Combination therapy including GDC-6036 and GDC-0077 for the treatment of cancer

Abstract

KRas G12C Provided herein are combination therapies comprising an inhibitor (eg, GDC-6036) and a PI3K inhibitor (eg, inavolisib), as well as methods of using such combination therapies.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328,149, filed April 6, 2022, which is incorporated herein in its entirety for all purposes.

[0002] FIELD OF THEINVENTION KRas G12C Provided herein are combination therapies comprising an inhibitor (e.g., GDC-6036) and a PI3K inhibitor (GDC-0077, inavolisib), as well as methods of using such combination therapies. [Background technology]

[0003] Kirsten rat sarcoma viral oncogene homolog (KRAS) is a central component of the RAS / MAPK signaling pathway, an intracellular network of proteins that transduce extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS are commonly found in solid tumors and can result in changes to several amino acids, including glycine 12 (G12), glycine 13, and glutamine 61, that are associated with tumorigenesis and aggressive tumor growth. Oncogenic KRAS mutations resulting in a G12 to cysteine ​​(G12C) change are common in non-small cell lung cancer (NSCLC) (~12%), colorectal cancer (CRC) (~4%), and other tumor types (≤4%).

[0004] For example, KRas, including lung cancer (e.g., NSCLC), CRC, and pancreatic cancer. G12C Advanced tumors with KRas mutations (hereafter referred to as KRas G12C Advanced stage KRas tumors (referred to as KRas positive tumors) are incurable and have a poor prognosis. G12C Patients with positive cancers may derive limited benefit from selected chemotherapy and targeted therapies, thus limiting the effective available treatment options.

[0005] Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that controls cell proliferation, survival, and migration upon activation by growth factor receptors and integrins. PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate the second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3), which is involved in the phosphorylation of AKT and other components in the AKT / mTOR pathway. Up to 70% of breast cancers harbor some form of molecular abnormality of the PI3K / AKT / mTOR pathway. Activating mutations in PIK3CA, which encodes the p110α subunit of PI3K, are highly common in breast cancer and solid tumor malignancies.

[0006] Inhibitors of PI3Kα are approved or in clinical development for the treatment of patients with hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer harboring PIK3CA mutations, whereas KRas G12C There remains a need for effective therapies and combination therapies to treat cancers such as lung, colorectal, and pancreatic cancers that harbor mutations. Summary of the Invention

[0007] Solutions to these and other problems in the art are provided herein.

[0008] In one aspect, provided herein is a combination therapy comprising GDC-6036, or a pharma- ceutically acceptable salt thereof, and inavolisib, or a pharma- ceutically acceptable salt thereof, as described herein.

[0009] In another embodiment, KRas G12CProvided herein is a method for treating a patient with a lung cancer mediated by mutation, comprising administering an effective amount of a combination therapy comprising QD administration of an effective amount of GDC-6036 or a pharmaceutically acceptable salt thereof according to a dosing regimen comprising one or more cycles, and QD administration of an effective amount of inavolisib or a pharmaceutically acceptable salt thereof as described herein according to a dosing regimen comprising one or more cycles.In one such embodiment, the dosing regimen comprises 21 days or 28 days.

[0010] In another embodiment, KRas G12C Provided herein is a method of treating a mutation-mediated lung cancer in a patient having such cancer, comprising administering an effective amount of a combination therapy comprising GDC-6036, or a pharmaceutically acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more 21-day cycles, and an effective amount of inavolisib, or a pharmaceutically acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more 21-day cycles.

[0011] In another embodiment, KRas G12C Provided herein are methods of treating such cancers in patients with mutation-mediated solid tumors comprising administering an effective amount of a combination therapy comprising GDC-6036, or a pharmaceutically acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles, and an effective amount of inavolisib, or a pharmaceutically acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles.

[0012] In another embodiment, KRas G12CProvided herein is a method of treating a tissue-independent cancer in a patient having such a cancer, comprising: (i) determining the absence or presence of a KRasG12C mutation in a sample taken from the patient diagnosed with a suspected cancer; and (ii) if the patient sample contains a KRasG12C mutation, administering an effective amount of a combination therapy comprising: (a) GDC-6036, or a pharmaceutically acceptable salt thereof, administered QD according to a dosing regimen comprising one or more cycles as described herein; and (b) inavolisib, or a pharmaceutically acceptable salt thereof, administered QD according to a dosing regimen comprising one or more cycles as described herein.

[0013] In another aspect, provided herein is the use of a combination therapy comprising GDC-6036, or a pharmaceutically acceptable salt thereof, and inavolisib, or a pharmaceutically acceptable salt thereof, for treating lung cancer, CRC, or pancreatic cancer as described herein.

[0014] In another aspect, provided herein is the use of a combination therapy comprising GDC-6036, or a pharmaceutically acceptable salt thereof, and inavolisib, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating lung cancer, CRC, or pancreatic cancer.

[0015] In embodiments of the methods and uses described herein, administration of inavolisib (GDC-0077) does not require prior testing or assessment for the presence of one or more PI3KCA mutations. [Brief description of the drawings]

[0016] [Figure 1] Figure 1 shows the matched tumor volumes of treatment with GDC-6036 alone, GDC-0077 alone, or the combination of GDC-6036 and inavolisib. NCI-H2122 is less sensitive to KRAS-G12C inhibition, and the maximum effect is plateaued. GDC-6036 alone: ​​TGI=93%; GDC-0077 alone: ​​TGI=74%; combination: TGI=113%.

[0017] [Diagram 2] Figure 2 shows the change in body weight for administration of GDC-6036 alone, GDC-0077 alone, or the combination of GDC-6036 and inavolisib. All treatments were well tolerated.

[0018] [Diagram 3] Figures 3A-H show synergy plots of the combination of GDC-6036+GDC-0077 against various NSCLC KRas G12C mutant cell lines (Figure 3A=H23 P; Figure 3B=YSE410; Figure 3C=H1792; Figure 3D=H2122; Figure 3E=HOP62; Figure 3F=H2030; Figure 3G=HCC4017; Figure 3H=HCC4019).

[0019] [Figure 4] FIG. 4 shows matched tumor volumes upon treatment with GDC-6036 alone, GDC-0077 alone, or the combination of GDC-6036 and inavolisib in a CR5048 CRC xenograft model.

[0020] [Diagram 5] Figures 5A-C show synergy plots of the GDC-6036+GDC-0077 combination for various CRC KRas G12C mutant cell lines (Figure 5A=SW1463; Figure 5B=SW837; Figure 5C=HCC1263). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J.Wiley&Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989).In carrying out the present invention, any method, device and material similar or equivalent to those described herein can be used.

[0022] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0023] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percent of a component of a composition or dosage form, means a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent may be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0024] As used herein, "KRas G12C "inhibitor" refers to a covalent inhibitor that specifically binds to a mutant KRas protein containing a Gly to Cys mutation at the position corresponding to residue 12.

[0025] "GDC-6036" is a structure [ka] and refers to the compound having the chemical name 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. In one embodiment, GDC-6036 is an adipate salt.

[0026] Inavolisib, CAS Registry Number 2060571-02-8, Genentech, Inc., U.S. Patent No. 9,650,393; named (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-)yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, has the following structure: [ka] and refers to the compound having the chemical name (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide. Inavolisib is also known as GDC-0077, RG6114 or RO7113755.

[0027] Inavolisib is a potent, orally bioavailable, clinical-stage selective inhibitor of class I PI3K alpha isoform (PI3Kα) with >300-fold lower potency biochemical inhibition of other class I PI3K beta, delta, and gamma isoforms, and increased efficacy in tumor cells harboring mutant PI3K over wild-type (WT) PI3K cells (Braun, M. et al “Discovery of GDC-0077: A highly selective inhibitor of PI3K-alpha that induces degradation of mutant-p110 alpha protein” Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-22; Garland, K. et al “Discovery of novel class of alpha selective PI3K inhibitors” Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24,2017,MEDI-103;Hong,R.et al“GDC-0077 is a selective PI3K alpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies”2017 San Antonio Breast Cancer Symposium,Dec.5-9 2017,San Antonio,TX,Abstract Publication Number:PD4-14;Edgar,K.et al “Preclinical characterization of GDC-0077, a specific PI3K alpha inhibitor in early clinical development” Cancer Research 77(13 Supplement): Abstract 156·July 2017). .

[0028] GDC-0077 exerts its activity by binding to the ATP-binding site of PI3K, thereby inhibiting the phosphorylation of membrane-bound 4,5-phosphatidylinositol bisphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3). Inhibiting the phosphorylation of PIP2 to PIP3 reduces downstream activation of AKT and pS6, resulting in reduced cell proliferation, metabolism, and angiogenesis. Preclinical studies have demonstrated that GDC-0077 specifically degrades mutant p110alpha, inhibits proliferation and induces apoptosis in PIK3CA-mutant breast cancer cell lines, inhibits tumor growth in human breast cancer xenograft models harboring PIK3CA mutations, and reduces downstream PI3K pathway markers, including the phosphorylated form of protein kinase B (pAKT), PRAS40 phosphorylated at threonine 246 (pPRAS40), and S6RP phosphorylated at serine 235 / 236 (pS6RP).

[0029] The term "pharmaceutical acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other side reactions when properly administered to an animal, such as a human.

[0030] The compounds of the present invention may be in the form of salts, such as pharma- ceutically acceptable salts. "Pharmaceutically acceptable salts" includes both acid and base addition salts. By "pharmaceutically acceptable acid addition salts" is meant salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids which may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In one embodiment, the salt is formed with adipic acid.

[0031] "Pharmaceutically acceptable base addition salts" include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0032] In some embodiments, the salt is a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisilate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid), salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate), phthalenesulfonate), camsylate (camphor 10-sulfonate, e.g. (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0033] The terms "inhibit" and "reduce / diminish" or any variation of these terms include any measurable reduction / diminishment or complete inhibition to achieve a desired result. For example, there may be a decrease in activity compared to normal, of about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any of these range variables.

[0034] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one embodiment, the cancer is lung cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC). In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is colorectal cancer (e.g., metastatic CRC), breast cancer, or pancreatic cancer. As used herein, "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one embodiment, the cancer is lung cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC). In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is colorectal cancer (e.g., metastatic CRC), breast cancer, or pancreatic cancer. G12C This refers to cancer that is characterized by the presence of mutations.

[0035] As used herein, "treating" includes treatment with an effective amount of a therapeutic agent (e.g., GDC-6036 or inavolisib) or a combination of therapeutic agents (e.g., GDC-6036 or inavolisib). In one embodiment, treating refers to treatment with an effective amount of GDC-6036 or a pharma- ceutically acceptable salt thereof and inavolisib. Treatment can be a first-line treatment (e.g., the patient may not have been previously treated or has not received prior systemic therapy) or a second-line or subsequent treatment. For example, a patient is successfully "treated" if one or more symptoms associated with cancer as described herein are reduced or eliminated, including, but not limited to, reduced proliferation (or destruction) of cancerous cells, alleviation of symptoms attributable to the disease, improved quality of life for those suffering from the disease, reduced doses of other medications required to treat the disease, and / or increased survival of the patient.

[0036] The term "delay in progression" of disease refers to postpone, prevent, delay, retard, stabilize and / or postpone the onset of cancer as described herein. This delay can be of various lengths of time, depending on the cancer as described herein being treated and / or the medical history of the patient. As will be apparent to those skilled in the art, a sufficient or significant delay can actually encompass prevention, in that the patient does not develop cancer.

[0037] As used herein, "effective amount" refers to the amount of a therapeutic agent (e.g., GDC-6036 and / or inavolisib) described herein that achieves a therapeutic result. In some examples, an effective amount of a therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves the clinical endpoint provided herein. In one embodiment, the effective amount refers to the amount of GDC-6036 or a pharma- ceutically acceptable salt thereof and the amount of inavolisib. An effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to elicit a desired response in the patient. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. In some embodiments, an effective amount of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing or stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., slowing or stopping) tumor metastasis, inhibiting (i.e., slowing or stopping) tumor growth, and / or alleviating one or more of the symptoms associated with the disease. An effective amount can be administered in one or more administrations. An effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein can be an amount sufficient to effect therapeutic treatment directly or indirectly.

[0038] "Objective Response Rate" or "ORR" refers to the proportion of patients experiencing a confirmed complete or partial response on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1.

[0039] "Duration of response" or "DOR" refers to the time from the first occurrence of a documented objective response to the date of investigator-determined disease progression per RECIST v1.1, or death from any cause, whichever occurs first.

[0040] "Progression-free survival" or "PFS" refers to the time from enrollment to the occurrence of first documented disease progression or death from any cause, whichever occurs first, as determined by the investigator using RECIST v1.1.

[0041] As used herein, "complete response" and "CR" refer to the disappearance of all target lesions and normalization of tumor marker levels (if applicable).

[0042] As used herein, "partial response" and "PR" refer to the persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits (where applicable). PR may also refer to a ≥ 30% reduction in the sum of the diameters of target lesions in the absence of CR, new lesions, and definite progression in non-target lesions.

[0043] "Administration period" or "cycle" refers to a period that includes administration of one or more agents described herein (e.g., GDC-6036 and inavolisib) and any period that does not include administration of one or more agents described herein. For example, a cycle can be for a total of 21 days, including administration of one or more agents described herein (e.g., GDC-6036 and inavolisib) on each day of the cycle. In another example, a cycle can be for a total of 28 days, including administration of one or more agents described herein (e.g., GDC-6036 and inavolisib) for 21 days and a rest period of 7 days. A "rest period" refers to a period during which at least one of the agents described herein (i.e., GDC-6036 and inavolisib) is not administered. In one embodiment, a rest period refers to a period during which none of the agents described herein (i.e., GDC-6036 and inavolisib) is administered. The rest periods provided herein can optionally include administration of another agent that is not GDC-6036 and inavolisib. In such cases, administration of another drug during the rest period should not interfere with or be detrimental to administration of the drug described herein.In one example, as used herein, cycle refers to a 21-day cycle with no rest period.In another example, cycle can be 28 days in length and includes QD administration of one or more drugs described herein (e.g., GDC-6036 and inavolisib) for each day of the cycle.

[0044] "Dosing regimen" refers to a period of administration of an agent described herein, which may include one or more cycles, each cycle may include administration of an agent described herein at a different time or in a different amount.

[0045] "QD" refers to once daily administration of the agents described herein.

[0046] "BID" refers to administration of the agents described herein twice daily.

[0047] "PO" refers to oral administration of the agents described herein.

[0048] "IV" refers to intravenous administration of any agent described herein.

[0049] Graded adverse events refer to the severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table: [Table 1]

[0050] The term "patient" refers to a human patient. The patient may be an adult.

[0051] The term "package insert" is used to refer to instructions typically included in commercial packaging of a therapeutic product that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings for the use of such therapeutic product.

[0052] As used herein, "in combination with" refers to the administration of one therapy in addition to another therapy, for example, a treatment regimen that includes the administration of inavolisib and GDC-6036 or a pharma- ceutically acceptable salt thereof, as described herein. Thus, "in combination with" refers to the administration of one treatment modality before, during, or after the administration of another treatment modality to a patient.

[0053] A drug that is administered "concurrently" with one or more other drugs is administered on the same treatment day as the one or more other drugs, and optionally at the same time as the one or more other drugs, during the same treatment cycle. For example, in the case of a cancer treatment administered every three weeks, each of the concurrently administered drugs is administered on day 1 of a three-week cycle. Combination therapy

[0054] KRas as described herein G12C Provided herein are combination therapies (compositions) comprising an inhibitor (e.g., GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate)) and a PI3K inhibitor (e.g., inavolisib).

[0055] In one aspect, provided herein is a combination therapy comprising GDC-6036, or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), and inavolisib. In one embodiment, the combination therapy described herein is a combination therapy for treating KRas G12C It is useful in the treatment of certain solid tumors that contain the mutation.

[0056] In one embodiment, the combination therapy described herein inhibits KRas G12C In one such embodiment, the lung cancer is a KRas G12C Non-small cell lung cancer (NSCLC) containing the mutation.

[0057] In another embodiment, the combination therapy described herein inhibits KRas G12C It is useful for the treatment of other solid tumors that contain the mutation. In one embodiment, the solid tumor is colorectal cancer, pancreatic cancer, or breast cancer.

[0058] In one aspect, the present disclosure provides a combination therapy comprising GDC-6036 or its pharma- ceutically acceptable salt, which is administered QD according to a dosing regimen comprising one or more cycles, and inavolisib, which is administered QD according to a dosing regimen comprising one or more cycles.In such an embodiment, assessment is performed for the presence of KRasG12C mutation, and the combination therapy described herein is administered only if KRasG12C mutation is present.In such an embodiment, assessment is not performed for the presence of mutant PIK3CA.

[0059] In one embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 21-day cycles, and inavolisib or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, when the dosing regimen comprises one or more 21-day cycles, the dosing regimen comprises a rest period during which one or both of GDC-6036 and inavolisib are not administered. In such an embodiment, the combination therapy comprises a KRas inhibitor as described herein. G12C Useful for treating solid tumors that contain mutations (e.g., lung cancer). In one such embodiment, no assessment is made for the presence of mutant PIK3CA.

[0060] In another embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 28-day cycles, and inavolisib or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 28-day cycles. In such an embodiment, the combination therapy comprises a KRas G12C It is useful for treating solid tumors that contain a mutation (e.g., lung cancer). In one such embodiment, no assessment is made for the presence of mutant PIK3CA.

[0061] In one embodiment of the combination therapy described herein, GDC-6036 or a pharmaceutically acceptable salt thereof is administered as a fixed dose QD administration. In one embodiment, administration is oral (PO), and GDC-6036 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is formulated (and administered) as a film-coated tablet.

[0062] In one embodiment of the combination therapy described herein, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 25 mg, 25 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In one such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, or 400 mg. In one such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100-300 mg. In one such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 200 mg. In one such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 300-600 mg. In another such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 400 mg. In a preferred embodiment, GDC-6036 in the combination therapy described herein is administered as the adipate salt. In such an embodiment, the amount of GDC-6036 or a pharma- ceutically acceptable salt thereof is administered relative to the free base form.

[0063] The inclusion of one or more therapeutic agents in a combination therapy may alter the efficacy and dosage of each agent in the dosing regimen. Thus, in one embodiment, the amount of GDC-6036 or a pharma- ceutically acceptable salt thereof is administered as described herein at a lower starting dose for a full or partial cycle as described herein. In one embodiment, GDC-6036 may be administered at a lower dose for at least 1, 2, or 3 days before increasing the dose. In one such embodiment, the amount of GDC-6036 or a pharma- ceutically acceptable salt thereof is a starting dose of 200 mg. In another such embodiment, the amount of GDC-6036 or a pharma- ceutically acceptable salt thereof is a starting dose of 300 mg. In such an embodiment, the amount of GDC-6036 may be increased to a 50 or 100 mg amount (e.g., from a starting dose of 200 mg to a dose of 250 or 300 mg: from a dose of 300 mg to a dose of 400 mg). In one embodiment, the starting dose of GDC-6036 is 200 mg and the dose is increased to 400 mg.

[0064] In some embodiments, inavolisib is administered in an amount of 3, 6 or 9 mg, e.g., in one or more oral tablets. In some embodiments, inavolisib is administered orally in a daily dose of 9 mg. In some of these embodiments, inavolisib is administered in an amount of 9 mg in an oral tablet, in some embodiments, inavolisib is administered orally in a daily dose of 6 mg, e.g., in one or more oral tablets. In some of these embodiments, inavolisib is administered in an amount of 3 mg in an oral tablet,

[0065] In one embodiment, inavolisib is administered as a component of the combination therapy described herein in an amount of 6 mg QD in a dosing regimen that includes administration of each drug QD in a 21-day cycle. In another embodiment, inavolisib is administered as a component of the combination therapy described herein in an amount of 9 mg QD in a dosing regimen that includes administration of each drug QD in a 21-day cycle. In another embodiment, inavolisib is administered as a component of the combination therapy described herein in an amount of 3 mg QD in a dosing regimen that includes administration of each drug QD in a 21-day cycle. In such an embodiment, the amount of inavolisib administered is reduced from the starting dose to 6 mg or 3 mg as described herein.

[0066] In one embodiment, the amount of inavolisib is lower as a starting dose.In one such embodiment, the amount of inavolisib is 6 mg.In one such embodiment, the amount of inavolisib can be increased to 9 mg.

[0067] In one embodiment, the starting dose of GDC-6036 is 200 mg and the starting dose of inavolisib is 6 mg. In another embodiment, the starting dose of GDC-6036 is 400 mg and the starting dose of inavolisib is 6 mg. In yet another embodiment, the starting dose of GDC-6036 is 200 mg and the starting dose of inavolisib is 9 mg.

[0068] In one embodiment, the combination therapy described herein inhibits KRas G12CIt is used to treat lung cancers that contain mutations. In one such embodiment, the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) and inavolisib, both of which are administered according to a dosing regimen that comprises administration of each drug QD in a 21-day cycle. In another such embodiment, the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) and inavolisib, both of which are administered according to a dosing regimen that comprises administration of each drug QD in a 28-day cycle. In such an embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In one such embodiment, the lung cancer is adenocarcinoma, squamous cell lung cancer or large cell lung cancer. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0069] In another embodiment, KRas G12C A combination therapy useful for treating lung cancers that contain a mutation, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD according to a dosing regimen that includes one or more 21-day cycles, and inavolisib is administered QD according to a dosing regimen that includes one or more 21-day cycles. G12C The combination therapy useful for treating lung cancer comprising mutations includes GDC-6036 or its pharmaceutically acceptable salt (e.g., GDC-6036 adipate), GDC-6036 is administered QD according to a dosing regimen comprising one or more 28-day cycles, and inavolisib is administered QD according to a dosing regimen comprising one or more 28-day cycles.In a preferred embodiment, the lung cancer is NSCLC (e.g., metastatic NSCLC).

[0070] In yet another embodiment, KRas G12CCombination therapies useful for treating lung cancers comprising mutations, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD in an amount of about 50 mg to 500 mg according to a dosing regimen comprising one or more 21-day cycles, and inavolisib is administered QD in an amount of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, inavolisib is administered in an amount of 6 mg. In another embodiment, inavolisib is administered in an amount of 9 mg. In another embodiment, inavolisib is administered in an amount of 3 mg. In one embodiment, the lung cancer is NSCLC. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0071] In yet another embodiment, KRas G12C Combination therapies useful for treating lung cancers comprising mutations, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD in an amount of about 50 mg to 500 mg according to a dosing regimen comprising one or more 28-day cycles, and inavolisib is administered QD in an amount of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, inavolisib is administered in an amount of 6 mg. In another embodiment, inavolisib is administered in an amount of 9 mg. In another embodiment, inavolisib is administered in an amount of 3 mg. In one embodiment, the lung cancer is NSCLC. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0072] In yet another embodiment, KRas G12C The combination therapy described herein is useful for treating solid tumors that contain a mutation. In one particular embodiment, the combination therapy includes GDC-6036 or a pharma- ceutical acceptable salt thereof (e.g., GDC-6036 adipate) and inavolisib, and the combination therapy is a combination therapy that is useful for treating solid tumors that contain a mutation in KRas as described herein. G12CFor treating solid tumors containing mutations.In one such embodiment, the solid tumor is CRC, breast cancer, or pancreatic cancer.In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0073] In another embodiment, KRas G12C Combination therapies useful for treating the solid tumors described herein that contain mutations, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD in an amount described herein according to a dosing regimen comprising one or more 21-day cycles, and inavolisib is administered QD in an amount of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0074] In another embodiment, KRas G12C Combination therapies useful for treating the solid tumors described herein that contain mutations, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD in an amount described herein according to a dosing regimen comprising one or more 28-day cycles, and inavolisib is administered QD in an amount of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0075] In yet another embodiment, KRas G12C The combination therapy described herein is useful for treating tissue-independent cancers that contain a mutation. In one particular embodiment, the combination therapy includes GDC-6036 or a pharma- ceutical acceptable salt thereof (e.g., GDC-6036 adipate) and inavolisib, and the combination therapy includes a KRas mutation described herein. G12CIt is intended to treat tissue-independent cancers that contain mutations.

[0076] In another embodiment, KRas G12C Combination therapies useful for treating tissue-independent cancers comprising mutations, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD in an amount described herein according to a dosing regimen comprising one or more 21-day cycles, and inavolisib is administered QD in an amount of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0077] In another embodiment, KRas G12C Combination therapy useful for treating tissue-independent cancers comprising mutations, the combination therapy comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered QD in an amount described herein according to a dosing regimen comprising one or more 28-day cycles, and inavolisib is administered QD in an amount of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg.

[0078] Treatment In one embodiment, KRas G12C Provided herein is a method of treating a lung cancer in a patient having such a mutation-containing lung cancer, the method comprising administering to the patient an effective amount of a combination therapy comprising GDC-6036, or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate), and inavolisib.

[0079] In one embodiment provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In another embodiment of the method provided herein, the lung cancer is adenocarcinoma, squamous cell lung cancer or large cell lung cancer. In one such embodiment, the cancer is lung adenocarcinoma. In another such embodiment, the lung cancer is small cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0080] KRas G12C Also provided herein is a method (M1) of treating such cancer in a patient with NSCLC comprising a mutation, comprising administering to the patient an effective amount of a combination therapy described herein, comprising (i) a QD of GDC-6036 or a pharma- ceutically acceptable salt thereof, according to a dosing regimen comprising one or more 21-day cycles, and (ii) a QD of inavolisib, according to a dosing regimen comprising one or more 21-day cycles. In one embodiment of the method provided herein, the method is for treating adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In one such embodiment, the method is for treating first-line NSCLC.

[0081] KRas G12C Also provided herein is a method (M2) of treating such cancer in a patient with NSCLC comprising a mutation, comprising (i) administering to the patient an effective amount of a combination therapy described herein comprising GDC-6036 or a pharma- ceutically acceptable salt thereof QD according to a dosing regimen comprising one or more 28-day cycles, and (ii) administering inavolisib QD according to a dosing regimen comprising one or more 28-day cycles. In one embodiment of the method provided herein, the method is for treating adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In one such embodiment, the method is for treating first-line NSCLC.

[0082] Also, KRas G12C Also provided herein is a method of treating such cancers in patients with NSCLC containing a mutation (M3), comprising administering to the patient an effective amount of a combination therapy described herein comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of GDC-6036 or a pharma- ceutically acceptable salt thereof QD according to a dosing regimen comprising one or more 21-day cycles; and (ii) administering about 3 mg, 6 mg, or 9 mg of inavolisib QD according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, the dosing regimen includes a rest period during which one or both of GDC-6036 and / or inavolisib are not administered. In one embodiment, GDC-6036 is administered at 200 or 400 mg and inavolisib is administered at 6 or 9 mg.

[0083] Also, KRas G12C Also provided herein is a method of treating such cancers in patients with NSCLC comprising a mutation (M4), comprising administering to the patient an effective amount of a combination therapy described herein comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of GDC-6036 or a pharma- ceutically acceptable salt thereof QD according to a dosing regimen comprising one or more 28-day cycles; and (ii) administering about 3 mg, 6 mg, or 9 mg of inavolisib QD according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg and inavolisib is administered at 6 or 9 mg.

[0084] In embodiments M1-M4, the method can further include (a) determining the absence or presence of a KRasG12C mutation in a sample taken from a patient diagnosed with suspected cancer, and (b) administering to the patient an effective amount of GDC-6036, or a pharma- ceutical acceptable salt thereof, as described herein, and a combination therapy comprising inavolisib. In one such embodiment, the method further includes (c) not assessing for the presence of mutant PIK3CA prior to administration of inavolisib as described herein.

[0085] In another embodiment, KRas G12C Provided herein is a method (M5) for treating a solid tumor in a patient having such a solid tumor comprising a mutation, comprising administering to the patient a combination therapy comprising an effective amount of GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate) and inavolisib. In one such embodiment, the method comprises administering to the patient an effective amount of the combination therapy described herein, wherein (i) GDC-6036 or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 21-day cycles, and (ii) inavolisib or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, the dosing regimen comprises a rest period during which one or both of GDC-6036 and / or inavolisib are not administered. In one such embodiment, the rest period is 7 days.

[0086] In another embodiment, KRas G12CA method (M6) of treating a solid tumor comprising a mutation in a patient having such a solid tumor, comprising administering to the patient an effective amount of a combination therapy described herein, wherein (i) GDC-6036 or a pharmaceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 28-day cycles, and (ii) inavolisib or a pharmaceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 28-day cycles. In one embodiment of method M5 or M6 provided herein, the method comprises two or more cycles. In one such embodiment of method M5 or M6, GDC-6036 is administered in an amount of about 50 mg to 500 mg, and inavolisib is administered in an amount of 3 mg, 6 mg, or 9 mg. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of KRasG12C mutation, but is not evaluated for the presence of mutant PIK3CA before administering the combination therapy described herein.In one embodiment of the method M5 or M6 described herein, the solid tumor is colorectal cancer (CRC).In one such embodiment, the CRC is metastatic CRC (mCRC).

[0087] Further provided herein is a method (M7) of treating a tissue-independent cancer in a patient having such cancer, comprising: (i) determining the absence or presence of a KRasG12C mutation in a sample taken from a patient diagnosed with a suspected cancer; and (ii) administering an effective amount of a combination therapy comprising: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 21-day cycles; and (b) inavolisib or a pharmaceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, the patient sample is not evaluated for the presence of mutant PIK3CA prior to administration of inavolisib as described herein. In one such embodiment of method M7, the dosing regimen comprises a rest period during which one or both of GDC-6036 and / or inavolisib are not administered. In one such embodiment, the resting period is 7 days.

[0088] Further provided herein is a method (M8) for treating a tissue-independent cancer in a patient having such cancer, comprising: (i) determining the absence or presence of a KRasG12C mutation in a sample taken from a patient diagnosed with a suspected cancer; and (ii) if the patient sample contains a KRasG12C mutation, administering an effective amount of a combination therapy comprising: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 28-day cycles; and (b) inavolisib or a pharmaceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, the patient sample is not evaluated for the presence of mutant PIK3CA prior to administration of inavolisib as described herein.

[0089] In one embodiment of methods M7 and M8, the patient sample is further analyzed for the absence or presence of a PI3K mutation, such as those described herein.

[0090] In one embodiment of the methods described herein, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 300 mg, 5 mg to 500 mg, ...500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, 5 mg to 500 mg, In another embodiment, GDC-6036 or a pharmacologic acceptable salt thereof is administered in an amount of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 25 mg, 100 mg, 25 mg, 50 mg, 50 mg, 800 mg, 50 mg, 700 mg, 50 mg, 600 mg, 50 mg, 50 mg, 500 mg, 50 mg, 400 mg, 50 mg, 300 mg, 50 mg, 250 mg, 50 mg, 200 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In another embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, or 400 mg. In one embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered QD in an amount of 100 mg as described herein. In one embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered QD in an amount of 200 mg as described herein. In one embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered QD in an amount of 400 mg as described herein. In another embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100-300 mg. In another such embodiment, GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 300-600 mg. In a preferred embodiment, GDC-6036 in the combination therapy described herein is administered as the adipate salt.In such embodiments, the amount of GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered relative to the free base form.

[0091] In one embodiment, inavolisib is administered QD in an amount of 6 mg as described herein. In another embodiment, inavolisib is administered QD in an amount of 9 mg as described herein. In another embodiment, inavolisib is administered QD in an amount of 3 mg as described herein.

[0092] In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 200 mg according to the methods described herein, and inavolisib is administered in an amount of 6 mg according to the methods described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 400 mg according to the methods described herein, and inavolisib is administered in an amount of 6 mg according to the methods described herein.

[0093] In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 200 mg according to the methods described herein, and inavolisib is administered in an amount of 3 mg according to the methods described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 200 mg according to the methods described herein, and inavolisib is administered in an amount of 9 mg according to the methods described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 400 mg according to the methods described herein, and inavolisib is administered in an amount of 3 mg according to the methods described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 400 mg according to the methods described herein, and inavolisib is administered in an amount of 9 mg according to the methods described herein.

[0094] In certain cases, the amount of inavolisib administered may be adjusted from a starting dose of 6 mg to 9 mg. If a patient described herein is administered 6 mg of inavolisib as described herein and such administration is not tolerated, the amount of inavolisib administered to the patient may be reduced to 3 mg. Similarly, if a patient described herein is administered 9 mg of inavolisib as described herein and such administration is not tolerated, the amount of inavolisib administered to the patient may be reduced to 6 mg or 3 mg. As used herein, "tumor independent" refers to a tumor-specific inhibitor of KRas as described herein. G12C It refers to any solid tumor that has been tested for the presence of mutations.

[0095] The methods provided herein may include administration of a combination therapy described herein as part of a dosing regimen. In one such embodiment, the dosing regimen includes one or more cycles. In another embodiment, the dosing regimen includes at least two cycles. In another embodiment, the dosing regimen includes 2-3 cycles. In yet another embodiment, the dosing regimen includes at least 4, 6, 8, 10, or 12 cycles. In another aspect, the dosing regimen provided herein includes 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles. In yet another embodiment, the dosing regimen includes about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, 2-12, or 2-6 cycles. In one embodiment, the dosing regimen includes administration of the combination therapy described herein in any number of cycles until the desired response (e.g., PFS, OS, ORR, and / or DOR) reaches the desired outcome (e.g., PFS, OS, ORR, and / or DOR increased compared to a control described herein). In another embodiment, the dosing regimen includes administration of the combination therapy described herein in any number of cycles until toxicity occurs or the patient otherwise experiences one or more adverse events (AEs) that prevent further administration. In such an embodiment, the amount of agent (e.g., GDC-6036 or a pharmacologic acceptable salt thereof or inavolisib) administered can be adjusted to reduce or eliminate the AEs and allow for additional cycles in the dosing regimen. In yet another embodiment, the dosing regimen includes administration of the combination therapy described herein in any number of cycles until disease progression.

[0096] In some examples, the methods described herein include administration of one or more additional therapies, where the additional therapies are one or more side effect limiting agents (e.g., agents intended to reduce the occurrence and / or severity of side effects of the treatment, e.g., anti-nausea agents, corticosteroids (e.g., prednisone or equivalent, e.g., at a dose of 1-2 mg / kg / day), hormone replacement medication(s), etc.).

[0097] The patients provided herein must be evaluated and have a KRas G12C In one such embodiment, the patient has been treated with one or more prior therapies. G12C Patients described herein who test for a confirmed mutation must not have a known concomitant second oncogenic driver (e.g., for NSCLC: susceptibility EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; or for colon or rectal adenocarcinoma: BRAF V600E mutation, ERBB2 amplification). In one such embodiment, the patient has been treated with one or more prior therapies. In one embodiment, such second oncogenic drivers are determined using NGS (e.g., NGS assay by Foundation Medicine, Inc. (FMI)).

[0098] In one embodiment, the patient provided herein must be evaluated for KRas as described herein. G12C Must have confirmed test results for mutations and patients have not been evaluated for the presence of mutant PIK3CA with a mutation at one or more of positions 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047 and 1049 (e.g., H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88).

[0099] In one embodiment, the patient described herein has KRas G12C Prior treatment with specific inhibitors.

[0100] In another embodiment, the patient described herein has not been treated with chemotherapy within 3 weeks prior to administration of the combination therapy described herein, immunotherapy or biologic therapy as anti-cancer therapy, or endocrine therapy within 2 weeks prior to administration of the combination therapy described herein, with the exception of: (a) Hormone therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer), (b) a regulatory approved kinase inhibitor may be used up to 2 weeks prior to administration of the combination therapy described herein, provided that any drug-related toxicity has fully resolved; or (c) Treatment with an investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of a combination therapy described herein.

[0101] In another embodiment, the patient described herein has not received radiation therapy (other than palliative radiation for bone metastases and radiation for CNS metastases as described above) as cancer therapy within 4 weeks prior to initiating administration of the combination therapy described herein. In yet another embodiment, the patient described herein has not received palliative radiation for bone metastases within 2 weeks prior to initiating administration of the combination therapy described herein.

[0102] In another embodiment, the patient described herein does not have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on a screening chest computed tomography (CT) scan.

[0103] Further provided herein is the use of the combination therapy described herein comprising GDC-6036 or a pharmaceutically acceptable salt thereof and inavolisib for treating lung cancer as described herein (UL1).In one embodiment, the use of the combination therapy described herein comprising GDC-6036 or a pharmaceutically acceptable salt thereof and inavolisib for treating NSCLC as described herein (UL2).

[0104] Further provided herein is a use of a combination therapy for the treatment of lung cancer (UL3) as described herein, wherein the combination therapy comprises (i) GDC-6036 or a pharma- ceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 21-day cycles, and (ii) inavolisib administered QD according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, inavolisib is administered in an amount of about 6 mg. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but is not evaluated for the presence of a mutant PIK3CA prior to administration of the combination therapy as described herein.

[0105] Further provided herein is a use of a combination therapy for the treatment of lung cancer (UL4) as described herein, wherein the combination therapy comprises (i) GDC-6036 or a pharma- ceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 28-day cycles, and (ii) inavolisib administered QD according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, inavolisib is administered in an amount of about 6 mg. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but not for the presence of a mutant PIK3CA prior to administration of the combination therapy as described herein.

[0106] Further provided herein is a use of the combination therapy described herein for the treatment of lung cancer (UL5), wherein the combination therapy comprises (i) GDC-6036 or a pharma- ceutically acceptable salt thereof administered QD in an amount of about 50-500 mg according to a dosing regimen comprising one or more 21-day cycles, and (ii) inavolisib administered QD in an amount of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, the dosing regimen comprises two or more cycles described herein. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but evaluation for the presence of mutant PIK3CA is not performed prior to administration of the combination therapy described herein.

[0107] Further provided herein is a use of the combination therapy described herein for the treatment of lung cancer (UL6), wherein the combination therapy comprises (i) GDC-6036 or a pharma- ceutically acceptable salt thereof, administered QD in an amount of about 50-500 mg according to a dosing regimen comprising one or more 28-day cycles, and (ii) inavolisib administered QD in an amount of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, the dosing regimen comprises two or more cycles described herein. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutant, but is not evaluated for the presence of a mutant PIK3CA prior to administration of the combination therapy described herein.

[0108] Further provided herein is the use of a combination therapy described herein comprising GDC-6036, or a pharma- ceutically acceptable salt thereof, and inavolisib (UL7), for the manufacture of a medicament for the treatment of lung cancer as described herein.

[0109] Further provided herein is a use of a combination therapy as described herein for the manufacture of a medicament for the treatment of lung cancer as described herein (UL8), wherein the combination therapy comprises (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 21-day cycles, and (ii) inavolisib administered QD according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, inavolisib is administered in an amount of about 3 mg, 6 mg, or 9 mg. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but evaluation for the presence of a mutant PIK3CA is not performed prior to administration of the combination therapy as described herein.

[0110] Further provided herein is a use of a combination therapy as described herein for the manufacture of a medicament for the treatment of lung cancer as described herein (UL9), wherein the combination therapy comprises (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered QD according to a dosing regimen comprising one or more 28-day cycles, and (ii) inavolisib administered QD according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, inavolisib is administered in an amount of about 3 mg, 6 mg, or 9 mg. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but evaluation for the presence of a mutant PIK3CA is not performed prior to administration of the combination therapy as described herein.

[0111] In such an embodiment of the uses (UL1-UL8) described herein, the patient described herein is a patient with KRas G12C Diagnosed with mutation-mediated NSCLC.

[0112] Further provided herein is the use of a combination therapy described herein comprising GDC-6036, or a pharma- ceutically acceptable salt thereof, and inavolisib (UC1) for treating a solid tumor described herein.

[0113] Further provided herein is a use of the combination therapy described herein for the treatment of a solid tumor described herein (UC2), wherein the combination therapy comprises (i) GDC-6036 or a pharma- ceutically acceptable salt thereof administered QD in an amount of about 50-500 mg according to a dosing regimen comprising one or more 21-day cycles, and (ii) inavolisib administered QD in an amount of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but is not evaluated for the presence of a mutant PIK3CA prior to administration of the combination therapy described herein.

[0114] Further provided herein is a use of the combination therapy described herein for the treatment of a solid tumor described herein (UC3), wherein the combination therapy comprises (i) GDC-6036 or a pharma- ceutically acceptable salt thereof administered QD in an amount of about 50-500 mg according to a dosing regimen comprising one or more 28-day cycles, and (ii) inavolisib administered QD in an amount of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but is not evaluated for the presence of a mutant PIK3CA prior to administration of the combination therapy described herein.

[0115] In such embodiments of the uses UC1-UC3 described herein, the patient described herein is a patient with KRas G12C Diagnosed with mutation-mediated CRC.

[0116] Further provided herein is a use of the combination therapy described herein for the treatment of a tissue-independent cancer comprising a KRasG12C mutation (UA1), comprising administering an effective amount of a combination therapy comprising: (a) GDC-6036 or a pharma- ceutically acceptable salt thereof, administered QD in an amount of about 50-500 mg according to a dosing regimen comprising one or more 21-day cycles; and (b) inavolisib, administered QD in an amount of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In such an embodiment, GDC-6036 and inavolisib may be administered according to the uses and methods provided herein, as described herein. In one embodiment, GDC-6036 is administered at 200 or 400 mg and inavolisib is administered at 6 or 9 mg. In another embodiment, the patient is evaluated for the presence of a KRasG12C mutation, but is not evaluated for the presence of mutant PIK3CA prior to administration of the combination therapy described herein.

[0117] Further provided herein is a use of the combination therapy described herein for the treatment of a tissue-independent cancer comprising a KRasG12C mutation (UA2), comprising administering an effective amount of a combination therapy comprising: (a) GDC-6036 or a pharma- ceutically acceptable salt thereof administered QD in an amount of about 50-500 mg according to a dosing regimen comprising one or more 28-day cycles; and (b) inavolisib administered QD in an amount of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In such an embodiment, GDC-6036 and inavolisib may be administered according to the uses and methods provided herein as described herein. In one embodiment, the patient sample is not assessed for the presence of mutant PIK3CA prior to administration of the combination therapy described herein.

[0118] In one embodiment of the use UA1 and UA2, the patient sample is further analyzed for the absence or presence of a PI3K mutation, such as those described herein.

[0119] The development of combination treatments has challenges, including, for example, the selection of agents for combination therapy that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the incremental toxicity of the combination. In one embodiment of the method described herein, the combination therapy described herein (e.g., GDC-6036 or its pharma- ceutically acceptable salt and inavolisib) is administered in a dosing regimen that includes a staggered dosing schedule. In one such embodiment, the patient has a reduction in the number or grade of adverse events (AEs) compared to a control (e.g., SOC therapy, treatment with one agent described herein (e.g., GDC-6036 or inavolisib) alone).

[0120] In the event of an adverse event, it is generally understood that there are four options: (1) continue treatment as is with any concomitant therapy, (2) adjust the dose of one or more agents in the dosing regimen, (3) suspend administration of one or more agents in the dosing regimen, or (4) discontinue administration of one or more agents in the dosing regimen. In one embodiment, the amount of GDC-6036 administered is not changed. In another embodiment, the amount of inavolisib administered is not changed. In one embodiment, if administration of an agent described herein (e.g., GDC-6036 or a pharma- ceutically acceptable salt thereof or inavolisib) is interrupted, the next administration of the respective agent is administered on the same day that administration of GDC-6036 is resumed. In one embodiment, GDC-6036 or a pharma- ceutically acceptable salt thereof is administered without food (i.e., the patient should not eat at least 2 hours before and 1 hour after administration).

[0121] In one embodiment, the patient described herein experiences gastrointestinal toxicity as grade 2 or less AE. In such an embodiment, the gastrointestinal toxicity is diarrhea, nausea or vomiting. In another embodiment, the patient described herein experiences phototoxicity. In such an embodiment, the patient should wear sunscreen and protective clothing outdoors.

[0122] Patients as described herein may also be administered concomitant therapy, including: (a) anticonvulsants or warfarin, (b) oral contraceptives or other possible maintenance therapy, (c) antiemetics and antidiarrheal medications, provided that such medications should not be administered prophylactically prior to initial treatment with the study drug, (d) analgesics administered in accordance with standard clinical practice, (e) bisphosphonates and denosumab therapy for bone metastases or osteopenia / osteoporosis, or (f) multivitamins, calcium, and vitamins C, D, and E supplements.

[0123] Patients described herein may not be concurrently taking therapies containing: (1) strong / moderate CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or grapefruit supplements), (2) strong / moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone).

[0124] In another embodiment, the patient described herein is not administered a drug that reduces gastric acid production, such as a proton pump inhibitor or an H2 receptor antagonist.

[0125] In another embodiment, the patient described herein is not administered any of the following therapies: (a) 3 weeks or 5 half-lives, whichever is shorter, prior to administration of a combination therapy described herein, or any other investigational therapy (excluding GDC-6036 or inavolisib) during such treatment, (b) Concomitant therapies intended to treat cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biological therapy, herbal therapy, or hormonal therapy, other than the following: (i) Hormone therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (ii) hormone replacement therapy or oral contraception; (c) Radiation therapy for unequivocal progressive disease, excluding new brain metastases in the setting of a systemic response as follows: Patients who have demonstrated systemic disease control (defined as having received clinical benefit [i.e., PR, CR, or SD for ≥ 3 months]) but who develop brain metastases treatable with radiation will be allowed to continue to receive treatment with GDC-6036 on the study until they experience either systemic progression of disease and / or further progression in the brain (based on the investigator's assessment). (d) quinidine or other antiarrhythmic drugs, or (e) Initiation or dose increase of hematopoietic colony-stimulating factors (CSFs; e.g., granulocyte CSF, filgrastim, granulocyte / macrophage CSF, sargramostim, pegfilgrastim, erythropoietin, darbepoietin, and thrombopoietin) from 7 days prior to day 1 of the first cycle.

[0126] In one embodiment of such method, the patient is diagnosed with cancer as described herein. In another embodiment of such method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any of the therapeutic methods described herein. In another such embodiment, the sample is taken before administration of at least one agent as described herein. In some embodiments, tumor samples can be taken at designated intervals during treatment with the combination therapy as described herein to evaluate treatment.

[0127] If the tumor or cancer is KRas G12C Determining whether or not a mutation is present can be performed by evaluating the nucleotide sequence encoding the K-Ras protein, by evaluating the amino acid sequence of the K-Ras protein, or by evaluating the properties of a predicted K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., Accession No. NP203524) is known in the art. In one such embodiment, a sample from a patient as described herein is subjected to KRas analysis, e.g., using immunohistochemistry (IHC) or NGS sequencing. G12C Evaluate for mutations.

[0128] In one embodiment of the present invention provided herein, the patient is diagnosed with CR after treatment with the combination therapy according to the method provided herein.In one embodiment of the present invention provided herein, the patient is diagnosed with PR after treatment with the combination therapy according to the method provided herein.In one embodiment of the method provided herein, the patient is diagnosed with stable disease (SD) after treatment with the combination therapy according to the method provided herein.

[0129] Also provided herein is a method of inhibiting tumor growth or causing tumor regression in a patient as described herein by administering the combination therapy described herein.In one embodiment, provided herein is a method of inhibiting tumor growth in a patient with a cancer as described herein by administering a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and inavolisib in one or more cycles as described herein (e.g., 21-day or 28-day cycle).In one embodiment, provided herein is a method of inhibiting tumor growth in a patient with a cancer as described herein by administering a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and inavolisib in one or more cycles as described herein (e.g., 21-day or 28-day cycle).

[0130] In one embodiment, provided herein is a method of causing or improving tumor regression in a patient with a cancer described herein by administering a combination therapy comprising administering GDC-6036 or a pharmaceutically acceptable salt thereof and inavolisib in one or more cycles (e.g., a 21-day cycle or a 28-day cycle) as described herein. In one embodiment, provided herein is a method of causing or improving tumor regression in a patient with a NSCLC or CRC described herein by administering a combination therapy comprising administering GDC-6036 or a pharmaceutically acceptable salt thereof and inavolisib in one or more cycles (e.g., a 21-day cycle or a 28-day cycle) as described herein.

[0131] kit The combination therapy described herein may be provided as a kit containing one or more agents described herein for administration. In one embodiment, the kit contains GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) for administration in combination with inavolisib. In another embodiment, the kit contains GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) packaged together with inavolisib, and the kit contains separate formulated dosages of each agent.

[0132] Also provided herein is an article of manufacture or kit comprising GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate) and inavolisib. In some examples, the article of manufacture further comprises one or more package inserts comprising instructions for using the agents described herein to treat or delay the progression of a solid tumor (e.g., lung cancer or CRC). In one such embodiment, the cancer is NSCLC.

[0133] In some cases, inavolisib and GDC-6036 or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate) are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The containers can be formed from a variety of materials, such as glass, plastic (e.g., polyvinyl chloride or polyolefin), or metal alloys (e.g., stainless steel or Hastelloy). In some examples, the container holds the formulation, and a label on or associated with the container can indicate instructions for use. The article of manufacture or kit can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some examples, the article of manufacture further includes one or more additional agents (e.g., additional chemotherapeutic or anti-neoplastic agents). Suitable containers for one or more agents include, for example, bottles, vials, bags, and syringes.

[0134] Any article of manufacture or kit described herein may include instructions for administering GDC-6036, or a pharma- ceutically acceptable salt thereof (e.g., GDC-6036 adipate) and / or inavolisib to a patient according to any of the methods described herein.

[0135] Biomarkers In one embodiment, the patient described herein must be evaluated for and have a confirmed KRasG12C mutation prior to administration of the combination therapy described herein. In one such embodiment, no evaluation for the presence of mutant PIK3CA is performed prior to administration of the combination therapy as described herein.

[0136] In one embodiment, the inhibition of KRas by GDC-6036 or a pharma- ceutically acceptable salt thereof is G12C In one such embodiment, the alkylation of KRas is measured in the patient. G12C In another embodiment, ctDNA biomarkers (e.g., KRas G12C ) is evaluated.

[0137] In one embodiment, modulation of KRAS / MAPK target genes (e.g., DUSP6, SPRY4), pathway components (e.g., pERK, pS6) and associated biomarkers (e.g., Ki67) is performed by analysis of paired pre- and on-treatment fresh tumor biopsies.

[0138] Inavolisib is a selective inhibitor of class I PI3Kα isoform (p110α). Without being bound to any particular theory, by inhibiting the phosphorylation of PIP2 to PIP3, inavolisib reduces downstream activation of pathway effectors including AKT, PRAS40 and S6RP, which may serve as PD biomarkers for treatment with GDC-6036 and inavolisib.

[0139] Embodiment Several exemplary embodiments of the present invention are provided below.

[0140] Embodiment 1. A combination therapy comprising: (a) GDC-6036, or a pharma- ceutically acceptable salt thereof, as described herein; (b) inavolisib, or a pharma- ceutical acceptable salt thereof, as described herein.

[0141] Embodiment 2. The combination therapy of embodiment 1, wherein GDC-6036 is its adipic acid salt.

[0142] Embodiment 3. The combination therapy of embodiment 1 or 2, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered QD according to a dosing regimen comprising one or more cycles.

[0143] Embodiment 4. The combination therapy of embodiment 3, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered QD on days 1-21 of a dosing regimen comprising one or more 21-day cycles, and wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered orally as a tablet or capsule.

[0144] Embodiment 5. The combination therapy of embodiment 3, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered QD according to a dosing regimen comprising one or more 28-day cycles, and wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered orally as a tablet or capsule.

[0145] Embodiment 6. The combination therapy of any one of embodiments 1-5, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 50 mg to 500 mg.

[0146] Embodiment 7. The combination therapy of any one of embodiments 1-6, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

[0147] Embodiment 8. The combination therapy of any one of embodiments 1-6, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 100 mg, 200 mg, or 400 mg.

[0148] Embodiment 9. The combination therapy of any one of embodiments 1-6, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 200 mg.

[0149] Embodiment 10. The combination therapy of any one of embodiments 1-6, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 400 mg.

[0150] Embodiment 11. The combination therapy of any one of embodiments 1-10, wherein inavolisib or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more cycles.

[0151] Embodiment 12. The combination therapy of embodiment 11, wherein inavolisib, or a pharma- ceutically acceptable salt thereof, is administered QD on days 1-21 of a dosing regimen comprising one or more 21-day cycles.

[0152] Embodiment 13. The combination therapy of any one of embodiments 1-12, wherein inavolisib or a pharma- ceutically acceptable salt thereof is administered QD according to a dosing regimen comprising one or more 28-day cycles.

[0153] Embodiment 14. The combination therapy of any one of embodiments 1-13, wherein the dosing regimen includes a rest period during which one or both of GDC-6036 and inavolisib are not administered.

[0154] Embodiment 15. The combination therapy of any one of embodiments 1-14, wherein inavolisib is administered in an amount of about 3, 6, or 9 mg.

[0155] Embodiment 16. The combination therapy of any one of embodiments 1 to 15, wherein inavolisib is administered in an amount of 6 mg.

[0156] Embodiment 17. The combination therapy of any one of embodiments 1 to 15, wherein inavolisib is administered in an amount of 9 mg.

[0157] Embodiment 18. KRas G12C 18. The combination therapy of any one of embodiments 1 to 17 for use in the treatment of lung cancer comprising a mutation.

[0158] Embodiment 19. The combination therapy of embodiment 18, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0159] Embodiment 20. KRas G12C The combination therapy according to any one of embodiments 1 to 17 for use in the treatment of mutation-containing colorectal cancer (CRC).

[0160] Embodiment 21. The combination therapy of any one of embodiments 1 to 20, wherein the patient is assessed for the presence of a KRasG12C mutation prior to administration.

[0161] Embodiment 22. The combination therapy of any one of embodiments 1 to 21, wherein assessment of the presence of mutant PIK3CA is not performed prior to administration.

[0162] 23. KRas G12C 1. A method of treating a mutation-mediated lung cancer in a patient having such lung cancer, the method comprising: (a) GDC-6036, or a pharma- ceutical acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles; (b) administering an effective amount of a combination therapy comprising inavolisib, or a pharma- ceutical acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles.

[0163] Embodiment 24 The method of embodiment 23, wherein the lung cancer is NSCLC.

[0164] Embodiment 25. The method of embodiment 23 or 24, wherein the lung cancer is adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma.

[0165] Embodiment 26. A method of treating such cancer in a patient having a solid tumor comprising a KRasG12C mutation, the method comprising: (a) GDC-6036, or a pharma- ceutical acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles; (b) administering an effective amount of a combination therapy comprising inavolisib, or a pharma- ceutical acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles.

[0166] Embodiment 27. The method of embodiment 26, wherein the solid tumor is colorectal cancer (CRC).

[0167] 28. (a) determining the absence or presence of a KRasG12C mutation in a sample obtained from a patient diagnosed with a suspected cancer; (b) administering to the patient a combination therapy described herein comprising an effective amount of GDC-6036, or a pharma- ceutical acceptable salt thereof, and inavolisib.

[0168] Embodiment 29. A method of treating a tissue-independent cancer comprising a KRasG12C mutation in a patient having such a cancer, said method comprising: (i) determining the absence or presence of a KRasG12C mutation in a sample obtained from a patient diagnosed with a suspected cancer; (ii) if the patient sample contains a KRasG12C mutation, (a) GDC-6036, or a pharma- ceutical acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles; (b) administering an effective amount of a combination therapy comprising inavolisib, or a pharma- ceutical acceptable salt thereof, as described herein, administered QD according to a dosing regimen comprising one or more cycles.

[0169] Embodiment 30. The method of any one of embodiments 23-29, wherein the dosing regimen includes one or more additional 21-day cycles.

[0170] Embodiment 31. The method of embodiment 30, wherein the dosing regimen includes a rest period during which one or both of GDC-6036 and inavolisib are not administered.

[0171] Embodiment 32. The method of any one of embodiments 23-29, wherein the dosing regimen includes one or more additional 28-day cycles.

[0172] Embodiment 33. A combination therapy according to any one of embodiments 23 to 32, wherein GDC-6036 is its adipic acid salt.

[0173] Embodiment 34. The method of any one of embodiments 23-33, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered orally as a tablet or capsule.

[0174] Embodiment 35. The method of any one of embodiments 23-34, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 50 mg to 500 mg.

[0175] Embodiment 36. The method of any one of embodiments 23-35, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

[0176] Embodiment 37. The method of any one of embodiments 23-36, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 100 mg, 200 mg, or 400 mg.

[0177] Embodiment 38. The method of any one of embodiments 23-37, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 200 mg.

[0178] Embodiment 39. The method of any one of embodiments 23-37, wherein GDC-6036, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 400 mg.

[0179] Embodiment 40. The method of any one of embodiments 23-39, wherein inavolisib is administered in an amount of about 3 mg, 6 mg, or 9 mg.

[0180] Embodiment 41. The method of any one of embodiments 23-40, wherein inavolisib is administered in an amount of 6 mg.

[0181] Embodiment 42. The method of any one of embodiments 23 to 40, wherein inavolisib is administered in an amount of 9 mg.

[0182] Embodiment 43 The method of any one of embodiments 23 to 42, wherein the patient is not assessed for the presence of mutant PIK3CA prior to administration.

[0183] Embodiment 44. Use of a combination therapy comprising GDC-6036, or a pharma- ceutically acceptable salt thereof, and inavolisib, or a pharma- ceutically acceptable salt thereof, for treating lung cancer, CRC or pancreatic cancer as described herein.

[0184] Embodiment 45. The use of embodiment 44, wherein the cancer is lung cancer or CRC, and further comprising a dosing regimen comprising: (i) QD administration of GDC-6036 or a pharmaceutically acceptable salt thereof according to a dosing regimen comprising one or more cycles; and (ii) QD administration of inavolisib according to said dosing regimen comprising one or more cycles.

[0185] Embodiment 46. Use of a combination therapy comprising GDC-6036, or a pharma- ceutically acceptable salt thereof, and inavolisib, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating lung cancer, CRC, or pancreatic cancer.

[0186] Embodiment 47. The use of embodiment 46, wherein the cancer is lung cancer or CRC, and further comprising a dosing regimen comprising: (i) QD administration of GDC-6036 or a pharmaceutically acceptable salt thereof according to a dosing regimen comprising one or more cycles; and (ii) QD administration of inavolisib according to said dosing regimen comprising one or more cycles.

[0187] Embodiment 48. The use of embodiment 46, wherein the cancer is CRC and further comprising a dosing regimen comprising: (i) administering GDC-6036, or a pharma- ceutically acceptable salt thereof, QD according to a dosing regimen comprising one or more 21-day cycles; and (ii) administering inavolisib according to a dosing regimen comprising one or more 21-day cycles.

[0188] Embodiment 49. The use of any one of embodiments 44 to 48, wherein the dosing regimen includes one or more additional 21-day cycles.

[0189] Embodiment 50. The use of any one of embodiments 44 to 48, wherein the dosing regimen includes one or more additional 28-day cycles.

[0190] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0191] Example 1: Combination of GDC-6036 and Inavolisib

[0192] The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a GTPase that plays a central role in mediating cell proliferation and survival signaling. Mutations in KRAS resulting in amino acid substitutions at glycine 12 (G12), glycine 13 (G13), and glutamine 61 (Q61) are common in tumors and are associated with tumorigenesis and the maintenance of invasive tumor growth (Der et al. Nature 1983;304(5926):507-13; Parada et al. Nature 1982;297(5866):474-8; Santos et al. Nature 1982;298(5872):343-7; Taparowsky et al. Nature 1982;300(5894):762-5; Capon et al. Nature 1983;304(5926):507-13). KRAS G12C Mutations are common in non-small cell lung cancer (NSCLC), colorectal cancer, and other tumor types (Prior et al. Cancer Res 2012;72(10):2457-67; Vogelestein et al. Science 2013;339(6127):1546-58).

[0193] GDC-6036 is a KRAS G12C Selectively targets KRAS G12C GDC-6036 is an oral anti-cancer therapeutic that covalently and irreversibly inhibits KRAS. GDC-6036 does not target KRAS, wild-type forms of KRAS, or other mutations in other members of the RAS family. G12C Treatment of positive cells or tumors results in a decrease in KRAS pathway signaling, inhibition of cell / tumor cell proliferation, and induction of apoptosis.

[0194] The in vivo antitumor efficacy of GDC-6036 (50 mg / kg, PO, QD) alone or in combination with GDC-0077 (25 mg / kg, PO, QD) was evaluated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenograft tumor models harboring the KRasG12C mutation. Single-agent GDC-6036 treatment resulted in near tumor stasis (93% tumor growth inhibition [TGI]), whereas treatment with GDC-0077 resulted in tumor growth inhibition (74% TGI). Improved antitumor efficacy was observed with the combination of GDC-6036 and inavolisib (113% TGI).

[0195] Mice: Nine to ten week old female nude mice with an average weight of 24.5 g were obtained from Charles River Laboratory (Hollister, CA). Mice were housed in standard rodent microisolator cages from Genentech and acclimated to study conditions for at least 3 days prior to tumor cell implantation. Only animals that appeared healthy and had no obvious abnormalities were used in the study.

[0196] Study human non-small lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, MD), which harbored a G12C oncogenic mutation in K-RAS. Cells were cultured in vitro, harvested at logarithmic growth phase, and resuspended in Hanks' balanced salt solution containing Matrigel (BD Biosciences; San Jose, CA) at a 1:1 ratio. Cells were then implanted subcutaneously in the right thorax of 160 nude mice. Each mouse received 10x10 cells in a volume of 100 μL. 6 cells were injected. Tumors were monitored until they reached a mean tumor volume of 150-290 mm3. Mice were distributed into 10 groups based on tumor volume, with n=10 mice per group. The mean tumor volume across all groups was 213 mm3 at the start of treatment. 3 It was.

[0197] Mice were administered vehicle (150 μL of 0.5% MC and 100 μL of 0.5% MCT), 50 mg / kg of GDC-6036 (expressed as free base equivalent) or 25 mg / kg of GDC-0077 (expressed as free base equivalent) or a combination of GDC-6036 and inavolisib. All treatments were administered orally (PO) once daily (QD) by oral gavage for 21 days. The study design is summarized in Table 1.

[0198] [Table 2]

[0199] Tumor and body weight measurements. Tumor volumes were measured in two dimensions (length and width) using Ultra Cal-IV calipers (model 54-10-111; Fred V. Fowler Co.; Newton, Massachusetts) and analyzed using Excel, version 14.2.5 (Microsoft Corporation; Redmond, Wash.). Tumor volumes were calculated using the following formula: Tumor size (mm 3 ) = (longer measurement x shorter measurement 2 )×0.5

[0200] Antitumor responses were observed, with partial response (PR) defined as a >50% reduction from the initial tumor volume and complete response (CR) defined as a 100% reduction in tumor volume. Animal body weights were measured using an Adventura Pro AV812 scale (Ohaus Corporation; Pine Brook, NJ). Percent weight change was calculated using the following formula: Weight change (%) = [(current weight / initial weight)-1) × 100].

[0201] Tumor growth analysis. Generalized additive mixed models (GAMMs) were used to analyze transformed tumor volumes over time, as this approach addresses both repeated measurements from the same subject and moderate dropout before termination. Because tumors generally exhibit exponential growth, tumor volumes were subjected to natural log transformation before analysis. Changes in tumor volume over time in each group are described by fits (i.e., regression splines with an automatically generated three-spline basis) generated using customized functions in R version 3.4.2 (2017-09-28) (R Development Core Team 2008; R Foundation for Statistical Computing; Vienna, Austria), which integrates software from several open-source packages, including ime4, mgcv, gamm4, multcomp, setting, plyr, and tidyverse, e.g., magrittr, dplyr, tidyr, and ggplot2.

[0202] Body weight analysis. A generalized additive mixed model (GAMM) was also used to analyze live weight (i.e., grams) over time. After data fitting, live weight data at each time point from all individual animals and all group fits were normalized and replotted separately in two different ways: 1) normalized to starting weight and reported as a percentage resulting in % body weight change; 2) normalized to maximum weight to date and reported as a percentage resulting in % body weight loss.

[0203] Results. Efficacy and Body Weight NCI-H2122 Xenografts. Antitumor efficacy was evaluated in nude mice bearing human NCI-H2122 NSCLC xenografts following treatment with GDC-6036 (50 mg / kg, PO, QD) alone, single agent GDC-0077 (25 mg / kg, PO, QD) or the doublet combination of GDC-6036 and GDC-0077. Single agent treatments resulted in tumor growth inhibition (TGI), with GDC-6036 resulting in a TGI of 93% versus vehicle control and GDC-0077 resulting in a TGI of 74% (Figure 1 and Tables 2, 3). Antitumor improvement was observed with the combination of GDC-6036 and inavolisib, resulting in a TGI of 113% and 2 / 10 PRs (Figure 1). All treatments were well tolerated as determined by percent body weight change (Figure 2 and Table 2).

[0204] [Table 3]

[0205] The combination of GDC-6036 and inavolisib was further tested in various other NSCLC cell lines harboring the KRasG12C mutation, including H23 P, KYSE410, H1792, H2030, HCC4017, HCC4019 and HOP62. Synergistic effects were observed at concentrations as low as 40 nM in certain cell lines (Figures 3A-H).

[0206] The combination of GDC-6036 and inavolisib was further tested in various CRC cell lines harboring the KRasG12C mutation. The addition of GDC-0077 to GDC-6036 further suppressed cell proliferation, even in the most resistant line (SW1436). See Figure 5A-C. A synergistic effect of the combination of GDC-6036 and GDC-0077 was observed in the CR5048 patient-derived xenograft model (Figure 4 and Table 3).

[0207] [Table 4]

[0208] Combination antitumor efficacy studies conducted in various human NSCLC and CRC xenograft tumor models, as well as cell lines harboring the KRas G12C mutation, demonstrated that the KRAS-G12C inhibitor, GDC-6036, suppressed tumor growth as a single agent. These data demonstrate that the combination of GDC-6036 with GDC-0077 resulted in improved antitumor activity compared to the single-agent observations resulting in partial tumor regression in human NSCLC and CRC xenograft tumor models.

[0209] Example 2: KRAS is the most frequently mutated oncogene in up to 25% of cancers and is associated with resistance to select standard treatments and poor overall prognosis. Although selective inhibitors have been developed as anti-cancer therapies targeting other nodes in the RAS / MAPK pathway, the KRAS oncoprotein was thought to be undruggable until the recent discovery of the switch II pocket (Ostrem, et al. Nature 2013;503:548-51). This knowledge has led to the discovery of a novel inhibitor of KRAS, specifically KRAS G12C Covalent small molecule inhibitors aimed at targeting mutations are being evaluated in early clinical development.

[0210] Other KRAS G12C Inhibitor: AMG 510 (sotorasib) is a KRAS G12CAMG 510 is a small molecule that irreversibly inhibits EGFR by locking it in its inactive GDP-bound state. AMG 510 is currently being investigated in ongoing clinical studies. Patients in these studies received a median of 3 (range 0-11) prior lines of anticancer therapy for metastatic disease prior to study entry. Overall, treatment-related adverse events were reported in 56.6% of patients, with 11.6% of patients experiencing treatment-related grade 3 or 4 events and 1.6% of patients experiencing treatment-related serious adverse events. Grade 3 events occurring in multiple patients included ALT increase, diarrhea, anemia, AST increase, and alkaline phosphatase increase. One patient experienced a grade 4 treatment-related ALT increase and one patient discontinued AMG 510 due to grade 3 treatment-related increases in ALT and AST. Although antitumor activity has been reported, there are adverse events associated with AMG-510. Patients had confirmed objective responses in 32.2% of patients with NSCLC, with a median response duration of 10.9 months (range 1.1+ to 13.6) in patients with NSCLC. Median PFS was reported to be 6.3 months (range 0.0+ to 14.9+) in patients with NSCLC (Hong et al. New Eng J Med 2020;383:1207-17).

[0211] MRTX849 is a KRAS G12C Mutant-selective small molecule being evaluated in clinical studies in patients with advanced solid tumors harboring KRAS mutations G12Cinhibitors. Recently, data from a total of 17 patients (including 10 with NSCLC and 4 with CRC) were reported, of which 12 patients had at least one on-treatment tumor evaluation (including 6 with NSCLC and 4 with CRC). Most patients had received ≥3 prior anticancer regimens prior to study entry (12 of 17 patients, 71%). The following treatment-related adverse events were reported in >10% of patients: diarrhea, nausea, increased AST, vomiting, fatigue, increased ALT, increased creatinine, abdominal distension, abdominal pain, increased ALP, anemia, anorexia, dehydration, dry mouth, dysgeusia, dyspnea, QT prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, anorexia, and dyspnea (1 patient each). Antitumor activity with PR was achieved in 3 of 6 patients with NSCLC and 1 of 4 patients with CRC across all dose levels evaluated (Janne et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 2019).

[0212] GDC-6036.KRAS G12C The specificity of GDC-6036 against KRAS, along with its mechanism of action, G12C These compounds are expected to result in potent and irreversible inhibition of KRAS, allowing for a broad therapeutic index that maximizes antitumor activity while minimizing treatment-related toxicity. G12C Specific therapy aimed at KRAS positive cancers G12C This could provide a more tolerable and effective treatment option for patients with advanced stage cancer.

[0213] In vitro and in vivo pharmacology studies demonstrated that GDC-6036 inhibits KRAS G12C It is a highly potent and selective covalent inhibitor of KRAS G12C than KRAS-negative cancer cell lines G12CMechanism of action studies with GDC-6036 have demonstrated that in addition to KRAS target genes such as DUSP6 and SPRY4, downstream MAPK pathway components such as phosphorylated (p)ERK and pS6 are inhibited, resulting in the inhibition of KRAS. G12C We demonstrate that GDC-6036 has potent single-agent activity and induces apoptosis in KRAS-positive cancer cell lines. G12C Inhibits tumor growth in several preclinical xenograft models of KRAS-positive lung tumors. These in vitro and in vivo pharmacological studies demonstrate that G12C The present invention supports the use of GDC-6036 for the treatment of patients with positive solid tumors.

[0214] The results of the nonclinical toxicology studies completed to date provide a robust characterization of the toxicity profile of GDC-6036 and support the dosing of GDC-6036 in patients with cancer. Comprehensive nonclinical toxicology studies have been completed to evaluate the potential single and repeated dose oral toxicity, genotoxicity, phototoxicity and safety pharmacology of GDC-6036. G12C The KRAS mutation is not present in healthy animals. G12C There are no pharmacologically relevant nonclinical species for inhibition.

[0215] Initial Phase I clinical data from ongoing studies of AMG 510 and MRTX849 as single agents are G12C Inhibitors have been shown to be tolerable and have promising antitumor activity in patients with metastatic NSCLC and CRC (Janne et al. 2019; Hong et al. New Eng J Med 2020; 383: 1207-17). However, there remains a significant unmet need to use this class of inhibitors as single agents to improve the reported antitumor activity and durability in NSCLC and CRC, while, more importantly, retaining their tolerable safety profile.

[0216] Rationale for Combination Therapy. Based on the mechanistic understanding of the RTK-RAS-MAPK pathway, it is hypothesized that RAS / MAPK and PI3K / AKT are intricately interconnected signaling pathways that are frequently deregulated in human cancers. These two pathways not only share common upstream signaling inputs but can play compensatory roles when one or the other is inhibited by targeted therapy. Recent studies have also identified the emergence of genetic alterations in key PI3K pathway components (including PIK3CA and PTEN) when tumors develop resistance to KRAS G12C inhibitors in the clinic (Awad et al. 2021; Zhao et al. 2021), indicating that activation of the PI3K signaling pathway may act as a mechanism of resistance to KRAS G12C inhibitors. As a result, simultaneous blockade of both the RAS / MAPK and PI3K / AKT pathways may be required to maximize clinical benefit. The combination of GDC 6036, a highly mutant selective KRAS G12C inhibitor, and inavolisib, a PI3K alpha isoform selective inhibitor, may offer a better therapeutic window based on the single agent safety profile and selectivity for oncogenic targets.

[0217] Multiple preclinical studies have shown that combining KRAS G12C inhibitors with PI3K inhibitors exhibits extensive synergistic effects across multiple in vitro and in vivo models, most of which are not accompanied by deregulated changes in PI3K pathway components (Misale et al. 2015; Canon et al. 2019; Lou et al. 2019). Mechanistically, the combination of KRAS G12C inhibitors with PI3K inhibitors can simultaneously downregulate both phosphorylated-AKT and phosphorylated-S6RP, resulting in more robust induction of cell death and inhibition of proliferation compared to KRAS G12C inhibitors alone (Misale et al. 2018). Consistent with these findings, preclinical data combining GDC-6036 with inavolisib (Example 1) also demonstrated synergistic effects with greater tumor reduction in KRAS G12C-positive cell lines and multiple xenograft mouse models compared to the use of either treatment alone.

[0218] The starting dose of inavolisib in combination with GDC-6036 is 6mg PO QD for each 21-day cycle. The combination of GDC-6036 and inavolisib is expected to have acceptable tolerability. Potential overlapping toxicities include GI toxicity and oral mucosal irritation, which are expected to be monitorable and manageable with supportive care and potential dose modifications.

[0219] Patients will have locally advanced, recurrent or metastatic incurable solid tumors with KRAS G12C mutations and have progressed after at least one available standard of care therapy, or for whom standard of care therapy has proven ineffective or intolerable or is considered inappropriate, or for whom an investigational agent is an accepted standard of care. Additionally, patients may have received prior KRAS G12C inhibitor therapy.

[0220] Biomarkers. This study aims to identify biomarkers that predict response to GDC-6036 as a single agent or in combination with a PI3K inhibitor (i.e., predictive biomarkers), early surrogates of activity, associated with progression to a more severe disease state (i.e., prognostic biomarkers), and KRAS G12C Identify and / or evaluate biomarkers that are related to acquired resistance to inhibitors (e.g., GDC-6036), related to susceptibility to the occurrence of adverse events, or that may result in improved adverse event monitoring or surveillance (i.e., safety biomarkers), that may provide evidence of activity of GDC-6036 in combination with inavolisib (i.e., pharmacodynamic [PD] biomarkers), or that may increase knowledge and understanding of disease biology and drug safety. Corresponding biomarker endpoints include relationships between exploratory biomarkers in blood, plasma, and tumor tissue and safety, PK, activity, or other biomarker endpoints.

[0221] Patients will be screened for a period of up to 28 days, followed by a treatment period and a safety follow-up period in which patients will be followed for safety outcomes for treatment-specific periods after their last dose of study drug or until they receive another anti-cancer therapy, whichever occurs first.

[0222] In the absence of unacceptable toxicity and overt disease progression as determined by the investigator, patients may continue treatment with GDC-6036 until the end of the study.

[0223] All patients will be closely monitored for adverse events throughout the study and for treatment-specific periods after the last dose of study treatment or until the start of another anticancer therapy, whichever occurs first. Adverse events will be graded according to NCI CTCAE v5.0.

[0224] Inavolisib is a selective inhibitor of class I PI3Kα isoform (p110α). By inhibiting phosphorylation of PIP2 to PIP3, inavolisib reduces downstream activation of pathway effectors including AKT, PRAS40 and S6RP, which may serve as PD biomarkers for treatment with GDC-6036 and inavolisib.

[0225] KRas from tissue and circulating tumor DNA assessment G12C Approximately 12% of NSCLCs, 4% of CRCs, 2% of pancreatic cancers, and many other solid tumors (each with a prevalence of ≤4%) harbor KRas G12C GDC-6036 is a KRas G12C It is a potent and highly selective inhibitor that targets KRAS, but not the wild-type form of KRAS, or other mutations in other members of the RAS family. G12C Only patients with tumors that harbor mutations are eligible to receive the combination therapy described herein. KRAS mutation status may be determined using the FoundationOne™ CDx (F1CDx) assay, a U.S. Food and Drug Administration (FDA)-approved broad companion diagnostic (CDx) assay, the FoundationOne™ Liquid CDx (F1L CDx) assay, as well as other FDA-approved (FDA 2020) or fully validated laboratory-developed tests performed in a Clinical Laboratory Improvement Amendments (CLIA)-validated or equivalently certified laboratory. Previous studies have demonstrated that KRas G12C The emergence of the mutation was shown to be an early event (Jamal-Hanjani et al. N Engl J Med 2017;376:2109-21), and analysis of archival tissues demonstrated a KRas mutation suppression effect for GDC-6036 treatment. G12C This suggests that it is a sufficient surrogate for selection of patients with positive tumors.

[0226] Pharmacodynamic pathway modulation. GDC-6036 inhibits KRas G12CKRas, which locks KRasG12C in its inactive GDP-bound state by suppressing downstream MAPK signaling through alkylation of KRas G12C In preclinical models, GDC-6036 inhibited KRas G12C The level of alkylation and the degree of MAPK pathway inhibition correlate with response to GDC-6036. Tumor tissue collection pre- and during treatment will allow for assessment of MAPK pathway inhibition and correlation of antitumor activity with GDC-6036 treatment. The degree of MAPK pathway inhibition can be assessed using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemistry (IHC) analysis of phosphorylated downstream markers (e.g., pERK, pS6). Additionally, tumor tissue biopsies during treatment will be used to assess the inhibition of KRas by GDC-6036. G12C It may allow direct assessment of the level of alkylation. Assessment of these PD biomarkers may inform future dose selection.

[0227] Sequencing of genes associated with resistance to GDC-6036. DNA sequencing technologies such as targeted next-generation sequencing (NGS) and whole-exome sequencing may offer unique opportunities to identify biomarkers of response and / or resistance to GDC-6036. Sequencing of cancer-associated genes may lead to the identification of de novo and acquired resistance mechanisms to GDC-6036.

[0228] Analysis of proteins, RNA and DNA. In addition to mutational activation of proteins, changes in the expression levels of RNA or DNA can also modulate the activity of signaling pathways. RNA profiling of tumors allows for unique subtyping of patients enrolled in the study. Analysis of potential associations between subtypes and patient outcomes may identify subpopulations of patients most likely to respond to GDC-6036.

[0229] Plasma samples for somatic tumor mutation analysis and other biomarkers. There is growing evidence that cell-free DNA obtained from blood specimens of patients with cancer contains ctDNA, which represents the DNA and mutational status of cells within the tumor (Diehl et al. 2008; Maheswaran et al. 2008). Assays have been validated to detect cancer-associated mutations (e.g., KRAS) from plasma. Results of these assays can be correlated with mutational status determined from analysis of tumor specimens. The use of ctDNA to monitor response to treatment is an area of ​​great interest and may enable an early, non-invasive and quantifiable method for use in clinical settings to identify candidates for specific treatments and monitor the mutational status of cancer over time (Wan et al. Nat Rev Cancer 2017;17:223-38). Analysis of ctDNA collected at various time points during study treatment and after patients have progressed on GDC-6036 may help identify mechanisms of response and acquired resistance to study treatment.

[0230] Blood samples for next-generation sequencing. Next-generation sequencing (NGS) technology can generate large amounts of sequencing data. Tumor DNA may contain both reported and unreported chromosomal alterations due to the tumorigenesis process. To help control for sequencing calls on previously unreported genomic alterations, a pre-dose blood sample is taken to determine whether the alterations are somatic.

[0231] Inclusion Criteria. Patients must meet the following study entry criteria: Age ≥ 18 years old; -Evaluable or measurable disease by RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 life expectancy ≥ 12 weeks, Adequate hematologic and organ function within 14 days prior to initiation of study treatment as defined by: Absolute neutrophil count ≥ 1200 / μL; Hemoglobin ≥ 9g / dL, ·Platelet count ≥100,000 / μL, Total bilirubin ≤ 1.5 × ULN Serum albumin ≥ 2.5g / dL, AST and ≤ 2.5 × ULN, with the following exceptions: Patients with documented liver metastases may have AST and / or ALT ≤ 5.0 x ULN. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL / min (based on Cockcroft-Gault glomerular filtration rate estimates). (140-age) x (weight in kg) x (0.85 for women) 72×(serum creatinine (mg / dL)) · For women of childbearing potential: agreement to maintain abstinence (abstain from heterosexual intercourse) or to use contraception and to refrain from donating eggs. · For unsterilized men: Agreement to maintain abstinence (refrain from heterosexual intercourse) or to use contraception and to refrain from donating sperm. Biomarker qualification: KRas G12C Validated results from either central testing of blood or local testing of blood or tumor tissue demonstrating the presence of the mutation (e.g., a validated polymerase chain reaction (PCR)-based assay or NGS assay performed in a CLIA or equivalent accredited laboratory).

[0232] Additional inclusion criteria Histologically proven locally advanced, recurrent or metastatic incurable malignancies. Patients with disease that has progressed after at least one available standard of care, or for whom standard care has proven ineffective or intolerable, or for whom a clinical trial of an investigational agent is the accepted standard of care Fasting blood glucose ≦140mg / dL and glycosylated hemoglobin (HbA1c) <7% Patients with KRas G12C They may have been pretreated with specific inhibitors. Histologically proven, locally advanced, recurrent or metastatic refractory NSCLC (which may include monotherapy or combination therapy with investigational or approved PD-L1 / PD-1 inhibitors)

[0233] General Exclusion Criteria. Patients meeting any of the following criteria will be excluded. -Unable or unwilling to swallow pills, Failure to comply with study and follow-up procedures; Malabsorption syndromes or other conditions that interfere with enteral absorption, Known and untreated or active central nervous system (CNS) metastases, Patients with a history of treated CNS metastases must meet all of the following criteria: Measurable or evaluable disease outside the CNS, No history of intracranial or spinal bleeding, - there is no ongoing need for corticosteroids as treatment for CNS metastases, corticosteroids have been discontinued for ≥2 weeks prior to administration of the agents described herein, and there are no ongoing symptoms attributable to CNS metastases, No stereotactic radiation therapy within 7 days prior to day 1 of cycle 1 or no whole brain radiation therapy within 14 days; No evidence of interim progression between completion of CNS-directed therapy and screening radiology studies; Leptomeningeal disease or carcinomatous meningitis, Uncontrolled pleural, pericardial, or ascites effusion requiring recurrent drainage procedures every other week or more frequently If the patient has sufficiently recovered from the procedure and is hemodynamically stable and symptomatically improving, an indwelling thoracic or abdominal catheter may be possible. Any active infection that may affect patient safety or a serious infection requiring intravenous antibiotics within 7 days prior to Day 1 of Cycle 1, · History of clinically significant liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis; Known HIV infection, Uncontrolled hypercalcemia (ionized calcium >1.5 mmol / L or calcium >12 mg / dL, or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab, Significant traumatic injury or major surgical procedure within 4 weeks prior to Day 1 of Cycle 1, Patients with chronic diarrhea, short bowel syndrome or major upper gastrointestinal surgery including gastrectomy, a history of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) or any active intestinal inflammation (including diverticulitis), Treatment with chemotherapy, immunotherapy, or biologic therapy as anti-cancer therapy within 3 weeks prior to administration of an agent described herein, or endocrine therapy within 2 weeks prior to administration of an agent described herein, except for the following: Hormone therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer), Regulatory approved kinase inhibitors may be used up to 2 weeks prior to the start of study treatment. Treatment with an investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of any agent described herein. Radiation therapy for cancer within 4 weeks prior to administration of the agents described herein (other than palliative radiation for bone metastases and radiation for CNS metastases); Palliative radiation therapy for bone metastases within 2 weeks prior to administration of GDC-6036. Unresolved adverse events from previous anticancer therapy, History of other malignancies within 5 years prior to screening, History of or active clinically significant cardiovascular insufficiency, including: History of stroke or transient ischemic attack within 6 months prior to administration of the drugs described herein; History of myocardial infarction within 6 months prior to administration of the agents described herein; New York Heart Association Class III or IV heart disease or congestive heart failure requiring medical treatment History of uncontrolled arrhythmias, pharmacological treatment-requiring or active ventricular arrhythmias, Coronary heart disease, symptomatic or unstable angina, Congenital long QT syndrome or QT interval >470 ms corrected using the Fridericia formula (QTcF), current treatment with medications known to prolong the QT interval, - pregnant or nursing, or intending to become pregnant during the study or within 6 months after the last dose of GDC-6036; History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on a screening chest computed tomography (CT) scan

[0234] Other Exclusion Criteria Type 1 and type 2 diabetes requiring antihyperglycemic drug therapy Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator and / or study ophthalmologist, requires medical or surgical intervention during the study period to prevent or treat vision loss that may result from that condition. Active inflammatory (e.g., uveitis or vitritis) or infectious conditions (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) in either eye, or a history of idiopathic or autoimmune-related uveitis in either eye -Patients who require any form of daily supplemental oxygen History of or active inflammatory disease (e.g., Crohn's disease or ulcerative colitis), or any active bowel inflammation, including patients currently receiving immunosuppressants (e.g., sulfasalazine), are considered to have active disease and therefore ineligible. History of previous significant toxicity associated with another PI3K or mTOR inhibitor requiring discontinuation of treatment

[0235] Study treatment formulation, packaging and handling

[0236] GDC-6036 is supplied as an active pharmaceutical ingredient (API) powder capsule (PIC) formulation in three strengths: 5 mg, 25 mg, and 100 mg (free base equivalent). GDC-6036 formulations should be stored at or below 86 degrees Fahrenheit (30 degrees Celsius) and protected from moisture.

[0237] To administer a dose of GDC-6036 at home, the patient should be dispensed a sufficient number of capsules or tablets to last until the next clinic visit or for one cycle. The patient will self-administer GDC-6036 as provided herein, except when the patient visits the clinic. The patient should take GDC-6036 at approximately the same time each day unless otherwise instructed. The patient will receive instructions regarding the number and strength of capsules or tablets to take according to the assigned dose level and schedule.

[0238] Unless otherwise instructed, GDC-6036 should be taken on an empty stomach, i.e., food should be avoided at least 2 hours before and 1 hour after dosing. There are no restrictions on fluid intake. Importantly, GDC-6036 capsules or tablets are swallowed completely (without chewing) with a minimum of 240 mL (8 fluid ounces) of water. If the patient misses any dose of GDC-6036 or spits out the capsule or tablet, the patient should be instructed to skip that dose and resume dosing at the next scheduled dose. Do not make up missed doses.

[0239] Inavolisib will be supplied by the sponsor as tablets in two strengths, 3 mg and 9 mg. Inavolisib will be administered PO QD in 21-day cycles starting at 6 mg and not exceeding the single-agent MTD of 9 mg QD. Inavolisib may be administered simultaneously with GDC-6036, with a sip of water in between. Patients will self-administer inavolisib, except on study visit days when inavolisib will be administered in the clinic.

[0240] Patients should take inavolisib at approximately the same time each day, regardless of the timing of food, unless otherwise instructed. If a patient misses any dose of inavolisib (not taken within 6 hours of the scheduled dosing time) or spits out the tablet, they should skip that dose, record it, and resume dosing at the next scheduled dose.

[0241] Concomitant therapy. Concomitant therapy consists of any medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, dietary supplements) used by a patient in addition to the agents described herein from 7 days prior to the first administration of at least one agent described herein until the last administration of at least one agent described herein.

[0242] Permitted Treatments. Patients may take (a) anticonvulsants or warfarin, (b) oral contraceptives or other possible maintenance therapies as specified in the eligibility criteria, (c) antiemetics and antidiarrheal drugs should not be administered prophylactically prior to initial treatment with study drug, (d) analgesics, (e) bisphosphonates and denosumab therapy for bone metastases or osteopenia or osteoporosis, or multivitamins, calcium, and vitamins C, D, and E supplements are acceptable.

[0243] Treatment with Caution. Medications given with caution due to CYP enzyme and GDC-6036 related effects include, for example, (1) strong / moderate CYP3A4 inhibitors (including but not limited to atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivapeptide, cyclosporine ... (2) strong / moderate CYP3A4 inducers (including but not limited to rifampin, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or grapefruit supplements); (3) strong / moderate CYP3A4 inducers (including but not limited to rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone). Use of full doses of oral or parenteral anticoagulants for therapeutic purposes, as long as the INR and / or aPTT were within therapeutic limits (per institutional standards) within 14 days prior to administration of any agent described herein and the patient has been on a stable dose of anticoagulant for ≥ 1 week prior to the start of study treatment. The list of drug treatments is not intended to be comprehensive.

[0244] Coumarins (Coumadin®, warfarin) are strongly discouraged during treatment. If the patient requires anticoagulant therapy, the use of low molecular weight heparins instead of coumarins is encouraged, if clinically feasible. In the absence of a clinically feasible alternative to coumarins, frequent monitoring of INR and prothrombin time should be performed.

[0245] Prohibited Treatments. The use of the following concomitant therapies is prohibited during and for at least 7 days prior to the first administration of the drugs described herein: Investigational therapy within 3 weeks or 5 half-lives (whichever is shorter) prior to the first dose of a drug described herein Concomitant therapies intended to treat cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biological therapy, herbal therapy, or hormonal therapy, except for the following: Hormone therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer), · Hormone replacement therapy or oral contraception. Radiation therapy for unequivocal progressive disease, excluding new brain metastases in the setting of a systemic response: Patients who demonstrate systemic disease control (defined as having received clinical benefit [i.e., PR, CR, or SD for ≥ 3 months]) but who develop brain metastases treatable with radiation will be allowed to continue to receive treatment with GDC-6036 on the study until they experience either systemic progression of disease and / or further progression in the brain (based on investigator assessment); quinidine or other antiarrhythmic drugs, Initiation or dose increase of hematopoietic colony-stimulating factors (CSFs, e.g., granulocyte CSF, filgrastim, granulocyte / macrophage CSF, sargramostim, pegfilgrastim, erythropoietin, darbepoietin, and thrombopoietin) from 7 days prior to day 1 of the first cycle

[0246] Caution Risk Strong CYP3A4 inhibitors, including but not limited to atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, posaconazole, conivaptan, diltiazem, nefazodone and mibefradil. Strong CYP3A4 inducers, including but not limited to rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, nevirapine, hyperforin (St. John's wort) and cyproterone. Inhibitors of P-gp, including but not limited to ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, elacridar, and valspodar Inhibitors of BCRP, including but not limited to curcumin, cyclosporine A, and eltrombopag

[0247] Risks Associated with GDC-6036.Administration of GDC-6036 has been associated with diarrhea, nausea, vomiting, and minimal to mild transaminase elevations.Other potential risks include oral mucosal irritation.

[0248] Risks Associated with Inavolisib.Based on the established class effect of PI3K and mTOR inhibitors in patients with cancer, as well as nonclinical data and clinical experience with Inavolisib, hyperglycemia, stomatitis / oral mucositis, rash, diarrhea / colitis, and pneumonitis are safety concerns with Inavolisib. Given that these adverse events may require either dose interruption and / or dose reduction, or may have the potential to cause life-threatening symptoms, close monitoring and robust risk mitigation strategies are warranted.

[0249] Hyperglycemia Effects on glucose and / or insulin metabolism are known effects of PI3K inhibitors. Increases in glucose were observed in toxicity studies in rats and dogs at all doses tested and appeared to be dose-dependent. Hyperglycemia has been reported in patients receiving inavolisib and is an identified risk of inavolisib. Therefore, patients with type I or type II diabetes requiring drug therapy and those with elevated fasting plasma glucose at baseline (fasting plasma glucose >140 mg / dL or HbA 1cPatients with hyperglycemia are excluded if their fasting glucose level is > 7%). Assess fasting glucose levels at baseline and monitor fasting glucose levels. Patients should be advised to report symptoms associated with hyperglycemia such as polydipsia, polyuria, hyperphagia, blurred vision, or symptoms associated with acidosis such as rapid or shallow breathing, confusion, fatigue, headache, or drowsiness. Patients are given metformin as the first-line agent for management of hyperglycemia.

[0250] Stomatitis and oral mucositis. Treatment-related stomatitis / oral mucositis has been reported with the use of inavolisib. Patients should be advised to report symptoms immediately. Intervention should begin at the earliest sign of oral mucosal inflammation. When available topically, a formulated alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) is recommended for the prevention or treatment of stomatitis / mucositis. As in the SWISH study (Rugo et al. 2017), patients may use it 4 times daily (10 mL swished for 2 min and expectorated) for 8 weeks starting concurrently with study treatment and / or reactively to the first appearance of symptoms. Additional mouthwash preparations (e.g., combinations of local anesthetics, antihistamines, corticosteroids, antacids, antifungals, and / or antibiotics) or topical corticosteroids (e.g., triamcinolone acetonide 0.05%-0.5%, fluocinolone acetonide 0.025%-0.05%, clobetasol propionate 0.025%) may be implemented. Patients should avoid alcohol, hydrogen peroxide, iodine, or thymus-containing products, as these may worsen symptoms. Harsh mouthwashes (e.g., Listerine®) should also be avoided. Diet should be modified (e.g., avoidance of harsh foods).

[0251] Gastrointestinal Toxicity. GI inflammation was observed in a 4-week toxicity study of inavolisib in dogs. Patients with inflammatory bowel disease such as Crohn's disease or ulcerative colitis and active bowel inflammation (e.g., diverticulitis) are excluded. GI effects are closely monitored by interval history and physical examination. The occurrence of abdominal pain, nausea, vomiting, clinically significant changes in stool (e.g., diarrhea, bloody stools) may require more frequent monitoring, and study drug may be held if symptoms are prohibitive to normal function. Clinical evaluation for infectious (e.g., Clostridium difficile, Enterobacteriaceae, and cytomegalovirus) or inflammatory (e.g., inflammatory bowel disease) etiology for diarrhea should be performed.

[0252] Skin Disorders. Treatment-related rash has been reported with other PI3K inhibitors in clinical studies and commonly manifests as a maculopapular rash with or without pruritus. Rashes and other dermatological events should be closely monitored and managed per standard of care.

[0253] Other potential risks of inavolisib:

[0254] Pulmonary inflammation / pneumonitis. Pulmonary inflammation was observed in an inavolisib 4-week toxicity study in dogs at the highest dose tested. This finding was only observed at dose levels considered to be intolerable in this species. Interstitial lung disease / pneumonitis has been observed in clinical trials with other PI3K inhibitors.

[0255] Effects of immunosuppressants. Immunosuppression and increased risk of infections are known to be associated with commercially available PI3K / mTOR pathway inhibitors. Toxicology studies have demonstrated reductions in reticulocyte, white blood cell and absolute lymphocyte counts in animals treated with inavolisib. Patients who are immunocompromised as a result of HIV or receiving immunosuppressive therapy will be excluded. Patients should be routinely monitored for changes in circulating blood counts, including white blood cell differential, and monitored for fever and signs of infection.

[0256] Reproductive Effects.In a 4-week repeated-dose toxicity study, potential adverse effects on male reproductive function were observed in one or more dogs, including focal condensation of seminiferous tubule contents and multinucleated spermatids in the testes and epithelial degeneration / necrosis in the epididymis. At the end of the 4-week recovery period, focal condensation of seminiferous tubule contents persisted in one animal.

[0257] Ocular Toxicity. In a 4-week toxicology study in rats, lens degeneration was noted in the highest inavolisib dose group (10 mg / kg; 4 of 30 rats). This finding was characterized by minimal to mild lens fiber swelling, lens fiber separation, and / or accumulation of subcapsular proteinaceous material. It is unclear whether this lens finding was a direct effect of inavolisib in this dose group or an indirect effect secondary to significant hyperglycemia. No inavolisib-related ocular findings were observed in lower dose rats. In dogs, ocular-related findings included inflammation and lens fiber swelling. In dogs treated with inavolisib (treated at 1.5 mg / kg and then reduced to 1.0 mg / kg) for 3 months, ocular inflammation was limited to focal minimal neutrophilic infiltrates in the stroma at the corneal-limbic junction of the eye. In a 4-week study in dogs, neutrophil infiltration in the limbus and sclera, mild endophthalmitis, and low-grade uveitis were observed in the highest dose group (treated at 5 mg / kg and reduced to 3 mg / kg), which was not considered tolerable. These findings were reversible and may have been part of a systemic inflammatory state. In dogs receiving ≥ 0.3 mg / kg inavolisib in a 3-month toxicity study, bilateral reversible very slight swelling of fibers in the equatorial region of the lens was observed in one male and one female at 0.3 mg / kg and in one male and one female treated at 1.5 mg / kg and reduced to 1.0 mg / kg. Patients with any concurrent ocular or intraocular condition requiring medical or surgical intervention, such as cataracts or diabetic retinopathy, are excluded. Additionally, patients with active uveitis or vitritis, a history of uveitis, or an active intraocular infectious process will be excluded.

[0258] Treatment interruption. If GDC-6036 is held for >21 days from previous study treatment due to toxicity, study treatment should not be resumed. GDC-6036 may be stopped for up to 21 days for toxicity of study treatment or unanticipated intercurrent medical events not related to disease progression.

[0259] Adverse Events. Adverse events, as defined herein, refer to any untoward medical occurrence in a clinical trial subject administered an agent described herein in a combination therapy described herein, regardless of attribution of cause. The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the adverse event (e.g., rated as mild, moderate, or severe or according to NCI CTCAE), and the event itself may be relatively medically insignificant (such as a severe headache with no further findings).

[0260] Adverse events to monitor for include nausea, vomiting, diarrhea, stomatitis, mucositis, hepatitis, or elevations in ALT or AST, elevated bilirubin or clinical jaundice, systemic lupus erythematosus, nephritis, events suggestive of hypersensitivity, infusion-mediated reactions, CRS, influenza-like illness, and systemic inflammatory response syndrome, atrial fibrillation, myocarditis, pericarditis, vasculitis, myositis, uveitis, retinitis, optic neuritis, autoimmune hemolytic anemia, Stevens-Johnson syndrome, bullous dermatitis, and toxic epidermal necrolysis.

[0261] Adverse events of particular interest specific to inavolisib include: Grade ≥3 hyperglycemia Grade ≥3 rash Grade ≥ 3 diarrhea Grade ≥2 pneumonitis Grade ≥2 colitis or enteritis Grade ≥ 3 stomatitis or mucosal inflammation Grade ≥3 elevation of ALT or AST

[0262] Throughout this specification and the claims, the words "comprise / comprises and comprising" are used in an open-ended sense unless the context is contradictory. The embodiments described herein are understood to include "consisting of" and / or "consisting essentially of" embodiments. As used herein, reference to "GDC-6036" is further understood to refer to the free base compound as well as GDC-6036-adipate or other pharma-ceutically acceptable salts thereof.

[0263] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is to be understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of the range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges that may be independently included in the smaller ranges are also included herein, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included herein.

[0264] Many modifications and other embodiments of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. KRas Ｇ１２Ｃ A pharmaceutical product for treating lung cancer in patients with mutation-mediated lung cancer, (a) GDC-6036 【Transformation 3】 or a pharmaceutically acceptable salt thereof, (b) Inaboricib 【Chemistry 4】 or a pharmaceutically acceptable salt thereof Includes, The pharmacopoeia comprises a drug regimen comprising one or more cycles, each drug cycle comprising (i) administration of a QD of GDC-6036 in amounts of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, and (ii) administration of a QD of inavolisib in amounts of 3 mg, 6 mg, or 9 mg.

2. The pharmaceutical product according to claim 1, wherein the lung cancer is NSCLC.

3. The pharmaceutical product according to claim 1, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

4. A pharmaceutical product for treating colorectal cancer (CRC) in patients with KRasG12C mutations, (a) GDC-6036 【Transformation 5】 or a pharmaceutically acceptable salt thereof, (b) Inaboricib 【Transformation 6】 or a pharmaceutically acceptable salt thereof Includes, The pharmacopoeia comprises a drug regimen comprising one or more cycles, each drug cycle comprising (i) administration of a QD of GDC-6036 in amounts of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, and (ii) administration of a QD of inavolisib in amounts of 3 mg, 6 mg, or 9 mg.

5. A pharmaceutical product for treating tissue-independent cancers, including those involving the KRasG12C mutation, (a) GDC-6036 【Transformation 7】 or a pharmaceutically acceptable salt thereof, (b) Inaboricib 【Transformation 8】 or a pharmaceutically acceptable salt thereof Includes, The aforementioned pharmaceutical product comprises a drug regimen comprising one or more cycles, each drug cycle comprising the administration of (i) a QD of GDC-6036 in amounts of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg and (ii) a QD of inavolisib in amounts of 3 mg, 6 mg, or 9 mg, wherein the patient has a confirmed KRasG12C mutation in a sample taken from the patient.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein each of the aforementioned one or more cycles is a 21-day cycle.

7. The pharmaceutical product according to claim 6, wherein the drug regimen includes a rest period during which GDC-6036 and inavolicib, or both, are not administered.

8. The pharmaceutical product according to any one of claims 1 to 5, wherein each of the aforementioned one or more cycles is a 28-day cycle.

9. The pharmaceutical product according to any one of claims 1 to 5, wherein GDC-6036 is its adipine salt.

10. The pharmaceutical product according to any one of claims 1 to 5, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

11. A pharmaceutical product according to any one of claims 1 to 5, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 100 mg, 200 mg, or 400 mg.

12. A pharmaceutical product according to any one of claims 1 to 5, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 200 mg.

13. A pharmaceutical product according to any one of claims 1 to 5, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of 400 mg.

14. The pharmaceutical product according to any one of claims 1 to 5, wherein inavolicib is administered in a dose of 6 mg.

15. The pharmaceutical product according to any one of claims 1 to 5, wherein inavolicib is administered in an amount of 9 mg.

16. The pharmaceutical product according to any one of claims 1 to 5, wherein the patient is not evaluated for the presence of mutant PIK3CA before administration.

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