WO2025202971A1 - Kras g12c inhibitor for use for the treatment of non-small cell lung cancer - Google Patents

Abstract

The present invention relates to a method of treating non-small cell lung cancer (NSCLC) which harbors a KRAS G12C mutation, wherein the method comprises the administration of KRAS G12C inhibitor 1-{6-[(4M)-4-(5-Chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab; in particular the present invention relates to a method of treating NSCLC wherein the NSCLC expresses at least 1% PD-L1 according to the tumor proportion score (TPS), more particularly the NSCLC expresses at least 50% PD-L1 according to the tumor proportion score (TPS).

Description

KRAS G12C INHIBITOR FOR USE FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. Provisional Application Serial No. 63/570,545 filed March 27, 2024, which is hereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method of treating non-small cell lung cancer (NSCLC) which harbors a KRAS G12C mutation, wherein the method comprises the administration of a therapeutically effective amount of KRAS G12C inhibitor 1-{6-[(4M)-4-(5-Chloro-6-methyl- 1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab; in particular the present invention relates to a method of treating NSCLC wherein the NSCLC expresses at least 1% PD-L1 according to the tumor proportion score (TPS), more particularly the NSCLC expresses at least 50% PD-L1 according to the tumor proportion score (TPS).

BACKGROUND

Cancer growth is driven by many diverse complex mechanisms. Resistance to a given therapy inevitably occurs in some cancers. Inhibiting the MAPK pathway induces feedback mechanisms and pathway rewiring causing its subsequent reactivation. One common mechanism is for example the activation of Receptor Tyrosine Kinases (RTKs).

Despite the recent successes of targeted therapies and immunotherapies, some cancers, in particular, metastatic cancers remain largely incurable.

The KRAS oncoprotein is a GTPase with an essential role as regulator of intracellular signaling pathways, such as the MAPK, PI3K and Rai pathways, which are involved in proliferation, cell survival and tumorigenesis. Oncogenic activation of KRAS occurs predominantly through missense mutations in codon 12. KRAS gain-of-function mutations are found in approximately 30% of all human cancers. KRAS G12C mutation is a specific sub-mutation, prevalent in approximately 13% of lung adenocarcinomas, 4% (3-5%) of colon adenocarcinomas and a smaller fraction of other cancer types.

In normal cells, KRAS alternates between inactive GDP-bound and active GTP-bound states. Mutations of KRAS at codon 12, such as G12C, impair GTPase-activating protein (GAP)-stimulated GTP hydrolysis. In that case, the conversion of the GTP to the GDP form of KRAS G12C is therefore very slow. Consequently, KRAS G12C shifts to the active, GTP- bound state, thus driving oncogenic signaling.

Lung cancer remains the most common cancer type worldwide and the leading cause of cancer deaths in many counties, including the United States. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer diagnoses. KRAS mutations are detected in approximately 25% of patients with lung adenocarcinomas (Sequist et al., 2011 , Ann. Oncol., 22(12): 2616-24). They are most commonly seen at codon 12, with KRAS G12C mutations being most common (40% overall) in both adenocarcinoma and NSCLC. The presence of KRAS mutations is prognostic of poor survival and has been associated with reduced responsiveness to EGFR TKI treatment.

Immunotherapy for NSCLC with immune checkpoint inhibitors has demonstrated promise, with some NSCLC patients experiencing durable disease control for years. However, such long-term non-progressors are uncommon, and treatment strategies that can increase the proportion of patients responding to and achieving lasting remission with therapy are urgently needed.

Approximately 40 to 50% of the patients with advanced NSCLC are not eligible to subsequent treatments after discontinuation of first-line therapy, mainly due to clinical deterioration at the moment of disease progression. Hence, effective treatments administered at early lines of treatment have the potential to benefit more patients with NSCLC.

There thus remains a high unmet medical need for new treatment options for patients suffering from NSCLC, in particular from advanced and/or metastatic NSCLC, especially when the cancer or solid tumor harbors a KRAS G12C mutation.

SUMMARY OF THE INVENTION

The invention provides new methods of treating non-small cell lung cancer (NSCLC). In particular, the invention provides a method of treating NSCLC in a subject in need thereof, and which cancer harbors a KRAS G12C mutation, wherein the method comprises administering to the subject a therapeutically effective amount of 1-{6-[(4M)-4-(5-Chloro-6- methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab. In one embodiment, the NSCLC expresses at least 1 % PD-L1 according to the tumor proportion score (TPS), more particularly, the NSCLC expresses at least 50% PD-L1 according to the tumor proportion score (TPS), even more particularly the NSCLC expresses at least 90% PD-L1 according to the tumor proportion score (TPS).

In another embodiment, the invention provides a compound 1-{6-[(4M)-4-(5-Chloro-6-methyl- 1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating NSCLC wherein the method comprises administering to the subject a therapeutically effective amount of 1-{6-[(4M)-4-(5- Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab.

In another embodiment, the invention provides the use of compound 1-{6-[(4M)-4-(5-Chloro- 6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the manufacture of a medicine for a method of treating NSCLC comprising administering to the subject a therapeutically effective amount of 1 -{6- [(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H- pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab.

In another embodiment, the invention provides a pharmaceutical combination comprising 1 - {6-[(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H- pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically acceptable amount of pembrolizumab.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : PET scans showing a substantial reduction in the 2-[fluorine-18]-fluoro-2-deoxy-d- glucose (18-F-FDG) avidity of the tumor mass after four cycles of treatment with Compound A administered at 200 mg BID (= two times a day) to a patient with NSCLC. CT: computerized tomography; PET, positron emission tomography. Arrows indicate sites of tumor. DESCRIPTION OF THE INVENTION

KRAS G12C inhibitor Compound A (INN: opnurasib):

Compound A is KRAS G12C inhibitor with the chemical name 1-{6-[(4M)-4-(5-Chloro-6- methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)- 1 H-pyrazol-1 -yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one. Compound A is also known by the chemical name a(R)-1 -(6-(4-(5-chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H- pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one. Compound A is an atropisomer.

The synthesis of Compound A is described in Example 1 of WO2021/124222, published 24 June 2021 . Uses of Compound A, alone or in combination with an additional therapeutic agent are described in WO2022/135346 and WO2022/269525. Polymorphic forms of Compound A are described in W02022/089604. Further synthetic methods for preparing Compound A are described in WO2023/143605.

The structure of Compound A is as follows:

Alternatively, the structure of Compound A may be drawn as follows: Compound A is a potent and selective KRAS G12C small molecule inhibitor that covalently binds to mutant Cys12, trapping KRAS G12C in the inactive GDP-bound state. Compound A is structurally unique compared with sotorasib or adagrasib; its binding mode is a novel way to reach residue C12 and has no direct interaction with residue H95.

Preclinical data indicate that Compound A binds to KRAS G12C with low reversible binding affinity to the RAS SWII pocket, inhibiting downstream cellular signaling and proliferation specifically in KRAS G12C-driven cell lines but not KRAS wild-type (WT) or MEK Q56P mutant cell lines. Compound A showed deep and sustained target occupancy resulting in anti-tumor activity in different KRAS G12C mutant xenograft models.

Thus, Compound A may thus be useful in the treatment of cancer and in cancers or tumors which are KRAS G12C mutated. In particular, Compound A may be useful as first-line treatment for NSCLC which harbors a KRAS G12C mutation. Particularly, the Compound A may be useful as first-line treatment for NSCLC with a PD-L1 expression of at least 1% PD- L1 according to the tumor proportion score (TPS), more particularly wherein the NSCLC expresses at least 50% PD-L1 according to the tumor proportion score (TPS), even more particularly wherein the NSCLC expresses at least 90% PD-L1 according to the tumor proportion score (TPS).

The cancer may be at an early, intermediate, late stage or may be metastatic NSCLC. In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a relapsed cancer. In some embodiments, the cancer is a refractory cancer. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer is an unresectable cancer. The cancer may be at an early, intermediate, late stage or metastatic cancer.

Thus, in an embodiment 1 , there is provided a method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, and which cancer harbors a KRAS G12C mutation, wherein the method comprises administering to the subject a therapeutically effective amount of 1 -{6-[(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H- indazol-5-yl)-1 H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab. In an embodiment 2, there is provided a method of treating according to embodiment 1 , wherein the NSCLC expresses at least 1% PD-L1 according to the tumor proportion score (TPS).

In an embodiment 3, there is provided a method of treating according to embodiments 1 or 2, wherein the NSCLC expresses at least 50% PD-L1 according to the tumor proportion score (TPS).

In an embodiment 4, there is provided a method of treating according to any one of embodiments 1 to 3, wherein the NSCLC expresses at least 90% PD-L1 according to the tumor proportion score (TPS).

In an embodiment 5, there is provided a method of treating according to any one of embodiments 1 to 4, wherein Compound A is administered at a dose of 200 mg per day or 400 mg per day in a single dose or divided doses.

In an embodiment 6, there is provided a method of treating according to any one of embodiments 1 to 5, wherein Compound A is administered once daily or twice daily.

In an embodiment 7, there is provided a method of treating according to any one of embodiments 1 to 6, wherein Compound A is administered at a dose of 100 mg twice daily or 200 mg twice daily.

In an embodiment 8, there is provided a method of treating according to any one of embodiments 1 to 7, wherein Compound A is administered during or after consuming food.

In an embodiment 9, there is provided a method of treating according to any one of embodiments 1 to 8, wherein pembrolizumab is administered at a dose of 200 mg.

In an embodiment 10, there is provided a method of treating according to embodiment 9, wherein pembrolizumab is administered via intravenous infusion.

In an embodiment 11 , there is provided a method of treating according to embodiment 9 or 10, wherein pembrolizumab is administered at the beginning of every treatment cycle.

In an embodiment 12, there is provided a method of treating according to embodiment 11 , wherein the treatment cycle consists of 21 (±3) days. In an embodiment 13, there is provided a method of treating according to any one of embodiments 1 to 12, wherein the treatment is given as first-line treatment.

In an embodiment 14, there is provided a method of treating according to any one of embodiments 1 to 13, wherein the progression-free survival (PFS) as determined by response evaluation criteria in solid tumors version 1 .1 (RECIST 1.1) is increased compared to treatment with pembrolizumab alone.

In an embodiment 15, there is provided a method of treating according to any one of embodiments 1 to 14, wherein the overall survival (OS) is increased compared to treatment with pembrolizumab alone.

In an embodiment 16, there is provided a method of treating according to any one of embodiments 1 to 15, wherein the disease control rate (DCR) as determined by response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) is increased compared to treatment with pembrolizumab alone.

In an embodiment 17, there is provided a method of treating according to any one of embodiments 1 to 16, wherein the objective response rate (ORR) as determined by response evaluation criteria in solid tumors version 1 .1 (RECIST 1.1) is increased compared to treatment with pembrolizumab alone.

In an embodiment 18, there is provided a method of treating according to any one of embodiments 1 to 16, wherein the duration of response (DOR) as determined by response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) is increased compared to treatment with pembrolizumab alone.

In an embodiment 19, there is provided a method of treating according to any one of embodiments 1 to 18, wherein the subject to be treated has locally advanced or metastatic non-squamous NSCLC.

In a further embodiment, there is provided compound 1-{6-[(4M)-4-(5-Chloro-6-methyl-1 H- indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2-azaspiro[3.3]heptan-2- yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating non-small cell lung cancer (NSCLC) according to any one of embodiments 1 to 19. In a further embodiment, there is provided the use of 1 -{6-[(4M)-4-(5-Chloro-6-methyl-1 H- indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2-azaspiro[3.3]heptan-2- yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the manufacture of a medicine for the treatment of a method according to any one of embodiments 1 to 19.

In a further embodiment, there is provided a pharmaceutical combination comprising 1 -{6- [(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H- pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically amount of pembrolizumab. In a further embodiment, the pharmaceutical combination is for use in therapy. In another embodiment, the pharmaceutical combination is for use in a method of treating NSCLC, in particular in a method of treating NSCLC according to any one of the above embodiments 1 to 19.

Definitions:

The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated, where more general terms whereever used may, independently of each other, be replaced by more specific definitions or remain, thus defining more detailed embodiments of the invention:

In particular, where a dose or dosage is mentioned, it is intended to include a range around the specified value of plus or minus 10%, or plus or minus 5%.

As is customary in the art, dosages refer to the amount of the therapeutic agent in its free form. For example, when a dosage of 200 mg of Compound A is referred to, and Compound A is used as a pharmaceutical salt thereof, the amount of the therapeutic agent used is equivalent to 200 mg of the free form of Compound A.

The term “subject” or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In an embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers. The terms “treating”, or “treatment”, as used herein comprise a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or partial or complete eradication of a disorder, such as cancer. Within the meaning of the present disclosure, the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

“Treatment” may also be determined by efficacy and/or pharmacodynamic endpoints and may be defined as an improvement in one or more of safety, efficacy and tolerability.

Efficacy of the monotherapy or the combination therapy may be determined by determining Best Overall Response (BOR), Overall Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), and Overall Survival (OS) per RECIST 1.1.

“Best overall response” (BOR) rate is defined as the best response recorded from the start of the treatment until disease progression/recurrence and according to RECIST 1 .1 .

“Overall response rate” (ORR) is defined as the proportion of patients with a BOR of CR or PR according to RECIST 1.1.

“Duration of Response” (DOR) per RECIST 1 .1 is the time between the first documented response (CR or PR) and the date of progression or death due to any cause. Here, death due to any cause is considered as an event to be conservative and align with PFS event definition.

“Disease control rate” (DCR) per RECIST 1 .1 is defined as the proportion of patients with a BOR of CR, PR, or SD according to RECIST 1 .1 .

“Progression Free Survival” (PFS) per RECIST 1 .1 is defined as the time from the date of start of treatment to the date of the first documented progression according to RECIST 1.1 , or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment.

“Overall survival” (OS) is defined as the number of days between the date of start of study treatment to the date of death due to any cause. If no death is reported prior to study termination or analysis cut off, survival will be censored at the date of last known date patient alive prior to/on the cut-off date. Survival time for patients with no post-baseline survival information will be censored at the date of start of treatment.

Response criteria according to RECIST 1.1 :

- Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

- Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

- Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

- Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

“Treatment” may also be defined as an improvement in a reduction of adverse effects of the therapy with Compound A, as described herein.

The terms “comprising” and “including” are used herein in their open-ended and non-limiting sense unless otherwise noted.

The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term "pharmaceutically-acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

In the methods and uses of the invention, Compound A, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated include isotopes, where possible, of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, 2H, 3H, 11C, 13C, 14C, 15N, 35S, 36CI. Isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Isotopically-labeled Compound A can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents.

Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of Compound A. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in the compounds of the present invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

In Compound A, a methyl group, e.g. on the indazolyl ring, may be deuterated or perdeuterated. Deuterated compounds of Compound A are described in CN116478141 B.

Pharmaceutical Compositions:

In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of Compound A, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.

Preferably, pharmaceutically acceptable carriers are sterile. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

In an embodiment, the pharmaceutical compositions are capsules comprising the active ingredient only.

Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include an effective amount of a compound in a combination of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs, solutions or solid dispersion. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.

Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein, a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant.

Products provided as a combined preparation include a composition comprising the compound of the present invention in the form of a kit.

In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. To assist compliance, the kit of the invention typically comprises directions for administration.

Pembrolizumab: Pembrolizumab (Merck & Co), also known as Lambrolizumab, MK-3475, MK03475, SCH- 900475, or KEYTRUDA®: Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013), New England Journal of Medicine 369 (2): 134-44, US 8,354,509, and WO 2009/114335, incorporated by reference in their entirety. Pembrolizumab is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

Pembrolizumab has been approved by the Food and Drug Administration (FDA) for treating NSCLC for the following indications:

- as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 >1 % according to the tumor proportion score (TPS).

- in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic non-squamous NSCLC,

- in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC.

The recommended dose for pembrolizumab for treating NSCLC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

The tumor proportion score (TPS) is a PD-L1 measurement which is applied, for example, to lung cancer, head and neck cancer and melanomas. Within this approach, only membranous staining of tumor cells is regarded as a significant staining. For example, the PD-L1 expression >50% can be assessed in tumor tissue by a PD-L1 IHC assay using either Agilent 22C3 using tumor proportion score (TPS) or Ventana SP263 Assay® using tumor cells (TC) scoring. The FDA approved the Ventana PD-L1 (SP142) Assay® (Ventana Medical Systems, Inc.). In contrast, the combined positivity score (CPS) and inflammatory cell (IC) scoring include or are restricted to PD-L1 expression in certain inflammatory cells, respectively. CPS and IC scoring are standard measurements of PD-L1 in urothelial carcinoma.

Patients with locally advanced or metastatic NSCLC harboring KRAS G12C mutations may benefit from a first-line treatment comprising the combination of KRAS G12C inhibitor Compound A with a PD1 -inhibitor. Hence, the current invention also provides a pharmaceutical combination comprising a Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab. In one embodiment, the pharmaceutical combination is for use in therapy. In one embodiment, the pharmaceutical combination is for use in a method of treating NSCLC. In a further embodiment, the pharmaceutical combination is for use in a method of treating patients with locally advanced or metastatic NSCLC. In another embodiment, the pharmaceutical combination is for use in a method of treating patients with locally advanced or metastatic NSCLC comprising the administration of Compound A at 200 mg or 400 mg per day and pembrolizumab at 200 mg every 3 weeks.

All publications, patents, and Accession numbers mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

References in this specification to "the invention" are intended to reflect embodiments of the several inventions disclosed in this specification and should not be taken as unnecessarily limiting of the claimed subject matter.

It is understood that the Examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

EXAMPLES

Example 1 : Clinical efficacy of Compound A

A phase Ib/ll open-label, multi-center, dose escalation study of Compound A (COMPOUND A) alone and in combination with specific agents is conducted in patients with advanced solid tumors harboring the KRAS G12C mutation, including KRAS G12C-mutated NSCLC and KRAS G12C-mutated colorectal cancer (KontRASt-01 (NCT04699188)). The study is conducted to evaluate the antitumor efficacy, safety and tolerability of COMPOUND A as a single agent and COMPOUND A in combination with other agents.

Patients to be treated include patients with advanced, KRAS G12C-mutated solid tumors who have received standard-of-care therapy, or who are intolerant of or ineligible for approved therapies; or , Eastern Cooperative Oncology Group Performance Status (ECOG PS 0-1); or had no prior treatment with KRASG12C inhibitors. Key exclusion criteria forthe COMPOUND A monotherapy arm are: active brain metastases and/or prior KRASG12C inhibitor treatment.

Patients with NSCLC include patients previously treated with a platinum-based chemotherapy regimen and an immune checkpoint inhibitor, either in combination or in sequence, unless ineligible to receive such therapy.

Patients with CRC include patients who have previously received standard-of-care therapy, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless ineligible to receive such therapy.

The preliminary data from the monotherapy dose escalation arm study are as follows.

At a cut-off date of January 5, 2022, 39 patients were treated with 200 mg QD, 400 mg QD, 200 mg BID or 300 mg BID of Compound A. Compound A was administered with food.

Patients had a median of 3 prior lines of anti-neoplastic therapy. The recommended dose for the monotherapy is a dose of 200 mg of Compound A taken orally twice daily (BID).

Efficacy data (cutoff of 05 Jan 2022) from the pooled Phase lb COMPOUND A single agent cohort (n=39) showed:

• 57% (4/7) confirmed overall response rate (ORR) at 200 mg BID in NSCLC

• 45% (9/20) confirmed and unconfirmed ORR across doses in NSCLC

• 35% (7/20) confirmed ORR across doses in NSCLC

• PD/PK modeling predicted sustained, high-level target occupancy at the recommended dose of 200 mg BID.

Compound A treatment was generally well tolerated. Most treatment-related adverse events (TRAEs) were Grade (Gr) 1-2. There were no Grade 4-5 TRAEs. Four Grade 3 TRAEs occurred in 4 separate pts;. The most common TRAEs were fatigue, nausea, edema, diarrhea, and vomiting. There was one DLT (Grade 3 fatigue) and one treatment-related serious AE (Grade 3 photosensitivity reaction), each in separate patients treated at 300 mg BID.

At the recommended dose of 200 mg BID, there was prolonged absorption, with a median time to maximum plasma concentration (Tmax) of 3-4 hrs following administration with food. No significant accumulation was observed at steady state, and there was no evidence of auto-induction. The half-life was about 7 hours, and steady-state area under the curve (AUCss) was more than threefold above the exposure required for maximum efficacy in less- sensitive KRAS G12C xenograft models.

Patient PK and preclinical target occupancy models were integrated to predict target occupancy in patients at >90% in >82% patients. The models assume that COMPOUND A binding and target (KRAS) turn-over rates are the same in mice and humans (~25 hr half-life for KRAS) and that only free drug can bind the target.

The best overall response across dose levels and indications is shown in the Table below. The best overall response across dose levels in all patients with NSCLC is shown in the Table below. All patients with a Partial Response or unconfirmed Partial Response were ongoing treatment at the data cut-off.

NE, not evaluable; NSCLC, non-small cell lung cancer; ORR, overall response rate; PD, progressive disease; PR, partial response; QD, once daily.

Responses are investigator assessed per RECIST v1.1. Two (10.0%) patients had a uPR, which contributed toward the ORR (confirmed and unconfirmed). uPR = unconfirmed PR pending confirmation, treatment ongoing with no PD. One of two patients with a uPR had confirmed PR after the data cut-off.

Figure 1 shows PET scans showing a substantial reduction in the 2-[fluorine-18]-fluoro-2- deoxy-d-glucose (18-F-FDG) avidity of the tumor mass after four cycles of treatment with Compound A administered at 200 mg BID to a patient with NSCLC. The patient had received pemetrexed/pembrolizumab, docetaxel, tegafur/gimeracil/oteracil, and carboplatin/ paclitaxel/atezolizumab. Post-Cycle 2 scan showed a 30.4% reduction in the sum of the longest diameters of target lesions compared with baseline. PR was confirmed on subsequent scans.

A 57 year old male with metastatic KRAS G12C-mutated NSCLC. Local molecular testing using next generation sequencing (NGS) identified no mutations in TP53. Mutation status of STK11 , KEAP1 and NRF2 were unknown. The patient had received prior carboplatin/pemetrexed/pembrolizumab, docetaxel, tegafur-gimeracil-oteracil, and carboplatin/paclitaxel/atezolizumab. He was enrolled to the COMPOUND A monotherapy dose escalation part of the study at a dose of COMPOUND A 200 mg BID given continuously on a 21 -day cycle. Disease assessment after 2 cycles of treatment demonstrated a RECIST 1.1 partial response, with a -30.4% change in the sum of the longest diameters of target lesions compared with baseline. Partial response was confirmed on subsequent scans (Fig. 1) and the patient continued on treatment. Positron emission tomography imaging at baseline and after 4 cycles of treatment also showed substantial reduction in 2-[fluorine-18]-fluoro-2-deoxy-d-glucose avidity of the tumor mass.

Compound A in combination with PD-1 inhibitor tislelizumab:

Patients with NSCLC who had previously received anti-PD1 therapy, but had never received a KRAS G12C inhibitor before, were dosed with the combination of Compound A and PD-1 inhibitor tislelizumab. The dose of Compound A was 200 mg orally twice a day and the dose of tislelizumab was 200 mg IV (intravenous) every 3 weeks. This dosing regimen was generally well tolerated with the most common side effects being decreased appetite, nausea, vomiting, rash and fatigue. Compared with other known KRAS G12C inhibitors in combination with PD-1 inhibitors such as pembrolizumab, it appeared that the safety profile of the combination of Compound A and tislelizumab was favorable. Administering the above dose of Compound A in combination with tislelizumab, patients showed an overall response rate (ORR) of 31 .6% with a disease control rate (DCR) of 84.2%. Summarized, the safety and efficacy findings in this study were as follows:

Safety:

Compound A (200 mg BID) in combination with tislelizumab (200 mg q3W (= every 3 weeks)) remained well-tolerated with primarily grade 1-2 toxicities to include nausea, decrease appetite.

Efficacy:

In NSCLC, Compound A 200 mg BID with tislelizumab 200 mg q3W had a confirmed overall response rate (ORR) of 31.8% (7/25) with a disease control rate (DCR) of 86.4% (escalation and expansion). In expansion only, confirmed ORR is 33.3% (6/21) with a DCR 83.3% (15/21) in patients who have previously progressed on prior anti-PD-1 agents.

Example 2: Study of efficacy and safety of COMPOUND A single-agent as first-line treatment for patients with locally advanced or metastatic KRAS G12C-mutant non-small cell lung cancer with a PD-L1 expression <1 % or a PD-L1 expression >1% and a STK11 comutation:

A clinical study demonstrating the therapeutic use of Compound A may be carried out as follows.

This study aims to evaluate the antitumor activity and safety of COMPOUND A single-agent as first-line treatment for participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and have a PD-L1 expression <1%, % regardless of STK11 mutation status, (cohort A) or a PD-L1 expression >1% and STK11 co-mutations (cohort B).

Tests to determine PD-L1 expression status, KRAS G12C mutation and STK11 mutation status, e.g. in tumor tissue or blood samples, are known in the art.

Objectives and Endpoints:

The study will have 2 non-comparative cohorts that will recruit participants in parallel according to the following characteristics:

• Cohort A: participants whose tumors harbor a KRAS G12C mutation and a PD-L1 expression <1 %, regardless of STK11 mutation status (N=90). • Cohort B: participants whose tumors harbor a KRAS G12C mutation, a PD-L1 expression >1 % and a STK1 1 co-mutation (N=30).

Compound A administered to all subjects as study treatment:

■ COMPOUND A per os (PO) 200 mg twice a day continuously (i.e. with no drug holiday). Key Inclusion criteria

• Histologically confirmed locally advanced (stage lllb/lllc ineligible for definitive chemoradiation or surgery) or metastatic (stage IV) NSCLC participants without previous systemic treatment for metastatic disease. Prior (neo)adjuvant treatment with chemotherapy and/or immunotherapy, or prior radiotherapy administered sequentially or concomitantly with chemotherapy and/or immunotherapy for localized or locally advanced disease are accepted if the time between therapy completion and enrollment is > 12 months.

• Presence of a KRAS G12C mutation (all patients) and:

• Cohort A: PD-L1 expression <1%, regardless of STK11 mutation status

• Cohort B: PD-L1 expression >1 % and a STK11 co-mutation

• At least one measurable lesion per RECIST 1.1.

• ECOG performance status < 1 .

• Participants with brain metastases are allowed if clinically stable.

• Participants capable of swallowing study medication.

Key Exclusion criteria

• Participants with EGFR activating mutations or ALK rearrangements are not eligible. Participants with other targetable mutations diagnosed per local tests will be excluded if required by local guidelines.

• Previous use of a KRAS G12C inhibitor or previous systemic treatment for metastatic NSCLC.

• A medical condition that results in increased photosensitivity (i.e. solar urticaria, lupus erythematosus, etc).

• Participants who are taking a prohibited medication (strong CYP3A inducers) that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study

Example 3: A randomized, multicenter phase ll/lll study evaluating the efficacy and safety of opnurasib combined with pembrolizumab versus pembrolizumab as first-line therapy for adult participants with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and and have a PD-L1 expression > 50%:

A study to investigate the efficacy and safety of opnurasib and pembrolizumab as first-line therapy for adult participants with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors harbor KRAS G12C mutation and have a PD-L1 expression > 50%.

Objectives and endpoints: Objective(s) Endpoint(s)

Primary objective(s) Endpoint(s) for primary objective(s)

• Phase II • Overall response rate (ORR) defined as

To determine the dose of opnurasib (100 the proportion of participants with a mg BID vs 200 mg BID) in combination confirmed best overall response (BOR) of with pembrolizumab when given as first- complete response (CR) or partial line therapy for adult participants with response (PR) per RECIST 1.1 by local advanced KRAS G12C-mutated non- radiology assessment squamous NSCLC and PD-L1 expression • Safety: type, incidence and severity of >50% AEs, SAEs and deaths

• Tolerability: dose interruptions, reductions, dose intensity and duration of exposure to study treatment and for each study drug

• Phase III • Dual primary endpoints:

To determine whether treatment with the • PFS defined as the time from the date of combination of opnurasib + randomization to the date of the first pembrolizumab (Arm A) as first-line documented progression or death due to therapy for adult participants with any cause. PFS will be assessed per advanced KRAS G12C-mutated non- RECIST 1.1 by local radiology squamous NSCLC and PD-L1 expression assessment >50% is more efficacious compared to • OS defined as the time from the date of -placebo + pembrolizumab (Arm B). randomization to the date of death due to any cause.

Secondary objective(s) Endpoint(s) for secondary objective(s)

• Phase II • The following endpoints will be determined

To assess the anti-tumor activity of per RECIST 1.1 by local radiology opnurasiv + pembrolizumab (Arm 1 and assessment: Arm 2) 1 . Disease control rate (DCR), defined as the proportion of participants with a confirmed BOR of CR, PR, or stable disease (SD);DOR and proportion of participants with a duration of response (DOR) > 12 weeks. DOR is defined as the time between the date of the first Objective(s) Endpoint(s) documented response (CR or PR) and the date of the first documented progression or death due to any cause;

2. Time to response (TTR), defined as the time from the date of randomization to the date of the first documented response of either CR or PR;

3. PFS rates 12 weeks. PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause.

• Phase II Other safety parameters (e.g.

To characterize the safety profile of study electrocardiograms (ECGs), vital signs, treatment laboratory values)

• Phase II • Plasma concentrations vs time profiles

To characterize the pharmacokinetics and derived PK parameters (i.e. , AUC, (PK) of COMPOUND A and Cmax etc.) of COMPOUND A. pembrolizumab (Arm 1 and Arm 2). • Serum concentrations of pembrolizumab

• Phase III All following endpoints will be determined per

To assess the anti-tumor activity of RECIST 1.1 by local radiology assessment: opnurasib + pembrolizumab (Arm • ORR

A) compared to placebo + pembrolizumab • DCR (Arm B)

• DOR

• TTR

• Phase III All intracranial endpoints will be determined

To assess the intracranial anti-tumor per response assessment in neuro-oncology activity of opnurasib + pembrolizumab brain metastases (RANO-BM) criteria by local (Arm A) compared to placebo + radiology assessment: pembrolizumab (Arm B) in all randomized • Overall intracranial response rate (OIRR) participants who have measurable and/or • Intracranial disease control rate (IDCR) non-measurable brain metastases at

• Duration of intracranial response (DOIR) baseline

• Time to intracranial response (TTIR)

• Phase III • Safety: Type, incidence and severity of

To characterize the safety profile and AEs, deaths, changes in laboratory tolerability- of study treatment values, vital signs, ECGs Objective(s) Endpoint(s)

• Tolerability: dose interruptions, reductions, dose intensity and duration of exposure to study treatment and for each study drug.

• Phase III PFS-2 defined as the time from the date of

To assess the benefit of next-line therapy randomization to the first documented in the two arms. progression on next line therapy or death due to any cause, whichever occurs first. PFS-2 will be based on local assessment.

• Phase III • PK concentrations of COMPOUND A

To characterize the pharmacokinetics of • Serum concentration of pembrolizumab COMPOUND A and pembrolizumab (Arm A)

• Phase III Primary PRO variables of interest:

To complement other evidences of clinical Change from baseline overtime in disease outcomes (safety, efficacy) by assessing related symptoms of: patient reported symptoms, functioning • Dyspnea as measured by QLQ-C30 and and tolerability with patient-reported by QLQ-LC13 outcomes • Cough as measured by QLQ-LC13

• Chest pain as measured by QLQ-LC13

• Change from baseline over time in physical functioning as measured by QLQ-C30

Secondary PRO variables of interest:

• Change from baseline over time for all remaining QLQ-LC13 and QLQ-C30 scales and items

• Time to deterioration for the subscales for QLQ-LC13 and QLQ-C30

• Change from baseline to each scheduled assessment for EQ-5D-5L; utility index and VAS scores

• Phase III Time to definitive deterioration of the ECOG

To assess the effect of opnurasib + Performance Status pembrolizumab (Arm A) compared to Objective(s) Endpoint(s) placebo + pembrolizumab (Arm B) on participant performance status.

Study population:

Inclusion criteria:

Participants eligible for inclusion in this study must meet all of the following criteria prior to randomization:

1. Signed informed consent must be obtained prior to randomization in the study

2. Adult > 18 years old at the time of informed consent

3. Histologically confirmed locally advanced (stage lllb/lllc ineligible for definitive chemoradiation or surgery) or metastatic (stage IV) non-squamous NSCLC subjects (according to Version 8 of the American Joint Committee on Cancer) (Chun et al 2018). Subjects with mixed but predominant non-squamous histology are also eligible.

4. Subjects without previous systemic treatment for metastatic disease, eligible to receive treatment with an immune checkpoint inhibitor per Investigator's assessment. Subjects who received previous chemotherapy and/or immune checkpoint inhibitors in the (neo)adjuvant setting or concomitantly/sequentially with radiation therapy are allowed if previous treatment was completed at least 12 months before randomization. Prior KRAS inhibitors are not allowed.

5. KRAS G12C mutation positive status assessed as follows:

For phase 2: In tumor tissue or plasma by a local test, validated according to local regulation at a Clinical Laboratory Improvement Amendments (CLIA)-certified USA laboratory or an accredited local laboratory outside of the USA or centrally assessed on tissue or plasma (only if tissue is unavailable or results from tissue are indeterminant) at a Novartis-designated laboratory prior to enrolment.

For Phase 3: In tumor tissue by a local test, validated according to local regulation at a Clinical Laboratory Improvement Amendments (CLIA)-certified USA laboratory or an accredited local laboratory outside of the USA or centrally assessed on tissue or plasma (only if tissue is unavailable or results from tissue are indeterminant) at a Novartis-designated laboratory prior to enrolment.

6. High PD-L1 status as defined by a PD-L1 expression >50% as assessed in tumor tissue: For the phase II part: PD-L1 expression >50% as assessed in tumor tissue by any local PD-L1 assay validated according to local regulation at a Clinical Laboratory Improvement Amendments (CLIA)-certified USA laboratory or an accredited local laboratory outside of the USA; If local result for PD-L1 is not available at pre-screening, then PD-L1 status needs to be centrally assessed at a Novartis-designated laboratory prior to randomization.

For the phase III part: PD-L1 expression >50% locally assessed in tumor tissue by PD- L1 IHC assay using either Agilent 22C3 using tumor proportion score (TPS) scoring or Ventana SP263 using tumor cells (TC) scoring, validated according to local regulation at a Clinical Laboratory Improvement Amendments (CLIA)-certified USA laboratory or an accredited local laboratory outside of the USA; If local result for PD-L1 is not available at pre-screening, or if PD-L1 expression is assessed locally using PD-L1 assays other than Agilent 22C3 (TPS) or Ventana SP263 (TC), then PD-L1 status needs to be centrally assessed at a Novartis-designated laboratory prior to randomization

7. At least one measurable lesion as defined by RECIST 1.1 according to local radiology assessment at screening. A previously irradiated lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.

8. Adequate organ function including the following laboratory values at the screening visit: Subjects must not have required blood transfusion or growth factor support < 14 days before sample collection at screening.

• Absolute neutrophil count (ANC) > 1.5 x 10⁹/L,

• Platelets > 100 x 10⁹/L,

• Hemoglobin (Hgb) > 9 g/dL,

• Aspartate transaminase (AST) < 2.5 x upper limit of normal (ULN), or < 5 x ULN if hepatic metastases present,

• Alanine aminotransferase (ALT) < 2.5 x ULN, and or < 5 x ULN if hepatic metastases present,

• Total bilirubin < 1 .5 ULN (total bilirubin must be < 3 x ULN for patients with Gilbert syndrome),

• Serum amylase < 2 x ULN,

• Serum lipase < 1 .5 x ULN,

• Creatinine clearance > 45 mL/min by calculation using CKD-EPI equation

9. ECOG performance status < 1 .

10. Participant is capable of swallowing study medication and following instructions regarding study treatment administration, or have a daily caregiver(s) who will be responsible for administering study treatment.

11 . Participant is able to communicate with the Investigator and has the ability to comply with the requirements of the study procedures.

Exclusion criteria: Participants meeting any of the following criteria are not eligible for inclusion in this study:

1 . Subjects with squamous cell NSCLC. Tumors with mixed predominantly squamous histology are also ineligible.

2. Subjects whose tumors harbor an EGFR-sensitizing mutation and/or ALK rearrangement by local laboratory testing. Note: subjects with other known druggable alterations will be excluded if targeted therapy is available as per local guidelines.

3. Previous treatment with KRAS inhibitor.

4. Any condition that requires systemic treatment with either corticosteroid (equivalent to > 10 mg daily of prednisolone) or other immunosuppressive medication < 14 days before randomization. Use of corticosteroids (equivalent to prednisolone < 10 mg) for any indication, (including brain metastases), is allowed.

5. History of severe hypersensitivity reaction to monoclonal antibodies, opnurasib, or any known excipients of these drugs.

6. Presence or history of a malignant disease, other than the resected NSCLC, that has been diagnosed and/or required therapy within 3 years prior to randomization. Exceptions to this criterion are completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

7. Subject has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to randomization or has not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and subject can be enrolled in the study > 1 week after the procedure.

8. Thoracic radiotherapy to lung fields < 4 weeks prior to randomization or subjects who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs) radiotherapy < 2 weeks prior to randomization or has not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions < 2 weeks prior to randomization is allowed.

9. Known active (unstable/symptomatic) central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with brain metastasis found on screening are eligible to the study if asymptomatic. Subjects with previously treated and, at the time of screening, stable brain metastases may participate provided they meet the following criteria:

• Brain imaging at screening shows no evidence of interim progression since prior imaging;

• Clinically stable for > 2 weeks prior to randomization;

• Have measurable disease outside CNS as per RECIST 1.1 ; • Requirement for corticosteroids as therapy for CNS disease does not exceed the equivalent of 10mg of prednisolone daily;

• No stereotactic radiation or whole-brain radiation < 14 days prior to randomization;

• Recovered from brain metastasis surgery;Note: Stable brain metastasis by this definition should be established prior to randomization and subject must be clinically stable until the first dose of study treatment.

10. Clinically significant, uncontrolled cardiac disease and/or recent cardiac events (within 6 months), such as:

• Unstable angina or myocardial infarction within 6 months prior to screening.

• Symptomatic congestive heart failure (defined as New York Heart Association Grade II or greater).

• Documented cardiomyopathy.

• Clinically significant cardiac arrhythmias.

• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) > 160 mm Hg and/or Diastolic Blood Pressure (DBP) > 100 mm Hg, unless controlled prior to randomization.

11 . History or current diagnosis of ECG abnormalities indicating significant risk of safety for study participation such as:

• Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker.

• History of familial long QT syndrome or known family history of Torsades de Pointes.

• Resting QT interval corrected with Fridericia’s formula (QTcF) > 480 msec on screening ECG or congenital long QT syndrome.

12. Any medical condition that results in increased photosensitivity (i.e., solar urticaria, lupus erythematosus, etc.).

13. History of interstitial lung disease or pneumonitis grade > 2.

14. Current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (i.e., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes etc.).

15. Any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment cause unacceptable safety risks, contra-indicate participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, uncontrolled diabetes, hepatic disorders including cirrhosis).

16. Any other medical condition (such as active infection, treated or untreated), which in the opinion of the Investigator represents an unacceptable risk for participation in the study. Note: testing for hepatitis B virus (HBV) or hepatitis C virus infection, tuberculosis and/or HIV (by local laboratory) is not mandatory at screening unless if required by local regulations.

17. Any medical condition or prior surgical resection that may affect the absorption of the investigational drug. Examples of medical conditions that may affect investigational drug absorption include (but are not limited to) inflammatory bowel disease (i.e. ulcerative colitis, Crohn’s disease) and gastrointestinal disease such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, and malabsorption syndrome.

18. Subjects who are taking a prohibited medication (strong CYP3A inducers) that cannot be discontinued at least seven days prior to randomization and for the duration of the study.

19. Use of any live vaccines against infectious diseases within four weeks prior to randomization.

20. Subject is concurrently using other anti-cancer therapy.

21. Participation in any additional, parallel, investigational drug or device studies.

22. Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Subjects with the following diseases are not excluded and may proceed to further screening: a. Controlled Type I diabetes b. Hypothyroidism (provided it is managed with hormone replacement therapy only) c. Celiac disease controlled by diet alone d. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia) e. Any other disease that is not expected to recur in the absence of external triggering factors.

23. Prior allogeneic stem cell transplantation or organ transplantation.

24. Untreated HIV infection, if known. Subjects with known HIV infection are eligible if the following criteria are met: a. Stable on antiretroviral therapy for > 4 weeks prior to randomization b. Subject agrees to adhere to antiretroviral therapy per WHO guidelines c. No documented multidrug resistance that would prevent effective antiretroviral therapy d. Viral load of < 400 copies per mL at screening e. CD4+ T-cell count > 350 cells per pL at screening. If no history of an AIDS-defining opportunistic infection < 12 months prior to randomization.

25. Pregnant or breast-feeding women or women who plan to become pregnant or breastfeed during the study. Pregnant women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during the study and 7 days after the last dose of opnurasib or 120 days after the last dose of pembrolizumab (whichever is longer is applicable). Female participants must not donate oocytes for the time period specified above. • Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception,

• Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment,

• Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant,

• Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.

Treatment of patients:

Phase II

Participants will be randomized to one of the following two treatment arms in a ratio of 1 :1

• Arm 1 : opnurasib (COMPOUND A) 200 mg per oral BID + pembrolizumab 200 mg IV every 21 days

• Arm 2: opnurasib (COMPOUND A) 100 mg per oral BID + pembrolizumab 200 mg IV every 21 days

Pembrolizumab will be administered up to a maximum of 35 cycles, until disease progression per RECIST 1.1 by local radiology assessment, unacceptable toxicity, consent withdrawal or Investigator's decision (whichever occurs first); opnurasib will be administered until disease progression per RECIST 1.1 by local radiology assessment, unacceptable toxicity, consent withdrawal or Investigator's decision (whichever occurs first).

Phase III

Participants will be randomized to one of the following two treatment arms in a ratio of 1 :1

• Arm A: opnurasib (COMPOUND A) selected dose + pembrolizumab

• Arm B: placebo + pembrolizumab Pembrolizumab will be administered up to a maximum of 35 cycles, until disease progression per RECIST 1.1 by local radiology assessment, unacceptable toxicity, consent withdrawal or Investigator's decision (whichever occurs first); opnurasib will be administered until disease progression per RECIST 1.1 by local radiology assessment, unacceptable toxicity, consent withdrawal or Investigator's decision (whichever occurs first).

End of treatment

Participants who discontinue from study treatment for any reason will be asked to return to the clinic for the End of treatment (EOT Visit), which is required to be conducted as soon as possible after the Investigator decides to permanently discontinue study treatment or before the initiation of a new anticancer treatment, whichever occurs first.

Claims

1. A method of treating non-small cell lung cancer (NSCLC) in a subject in need thereof, and which cancer harbors a KRAS G12C mutation, wherein the method comprises administering to the subject a therapeutically effective amount of 1 -{6-[(4M)-4-(5-Chloro-6-methyl-1 H- indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)-1 H-pyrazol-1 -yl]-2-azaspiro[3.3]heptan-2- yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically effective amount of pembrolizumab.

2. The method according to claim 1 , wherein the NSCLC expresses at least 1 % PD-L1 according to the tumor proportion score (TPS).

3. The method according to claim 1 or 2, wherein the NSCLC expresses at least 50% PD-L1 according to the tumor proportion score (TPS).

4. The method according to any one of claims 1 to 3, wherein the NSCLC expresses at least 90% PD-L1 according to the tumor proportion score (TPS).

5. The method according to any one of claims 1 to 4, wherein Compound A is administered at a dose of 200 mg per day or 400 mg per day in a single dose or divided doses.

6. The method according to any one of claims 1 to 5, wherein Compound A is administered once daily or twice daily.

7. The method according to any one of claims 1 to 6, wherein Compound A is administered at a dose of 100 mg twice daily or 200 mg twice daily.

8. The method according to any one of claims 1 to 7, wherein Compound A is administered during or after consuming food.

9. The method according to any one of claims 1 to 8, wherein pembrolizumab is administered at a dose of 200 mg.

10. The method according to claim 9, wherein pembrolizumab is administered via intravenous infusion.

11. The method according to claim 9 or 10, wherein pembrolizumab is administered at the beginning of every treatment cycle.

12. The method according to claim 1 1 , wherein the treatment cycle consists of 21 (±3) days.

13. The method according to any one of claims 1 to 12, wherein the treatment is given as first-line treatment.

14. The method according to any one of claims 1 to 13, wherein the progression-free survival (PFS) as determined by response evaluation criteria in solid tumors version 1 .1 (RECIST 1.1) is increased compared to treatment with pembrolizumab alone.

15. The method according to any one of claims 1 to 14, wherein the overall survival (OS) is increased compared to treatment with pembrolizumab alone.

16. The method according to any one of claims 1 to 15, wherein the disease control rate (DCR) as determined by response evaluation criteria in solid tumors version 1.1 (RECIST

1.1) is increased compared to treatment with pembrolizumab alone.

17. The method according to any one of claims 1 to 16, wherein the objective response rate (ORR) as determined by response evaluation criteria in solid tumors version 1 .1 (RECIST

1.1) is increased compared to treatment with pembrolizumab alone.

18. The method according to any one of claims 1 to 16, wherein the duration of response (DOR) as determined by response evaluation criteria in solid tumors version 1 .1 (RECIST

1.1) is increased compared to treatment with pembrolizumab alone.

19. 1 -{6-[(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H-indazol-5-yl)- 1 H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating non-small cell lung cancer (NSCLC) according to any one of claims 1 to 18.

20. Use of 1 -{6-[(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1 -methyl-1 H- indazol-5-yl)-1 H-pyrazol-1 -yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the manufacture of a medicine for the treatment of a method according to any one of claims 1 to 18.

21. A pharmaceutical combination comprising 1-{6-[(4M)-4-(5-Chloro-6-methyl-1 H-indazol-4- yl)-5-methyl-3-(1-methyl-1 H-indazol-5-yl)-1 H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2- en-1-one (Compound A), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a therapeutically acceptable amount of pembrolizumab.

22. The pharmaceutical combination of claim 21 , for use in therapy.

23. The pharmaceutical combination of claim 21 or 22, for use in a method of treating NSCLC according to any one of claims 1 to 18.