MHz, CD3OD) 58.18 (s, 1H), 7.21-7.28 (m, IH), 7.01-7.07 (m, 1H), 6.73-6.92 (m, IH), 6.26-6.37 (m, 1H), 5.78-5.86 (m, 1H), 5.57 (d, J=52.4 Hz,lH), 4.27-4.74 (m, 4H), 3.81-4.10 (m, 5H), 3.42-3.59 (m, 1H), 2.52-2.79 (m, 2H), 2.11-2.49 (m, 5H), 1.62-1.64 (m, 1H),1.41- 1.56 (m, 3H), 1.21-1.38 (m, 3H).

[0294] The single diastereomers of 4-(4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)- 8-fluoro-2-(((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifhioromethyl)quinazohn-7-yl)-2-amino-7-fh orobenzo[b]thiophene-3-carbonitrile (Compound D) (134.4 mg) were separated with chiral chromatography condition [ChiralPak IH 3 cm x 25 cm, 5 pm, C02:Me0H (0.2% 2 mM ammonium in methanol)=70:30], 80 mL / min], The first compound off the column was identified as one atropisomer, 4-((S)-4- ((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7- fluorobenzo[b]thiophene-3-carbonitrile (Compound 1) (40.1 mg, 99.88% de); LCMS ESI (+) m / z 730.3 (M+H). ’HNMR (400 MHz, CD3OD) 6 8.13 (s, IH), 7.17-7.28 (m, IH), 7.02 (t, J = 8.8 Hz, IH), 6.91-6.73 (m, IH), 6.22-6.35 (m, IH), 5.81 (dd, J = 10.8, 4.0 Hz, IH), 5.33 (d, J = 53.6 Hz, IH), 4.93-5.01(m, IH), 4.56-4.67 (m, IH), 4.25-4.39 (m, 4H), 3.83 -4.06 (m, 2H), 3.36-3.59 (m, 2H), 3.22-3.28 (m, IH), 3.03-3.14 (m, IH), 1.82-2.46 (m, 6H), 1.48 (t, J = 6.0 Hz, 3H), 1.28 (dd, J = 24.4, 6.8 Hz, 3H). The second compound off the column was identified as the other atropisomer, 4-((R)-4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-l-yl)- 8-fluoro-2-(((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6- (trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound 2) (53.3 mg, 99.48% de). LCMS ESI (+) m / z 730.3 (M+H).JHNMR (400 MHz, CD3OD) 58.15 (s, IH), 7.17-7.28 (m, IH), 7.02 (t, J = 8.8 Hz, IH), 6.91-6.73 (m, IH), 6.22- 6.35 (m, IH), 5.78-5.92 (m, IH), 5.33 (d, J = 53.6 Hz, IH), 4.93-5.01 (m, IH), 4.20-4.61 (m, 4H), 3.83-4.06 (m, 2H), 3.48-3.59(m, IH), 3.12-3.28 (m, 3H), 3.03-3.14 (m, IH), 1.82-2.46 (m, 6H), 1.48 (t, I = 6.0 Hz, 3H), 1.28 (dd, J = 24.4, 6.8 Hz, 3H).Example 2: Phase la and Phase lb Clinical Study of Compound 1

[0295] Compound 1 is being developed to treat patients with advanced NSCLC harboring the KRASG12Cmutation. Compound 1 is a potent, selective, directly-binding, orally bioavailable, covalent inhibitor of KRASG12C, with activity against the active GTP -bound (ON) state and the inactive GDP-bound (OFF) state. Without wishing to be bound by theory,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Compound 1 is predicted to be more efficacious than the KRASG12Cinhibitors sotorasib and adagrasib, which bind to the inactive GDP-bound (OFF) form of KRASG12Cand have been approved for adult patients with / / ? / !. S'G / 2(-mutated locally advanced or metastatic NSCLC. Accordingly, without wishing to be bound by theory, it is believed that Compound 1 has the potential to avoid several sotorasib and adagrasib resistance mechanisms, including KRASG12Camplification and activating receptor tyrosine kinase (RTK) alterations.

[0296] This is a multicenter, open-label, Phase 1 study to evaluate the safety and preliminary antitumor activity of Compound 1, a direct inhibitor of KRASG12C(ON), alone and in combination with the ICI pembrolizumab in subjects with locally advanced and unresectable or metastatic (i.e., advanced) NSCLC with a KRASG12Cmutation.Pharmacokinetic (PK) and pharmacodynamic (PD) parameters will also be assessed. The study will be conducted at approximately 30 study sites worldwide.

[0297] The study will consist of 2 parts, Phase la (Dose Escalation for Compound 1 monotherapy) followed by Phase lb (Randomized Dose Optimization for Compound 1 monotherapy and Dose Expansion for Compound 1 monotherapy). This study will utilize a Safety Review Committee (SRC) to oversee the safety of subjects enrolled in the study.

[0298] In the Phase la Dose Escalation Compound 1 monotherapy part of the study, increasing doses of Compound 1 will be evaluated for safety and preliminary efficacy, and PK and PD parameters will be assessed. Based on review of all available data for Compound 1 at different doses in the Dose Escalation monotherapy part of the study, 2 doses of Compound 1 will be selected for evaluation in 2 Phase lb Randomized Dose Optimization monotherapy cohorts (subjects will be randomized 1: 1 to one of the 2 dose levels).

[0299] The Phase lb Dose Expansion part of the study will further evaluate the safety, efficacy, PK, and PD of Compound 1 monotherapy. Compound 1 dose levels for the Dose Expansion monotherapy cohorts will be based on SRC review of the totality of safety, efficacy, PK, and PD data in the Randomized Dose Optimization monotherapy part of the study.

[0300] Each phase of the study will consist of a Screening period of up to 30 days, a treatment period consisting of sequential consecutive 21 -day treatment cycles; End-of- Treatment (EOT) and Safety Follow-up visits at no later than 14 days and at 30 days after thePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 last dose of study treatment, respectively; and a Long-Term Follow-up period that will continue for up to 24 months after the last dose of study treatment.

[0301] All subjects will be enrolled based on the documented results of local testing for KRASG12Cif the results have been obtained within 2 years of screening. Subjects without prior documentation of presence of a KRASG12Cmutation must sign the molecular prescreening informed consent form (ICF) before blood sample collection for KRASG12Ctesting can be performed. Once consent is obtained, blood sample collection for testing for KRASG12Cmutation can be done any time prior to the initiation of screening; KRASG12Cmutation status for these subjects must be documented before signing the main study ICF and performing screening assessments. Subjects who meet all eligibility criteria will be enrolled.

[0302] During the treatment period, all eligible subjects will receive Compound 1 orally once daily in consecutive 21-day treatment cycles starting on Cycle 1 Day 1 (C1D1). A BID dosing schedule for Compound 1 may be investigated as a dosing alternative if deemed appropriate based on available data from the initial daily dosing cohort(s). Compound 1 administration will continue until disease progression, unacceptable toxicity, withdrawal of consent, or until other treatment discontinuation criteria are met.

[0303] All subjects will be evaluated radiographically for tumor response using RECIST vl. 1 and by CNS RECIST vl. 1 (for subjects with brain metastases at baseline) every 6 weeks (±7 days) after first dose of study drug, regardless of study drug dosing delays or discontinuations, until disease progression is confirmed by the investigator. If a subject is considered “clinically unstable” at any point during assessments with iRECIST or if disease progression by iRECIST is confirmed by the investigator, study treatment will be discontinued.

[0304] Subjects who discontinue study drug for reasons other than disease progression will continue to have radiographic assessments every 12 weeks (±7 days) until disease progression, the initiation of other anticancer therapies, death, or the subject withdraws consent for radiographic assessment, whichever occurs first.

[0305] Subjects in Compound 1 monotherapy cohorts will undergo an EOT visit as soon as possible after the decision to discontinue Compound 1 and within 14 days of last dose. A Safety Follow-up visit will be conducted 30 (+7) days after the last dose of Compound 1PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 unless one of the following occurs: death, loss to follow-up, initiation of other anti-cancer therapy, or withdrawal of consent.

[0306] Long-term follow-up for survival status and new anticancer therapy information will be via telephone contact every 12 weeks after the EOT visit until 24 months after the last dose of study treatment. Long-term follow-up also applies to subjects who discontinue study treatment for reasons other than radiographic progression but withdraw consent for further tumor assessments.PHASE la

[0307] Subjects enrolled in the Phase la Dose Escalation monotherapy part of the study must have had prior treatment with an ICI and may or may not have had prior treatment with a KRASG12C(OFF) inhibitor. Dose escalation of Compound 1 monotherapy will follow a Bayesian optimal interval (BOIN) design. Planned dose levels for Compound 1 evaluation in the Dose Escalation monotherapy cohorts are detailed in Table 3. Subjects will take Compound 1 orally, once daily in the morning in continuous 21-day cycles.Table 3: Phase la Dose Escalation Compound 1 Monotherapy Cohorts and Dose LevelsAbbreviations: BID=twice daily; DL=dose level; DLT=dose-limiting toxicity; KRASG12C=Kirsten rat sarcoma 2 viral oncogene homolog; with a glycine-to-cysteine point mutation at codon 12;PD=pharmacodynamics; SRC=safety review committee.aNumber of DLT-evaluable subjects required for each dose level is 3 to 5; approximately 10 additional subjects with no prior treatment with a KRASG12Cinhibitor may be enrolled to backfill cohorts at doses the SRC determine to be safe and tolerable to better characterize safety, efficacy, and PD.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1bAdditional dose levels, alternative dose levels, and / or alternative dose schedules (e.g., BID dosing) may be implemented following SRC review of the totality of the available data and after the SRC approves or makes a recommendation regarding the next dose cohort.cDe-escalation to a dose lower than the starting dose tDL-1) may be recommended based on SRC evaluation of all available data for DL1.

[0308] The dose-limiting toxicity (DLT) Assessment Period for Compound 1 monotherapy cohorts will be 21 days ( 1 treatment cycle) after the first dose of Compound 1. For each dose level, the SRC will evaluate all safety (including DLTs) data and all available PK, PD, and efficacy (if applicable) data at the end of the DLT Assessment Period, prior to opening the next dose level cohort. The SRC will make dosing and escalation decisions in accordance with the escalation and de-escalation rules of the BOIN design using a target toxicity rate of 27.0% with escalation and de-escalation thresholds of <21.3% and >32.2%, respectively.

[0309] Approximately 20 DLT-evaluable subjects are required for the Phase la Dose Escalation monotherapy part of the study. Further, additional subjects with no prior treatment with a KRASG12Cinhibitor (approximately 10 in total) may be enrolled to backfill cohorts at dose levels that the SRC determine to be safe and tolerable, defined as backfill enrollment. This backfill enrollment will be done to better characterize the safety, efficacy and PD of Compound 1 and may be concurrent with dose escalation to identify dose selection for the Phase lb Randomized Dose Optimization part of the study. A minimum of 4 subjects with no prior treatment with a KRASG12Cinhibitor will be required for each of the dose levels being considered to take forward into the Phase lb Randomized Dose Optimization part of the study.Dose-Limiting Toxicities

[0310] A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value excluding toxicities clearly related to disease progression or intercurrent illness, and occurring during the DLT assessment period that meets any of the following criteria:Hematological toxicity:Grade >3 febrile neutropeniaGrade >4 neutropenia for >7 daysGrade 3 thrombocytopenia for >7 daysPATENTAttorney Docket No. 2014229-0161 Thera-23.WO 1• Grade 3 thrombocytopenia with Grade >2 bleeding• Grade >4 thrombocytopenia• Grade >4 anemiaNon-hematological toxicity:• Grade 4 nausea, vomiting, or diarrhea• Grade 3 nausea, vomiting, or diarrhea lasting more than 3 days with adequate medical supportive care• Grade >3 increase in total bilirubin• Grade >3 increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) for >7 days- For subjects with Grade <2 ALT and / or AST increases at baseline due to liver metastases, only a level >10 x UNL lasting for >7 days will be considered a DLT.• AST or ALT >3 x ULN (or >3 x baseline value for subjects with liver metastases) and increase in total bilirubin >2 x ULN without alternate etiology (e.g., cholestasis).• Any other Grade >3 clinically significant or persistent toxicity that may be considered a DLT following review by the SRC.

[0311] A DLT-evaluable subject is defined as a subject who has completed >80% of Compound 1 doses within the DLT assessment period (i.e., >17 of 21 days of treatment for subjects in Dose Escalation monotherapy cohorts). A subject who experiences a DLT within the first treatment cycle is DLT evaluable regardless of number of doses taken. During the Phase la Dose Escalation part of the study, if a subject is withdrawn from study for any reason other than a DLT prior to completion of the DLT Assessment Period, a replacement subject will be assigned the same study drug dose as the withdrawn subject.PHASE lb

[0312] Based on SRC review of all available safety, PK, PD, and preliminary efficacy data for Compound 1 at different dose levels in the Phase la Dose Escalation monotherapy part of the study, 2 dose levels of Compound 1 will be selected for evaluation in Phase lb Randomized Dose Optimization cohorts (e.g., the highest dose and 1 or 2 dose levels below the highest dose tested and deemed safe in the Dose Escalation monotherapy part of thePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 study). Approximately 44 evaluable subjects who have had progression on or disease recurrence after at least 1 prior line of systemic therapy (must include platinum-based doublet chemotherapy, ICI, or both given together as 1 line or as individual lines) and no prior treatment with a KRASG12Cinhibitor are planned for enrollment. Subjects will be randomized at a 1: 1 ratio to one of the 2 dose levels (same dosing schedule established in dose escalation). This Randomized Dose Optimization part of the study will only be conducted if a single definitive dose level is not identifiable for expansion based on the entirety of PK, PD / biomarker, efficacy, and safety data from the Dose Escalation monotherapy cohorts.

[0313] A Simon 2-stage design will be utilized. An interim analysis will be conducted after planned Stage 1 modified intent-to-treat (mITT) subjects complete prespecified study assessments and follow-up. If only one of the 2 Compound 1 doses is chosen to take forward after the interim analysis data review, the SRC can recommend that subjects currently receiving treatment with the dose that was not selected can have their dose escalated or deescalated to the chosen dose as applicable.

[0314] The SRC will conduct periodic reviews during Phase lb Randomized Dose Optimization, including the assessment of antitumor activity; details are provided in the SRC Charter.

[0315] The Compound 1 dose for evaluation in the Dose Expansion Compound 1 monotherapy part of the study will be based on SRC review of all available safety, PK, PD / biomarker, and preliminary efficacy data for Compound 1 at different doses in the Phase la Dose Escalation and Phase lb Randomized Dose Optimization monotherapy cohorts. Approximately 45 subjects are planned for enrollment in these 2 cohorts, including approximately 25 subjects with no prior treatment with a KRASG12Cinhibitor and prior treatment with an ICI and / or platinum-based doublet chemotherapy, and approximately 20 subjects with prior treatment with a KRASG12C(OFF) inhibitor (e.g., sotorasib, adagrasib, JDQ443, LY3537982, GDC-6036, and others as approved by the medical monitor) and an ICI. Subjects with no prior treatment with a KRASG12Cinhibitor and treated at the same dose level and dosing schedule in Phase la Dose Escalation and Phase lb Randomized Dose Optimization parts of the study may be included in the total number of subjects enrolled in the dose expansion monotherapy part of the study.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0316] The SRC will conduct periodic reviews during Phase lb Dose Expansion, including the assessment of antitumor activity; details are provided in the SRC Charter.

[0317] A subject may stop participation in the study at any time, for any reason (e.g., withdrawal of consent, AEs). The investigator and / or sponsor can withdraw a subject from the study at any time for any reason (such as noncompliance with the protocol or AEs). In such instances, all efforts to complete and report the observations to the time of withdrawal should be made.

[0318] The SRC will be involved in any decisions regarding terminating the study, temporarily suspending enrollment, or stopping ongoing study treatment.

[0319] Rules for escalating / de-escalating and stopping dosing in the Dose Escalation Compound 1 monotherapy cohorts will be in accordance with the BOIN design, with definitions for DLTs. The SRC may recommend halting enrollment at a specific dose cohort or discontinuing a cohort at any point if a safety signal or unacceptable toxicity is observed.

[0320] For Randomized Dose Optimization cohorts, stopping rules for futility follow the Simon 2-stage design. After testing the treatment on 8 evaluable (mITT) subjects in the first stage, if 1 or fewer subjects achieve objective response, the dose level will be closed unless the SRC recommends additional data at that dose level (e.g., if there are irregularities in the PK results in these subjects). If the cohort goes on to the second stage, a total of 22 evaluable (mITT) subjects within each cohort will be evaluated. The optimized dose would then be brought forward to Dose Expansion cohorts.

[0321] The study sponsor has the right to terminate the clinical study at any time.

[0322] Other reasons for terminating the clinical study or a study center’s participation include, but are not limited to, the following:• The incidence or severity of an AE related to treatment in this study or other studies indicates a potential health hazard to subjects• Data recording is significantly inaccurate or incomplete• Study center personnel are noncompliant with study procedures• Decision by sponsor to suspend or discontinue development of product• Failure of study center to enroll at an acceptable rateInclusion CriteriaPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0323] To be included in the study, subjects must meet the eligibility criteria listed below for all subjects and for subjects enrolled in the individual phases of the study, as applicable.1. Subjects must be >18 years old at signing of informed consent.2. Have histologically documented, locally advanced and unresectable, or metastatic (i.e., advanced) NSCLC with a KRASG12Cmutation: a. Documentation of KRASG12Cmutation within the last 2 years prior to screening.- Local documentation as evidenced by a laboratory test report is sufficient for study entry.- For subjects without prior documentation of KRASG12Cmutation, prospective confirmation of KRASG12Ctumor mutational status is required based on sponsor-provided central testing. b. Except for Dose Escalation cohorts (Compound 1), subjects with G12D, G12V, M72K, Q61H, R164Q, R68S, and T2S co-alterations in KRAS by local testing (if reported) will be excluded. c. Must have no other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2). d. In locally advanced and unresectable disease, progression on or within 6 months of the end of prior multimodal therapy with curative intent will count as a prior line of therapy.3. Have measurable disease by RECIST vl.l.4. Have a minimum life expectancy of > 12 weeks according to the investigator’s judgement.5. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0 or 1.6. Are willing and able to comply with study visits and study procedures.7. Contraceptive use by study participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies, a. Male subjects: Male subjects are eligible to participate if they agree to the following during the study treatment period and for at least 120 days after the last dose of study drug:• Refrain from donating spermPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1PLUS, either:• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.OR• Must agree to use contraception as detailed below:- Agree to use a male condom (with female partner use of an additional highly effective contraceptive method with a failure rate of < 1 % per year) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.- Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person. b. Female subjects: A female participant is eligible to participate if she is not pregnant or breastfeeding, or planning to become pregnant or breastfeed, and one of the following conditions applies:• Is a woman of nonchildbearing potential.OR• Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, during the study treatment period and for at least 45 days after the last dose of study drug and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study drug.• A subject who is a WOCBP must have a negative highly sensitive serum pregnancy test during screening and within 48 hours before the first dose of study drug. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.8. Subjects must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF (molecular prescreening and / or main study ICF) and in this protocol.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 19. Subjects Enrolled in Phase la Dose Escalation Compound 1 Monotherapy Cohorts Only: Have progression on or disease recurrence after available standard of care treatments, which must include an ICI. Subjects must have received prior standard therapy, or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. a. Prior treatment with a KRASG12C(OFF) inhibitor (e.g., sotorasib, adagrasib, JDQ443, LY3537892, GDC-6036) is allowed but not required.10. Subjects Enrolled in Phase lb Randomized Dose Optimization Compound 1 Monotherapy Cohorts Only: Have progression on or disease recurrence after at least 1 prior line of systemic therapy, which must include platinum-based doublet chemotherapy, ICI, or both given together as 1 line or as individual lines of therapy. a. No prior treatment with a KRASG12Cinhibitor.For Subjects Enrolled in Phase lb Dose Expansion Cohorts Only:11. Dose Expansion Compound 1 Monotherapy Cohort (no prior KRASG12Cinhibitor): have progression on or disease recurrence after at least 1 prior line of systemic therapy, which must include platinum-based doublet chemotherapy, ICI, or both given together as 1 line or as individual lines of therapy. a. No prior treatment with a KRASG12Cinhibitor.12. Dose Expansion Compound 1 Monotherapy Cohort (prior KRASG12C(OFF) inhibitor): have progression on or had disease recurrence after a KRASG12C(OFF) inhibitor (e.g., sotorasib, adagrasib, JDQ443, LY3537892, GDC-6036). Prior interim therapy (e.g., docetaxel) is allowed. a. Prior therapy must have included an ICI (e.g., pembrolizumab, atezolizumab, nivolumab + ipilimumab, durvalumab ± tremelimumab, cemiplimab-rwlc).Exclusion Criteria

[0324] Subjects are excluded from the study if any of the following criteria apply:1. Have inadequate organ function as defined below:Hematological: a. Absolute neutrophil count (ANC) < 1 ,500 / pL. b. Platelets <100,000 / pL. c. Hemoglobin <9 g / dL without transfusion for at least 2 weeks prior to enrollment.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 d. Hemoglobin <9 g / dL without erythropoiesis-stimulating agents (e.g., Epo, Procrit®) for at least <6 weeks prior to enrollment.Renal: e. Serum creatinine >1.5 x ULN, unless creatinine clearance >60 mL / min (measured or calculated using the Cockcroft- Gault formula: (140 - age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg / dL).Hepatic f. Serum total bilirubin > 1.5 x institutional ULN or >2.0 x ULN if the subject has a diagnosis of Gilbert syndrome. g. AST / serum glutamic-oxaloacetic transaminase (SGOT) and / or ALT / serum glutamic-pyruvic transaminase (SGPT) >2.5 x ULN or AST and / or ALT >5.0 x ULN with documented liver metastases.Coagulation: h. International normalized ratio (INR) or prothrombin time (PT) >1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants. i. aPTT >1.5 x ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.2. Have active hepatitis B infection (hepatitis B surface antigen [hBsAg] or hepatitis B virus [HBV] DNA), hepatitis C infection (hepatitis C virus [HCV] antibody and positive HCV RNA).3. Known positive HIV test.4. Have any other life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating subject’s safety, or interfere with or compromise the integrity of the study outcomes.5. Have any of the following cardiac -related issues or findings: a. History of significant cardiovascular disease, such as cerebrovascular accident, myocardial infarction or unstable angina, within the last 6 months before starting study treatment.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 b. Clinically significant cardiac disease, including New York Heart Association Class II or higher heart failure. c. History of left ventricular ejection fraction (LVEF) <50% within the previous 12 months before starting study treatment. d. Resting QT interval corrected for heart rate (QTc) >470 msec, derived as the average from 3 ECGs at screening. e. Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., third degree heart block, Mobitz Type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation). f. Subjects with a pacemaker may be allowed on study following review and agreement between the treating physician and medical monitor.6. Have a diagnosis of another invasive malignancy within the previous 2 years from time of informed consent other than curatively treated non-melanomatous skin cancer, superficial urothelial carcinoma, in situ cervical cancer, or any other curatively treated or closely monitored malignancy that is not expected to require treatment for recurrence or progress during the course of the study.7. Have untreated brain metastases (subjects with stable brain metastases are allowed). Subjects who have had brain metastases resected or have received radiation therapy ending at least 2 weeks prior to CID 1 are eligible if they are neurologically stable and meet all of the following criteria prior to first dose of study medication: a) residual neurological symptoms related to the CNS treatment Grade <2; b) on a stable or decreasing dose of <10 mg daily prednisone (or equivalent) for at least 2 weeks prior to CID 1; and c) follow-up magnetic resonance imaging (MRI) shows no new lesions appearing.8. Have gastrointestinal illness or inability to ingest the medication in its intended form that would preclude absorption of Compound 1 (e.g., swallowing issues, post gastrectomy, short bowel syndrome, uncontrolled Crohn’s disease, celiac disease with villous atrophy, or chronic gastritis).9. Pregnant or lactating subjects or subjects expecting to conceive children within the projected duration of the trial, starting with the Screening visit through 45 days after the last dose of Compound 1.10. Are on dialysis.11. Have a history of allogeneic bone marrow transplant.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 112. Have received prior treatment with a KRASG12C(ON) inhibitor (e.g., RMC-6291, FMC-376).13. Have undergone major surgery within 4 weeks prior to C1D1.Note: This does not include subjects who have had procedures such as peripherally inserted central catheter line placement, thoracentesis, paracentesis, biopsies, or abscess drainage.14. Have Grade >1 unresolved toxicides) from prior surgery or any anti-tumor therapy with exception of alopecia.15. Have participated in an interventional clinical study within the last 4 weeks OR, if applicable, be within 5-times the half-life of the investigational study drug(s), whichever is lesser, prior to the C1D1 visit. Subjects should always adhere to other eligibility criteria that apply to specified concomitant medication regarding washout periods as specified below.16. Have received radiotherapy or proton therapy with a limited field of radiation for palliation within 2 weeks of the start of study treatment, OR radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the start of study treatment. Palliative radiotherapy to non-target lesions may be allowed on a case-by-case basis by the medical monitor in consultation with the investigator.17. Have taken any of the following: a. Strong inducers or inhibitors of CYP3A or P-gp within 14 days or 5 half-lives of the agent (whichever is longer) prior to CID 1, or food products containing the fruit or juice from grapefruit, starfruit, pomegranates, or Seville oranges within 7 days prior to CID 1, and / or b. Use of known CYP3A substrates with a narrow therapeutic window, within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to CID 1, and / or c. Acid- reducing agents, such as proton pump inhibitors (PPIs) or histamine 2 (H2) receptor antagonists within 3 days of CID 1 and for the study duration.18. Have received more than 1 prior line of a KRASG12C(OFF) inhibitor (cohorts in which prior treatment with a KRASG12C(OFF) inhibitor is permitted).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 119. Are planning to receive any other systemic therapy intended to treat NSCLC while on this study.20. Have a history of hypersensitivity to Compound 1, active or inactive excipients of Compound 1 or drugs with a similar chemical structure or class to Compound 1.Lifestyle Considerations and Screen Failures

[0325] Consumption of food products containing the fruit or juice from grapefruit, starfruit, pomegranates, or Seville oranges should be stopped at least 7 days before the first dose of study drug, and consumption should be avoided while on study drug treatment. This is due to a potential CYP3A and P-gp interaction with Compound 1.

[0326] Subjects taking Compound 1 are advised to limit sun exposure, to avoid exposure to UV light, and to report any skin changes, including erythema, to the investigator immediately. Subjects should also be advised to use sunscreen and to wear sun-protective lenses while outdoors during daylight hours.

[0327] Compound 1 should be taken in the mornings, 1 hour before or at least 2 hours after a meal.

[0328] Screen failures are defined as subjects who consent to participate in the clinical study but are not subsequently entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse events (SAEs).

[0329] Individuals who do not meet the criteria for participation in this study (screen failures) may be rescreened once at the discretion of the medical monitor and should be assigned the same subject identifier number as from the initial screening. If a subject is rescreened, laboratory assessments performed within 30 days of new C1D1 do not need to be repeated if assessment results are within normal ranges; abnormal results should be repeated.

[0330] During the Phase la Dose Escalation part of the study, subjects who are withdrawn prior to completion of the DLT Assessment Period (Day 1 to 21) for any reason other than a DLT may be replaced. The replacement subject will be assigned the same study drug dose as the withdrawn subject.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0331] Subjects who withdraw from the Randomized Dose Optimization parts of the study may be replaced at the discretion of the SRC.

[0332] Subjects who withdraw from the Dose Expansion parts of the study will not be replaced.Example 3: Covalent Cysteine 12 modification analysis using Matrix Assisted Laser Desorption Ionization - Time of Flight Mass Spectrometry (MALDI-TOF MS)

[0333] The potency of Compound 1 was determined by MALDI-TOF MS, in which the affinity of a ligand is determined based on its ability to covalently modify the cysteine 12 from the pocket found within the KRASG12C protein in both its active GTP-bound and inactive GDP-bound state.

[0334] MALDI-TOF MS analysis was performed using two sets of conditions. 1 pM protein target, and 1:2.5 protein to compound ratio was used.

[0335] Reaction: 5 pM or 1 pM of GppNHp, GTP, or GDP-loaded KRAS4b (amino acids 1-169) G12C / C118S protein (produced in-house by Protein Expression Laboratory, FNLCR / Leidos Biomed) in 20 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES) buffer containing 150 mM NaCl, 1 mM MgCh, pH 7.3 was prepared freshly before assay. Ten-pL aliquots of protein were dispensed onto low volume 384-well plate, then 375 nL DMSO, and 25 nL of tested compounds from 5 mM DMSO stocks were added to appropriate wells using ECHO 555 acoustic liquid handler (Labcyte Inc.). For each reaction / assay, three blanks were prepared by mixing 10 pL of protein solution with 400 nL DMSO. The contents of the wells were carefully mixed by aspiration, and then each plate was sealed with an adhesive cover, centrifuged at 2000 g for 1 minute, and kept in the dark at room temperature until 5 min, 15 min, 30 min, 2 h, or 6 h collections.

[0336] Target prelrealment: Before each assay MALDI target (Bruker MPT 384 ground steel BC) was pre-treated by pipetting on each spot 0.75 pL of saturated sinapinic acid in acetonitrile (ACN). This step significantly improves uniformity of sample crystallization across the plate resulting in enhanced sensitivity.

[0337] Sample preparation: At collection time point, 2 pL of reaction mixtures were pipetted out into 20 pL MALDI matrix solution (saturated solution of sinapinic acid in 1:1 ACN:water solution containing 0.75% trifluoroacetic acid (TFA)) deposited on 384 wellPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 polypropylene plate. Resulting solution was mixed by aspiration, centrifuged at 2000 g for 1 minute, then 1 pL aliquots were dispensed on pre-treated MALDI target using Beckman Coulter Biomek FXP96 / 384-Span-8 Laboratory Automation Workstation. Finally, the MALDI target was dried under mild vacuum to produce spots with fine crystalline structure.

[0338] Measurements: MALDI-TOF measurements were performed on a Bruker Daltonics rapifleX Tissuetyper TOF-TOF mass spectrometer using linear mode and mass range from 18.6 to 21.6 kDa. Detector gain was set to 3.3x (483 V), sample rate to 5 GS / s, real time smoothing to medium (175 MHz), laser smart beam pattern was set to: “MS Thin Layer M5”, and the laser frequency was 10000 Hz. Spectra were automatically collected using custom AutoXecute method. Laser power was auto adjusted using fuzzy control. The peak selection range was set to be between 19000 and 21500 Da. Peak evaluation uses half width parameter set to be smaller than 40 Da for processed spectrograms (centroid peak detection; smoothed by SavitzkyGolay algorithm using 7 m / z width and 2 cycles; baseline was subtracted using median algorithm with flatness 1 and median level 0.01). Fuzzy control usedProteins / Oligonucleotides protocol with minimum half width 1 / 10 times above threshold. Up to 40000 satisfactory shots were collected in 10000 shot steps. Dynamic termination was implemented to finish data collection when peak signal / noise ratio was reaching value of 50.

[0339] Spectra processing: Spectra were smoothed by SavitzkyGolay algorithm using 7 m / z width and three cycles. Centroid peak detection algorithm was used with signal to noise threshold set to 6, relative intensity threshold 4%, peak width 10 m / z and median baseline subtraction using flatness of 1 and median level of 0.01. Peak intensity and area under the peak were evaluated and recorded for all peaks between 19,300 Da and 21,550 Da.

[0340] Calculation of percent modification: Percent modification was calculated as a ratio of peak height for protein modified by compound to sum of peak height of remaining protein plus peak height for protein modified by compound. If multiple modifications were observed each was calculated as a ratio of peak height for given modification versus sum of peak heights for all observed protein species.

[0341] The percent of modification of GppNHp, GTP, and GDP loaded KRAS G12C by MALDI-TOF MS at 15 minutes with Compound 1 was > 70%.

[0342] The time response MALDI spectrum results demonstrated that Compound 1 can quickly bind in the KRASG12Cpocket and make a covalent bond to cysteine 12 (Table 4).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Compound 1 covalently modified 70% to 100% of GTP-bound KRASG12Cand GDP-bound KRASG12Cfrom 5 to 60 minutes, with 97% of GTP-bound KRASG12Cand 100% of GDP- bound KRASG12Cmodified by 60 minutes.Table 4: Percent of Covalent Modification ofGTP-Bound and GDP-Bound KRASG12Cby Compound 1Abbreviations: GDP=guanosine diphosphate; GTP=guanosine triphosphate; KRASG12C=Kirsten rat sarcoma viral oncogene homolog with a glycine-to-cysteine point mutation at codon 12; MALDI-TOF MS=Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry; min=minute

[0343] Note: 1 pM solutions of GTP- and GDP-loaded KRAS4b(amino acids 1-169)- G12C / C118S protein were prepared and dispensed onto plates and then 30 nL of tested compounds from 1 mM DMSO stocks were added to the appropriate wells. At each indicated collection timepoint, 2 pL of each reaction mixture was pipetted into 15 pL MALDI matrix solution deposited onto plates. The resulting solution was mixed by aspiration, centrifuged at 2000 g for 1 minute, and then 1.5 pL aliquots were dispensed on pretreated MALDI target. MALDI-TOF measurements were performed on Bruker Daltonics rapifleX Tissuetyper TOF- TOF mass spectrometer using linear mode and mass range from 18.6 to 21.6 kDa. Percent modification was calculated as a ratio of peak height for protein modified by compound to sum of peak height of remaining protein plus peak height for protein modified by compound. The mean percent modifications from 17 experiments are shown.

[0344] Thus, Compound 1 has high affinity for the KRASG12Cprotein and swiftly covalently modifies the cysteine 12 of KRASG12Cin both its active GTP-bound and inactive GDP-bound states.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Example 4: Disrupting KRAS G12C-effector binding (Protein:Protein Interaction HTRF assay)

[0345] A protein:protein interaction (PPI) Homogeneous Time Resolved Fluorescence (HTRF) assay was used to determine the effectiveness of compounds of the present disclosure in disrupting KRAS G12C protein and effector (RAFI) binding.

[0346] The HTRF assay used the following reagents and proteins: 50 nM Avi-KRAS G12C Q25A (1-169) GppNHp / 3xFLAG-PI3K CA (157-299); 50 nM Avi-KRAS G12C (1-169) GppNHp / RAFI RBD-3xFLAG (52-151); 35 nM Avi-PI3K RBD-3xFLAG; Assay Buffer: 50 mM Tris pH 7.5, 100 mM NaCl, 5 mM MgCh, 0.1% BSA, 0.01% Tween 20, 10% DMSO; Bead Buffer: 50 mM Tris pH 7.5, 0.01% Tween 20; Assay volume: 20 pL (384 well plate- low volume format); and Compound titration: 30-0.02 pM, 3x dilution series.

[0347] The HTRF assay employed the following protocol:

[0348] Compounds were dispensed in assay plate (384-well, Grenier Bione #784075) using Echo (model 555) with dose response settings: 200 nL final volume, titration from 100 pM as a 10-point dilution series. KRAS proteins were prepared in assay buffer, and dispensed on plates, 5 pL per well, then incubated for Ih at room temperature, with 700 rpm shaking.RAFI RBD were prepared in assay buffer, dispensed onto plates, 5 pL per well, and then incubated for 1 h at room temperature, with 700 rpm shaking. Reagent mix was then prepared and dispensed on plates, 10 pL per well, and then incubated for 1 h at room temperature, with 700 rpm shaking.

[0349] Plates were analyzed on an Envision plate reader using the following setting: Excitation 320 nm, Bandwidth 75 nm; Emission 615 nm, Bandwidth 85 nm; Gain 100%; Flashes 100; Lag 60 ps. Data was reported as percentage of activity, with DMSO as 100%. Data was plotted and analyzed using Prism 8. Table 5 summarizes parameters used with the Envision plate reader.Table 5. Envision plate reader settingsPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0350] The biochemical Rafi RBD-KRAS G12C-GppNHp disruption assay IC50 for Compound 1 was < 0.5 pM.

[0351] The HTRF assay was also performed using KRAS G12C-GTP.

[0352] Compound 1 was dispensed in 384-well plates using a titration from 30 pM in a 10- point dilution series. Avi-KRAS G12C (2-169) GppNHp and RAFI RBD-3xFLAG (amino acids 51-131) and HTRF reagents were mixed and dispensed onto plates and then incubated for 1 hour at room temperature with shaking. Plates were analyzed on an Envision plate reader. Data was reported as percentage of activity with DMSO as 100% and plotted and analyzed using Graph Prism 8.

[0353] The results demonstrated that Compound 1 can bind KRASG12C in its active GTP- bound conformation and potently disrupt KRASG12C-effector (RAFI) binding with an IC50 of 25 nM (FIG. 1) (shown in the mean IC50 values from 10 experiments). Thus, Compound 1 can potently disrupt the PPI of GTP-bound KRASG12C to RAFI.

[0354] Abbreviations: GTP=guanosine triphosphate; DMSO=dimethyl sulfoxide; HTRF=homogeneous time resolved fluorescence; IC50=half maximal inhibitory concentration; KRASG12C=Kirsten rat sarcoma viral oncogene homolog with a glycine-to- cysteine point mutation at codon 12; RAFl=rapidly accelerated fibrosarcoma 1; RBD=RAS binding domain.Example 5: Cell-based pERK HTRF assay

[0355] pERK HTRF assays (Perkin Elmer) were used to determine the effectiveness of compounds of the present disclosure in disrupting KRAS G12C protein / effector signaling in cells.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0356] On Day 1, cells (NCI-H358) were seeded into 96-well plates at 4xl04cells / well in complete growth media (RPMI, 10% FBS).

[0357] On Day 2, cells were treated with compounds at 0.25% DMSO. The source plate was created with compounds diluted in media at 5-fold the final assay concentration. The compounds were run in a 9-point concentration curve starting at 75 pM, with a 3 -fold dilution between concentrations. 20 pL was transferred onto the cell plates (final volume in wells was 100 pL). Plates were harvested after 30 min incubation by aspirating media and adding kit- supplied lx supplemented lysis buffer to all wells (75 pl per well). Plates were then placed on a plate shaker and incubated at 850 rpm for an additional 30 min.

[0358] Antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit supplied detection buffer, then mixed the diluted antibodies solutions (1:1 v:v). 4 pL of this solution was then added to a 384-well detection plate (Perkin Elmer; 6008230).

[0359] Samples were homogenized by pipetting up and down and then transferred (16 pL of cell lysates) from the 96-well cell culture plate to two wells of the HTRF 384-well detection plate containing the antibody solution. Plates were centrifuged (524 g for Imin) and allowed to incubate between 4 and 24 h at room temperature. Maximum signal is reached after 4 h incubation time and remains stable over a period of 24 hours. Therefore, readings can be made between 4 and 24 h of incubation. Plates were centrifuged again (524 g for Imin), and analyzed on the EnVision plate reader using the following settings: Excitation 320 nm, Bandwidth 75 nm; Emission 615 nm, Bandwidth 85 nm; Gain 100%; Flashes 100; Lag 60 ps.

[0360] The pERK inhibition ICso of Compound 1 in H358 cell assay was < 0.1 pM.

[0361] Results of MALDI, PPI, and ERK phosphorylation assays for Compound 1 , sotorasib, and adagrasib are included in Table 6.Table 6. Compound 1 modifies both GDP- and GTP-bound KRAS G12C and inhibits effector bindingPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Example 6: Determination of the kinact / Ki (M’1) of Compound 1

[0362] While IC50 values are often used as an effective potency metric in drug discovery, in the case of irreversible covalent inhibitors, alkylation results in an inactive target adduct where the reactants and adduct are not in equilibrium. Since covalent inhibition is timedependent, the preferred quantitative potency metric of irreversible inhibitors is the second- order rate constant fanact / Ki, which accounts for both the affinity of the initial reversible noncovalent interaction and the maximal rate of covalent bond formation. Intact protein analysis using MALDI-TOF MS was therefore used to find percent modification of Compound 1 to KRASGI2Cprotein in both its active GTP-bound and inactive GDP-bound states.

[0363] Eight concentrations of Compound 1 were mixed with 0.102 M (A) GTP-loaded and (B) GDP-loaded KRAS4b( amino acids 1-169)-G12C / C118S protein (20, 17.5, 15. 12.5, 10, 7.5, 5 and 2.5 pM for GTP-loaded protein and 320, 160, 80. 40, 20, 10, 5 and 2.5 pM for GDP-loaded protein) and 100 mM HC1 stop solution was added from 10 to 90 seconds as indicated. Protein was then concentrated and plated on a MALDI target. MALDI-TOF measurements were performed on a Bruker Daltonics rapifleX Tissuetyper TOF-TOF mass spectrometer using linear mode and mass range from 18.6 to 21.6 kDa. Percent modification was calculated as a ratio of peak height for protein modified by compound to sum of peak height of remaining protein plus peak height for protein modified by compound. The reaction curves were fit to a bimolecular reaction model to extract fanact / Ki values (Li 2022). Fitting was conducted using Graph Pad Prism 9.

[0364] GTP-bound KRASG12Cprotein was 42% modified and GDP-bound KRASG12Cprotein was 100% modified after 90 seconds by Compound 1 at the highest concentration tested (FIGs. 2A-2B). The fanact / Kj for Compound 1 against GTP-bound and GDP-bound KRASG12Cwas determined to be 20,000 M ’s1and 2,743,000 M ’s1, respectively.

[0365] Abbreviations: GDP=guanosine diphosphate; GTP=guanosine triphosphate; KRASG12C=Kirsten rat sarcoma viral oncogene homolog with a glycine-to-cysteine pointPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 mutation at codon 12; MALDI-TOF MS=Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry.Example 7: Compound 1 shows sub-nanomolar potency in multiple KRASG12C models and is selective for KRASG12C

[0366] The effect of Compound 1 on cellular MAPK signaling, viability, and long-term growth suppression was assessed. The potency of Compound 1 was evaluated across a diverse panel of 12 human cell cancer lines bearing KRASG12C mutations on pERK inhibition and 3D cellular viability. pERK was assessed by AlphaLISA and cellular viability by 3D CellTiter-Glo® (CTG) reagent. Compound 1 displayed potent inhibition of pERK across all 12 KRASG12C cell lines tested with the IC50 values ranging from 0.31 to 2.50 nM. Compound 1 similarly demonstrated sub-nM to single digit nM potency with IC50 values ranging from 0.15 to 1.20 nM in 3D viability assays (FIGs. 3A-3B).Example 8: Potency profile of Compound 1 on active GTP-bound KRASG12C signaling

[0367] The activity of Compound 1, sotorasib, divarasib, and adagrasib were evaluated on the inhibition of active GTP-bound KRASG12Csignaling using a RAS-RAF ELISA and by measuring potency shifts in pERK and 3D viability upon growth factor stimulation, which increases the levels of GTP-bound KRASG12C. Sotorasib, divarasib, and adagraib, which only bind the inactive GDP-bound state of KRASG12C, were included as controls. In the active GTP-bound state, KRASGI2Cbinds to its effector RAF, so a RAS GTPase ELISA kit was used to measure the fraction of RAS bound to RAF across early compound treatment time points in pancreatic carcinoma MIA PaCa-2 cells, which bear a KRASG12Cmutation.

[0368] MIA PaCa-2 cells were treated for 5, 15, 30 and 60 minutes with 1 pM of BBO- 8520, sotorasib, divarasib, or adagraib, and the amount of active RAS was quantified using a RAS GTPase ELISA kit (Abeam). Cells were treated for the indicated timepoints, lysed, and incubated in a well containing a RAF-RBD fusion protein coated to the bottom of the well. After incubating the lysates with the RAF-RBD, RAS capture antibody was added to quantify the amount of RAS bound to RAF in the sample, followed by a detection antibody that was quantified with luminescence. Data was imported into GraphPad Prism 9 for analysis.

[0369] Compound 1 inhibited 70% of RAF bound to RAS within 5 minutes of treatment and completely suppressed RAS activation after 15 minutes (FIG. 4). In comparison,PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 sotorasib reached 50% inhibition after 22 minutes and failed to achieve greater than 75% inhibition within 1 hour of treatment. BBO-8520 demonstrated rapid disruption of RAS-RAF signaling compared to sotorasib. Divarasib and adagrasib performed similarly. Table 7 summarizes the observed inhibition.Table 7: MIA PaCa-2 RAS-RAF ELISA - measurement of activated (GTP) RAS for selected compounds

[0370] Abbreviations: ELISA= enzyme-linked immunosorbent assay; GTP=guanosine triphosphate; RAF=rapidly accelerated fibrosarcoma; RAS=rat sarcoma viral oncogene homolog; RBD=RAS binding domain.

[0371] The potency of Compound 1, sotorasib, and adagrasib were also evaluated on active RAS using EGF or HGF to shift the fraction of RAS towards the active GTP-bound KRASG12Cstate (FIGs. 5A-5C).

[0372] NCI-H358 cells were serum starved for 24 hours and then treated with (A) vehicle or (B) 100 ng / mL of recombinant human EGF before a dose titration of BBO-8520, sotorasib, or adagrasib was added for a period of 20 minutes. pERK signal was then quantified using an Alphalisa (Perkin Elmer). Data was imported into GraphPad Prism 9, log transformed, and curve fitted for IC50 concentrations. BBO-8520 had an IC50 of 7.4 nM and 49.7 nM in vehicle and 100 ng / mL EGF, respectively, compared to sotorasib which had an IC50 of 269.2 nM in vehicle and greater than 10 pM in EGF, respectively.

[0373] In NSCLC NCI-H358 cells treated with Compound 1 and EGF, the pERK IC50 values shifted only 7-fold, to 49.7 nM compared to 7.4 nM when cells were treated with Compound 1 and vehicle (FIGs. 5A-5B). In contrast, in NCI-H358 cells treated with sotorasib and EGF, the pERK IC50 values shifted over 35-fold to greater than 10 pM compared to 269.2 nM when cells were treated with sotorasib and vehicle.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0374] Abbreviations: EGF=epidermal growth factor; ICso= half maximal inhibitory concentration; pERK=phosphorylated extracellular signal-regulated kinase P2.

[0375] To assess this effect in a more chronic assay, the NCI-H358 cell line was engineered to express HGF upon doxycycline treatment, and Compound 1 and sotorasib were evaluated in a 5-day 3D viability assay (FIGs. 6A-6C).

[0376] NCI-H358 cells, which were engineered to induce HGF in the presence of doxycycline, were plated in ultra-low attachment 3D viability plates and stimulated with (A) vehicle, (B) doxycycline to induce HGF expression, or (C) 100 ng / mL recombinant HGF in the presence of the indicated range of concentrations of BBO-8520 or sotorasib. 5 days post treatment, cells were lysed by addition of 3D CTG reagent and luminescence was read. Data was imported into GraphPad Prism 9, log transformed, and curve fitted for IC50 concentrations. The IC50 values of BBO-8520 were 0.1, 0.5, and 0.3 nM while the sotorasib IC50 values were 1.7, 32.4, and 19.1 nM in the vehicle, doxycycline and HGF groups, respectively.

[0377] When treated with Compound 1 in the presence of doxycycline, thereby inducing HGF, the 3D viability IC50 values shifted only 5-fold to 0.5 nM compared to 0.1 nM without doxycycline. However, when these cells were treated with sotorasib in the presence of doxycycline to induce HGF, the 3D viability IC50 values shifted 19-fold to 32.4 nM compared to 1.7 nM without doxycycline. Similar results were observed with these NCI-H358 cells when they were alternatively treated with exogeneous HGF. When cells were treated with Compound 1 and HGF, the 3D viability IC50 values shifted only 3-fold to 0.3 nM compared to 0.1 nM when cells were treated with Compound 1 and vehicle. In contrast, when cells were treated with sotorasib and HGF, the 3D viability IC50 values shifted 11-fold to 19.1 nM compared to 1. nM when cells were treated with sotorasib and vehicle.

[0378] Abbreviations: 3D=3-dimensional; CTG= CellTiter-Glo®; HGF=hepatocyte growth factor; lC5o=half maximal inhibitory concentration.

[0379] These results with Compound 1 in the presence of growth factor stimulation, demonstrate rapid inhibition of RAS bound to RAF wherein the compound retains potency upon growth factor stimulation in both the pERK and 3D viability assay. These results support that Compound 1 is a potent inhibitor of KRASG12Cin the GTP-bound state.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Example 9: Compound 1 has a favorable ADME and PK profile and is orally bioavailable

[0380] Compound 1 was administered at single dose of 1 or 3 mg / kg intravenously and 5, 10, 30, or 100 mg / kg orally. Plasma was collected and then pharmacokinetic parameters were assessed. Table 8 includes ADME and PK parameters for Compound 1 measured in various species and in whole blood.Table 8: ADME and PK parameters for Compound 1Example 10: Compound 1 demonstrates dose- and time-dependent inhibition of pERK in pharmacodynamic (PD) studies: Pharmacokinetic and pharmacodynamic effect of Compound 1 in the MIA PaCa-2 cell line-derived Matrigel plug model of KRASG12Cpancreatic carcinoma

[0381] In vivo pharmacology studies were performed to characterize the PK / PD relationship of BBO-8520 in the pancreatic carcinoma MIA PaCa-2 model, which bears a homozygous KR ASG12Cmutation. The relationship between the level of pERK inhibition and direct target engagement of BBO-8520 in MIA PaCa-2 tumors was also determined.

[0382] An in vivo dose and time response PK / PD study was performed to determine the pERK ECso and EC90 of BBO-8520 and the duration of pERK inhibition following a single oral dose of 30 mg / kg BBO-8520 in the MIA PaCa-2 Matrigel plug model. MIA PaCa-2 subcutaneous Matrigel plug-bearing female athymic nude mice (4 animals / group) were administered a single oral dose of vehicle or BBO-8520. For the dose response portion of thePATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 study, plasma and Matrigel plugs were collected for PK and PD analyses, respectively, at 6 hours following a single oral dose of vehicle, 3 mg / kg BBO-8520, 10 mg / kg BBO-8520, or 30 mg / kg BBO-8520. For the time response portion of the study, plasma and Matrigel plugs were collected for PK and PD analyses, respectively, at 2, 6, 24, 48, and 72 hours following a single oral dose of 30 mg / kg BBO-8520. Matrigel plugs were processed to lysates and used to measure pERK levels by Meso Scale Discovery (MSD) for PD analyses.

[0383] For FIG. 7A: Female athymic nude mice were inoculated subcutaneously with MIA PaCa-2 tumor cells suspended in growth factor reduced Matrigel. The following day, mice (n=4 per group) were administered a single oral dose of vehicle or 3, 10, or 30 mg / kg BBO- 8520. Six hours after administration of vehicle or BBO-8520, the mean (± SEM) percentage of plasma compound concentrations (pM) and pERK Matrigel plug levels normalized to vehicle Matrigel plug levels (% pERK (normalized to vehicle) = (experimental (pERK / ERK) ) / (vehicle (pERK / ERK)) x 100) were measured. Mean pERK levels (± SEM) with one-way ANOVA of all group means followed by post hoc Dunnett’s multiple comparisons showed the following groups had statistically significant inhibition of pERK as follows compared to the vehicle group: *p<0.01, **p<0.0001. Dotted line: BBO-8520 MIA PaCa-2 pERK FF adj IC50 of 55 nM.

[0384] For FIG. 7B: Female athymic nude mice were inoculated subcutaneously with MIA PaCa-2 tumor cells suspended in growth factor reduced Matrigel. The following day, mice (n=4 per group) were administered a single oral dose of vehicle or 30 mg / kg BBO-8520. Six hours after administration of vehicle or 2, 6, 24, 48, or 72 after administration of BBO-8520, the mean (± SEM) percentage of plasma compound concentrations (pM) and pERK Matrigel plug levels normalized to vehicle Matrigel plug levels (% pERK (normalized to vehicle) - (experimental (pERK / ERK) ) / (vehicle (pERK / ERK)) x 100) were measured. Mean pERK levels (± SEM) with one-way ANOVA of all group means followed by post hoc Dunnett’s multiple comparisons showed the following groups had statistically significant inhibition of pERK as follows compared to the vehicle group: *p<0.01, **p<0.0001. Dotted line: BBO- 8520 MIA PaCa-2 pERK FF adj IC50 of 55 nM.

[0385] Abbreviations in FIGs. 7A-7B: ANOVA=analysis of variance; FF adj ICso=free fraction adjusted half maximal inhibitory concentration; n=number; pERK=phosphorylatedPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 extracellular signal-regulated kinase 1 / 2; PK=pharmacokinetic; SEM=standard error of the mean.

[0386] The dose response PK / PD results showed a statistically significant dose dependent decrease in pERK at 6 hours following a single dose of BBO-8520. Six hours following a single oral dose of 3, 10, or 30 mg / kg BBO-8520, a statistically significant reduction of 46%, 73%, and 92% in pERK Matrigel plug levels, respectively, was observed compared to the vehicle group (FIG. 7A and Table 9). The pERK ECso was 85 nM [95% CT: 58 to 127] and the EC90 was 458 nM [95% CI: 208 to 1441]. The pERK EC50 also correlated well to the in vitro MIA PaCa-2 cell line pERK free fraction adjusted IC50 of 55 nM.Table 9: Dose response summary of pERK Matrigel plug inhibition following a single dose of Compound 1 in athymic nude mice bearing MIA PaCa-2 cell line-derived subcutaneous Matrigel plugsAbbreviations: ANOVA=analysis of variance; n=number; pERK=phosphorylated extracellular signal- regulated kinase 1 / 2; po=per os (oral gavage by mouth); QD= quaque die (once per day);SEM=standard error of the mean

[0387] The time response PK / PD results showed statistically significant inhibition of pERK levels for up to 72 hours following a single oral dose of 30 mg / kg BBO-8520 in the MIA PaCA-2 Matrigel plug model. At 2, 6, 24, 48, and 72 hours following a single oral dose of 30 mg / kg BBO-8520, a statistically significant reduction of 40%, 92%, 83%, 57%, and 41% in pERK Matrigel plug levels, respectively, was observed compared to the vehicle group at 6 hours (FIG. 7B and Table 10).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Table 10: Time Response Summary of pERK Matrigel Plug Inhibition Following a Single Dose of BBO-8520 in Athymic Nude Mice Bearing MIA PaCa-2 Cell Line- Derived Subcutaneous Matrigel PlugsAbbreviations: ANOVA=analysis of variance; n=number; BLQ=below limit of quantification; pERK=phosphorylated extracellular signal-regulated kinase 1 / 2; po=per os (oral gavage by mouth); QD= quaque die (once per day); SEM=standard error of the mean

[0388] Thus, Compound 1 demonstrated a robust PK / PD response in the MIA PaCa-2 cell line-derived Matrigel plug model of KRASG12Cpancreatic carcinoma, with a strong and statistically significant dose- and time-dependent effect on pERK reduction.Example 11: Efficacy of Compound 1 in KRASG12C xenograft models: Efficacy of Compound 1 in the MIA PaCa-2 cell line-derived xenograft model of KRASG12C pancreatic carcinoma

[0389] An in vivo efficacy study was performed to evaluate the anti-tumor activity of BBO-8520 and determine the ED50 and ED90 of BBO-8520 in the pancreatic carcinoma MIA PaCa-2 CDX model, which bears a homozygous KRASG12Cmutation. MIA PaCa-2 subcutaneous tumor-bearing female athymic nude mice (10 animals / group) were administered vehicle, 0.1 mg / kg BBO-8520, 0.3 mg / kg BBO-8520, 1 mg / kg Compound 1, 3 mg / kg BBO-8520, or 10 mg / kg Compound 1 once daily by oral gavage for a period of 27 to 28 days. Animals were monitored twice weekly for changes in tumor volume and body weight.

[0390] Female athymic nude mice were inoculated subcutaneously with MIA PaCa-2 tumor cells suspended in a 1 :1 ratio of PBS:Matrigel. When tumors reached a mean size of 177 mm3, mice were randomized into treatment groups (n=10 per group) and orally dosedPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 daily with vehicle or 0.1, 0.3, 1, 3, or 10 mg / kg BBO-8520 from day 1 to day 28, unless described differently above. Tumor volumes were measured twice weekly until day 28 and mean tumor volume (±SEM) (mm3) were calculated. Mice in the 0.3 mg / kg BBO-8520 group were dosed with 0.3 mg / kg BBO-8520 from days 1 to 27 and then 0.3 mg / kg BBO-8520 (n=4), 3 mg / kg BBO-8520 (n=3), or 10 mg / kg BBO-8520 (n=3) on day 28 for an end of efficacy study PK / PD study. Mean tumor volume (±SEM) with two-way repeated measures ANOVA followed by Dunnett’s multiple comparison test from day 3 to day 28 showed the indicated treatment groups had statistically significant anti-tumor activity compared to the vehicle group (*p<0.0001).

[0391] The results showed that BBO-8520 had dose dependent and robust anti-tumor activity. Following daily oral administration of 0.1, 0.3, 1, 3, or 10 mg / kg Compound 1, a statistically significant reduction in tumor volume compared to vehicle group was observed on day 28, with % tumor growth inhibition (TGI) ranging from 21-99% for the 0.1-3 mg / kg dose groups (FIG. 8). For the 10 mg / kg dose group, 90% regression was observed, with 4 of 10 mice showing a complete response.

[0392] All treatments were well tolerated. There was no impact of BBO-8520 treatments on body weights.

[0393] Thus, Compound 1 was highly potent, exhibited robust anti-tumor efficacy, and was well tolerated in the MIA PaCa-2 CDX model of KRASG12Cpancreatic carcinoma.Compound 1 plasma exposure above the in vitro MIA PaCa-2 cell line free fraction adjusted ICso for 8 hours (3 mg / kg dose) caused tumor regression in the model.

[0394] Abbreviations: ANOVA=analysis of variance; n=number; PBS=phosphate buffered saline; PK=pharmacokinetic; PD=pharmacodynamic; SEM=standard error of the mean.Example 12: Efficacy of Compound 1 in KRASG12C xenograft models: Efficacy of BBO-8520 in the NCI-H358 Cell Line-Derived Xenograft Model of KRASG12CNonSmall Cell Lung Cancer

[0395] An in vivo efficacy study was performed to evaluate the anti-tumor activity of BBO-8520 and determine the ED50 and ED90 of BBO-8520 in the NSCLC NCI-H358 CDX model, which bears a heterozygous KRASG12Cmutation. NCLH358 subcutaneous tumorbearing female nonobese diabetic / severe combined immunodeficiency (NOD / SCID) mice (10PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 animals / group) were administered vehicle, 0.3 mg / kg BBO-8520, 1 mg / kg BBO-8520, 3 mg / kg BBO-8520, or 10 mg / kg BBO-8520 once daily by oral gavage for a period of 28 days. Animals were monitored twice weekly for changes in tumor volume and body weight.

[0396] Female NOD / SCID mice were inoculated subcutaneously with NCI-H358 tumor cells suspended in a 1:1 ratio of PBS:Matrigel. When tumors reached a mean size of 177 mm3, mice were randomized into treatment groups (n=10 per group) and orally dosed daily with vehicle or 0.3, 1, 3, or 10 mg / kg BBO-8520 from day 1 to day 28. Tumor volumes were measured twice weekly until day 28 and mean tumor volume (±SEM) (mm3) were calculated. Mean tumor volume (±SEM) with two-way mixed-effects ANOVA followed by Dunnett’s multiple comparison test from day 5 to day 28 showed the indicated treatment groups had statistically significant anti-tumor activity compared to the vehicle group (*p<0.0001).

[0397] The results showed that BBO-8520 had dose dependent and robust anti-tumor activity. Following daily oral administration of 0.3, 1, 3, and 10 mg / kg BBO-8520, a statistically significant reduction in tumor volume compared to the vehicle group was observed for all treatment groups except the 0.3 mg / kg group on day 28, with 20% TGI, 71% TGI, 19% mean tumor regression, and 100% mean tumor regression, respectively (FIG. 9). In the 3 mg / kg and 10 mg / kg BBO-8520 groups, 1 / 10 and 10 / 10 mice had complete tumor regressions, respectively. The EDso was 0.6 mg / kg [95% CI: 0.4 to 1.0] and the ED90 was 1.6 mg / kg [95% CI: 1.0 to 2.8]. Three mg / kg BBO-8520 provided 9 hours of plasma exposure coverage above the in vitro NCI-H358 cell line free fraction adjusted IC50 of 36 ng / mL (50 nM) in a non-tumor-bearing NOD / SCID mouse PK study.

[0398] All treatments were well tolerated. There was no impact of 3 or 10 mg / kg BBO- 8520 treatments on body weights. Unexpectedly, one mouse in the 0.3 mg / kg BBO-8520 group and two mice in the 1 mg / kg BBO-8520 group had body weight loss over 15% and were therefore given several dosing holidays. All of the mice in both of these groups were placed on supportive diet gel for a portion of the study due to this body weight loss, so the assessment of the tolerability of 0.3 and 1 mg / kg BBO-8520 can therefore not be made. However, the cause of this weight loss is unknown and not attributed to BBO-8520 since body weights were not affected in the higher 3 and 10 mg / kg BBO-8520 dose groups. BBO- 8520 treatments were therefore considered well tolerated. No gross clinical abnormalitiesPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 were observed during the study. These results indicated that neither tumor burden nor compound treatment elicited toxicity.

[0399] Thus, Compound 1 was efficacious with all of the mice in the 10 mg / kg BBO-8520 group having complete tumor regressions with no palpable tumors left by the end of the study. BBO-8520 exhibited robust anti-tumor efficacy with an ED50 of 0.6 mg / kg [95% CI: 0.4 to 1.0] and ED90 of 1.6 mg / kg [95% CI: 1.0 to 2.8] and was well tolerated. BBO-8520 plasma exposure above the in vitro NCI-H358 cell line free fraction adjusted IC(, for 9 hours (3 mg / kg dose) caused tumor regression in the model.

[0400] Abbreviations: ANOVA=analysis of variance; n=number; NOD / SCID= nonobese diabetic / severe combined immunodeficiency; PBS=phosphate buffered saline; SEM=standard error of the mean.Example 13: Efficacy of Compound 1 in the LUN055 patient-derived xenograft model of KRASG12C non-small cell lung cancer

[0401] An in vivo efficacy study was performed to evaluate the anti-tumor activity of Compound 1 in the NSCLC LUN055 PDX model, which bears a homozygous KRASG12Cmutation and harbors overexpression of the RET RTK. Overexpression of RET is hypothesized to increase the amount of KRASG12Cloaded with GTP in the tumors, which would make this model more resistant to KRASG12Cinhibitors like sotorasib and adagrasib, which only bind the inactive GDP-bound state of KRASG12C(Lietman 2022). LUN055 subcutaneous tumor-bearing female BALB / c nude mice (10 animals / group) were administered vehicle, 30 mg / kg BBO-8520, or 100 mg / kg of sotorasib once daily by oral gavage for a period of 35 days. Animals were monitored twice weekly for changes in tumor volume and body weight. Plasma and tumor samples were collected for PK and PD analyses, respectively, 2, 6, and 24 hours after the final dose on day 35 in all groups (3 animals / group).

[0402] Female BALB / c nude mice were implanted subcutaneously with 15-30 mm3LUN055 tumor fragments. When tumors reached a mean size of 206 mm3, mice were randomized into treatment groups (n=10 per group) and orally dosed daily with vehicle or 30 mg / kg BBO-8520 or 100 mg / kg of sotorasib from day 1 to day 35. Tumor volumes were measured twice weekly until day 35 and mean tumor volume (±SEM) (mm3) were calculated. Mean tumor volume (±SEM) with two-way repeated measures ANOVA followed byPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1Dunnett’s multiple comparison test from day 4 to day 35 showed the indicated treatment groups had statistically significant anti-tumor activity compared to the vehicle group (*p<0.0001).

[0403] The results showed that Compound 1 had monotherapy anti-tumor activity (FIG. 10). Following daily oral administration of 30 mg / kg Compound 1, a statistically significant reduction in tumor volume compared to vehicle group was observed for both treatment groups on day 35, with 23% mean tumor regression. In contrast, a higher dose of sotorasib demonstrated only 71 % TGI.

[0404] Abbreviations: ANOVA=analysis of variance; BALB / c=Bagg Albino / c; n=number; SEM=standard error of the mean.Example 14: Efficacy of Compound 1 following resistance to sotorasib in the MIA PaCa-2 cell line-derived xenograft model of KRASG12C pancreatic carcinoma

[0405] An in vivo study was performed to evaluate the anti-tumor efficacy of Compound 1 in sotorasib-resistant pancreatic carcinoma MIA PaCa-2 cell line-derived xenograft (CDX) tumors, which bear a homozygous KRASG12Cmutation. For phase 1 of the study, MIA PaCa- 2 tumor-bearing female BALB / c nude mice were administered vehicle (n=10) or 10 mg / kg sotorasib (n=30) once daily by oral gavage for 36 days. When tumors in the 10 mg / kg sotorasib group developed resistance to treatment and reached -200 nun3on day 36, phase 2 dosing was initiated. For phase 2 of the study, mice in the vehicle group were dosed with vehicle for 18 days until day 54. Mice dosed with 10 mg / kg sotorasib in phase 1 were randomized and dosed daily with 10 mg / kg sotorasib for 49 days until day 85, 30 mg / kg Compound 1 for 61 days until day 97, or 100 mg / kg sotorasib for 61 days until day 97. Animals were monitored twice weekly for changes in tumor volume and body weight.

[0406] Female BALB / c nude mice were inoculated subcutaneously with MIA PaCa-2 tumor cells suspended in a 1 : 1 ratio of PBS:Matrigel. When tumors reached a mean size of 180 mm3, mice were orally dosed daily with vehicle (n=10) or 10 mg / kg sotorasib (n=30). Mice were treated daily with vehicle for 54 days. Mice were treated daily with 10 mg / kg sotorasib until resistance developed on day 36 when the mean tumor volume reached 188 mm3. These mice were then randomized (10 animals / group) and treated daily with 10 mg / kg sotorasib from day 37 to 85 or treated daily with 30 mg / kg BBO-8520 or 100 mg / kg sotorasibPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 from day 37 to 97. Tumor volumes were measured twice weekly until day 96. Tumor volumes through day 75 are shown because statistical analyses were performed on day 75 since one animal in the 10 mg / kg QD sotorasib group had to be euthanized due to large tumor volume on day 75. Mean tumor volume (±SEM) with two-way repeated measures ANOVA from day 40 to day 75 showed the indicated treatment groups had statistically significant antitumor activity: *p<0.05, **p<0.01.

[0407] The results showed a statistically significant reduction in tumor volume on day 75 in the mice treated daily with 30 mg / kg BBO-8520 or 100 mg / kg sotorasib compared to the group that was dosed daily with 10 mg / kg sotorasib (FIGs. 11A-11B). Statistical analyses were performed on day 75 because one animal in the 10 mg / kg sotorasib group had to be euthanized due to large tumor volume on day 75. The results showed that treatment with 30 mg / kg BBO-8520 drove a deep response in the MIA PaCa-2 sotorasib-resistant tumors. On day 92, 40% (3 / 8) of mice treated daily with 30 mg / kg BBO-8520 developed new complete tumor regressions with no palpable tumors left after switching to BBO-8520 treatment, while 0% (0 / 8) of mice in the 100 mg / kg sotorasib group developed new complete tumor regressions during this time period.

[0408] All treatments were well tolerated. There was no impact of sotorasib or BBO-8520 treatments on body weights. No gross clinical abnormalities were observed during the study. These results indicated that neither tumor burden nor compound treatment elicited toxicity.

[0409] In summary, mice with sotorasib-resistant tumors had a statistically significant reduction in tumor volume when treated with BBO-8520 or higher dose levels of sotorasib. This demonstrated that increased levels of KRASG12Cmay have contributed to the resistance of lower doses of sotorasib and that higher levels of sotorasib may have led to efficacy due to increased target coverage. BBO-8520 drove a deep response in the sotorasib-resistant tumors. Forty percent of the mice treated daily with 30 mg / kg BBO-8520 developed complete regressions, while 0% of the mice treated daily with 100 mg / kg sotorasib developed complete regressions during the new treatment period. BBO-8520 is hypothesized to be more efficacious than sotorasib in the sotorasib-resistant tumors due to increased target coverage since it can bind to both GTP- and GDP-bound KRASG12C. The results from this study support the evaluation of BBO-8520 in patients who have progressed on sotorasib in the clinic.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0410] A KRAS amplification study was also performed. Standard methods were used to extract genomic DNA from tumors and measure levels of KRAS amplification using predesigned ddPCR copy number assay probes for human KRAS and the reference gene RPP30. Results are shown in FIG. 11C.

[0411] Abbreviations: ANOVA=analysis of variance; BALB=Bagg Albino; n=number; PBS=phosphate buffered saline; QD=quaque die (once per day); SEM=standard error of the mean.Example 15: Compound 1 and anti-PD-1 cures 60% of mice bearing the KRASG12C CT26 syngeneic liver tumors

[0412] Compound 1 efficacy was assessed following once daily (QD) oral dosing of the indicated dose levels of BBO-8520 in a liver syngeneic tumor model bearing KRASG12Cmutations. Anti-PD-1 was administered twice weekly (BIW) as indicated by intraperitoneal administration. Tumor growth inhibition (TGI), mean tumor regression (REG), and number of complete regressions (CR) were calculated. Percent survival is summarized in FIG. 12 and Table 11 below.Table 11: Efficacy of Compound 1 in a syngeneic liver modelExample 16: Early Phase la Monotherapy Data

[0413] In total, 16 patients were enrolled in Phase la clinical study as described in Example 2, and treated at three dose levels (lOOmg, 200mg, 300mg QD).PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0414] Median lines of prior therapy in the metastatic setting were 1 (1-4), with 7 / 10 patients receiving prior platinum containing chemotherapy and 5 / 10 being exposed to prior PD-1 / PD-L1 inhibitors. As of the data cut (January 19, 2025), 10 patients were evaluated.

[0415] Six of ten patients had confirmed partial responses, for an ORR of 60% (n=6 / 10). Accordingly, three of three (receiving 200 mg QD) confirmed partial responses; two of three (receiving 300 mg QD) confirmed partial responses; and one (receiving 100 mg QD) confirmed partial responses. At the highest dose (300mg QD), the confirmed response is 66% (n=2 / 3). At the 200 mg dose group, the confirmed response is 100%.

[0416] FIG. 13 shows BBO-8520 anti-tumor activity in ten (10) efficacy evaluable patients with NSCLC. Responses appear durable, albeit with a relatively short follow up and 8 / 10 patients remaining on treatment (3 patients in cohort 1 remained on study >6 months).

[0417] FIG. 13: EDC data from ONKORAS-101 trial, extract date January 19, 2025. *Efficacy evaluable defined as at least two on treatment scans; ** Intra-cohort escalated to 200 mg QD; Patient chose to discontinue the treatment; — > Indicates patient is still on the treatment; E = Patient received KRAS G12C inhibitor prior to BBO-8520; and N = Patient is KRAS G12C inhibitor naive prior to BBO-8520.

[0418] Abbreviations: SD = stable disease; PR = partial response; and ORR = overall response rate.

[0419] In the preliminary safety dataset (16 patients), treatment-related adverse events (TRAE) were generally mild (Grade 1 / 2), with no serious (Grade 3 or higher) events and no liver enzyme (AST / ALT) elevation of any grade. The most common TRAEs were nausea (44% of patients), diarrhea (31%), and lower rates of fatigue, decreased white blood cell count, and increased lipase (all 12.5%). Overall, the safety profile was manageable and tolerable for this patient group. Table 12 shows the safety profile.Table 12: BBO-8520 Safety DataPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1

[0420] BBO-8520 has shown responses across all dose levels of monotherapy escalation while supporting a favorable safety profile.

[0421] It should be understood from the foregoing that, while particular implementations have been illustrated and described, various modifications may be made thereto and are contemplated herein. It is also not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the preferable embodiments herein are not meant to be construed in a limiting sense. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. Various modifications in form and detail of the embodiments of the invention will be apparent to a person skilled in the art. It is therefore contemplated that the invention shall also cover any such modifications, variations, and equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of the compound.

2. The method of claim 1, wherein the compound is Compound 1:or a pharmaceutically acceptable salt thereof.

3. The method of any one of claims 1 to 2, wherein the compound is Compound 1 :(Compound 1).

4. The method of any one of claims 1 to 3, wherein the cancer is a solid tumor.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 15. The method of any one of claims 1 to 4, wherein the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, esophageal / gastroesophageal cancer, small bowel cancer, breast cancer, glioblastoma, biliary tract cancer, appendiceal cancer, ovarian cancer, endometrial cancer, or lung cancer.

6. The method of any one of claims 1 to 5, wherein the cancer is pancreatic cancer pancreatic ductal adenocarcinoma, colorectal cancer, or lung cancer.

7. The method of claim 6, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC); and the lung cancer is non-small cell lung cancer (NSCLC).

8. The method of any one of claims 1 to 9, wherein the cancer is characterized by a mutation in a KRAS protein.

9. The method of any one of claims 1 to 8, wherein the cancer is a KRAS G12C positive cancer.

10. The method of any one of claims 1 to 9, wherein the cancer is resistant to a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the cancer is resistant to sotorasib, adagrasib, or divarasib.

12. The method of any one of claims 1 to 11, wherein the cancer is non-small cell lung cancer (NSCLC).

13. A method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1:PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 10 mg to about 2000 mg of Compound 1.

14. The method of claim 12 or 13, wherein the NSCLC is characterized by a mutation in a KRAS protein.

15. The method of any one of claims 12 to 14, wherein the NSCLC is a KRAS G12C positive cancer.

16. The method of any one of claims 12 to 15, wherein the NSCLC is resistant to a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 12 to 16, wherein the NSCLC is resistant to sotorasib, adagrasib, or divarasib.

18. The method of any one of claims 12 to 17, wherein the NSCLC is an advanced or metastatic NSCLC.

19. The method of any one of claims 13 to 18, wherein the subject does not have a KRAS mutation selected from G12D, G12V, M72K, Q61H, R164Q, R68S, and T2S.

20. The method of any one of claims 13 to 19, wherein the subject does not have a targetable driver mutation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, NTRK, or HER2.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 121. The method of any one of claims 13 to 20, wherein the subject has progression on or disease recurrence after available standard of care (SoC) treatments comprising an immune checkpoint inhibitor, a platinum-based doublet chemotherapy, or both.

22. The method of claim 21, wherein the immune checkpoint inhibitor is pembrolizumab, atezolizumab, nivolumab, ipilimumab, durvalumab, tremelimumab, cemiplimab-rwlc, or a combination thereof.

23. The method of any one of claims 13 to 20, wherein the subject has progression on or disease recurrence after available standard of care (SoC) treatments comprising a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1, or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the KRAS G12C inhibitor is sotorasib, adagrasib, divarasib, JDQ443, LY3537892, or a combination thereof.

25. The method of any one of claims 13 to 24, wherein the subject does not have tumors with other targetable driver mutations (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase, ROS1 / BRAF / RET / MET / EGFR exon20 insertion / NTRK / HER2).

26. The method of claim 1 or 13, wherein the subject has not previously undergone treatment with a KRAS inhibitor therapy.

27. The method of any one of claims 1 to 26, wherein the subject has not previously been treated with the compound of Formula (I), Compound 1, or a pharmaceutically acceptable salt thereof.

28. The method of any one of claims 1 to 25, wherein the subject was previously treated with a KRAS G12C inhibitor, wherein the KRAS inhibitor is other than the compound of Formula (I) or Compound 1 , or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the KRAS G12C inhibitor only binds to an inactiveGDP-bound state of KRAS G12C.PATENTAttorney Docket No. 2014229-0161Thera-23.WO 130. The method of claim 28 or 29, wherein the subject was previously treated with sotorasib, adagrasib, divarasib, JDQ443, LY3537892, or a combination thereof.

31. The method of any one of claims 1 to 30, wherein the subject is a human.

32. The method of any one of claims 1 to 31, wherein the subject is an adult of at least 18 years old.

33. The method of any one of claims 1 to 32, wherein the therapeutically effective amount is a total daily dosage of from about 50 mg to about 2000 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 100 mg to about 1500 mg, from about 50 mg to about 1200 mg, from about 100 mg to about 1200 mg, from about 200 mg to about 1200 mg, from about 300 mg to about 1200 mg, from about 400 mg to about 1200 mg, from about 500 mg to about 1200 mg, from about 600 mg to about 1200 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 100 mg to about 900 mg, from about 200 mg to about 900 mg, from about 300 mg to about 900 mg, from about 400 mg to about 900 mg, from about 500 mg to about 900 mg, from about 50 mg to about 800 mg, from about 100 mg to about 800 mg, from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, from about 400 mg to about 800 mg, from about 500 mg to about 800 mg, from about 50 mg to about 700 mg, from about 100 mg to about 700 mg, from about 200 mg to about 700 mg, from about 300 mg to about 700 mg, from about 400 mg to about 700 mg, from about 500 mg to about 700 mg, from about 50 mg to about 600 mg, from about 100 mg to about 600 mg, from about 200 mg to about 600 mg, from about 300 mg to about 600 mg, from about 400 mg to about 600 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 50 mg to about 400 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 50 mg to about 200 mg, or from about 100 mg to about 200 mg of the compound or Compound 1.

34. The method of claim 33, wherein the therapeutically effective amount is a total daily dosage of from about 200 mg to about 800 mg, from about 300 mg to about 800 mg, fromPATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 about 400 mg to about 800 mg, or from about 500 mg to about 800 mg of the compound or Compound 1.

35. The method of claim 33, wherein the therapeutically effective amount is a total daily dosage of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or about 1200 mg of the compound or Compound 1.

36. The method of claim 35, wherein the therapeutically effective amount is a total daily dosage of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 700 mg, or about 800 mg of the compound or Compound 1.

37. The method of any one of claims 1 to 36, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

38. The method of any one of claims 1 to 37, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

39. The method of any one of claims 1 to 38, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily.

40. The method of any one of claims 1 to 39, wherein the treating comprises one or more treatment cycles; and the administration of the compound or Compound 1 comprises a dose escalation or de-escalation after a previous treatment cycle, wherein the dose escalation or de- escalation is determined by a dose-limiting toxicity (DLT) assessment.

41. The method of any one of claims 1 to 40, wherein the compound, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 antibody.

42. The method of claim 41, wherein the anti-PD-1 antibody is pembrolizumab.

43. The method of claim 42, wherein pembrolizumab is administered by an intravenous infusion.

44. A method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, comprising administering:PATENTAttorney Docket No. 2014229-0161Thera-23.WO 1 i) a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof; and ii) a therapeutically effective amount of pembrolizumab.

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