Dosage regimen of KRAS G12C inhibitor

Abstract

Disclosed herein is a dosing regimen for administering to a patient in need of such treatment a compound of Formula I: # imgabs0 #, or a pharmaceutically acceptable salt thereof, or in combination with one or more second therapeutic agents.

Description

[0001] The present disclosure relates to the field of cancer treatment. Background Art

[0002] Oncogenic KRas mutations have been found in approximately 30% of human cancers and have been shown to activate multiple downstream signaling pathways. Despite the ubiquity of KRas mutations, it has been a difficult therapeutic target.

[0003] WO 2021 / 118877 and US2021 / 0179633 A1 each disclose compounds or salts thereof that can be used as KRas G12C inhibitors. An example of a notable KRas G12C inhibitor is 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, which has the following structure:

[0004]

[0005] This compound is disclosed in WO 2021 / 118877 and US2021 / 0179633 A1 as Example 35, respectively. As disclosed therein, the compound exists as atropisomers. In addition, as discussed in Preparations 167 and 168 of these references, atropisomers can be separated using silica gel flash column chromatography. Preparation 167 further indicates that the desired diastereomer is the second diastereomer to elute from the silica gel flash column when eluted with 0-30% acetone / hexanes.

[0006] The second diastereomer corresponds to the M-atropenemster. The compound is named 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazacyclooctatetraen-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M-atropenemster (hereinafter referred to as "Formula I"), which has the following structure:

[0007]

[0008] The compound of Formula I is currently undergoing clinical trials (ClinicalTrials.gov identifier: NCT04956640) to evaluate its utility in treating patients with cancers treatable by inhibition of KRAS G12C.

[0009] It would be useful to develop new treatment regimens and protocols for treating cancer using the compounds of Formula I, whether as a monotherapy, in combination with one or more other therapeutic agents, or as part of a neoadjuvant, adjuvant, advanced, or metastatic therapy. It would be useful to develop treatment regimens and protocols that are more tolerable than current treatment regimens and protocols. It would be useful to develop treatment regimens and protocols that are less toxic than current treatment regimens and protocols. Summary of the invention

[0010] Disclosed herein are methods and uses of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating cancers that are treatable by inhibiting KRAS G12C.

[0011] In one aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer comprising administering to a patient in need of such treatment a compound of Formula I at a dose between about 50 mg and about 200 mg:

[0012]

[0013] or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg.

[0015] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer comprising administering to a patient in need of such treatment a dose of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg.

[0017] In yet another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, wherein the KRAS G12C mutant cancer is KRAS G12C mutant advanced NSCLC.

[0018] In yet another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg, wherein the KRAS G12C mutant cancer is KRAS G12C mutant advanced NSCLC.

[0019] In yet another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, wherein the KRAS G12C mutant cancer is a KRAS G12C mutant advanced CRC.

[0020] In yet another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg, wherein the KRAS G12C mutant cancer is KRAS G12C mutant advanced CRC.

[0021] In yet another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, wherein the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer.

[0022] In yet another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg, wherein the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer.

[0023] In yet another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer.

[0024] In yet another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg, wherein the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer.

[0025] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising

[0026] administering to a patient in need of such treatment a first dose of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof;

[0027] Monitor patients for dose-limiting toxicities (DLTs); and

[0028] If the patient exhibits a DLT, a second dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

[0029] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising

[0030] administering a first dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment;

[0031] Monitor patients for DLTs; and

[0032] If the patient exhibits a DLT, a second dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

[0033] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, in combination with one or more of a second therapeutic agent simultaneously, separately or sequentially. In one embodiment, the second therapeutic agent is selected from the group consisting of: a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof, an EGFR inhibitor or a pharmaceutically acceptable salt thereof, an ERK inhibitor or a pharmaceutically acceptable salt thereof, a platinum agent or a pharmaceutically acceptable salt thereof, an antifolate or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, and one or more of a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg in combination simultaneously, separately or sequentially with a second therapeutic agent.

[0035] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 100 mg in combination simultaneously, separately or sequentially with a second therapeutic agent.

[0036] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0037] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately, or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC.

[0038] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg simultaneously, separately or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC.

[0039] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC.

[0040] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg simultaneously, separately or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC.

[0041] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC.

[0042] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC.

[0043] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC.

[0044] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC.

[0045] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC.

[0046] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC.

[0047] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 150 mg to treat KRAS G12C mutant advanced non-squamous NSCLC.

[0048] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 100 mg to treat KRAS G12C mutant advanced non-squamous NSCLC.

[0049] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 50 mg to treat KRAS G12C mutant advanced non-squamous NSCLC.

[0050] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 150 mg to treat KRAS G12C mutant advanced non-squamous NSCLC.

[0051] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 100 mg to treat KRAS G12C mutant advanced non-squamous NSCLC.

[0052] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 50 mg to treat KRAS G12C mutant advanced non-squamous NSCLC.

[0053] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately, or sequentially in combination with abemaciclib to treat KRAS G12C mutant advanced NSCLC.

[0054] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with abemaciclib at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC.

[0055] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with abemaciclib at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC.

[0056] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with abemaciclib at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC.

[0057] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with erlotinib to treat KRAS G12C mutant advanced NSCLC.

[0058] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with erlotinib at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC.

[0059] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with erlotinib at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC.

[0060] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with erlotinib at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC.

[0061] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately, or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced NSCLC or CRC.

[0062] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC.

[0063] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced NSCLC.

[0064] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC.

[0065] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose of about 150 mg to treat KRAS G12C mutant advanced CRC.

[0066] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose of about 100 mg to treat KRAS G12C mutant advanced CRC.

[0067] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose of about 50 mg to treat KRAS G12C mutant advanced CRC.

[0068] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC.

[0069] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC.

[0070] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC.

[0071] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC.

[0072] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC or CRC.

[0073] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC.

[0074] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 100 mg simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC.

[0075] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC.

[0076] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced CRC.

[0077] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with TNO155 at a dose of about 100 mg to treat KRAS G12C mutant advanced CRC.

[0078] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced CRC.

[0079] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with cetuximab to treat KRAS G12C mutant advanced CRC.

[0080] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with cetuximab at a dose of about 150 mg to treat KRAS G12C mutant advanced CRC.

[0081] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with cetuximab at a dose of about 100 mg to treat KRAS G12C mutant advanced CRC.

[0082] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg simultaneously, separately or sequentially in combination with cetuximab to treat KRAS G12C mutant advanced CRC.

[0083] In another aspect, disclosed herein are compounds of formula I:

[0084] or a pharmaceutically acceptable salt thereof for use in treating KRAS G12C mutant cancer, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose between about 50 mg and about 200 mg.

[0085] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating a KRASG12C mutant cancer, wherein the compound is administered at a dose of about 150 mg.

[0086] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating KRASG12C mutant cancer, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg.

[0087] In another aspect, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating KRASG12C mutant cancer, wherein a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof simultaneously, separately, or sequentially in combination with a second therapeutic agent at a dose between about 50 mg and about 200 mg.

[0088] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating KRASG12C mutant cancer, wherein a dose of about 150 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0089] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating KRASG12C mutant cancer, wherein a dose of about 100 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0090] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating KRASG12C mutant cancer, wherein a dose of about 50 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0091] On the other hand, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0092] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating KRASG12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately, or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, a patient in need is a first-time Treated with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0093] On the other hand, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0094] On the other hand, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0095] On the other hand, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 150 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0096] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 100 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0097] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 50 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0098] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0099] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / min, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, including a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0100] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / min, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, including a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0101] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 150 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0102] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 100 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0103] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 50 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0104] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0105] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, including a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0106] On the other hand, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof for treating KRASG12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0107] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose between about 50 mg and about 200 mg.

[0108] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 150 mg.

[0109] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg.

[0110] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein

[0111] The compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a first dose selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg;

[0112] Monitor patients for DLTs; and

[0113] If the patient exhibits a DLT, a second dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

[0114] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein

[0115] The compound of formula I or a pharmaceutically acceptable salt thereof is administered in a first dose of about 150 mg;

[0116] Monitor patients for DLTs; and

[0117] If the patient exhibits a DLT, a second dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

[0118] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein

[0119] The compound of formula I or a pharmaceutically acceptable salt thereof is administered in a first dose of about 100 mg;

[0120] Monitor patients for DLTs; and

[0121] If the patient exhibits a DLT, a second dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

[0122] In yet another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the KRAS G12C mutant cancer is KRAS G12C mutant advanced NSCLC.

[0123] In yet another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof:

[0124]

[0125] The invention relates to a method for manufacturing a drug for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the KRAS G12C mutant cancer is KRAS G12C mutant advanced NSCLC.

[0126] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein the compound is administered at a first dose selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg; monitoring the patient for DLT; and if the patient exhibits DLT, administering a second dose of the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the second dose is reduced compared to the first dose.

[0127] In another aspect, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating KRASG12C mutant cancer, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a first dose of about 150 mg; the patient's DLT is monitored; if the patient exhibits DLT, a second dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered, wherein the second dose is reduced compared to the first dose. In one embodiment, the KRAS G12C mutant cancer is selected from the group consisting of KRAS G12C mutant advanced NSCLC, KRAS G12C mutant lung cancer, KRAS G12C mutant colorectal cancer, KRAS G12C mutant pancreatic cancer, KRAS G12C mutant bladder cancer, KRAS G12C mutant cervical cancer, KRASG12C mutant endometrial cancer, KRAS G12C mutant ovarian cancer, KRAS G12C mutant cholangiocarcinoma, and KRAS G12C mutant esophageal cancer. In another embodiment, the KRAS G12C mutant cancer is selected from the group consisting of: KRAS G12C mutant non-small cell lung cancer, KRAS G12C mutant pancreatic cancer, or KRAS G12C mutant colorectal cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant non-small cell lung cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant colorectal cancer.

[0128] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent at a dose between about 50 mg and about 200 mg.

[0129] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0130] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0131] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0132] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0133] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRASG12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0134] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 100 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRASG12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0135] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 50 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRASG12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0136] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with abemaciclib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC.

[0137] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with abemaciclib to treat KRAS G12C mutant advanced NSCLC.

[0138] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with abemaciclib to treat KRAS G12C mutant advanced NSCLC.

[0139] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with abemaciclib to treat KRAS G12C mutant advanced NSCLC.

[0140] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 150 mg to treat KRASG12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0141] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 100 mg to treat KRASG12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0142] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 50 mg to treat KRASG12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0143] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg to treat KRASG12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is greater than or equal to 50%.

[0144] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg to treat KRASG12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0145] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg to treat KRASG12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0146] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 150 mg to treat KRASG12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is greater than or equal to 50%.

[0147] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 100 mg to treat KRASG12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is greater than or equal to 50%.

[0148] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating KRAS G12C mutant cancer, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 50 mg to treat KRASG12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is greater than or equal to 50%.

[0149] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg to treat KRASG12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0150] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg to treat KRASG12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0151] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of drugs for treating KRAS G12C mutant cancers, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg to treat KRASG12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In yet another embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0152] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 150 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0153] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 100 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0154] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 50 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0155] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / min, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0156] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0157] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg to treat KRAS G12C mutant advanced non-squamous NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In another embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In yet another embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / min, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In yet another embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, the patient in need has received at least one treatment including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is greater than or equal to 50%.

[0158] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with erlotinib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC.

[0159] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with erlotinib to treat KRAS G12C mutant advanced NSCLC.

[0160] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with erlotinib to treat KRAS G12C mutant advanced NSCLC.

[0161] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with erlotinib to treat KRAS G12C mutant advanced NSCLC.

[0162] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC or CRC.

[0163] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced NSCLC.

[0164] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced NSCLC.

[0165] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced NSCLC.

[0166] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced CRC.

[0167] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced CRC.

[0168] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib to treat KRAS G12C mutant advanced CRC.

[0169] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt at a dose of between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC.

[0170] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC.

[0171] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC.

[0172] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC.

[0173] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC or CRC.

[0174] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC.

[0175] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC.

[0176] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced NSCLC.

[0177] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced CRC.

[0178] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced CRC.

[0179] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 to treat KRAS G12C mutant advanced CRC.

[0180] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with cetuximab at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced CRC.

[0181] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with cetuximab to treat KRAS G12C mutant advanced CRC.

[0182] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with cetuximab to treat KRAS G12C mutant advanced CRC.

[0183] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with cetuximab to treat KRAS G12C mutant advanced CRC. BRIEF DESCRIPTION OF THE DRAWINGS

[0184] Figure 1 The background is KRAS G12C.

[0185] Figure 2 Eligibility, design, and objectives for the LOXO-RAS-20001 study.

[0186] Figure 3 for patient and disease characteristics—monotherapy.

[0187] Figure 4 The pharmacokinetics of LY3537982.

[0188] Figure 5 Safety Profile - Monotherapy Escalation.

[0189] Figure 5ASafety Profile - Single Agent Dose Escalation. 50 mg BID had the lowest LY3537982 concentration in plasma. 100 mg BID was the second lowest. 150 mg BID was the second highest. 200 mg BID had the highest LY3537982 concentration in plasma.

[0190] Figure 6 Efficacy of dose escalation for LY3537982 monotherapy.

[0191] Figure 7 Patients and disease characteristics of NSCLC, LY3537982 + pembrolizumab combination (cohort B4).

[0192] Figure 8 Safety profile of the NSCLC LY3537982 + pembrolizumab combination (cohort B4).

[0193] Fig. 8A Safety profile of the NSCLC LY3537982 + pembrolizumab combination (cohort B4).

[0194] Fig. 9 Safety profile of the NSCLC LY3537982 + pembrolizumab combination (cohort B4).

[0195] Fig.10 Efficacy and treatment duration of the LY3537982 + pembrolizumab combination (cohort B4) in NSCLC.

[0196] Fig.11 Patient and disease characteristics of CRC, LY3537982 + cetuximab combination (cohort C2).

[0197] Fig.12 Safety profile of the LY3537982+cetuximab combination (cohort C2) in CRC.

[0198] Fig.13 Efficacy and treatment duration of the LY3537982 + cetuximab combination (cohort C2) in CRC.

[0199] Fig.14 The LOXO-RAS-20001 trial is in progress conclusion. DETAILED DESCRIPTION

[0200] Methods and uses utilizing compounds of Formula I or pharmaceutically acceptable salts thereof are described below.

[0201] definition

[0202] As used herein, the term "+14 days" or "+14 day window" refers to an additional 14-day period outside of the treatment cycle days. For example, before administering a dose of a compound of Formula I to a patient in need, a 21-day cycle of pembrolizumab must be started within 35 days of administering a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need. It should be noted that in this embodiment, the cycle of pembrolizumab must be started within 35 days of administering a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0203] The 95% confidence intervals were calculated using the Clopper-Pearson method.

[0204] As used herein, the term "BOR" refers to the best overall response based on investigator assessment using RECIST criteria (version 1.1). The minimum duration of BOR for SD is at least 6 weeks after the date of the first dose of study drug.

[0205] As used herein, the term "CR" refers to a complete response.

[0206] As used herein, the term "confirmed CR" refers to a confirmed complete remission, wherein confirmation of the CR is required to be at least 4 weeks after the initial documented date of remission.

[0207] As used herein, the term "cycle" refers to a treatment cycle. In Phase 1a and Phase 1b, each treatment cycle is 21 days. It should be noted that, in one embodiment, pembrolizumab is administered for no more than thirty-five cycles. In this embodiment, pembrolizumab is administered simultaneously, separately or sequentially in combination with a compound of Formula I or a pharmaceutically acceptable salt thereof, pemetrexed and cisplatin or carboplatin for up to four cycles. It should be noted that, in this embodiment, cisplatin or carboplatin is no longer administered after four cycles. In this embodiment, pembrolizumab is administered simultaneously, separately or sequentially in combination with pemetrexed for up to an additional thirty-one cycles. In this embodiment, the additional thirty-one cycles of the compound of Formula I or a pharmaceutically acceptable salt thereof, pembrolizumab and pemetrexed are outside the four cycles of the compound of Formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and cisplatin or carboplatin, so the cycle of pembrolizumab does not exceed thirty-five.

[0208] The disease control rate was defined as the proportion of patients with a best overall response of CR, PR, uPR, or SD.

[0209] As used herein, the term "DOR" refers to duration of response, wherein DOR (in months) is calculated as: event date or censoring date minus response start date plus 1 day, and then divided by 30.4375.

[0210] The efficacy-evaluable analysis set was defined as all patients with baseline and greater than or equal to one postbaseline disease assessment after the baseline assessment or who discontinued study treatment before the first postbaseline assessment.

[0211] As used herein, the term "MTD" refers to maximum tolerated dose.

[0212] As used herein, the term "NE" means not estimable.

[0213] As used herein, the term "QT prolongation" refers to a measure of delayed ventricular repolarization (ie, a prolongation of the time between the onset of the Q wave and the end of the T wave in an electrocardiographic measurement).

[0214] As used herein, the term "ORR" refers to objective response rate, wherein the objective response rate is the proportion of patients with BOR of CR or PR. The unconfirmed objective response rate is the proportion of patients with BOR of CR, PR or uPR.

[0215] Overall response status was defined as the patient's status at the time of the last disease assessment, which was performed on or before the data cutoff date.

[0216] As used herein, the term "PD" refers to progressive disease.

[0217] As used herein, the term "Pd" refers to palladium.

[0218] As used herein, the term "PDX" refers to a patient-derived xenograft.

[0219] As used herein, the term "PD-1" refers to programmed death receptor 1. Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, and Retifanlimab are each PD-1 inhibitors.

[0220] As used herein, the term "PD-L1" refers to programmed death-ligand 1. Atezolizumab, Avelumab, and Durvalumab are each PD-L1 inhibitors.

[0221] As used herein, the term "PR" refers to partial remission.

[0222] As used herein, the term "uPR" refers to a partial response pending confirmation, wherein confirmation of a PR is required at least 4 weeks after the initial documented date of response.

[0223] As used herein, the term "confirmed PR" refers to a confirmed partial response, wherein confirmation of the PR is required at least 4 weeks after the initial documented date of response.

[0224] As used herein, the term "RP2D" refers to the recommended Phase 2 dose. It should be understood that RP2D can refer to the respective recommended Phase 2 doses of a monotherapy or a combination therapy.

[0225] As used herein, the term "RP2D M ” refers to the recommended Phase II monotherapy.

[0226] As used herein, the term "SD" refers to stable disease.

[0227] As used herein, the term "TPS" refers to Tumor Proportion Score. For example, a patient may have a PD-L1 positive (TPS ≥ 1%) tumor as determined by IHC using the anti-PD-L1 antibody clone 22C3 in a local or sponsor-designated laboratory with CLIA, ISO / IEC, CAP or other similar certification in accordance with local guidelines (including but not limited to appropriate IVDR compliance).

[0228] As used herein, the term "TRAE" refers to a treatment-related adverse event.

[0229] As used herein, the term "TTR" refers to time to remission, wherein TTR (in months) is calculated as the date of onset of remission minus the date of first dose plus 1 day, divided by 30.4375.

[0230] As used herein, the term "ILD" refers to interstitial lung disease.

[0231] As used herein, the term "AUC" refers to the area under the concentration-time curve.

[0232] As used herein, the term "AST / ALT ratio" refers to the concentration ratio of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the blood of humans or animals.

[0233] As used herein, the term "HBsAg" refers to hepatitis B surface antigen.

[0234] As used herein, the term "HBV" refers to hepatitis B virus.

[0235] As used herein, the term "AE" refers to an adverse event.

[0236] As used herein, the term "irAE" refers to immune-related adverse events.

[0237] As used herein, the term "Gy" refers to the total amount of radiation exposure to a patient.

[0238] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is considered acceptable for clinical and / or veterinary use. For examples of pharmaceutically acceptable salts and common methods of preparing them, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl et al., 2nd Revised Edition, Wiley-VCH, 2011 and SM Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66 (1), 1-19, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33 :201-217 (1986); Bastin, RJ, et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4 :427-435(2000).

[0239] Herein, "effective amount" refers to a dose that is effective in treating a disorder or disease (such as a cancerous lesion or the progression of abnormal cell growth and / or cell division). Factors considered in determining the effective amount or dose of a compound include: whether the compound or its salt will be administered; co-administered other agents, such as use; the type of patient to be treated; the size, age and general health of the patient; the degree or stage and / or severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; and the use of other concomitant drugs.

[0240] The preferred pharmaceutical composition may be formulated as a capsule for oral administration. The capsule may contain an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective for treating a patient in need of cancer treatment.

[0241] As used herein, the terms "treating", "to treat" or "treatment" include slowing, alleviating or reversing the progression or severity of an existing symptom, disorder or condition, which may include specifically slowing the growth of cancerous lesions or the progression of abnormal cell growth and / or cell division.

[0242] As used herein, the term "patient" refers to a mammal in need of treatment. Preferably, the patient is a human in need of treatment for cancer (eg, cancer with a KRas G12C mutant).

[0243] As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment.

[0244] The term "pediatric" can be further divided into multiple subgroups, which include: neonates (birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 years to 21 years (up to but not including the 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0245] In some embodiments, a pediatric patient is from birth to the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or from 12 years of age to 21 years of age (up to but not including the 22nd birthday). In some embodiments, a pediatric patient is from birth to the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than 7 years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0246] In one embodiment, the patient is a human who has not received prior KRAS G12C inhibitor (KRAS G12Ci) therapy and is described herein as a KRAS G12Ci naive human. The patient may have received other treatments, including surgery or other drugs, but has not received KRAS G12Ci therapy.

[0247] In a preferred embodiment, the patient is a human who has received at least one therapy, including prior treatment with a KRAS G12C inhibitor. The patient may have received an unlimited number of other therapies, including surgery or one other prior therapy, or two other prior therapies, three other prior therapies, or four or more other prior therapies.

[0248] Prior KRAS G12Ci therapy requires that the patient has been previously treated with a KRAS G12Ci (such as sotorasib or adagrasib).

[0249] Certain abbreviations are defined as follows: “DMEM” refers to Dulbecco’s modified Eagle’s medium; “DPEPhosPdCl2” refers to dichlorobis(diphenylphosphinophenyl) ether palladium(II); “ERK” refers to extracellular signal-regulated kinase; “HPLC” refers to high performance liquid chromatography; and “PCR” refers to polymerase chain reaction.

[0250] Salt

[0251] The compounds of formula I can be readily converted into pharmaceutically acceptable salts and can be isolated as pharmaceutically acceptable salts. Salt formation can occur when a pharmaceutically acceptable acid is added to form an acid addition salt. Salts can also be formed while nitrogen or oxygen is deprotected, i.e., the protecting groups are removed.

[0252] form

[0253] The compound of formula I can be in the form of, for example, a free base or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula I is not a pharmaceutically acceptable salt, for example, it is a free base. In an alternative embodiment, the compound of formula I is a pharmaceutically acceptable salt. In a preferred embodiment, the compound of formula I is a free base.

[0254] For the avoidance of doubt, the dosages described herein refer to the amount of free base (e.g., the non-salt form of the compound of Formula I administered). For example, a dose of 200 mg would require more than 200 mg of a pharmaceutically acceptable salt of the compound of Formula I, since the weight of the salt counterion must be included.

[0255] cancer

[0256] Cancers that can be treated using the methods and protocols described herein include those that can be treated by inhibiting KRAS G12C. In other embodiments, the cancer has one or more cancer cells that express a mutant KRas G12C protein.

[0257] Examples of such cancers include, but are not limited to, lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, and esophageal cancer.

[0258] In a preferred embodiment, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In a more preferred embodiment, the cancer is non-small cell lung cancer or colorectal cancer. In a more preferred embodiment, the cancer is non-small cell lung cancer. In a more preferred embodiment, the cancer is pancreatic cancer. In a more preferred embodiment, the cancer is colorectal cancer.

[0259] dose

[0260] In some embodiments, the dosage is about 5 mg to about 250 mg, or about 25 mg to about 250 mg, or about 50 mg and about 200 mg. In some embodiments, the dosage is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg or 250 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the dosage is about 50 mg, about 100 mg, about 150 mg or about 200 mg. In one embodiment, the dosage is about 50 mg. In one embodiment, the dosage is about 100 mg. In one embodiment, the dosage is about 150 mg. In one embodiment, the dosage is about 200 mg. In another embodiment, the dosage is about 5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage is about 50 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0261] As used herein, the term "dose" refers to the total amount of a compound of Formula I or a pharmaceutically acceptable salt thereof administered at one time.

[0262] Dosage frequency (or dosage)

[0263] The term "dose" refers to a dose administered at a specific frequency.

[0264] The compound can be administered as needed. Typically, administration is once a day, twice a day, three times a day, or four times a day. In a preferred embodiment, administration is administration BID (twice a day). Typically, when administered twice a day, the two doses are of the same strength, for example, both doses are 50 mg, both doses are 100 mg, both doses are 150 mg, or both doses are 200 mg. However, as described in other parts of this article, for example, if the patient exhibits DLT, the dosage may be different. In this case, the second dose will be reduced relative to the first dose. Alternatively, the first dose and the second dose may be lower than the first dose and the second dose administered the day before. For example, if about 150 mg is administered as the first dose and the second dose on the 15th day of treatment, the first dose and the second dose on the 16th day of treatment may be reduced relative to the dose on the 15th day; for example, the first dose and the second dose on the 16th day may be both about 100 mg.

[0265] In one embodiment, the administering step continues until the end of the patient's life.

[0266] Maximum daily dose

[0267] As used herein, the term "maximum daily dose" refers to the total amount of the compound of formula I or its pharmaceutically acceptable salt taken within a 24-hour period. The maximum daily dose depends on the dose and frequency of administration applied. For example, the maximum daily dose may be 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg. For example, if 50 mg is applied once a day, the maximum daily dose of that day is 50 mg. If 100 mg is applied twice a day, the maximum daily dose of that day is 200 mg. If 150 mg is applied three times a day, the maximum daily dose of that day is 450 mg. If 200 mg is applied four times a day, the maximum daily dose of that day is 800 mg.

[0268] Dose-limiting toxicity (DLT)

[0269] "DLT" is defined as any of the treatment-induced adverse events (TEAEs) defined by the National Cancer Institute Common Terminology Standards for Adverse Events Version 5.0 (NCICTCAEv5.0), unless the adverse event (AE) can be clearly related to the patient's underlying disease, other medical conditions or concomitant drugs (including the investigator attributing any AE to a separate combination drug), it is considered clinically significant and occurs during the first 21 days of each dose of the study drug in each patient. TEAE is defined as an AE that begins or worsens during the first dose of the study drug (e.g., study day 1) to 28 days (+14 day window) after the last dose of the study drug or the first date of starting a novel anticancer treatment, whichever is earlier. Severe TEAEs are defined as TEAEs that are assigned to grade 3 or higher based on the severity level as defined by the National Cancer Institute Common Terminology Standards for Adverse Events Version 5.0 (NCICTCAEv5.0). Fatal TEAEs were defined as TEAEs assigned a grade of 5 based on the severity grade as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0).

[0270] In one embodiment, the treatment-emergent adverse event is hematologic toxicity, febrile neutropenia, hepatotoxicity, mucositis, diarrhea, ocular toxicity, QT prolongation, confirmed ILD, pneumonia, constipation, nausea or vomiting, fatigue, AST / ALT ratio, increased creatinine, increased or elevated bilirubin, neutropenia, anemia, or thrombocytopenia.

[0271] If the patient exhibits one or more symptoms, such as toxicity, clinically significant adverse events, intolerance, and drug interactions, the dose of the drug may be reduced. As used herein, the term "first dose" with respect to DLT refers to the dose of the compound of formula I or its pharmaceutically acceptable salt administered before the second or subsequent dose. In one embodiment, the first dose is not required to refer only to the first dose of the compound of formula I or its pharmaceutically acceptable salt administered to the patient. For example, the first dose may refer to the third or fifth dose administered to the patient, as long as the first dose is before the patient experiences DLT. In one embodiment, the patient presents a clinically significant adverse event and the second and / or subsequent doses are reduced relative to the dose administered before identifying the TEAE.

[0272] The reduced dose should help alleviate one or more symptoms, and preferably help the patient adhere to treatment. When one or more symptoms occur, each dose will usually reduce by about 200mg, about 150mg, about 100mg or about 50mg. Of course, the dose cannot be reduced by more than the original dose. For example, if the patient receives a 150mg dose BID, it is impossible to reduce 200mg. In this case, most doses can be reduced by about 100mg or about 50mg. In some embodiments, compared with the first daily dose, the second daily dose is reduced. In one embodiment, compared with the first daily dose, the second daily dose is reduced by 50mg. In another embodiment, compared with the first and second daily doses applied the day before, the first and second daily doses are reduced. In one embodiment, compared with the first dose, the second dose is reduced by 50mg, but when the first dose is 50mg, except when the first dose is 50mg, when the first dose is 50mg, the second dose is reduced by 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg or 45mg. In another embodiment, the second dose is reduced by 100 mg compared to the first dose, except when the first dose is 50 mg or 100 mg, when the first dose is 50 mg, the second dose is reduced by 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg, and when the first dose is 100 mg, the second dose is reduced by 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg or 95 mg.In one embodiment, the second dose is reduced by 150 mg compared to the first dose, except when the first dose is 50 mg, 100 mg or 150 mg, when the first dose is 50 mg, the second dose is reduced by 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg, and when the first dose is 100 mg, the second dose is reduced by 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg , 70mg, 75mg, 80mg, 85mg, 90mg or 95mg. When the first dose is 50mg, the second dose is reduced by 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg or 145mg.

[0273] If necessary, the second daily dose can be reduced to the third daily dose. When one or more symptoms occur, the second daily dose is usually reduced to the third daily dose. The second daily dose can be reduced by about 200mg, about 150mg, about 100mg or about 50mg. As previously mentioned, the dosage can not be reduced by more than the amount of the original dose. In a preferred embodiment, the third daily dose is less than about 50mg of the second daily dose. It should be clear that the third daily dose is not necessarily the third dose in a single day. On the contrary, it is the dosage applied when the second daily dose causes symptoms or needs to be reduced (whether on the same day or the following day). For example, if the patient receives a 150mg dose BID that causes DLT, a second daily dose of 100mg BID can be applied. If the patient receives a 100mg BID dose that causes DLT, a third daily dose of 50mg BID can be applied.

[0274] Dose reduction

[0275] Also disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a first dose of a compound of Formula I or a pharmaceutically acceptable salt thereof between about 50 mg and about 200 mg to a patient in need of such treatment; monitoring the patient for DLT; if the patient develops DLT, administering a second dose of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the second dose is reduced compared to the first dose. In one embodiment, the first dose is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg. In one embodiment, the second dose is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and about 150 mg.

[0276] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a second dose of a compound of Formula I or a pharmaceutically acceptable salt thereof selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg; monitoring the patient for DLT; if the patient exhibits DLT, administering a third dose of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the third dose is reduced compared to the second dose. In one embodiment, the third dose is reduced by 50 mg compared to the second dose.

[0277] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, administering a dose of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent, wherein the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is a reduced dose selected from the group consisting of about 50 mg, about 100 mg and about 150 mg.

[0278] method

[0279] The methods of treating cancer described herein include administering the doses described herein at the dosing frequencies described herein. Specific examples of the methods are described below.

[0280] In one aspect, disclosed herein is a method for treating a KRAS G12C mutant cancer, comprising administering to a patient in need thereof a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0281] In one aspect, disclosed herein is a method for treating a KRAS G12C mutant cancer, comprising administering to a patient in need thereof a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0282] In one aspect, disclosed herein is a method of treating cancer comprising administering to a patient in need thereof a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0283] In another aspect, disclosed herein is a method for treating a KRAS G12C mutant cancer, comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg. In one embodiment, the KRAS G12C mutant cancer is selected from the group consisting of KRAS G12C mutant advanced NSCLC, KRAS G12C mutant lung cancer, KRAS G12C mutant colorectal cancer, KRAS G12C mutant pancreatic cancer, KRAS G12C mutant bladder cancer, KRAS G12C mutant cervical cancer, KRAS G12C mutant endometrial cancer, KRAS G12C mutant ovarian cancer, KRASG12C mutant cholangiocarcinoma, and KRAS G12C mutant esophageal cancer. In another embodiment, the KRAS G12C mutant cancer is selected from the group consisting of: KRAS G12C mutant non-small cell lung cancer, KRAS G12C mutant pancreatic cancer or KRASG12C mutant colorectal cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant non-small cell lung cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant colorectal cancer.

[0284] In one aspect, disclosed herein is a method for treating a KRAS G12C mutant cancer, comprising administering to a patient in need thereof a dose of about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0285] In one aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, wherein after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, the patient achieves a partial remission (PR).

[0286] In one aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, wherein after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, the patient achieves a complete remission.

[0287] In one aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, wherein after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, the patient achieves stable disease ("SD").

[0288] In another aspect, disclosed herein is a method for treating a KRAS G12C mutant cancer, comprising administering a first dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment; monitoring the patient for DLT; if the patient exhibits DLT, administering a second dose of the compound or a pharmaceutically acceptable salt thereof, wherein the second dose is reduced compared to the first dose. In one embodiment, the KRAS G12C mutant cancer is selected from the group consisting of KRAS G12C mutant advanced NSCLC, KRAS G12C mutant lung cancer, KRAS G12C mutant colorectal cancer, KRASG12C mutant pancreatic cancer, KRAS G12C mutant bladder cancer, KRAS G12C mutant cervical cancer, KRAS G12C mutant endometrial cancer, KRAS G12C mutant ovarian cancer, KRAS G12C mutant cholangiocarcinoma, and KRAS G12C mutant esophageal cancer. In another embodiment, the KRAS G12C mutant cancer is selected from the group consisting of: KRAS G12C mutant non-small cell lung cancer, KRAS G12C mutant pancreatic cancer, or KRAS G12C mutant colorectal cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant non-small cell lung cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant colorectal cancer.

[0289] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with one or more second therapeutic agents at a dose between about 50 mg and about 200 mg. In one embodiment, the second therapeutic agent is selected from the group consisting of: a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof, an EGFR inhibitor or a pharmaceutically acceptable salt thereof, an ERK inhibitor or a pharmaceutically acceptable salt thereof, a platinum agent or a pharmaceutically acceptable salt thereof, an antifolate or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, and one or more of a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0290] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg in combination simultaneously, separately or sequentially with a second therapeutic agent.

[0291] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 100 mg in combination simultaneously, separately or sequentially with a second therapeutic agent.

[0292] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0293] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately, or in combination sequentially with pembrolizumab to treat KRAS G12C mutant advanced NSCLC. In one embodiment, the simultaneous, separate, or sequential combination includes that the patient has received no more than one previous cycle of pembrolizumab. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1, or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, including a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0294] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In one embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In one embodiment, the tumor proportion score (TPS) status of patients in need is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of patients in need is greater than or equal to 50%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%. In one embodiment, the combination includes that the patient has received no more than one previous cycle of pembrolizumab at the same time, separately or sequentially. In one embodiment, pembrolizumab is administered (or applied) 200mg once every three weeks. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, patients in need have received at least one treatment, which includes a previous KRAS G12C inhibitor. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is 0% to 100%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%.In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of KRASG12C mutant advanced NSCLC is greater than or equal to 50%.

[0295] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 100 mg to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In one embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In one embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0296] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 50 mg to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In one embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In yet another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In one embodiment, the tumor proportion score (TPS) status of a KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0297] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 150 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, patients in need have received at least one treatment, including a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0298] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 100 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, patients in need have received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0299] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of 50 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In another embodiment, patients in need have received at least one treatment, including a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In another embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0300] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0301] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0302] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In another embodiment, the patient in need has received at least one treatment, which includes a previous KRAS G12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 100%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRASG12C mutant advanced NSCLC is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 1% to 49%. In another embodiment, the tumor proportion score (TPS) status of the patient in need is greater than or equal to 50%. In yet another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0303] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and cisplatin, wherein the combination of the compound of Formula I or its pharmaceutically acceptable salt, pembrolizumab, pemetrexed and cisplatin is administered for up to four cycles, and then administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, to treat KRASG12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, the patient in need is a KRAS G12Ci, PD-1 or PD-L1 therapy-naive patient.

[0304] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and cisplatin, wherein the combination of the compound of Formula I or its pharmaceutically acceptable salt, pembrolizumab, pemetrexed and cisplatin is administered for up to four cycles, and then administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, to treat KRASG12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, the patient in need is a KRAS G12Ci, PD-1 or PD-L1 therapy-naive patient.

[0305] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and cisplatin, wherein the combination of the compound of Formula I or its pharmaceutically acceptable salt, pembrolizumab, pemetrexed and cisplatin is administered for up to four cycles, and then administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, to treat KRASG12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, the patient in need is a KRAS G12Ci, PD-1 or PD-L1 therapy-naive patient.

[0306] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and carboplatin, wherein the combination of the compound of Formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and carboplatin is administered for up to four cycles, followed by administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, at a dose of about 150 mg, to treat KRASG12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or applied) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0307] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and carboplatin, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and carboplatin is administered for up to four cycles, followed by administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, at a dose of about 150 mg, to treat KRASG12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or applied) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0308] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and carboplatin, wherein the combination of the compound of Formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and carboplatin is administered for up to four cycles, followed by administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, at a dose of about 150 mg, to treat KRASG12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or applied) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0309] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a first dose selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg; the patient's DLT is monitored; if the patient exhibits DLT, a second dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered, wherein the second dose is reduced compared to the first dose.

[0310] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a KRAS G12C mutant cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a first dose of about 150 mg; monitoring the patient's DLT; if the patient exhibits DLT, administering a second dose of the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the second dose is reduced compared to the first dose. In one embodiment, the KRAS G12C mutant cancer is selected from the group consisting of KRAS G12C mutant advanced NSCLC, KRAS G12C mutant lung cancer, KRASG12C mutant colorectal cancer, KRAS G12C mutant pancreatic cancer, KRAS G12C mutant bladder cancer, KRAS G12C mutant cervical cancer, KRAS G12C mutant endometrial cancer, KRAS G12C mutant ovarian cancer, KRAS G12C mutant cholangiocarcinoma, and KRAS G12C mutant esophageal cancer. In another embodiment, the KRAS G12C mutant cancer is selected from the group consisting of: KRAS G12C mutant non-small cell lung cancer, KRAS G12C mutant pancreatic cancer, or KRAS G12C mutant colorectal cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant non-small cell lung cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer. In another embodiment, the KRAS G12C mutant cancer is KRAS G12C mutant colorectal cancer.

[0311] KRAS G12C mutation status

[0312] The KRAS G12C mutation status of one or more cancer cells can be determined by a variety of detection methods known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained and sequenced and / or polymerase chain reaction (PCR) is performed. Circulating cell-free DNA can also be used, for example, in advanced cancer. Non-limiting examples of sequencing and PCR techniques for determining mutation status (e.g., G12C mutation status in one or more cancer cells or circulating cell-free DNA) include direct sequencing, next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrophosphate sequencing and multi-analyte analysis.

[0313] Combination - Methods and Uses

[0314] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with a second therapeutic agent. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg.

[0315] In one embodiment, the second therapeutic agent is selected from the group consisting of: a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof, an EGFR inhibitor or a pharmaceutically acceptable salt thereof, an ERK inhibitor or a pharmaceutically acceptable salt thereof, a platinum agent or a pharmaceutically acceptable salt thereof, an antifolate or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, and one or more of a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0316] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with a PD-1 or PD-L1 inhibitor at a dose between about 50 mg and about 200 mg, for the treatment of KRAS G12C mutant cancer. On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose between about 50 mg and about 200 mg, for the treatment of KRAS G12C mutant advanced NSCLC. In another embodiment, the PD-1 or PD-L1 inhibitor is pembrolizumab, which is administered (or administered) 200 mg once every three weeks. In another embodiment, the PD-1 or PD-L1 inhibitor is nivolumab. In another embodiment, the PD-1 or PD-L1 inhibitor is cimiplimab. In another embodiment, the PD-1 or PD-L1 inhibitor is sintilimab. In another embodiment, the PD-1 or PD-L1 inhibitor is atilizumab. In another embodiment, the PD-1 or PD-L1 inhibitor is avelumab. In another embodiment, the PD-1 or PD-L1 inhibitor is durvalumab. In another embodiment, the PD-1 or PD-L1 inhibitor is lodapilimab. In one embodiment, the dose of the compound of formula I or its pharmaceutically acceptable salt is administered once daily. In one embodiment, the dose of the compound of formula I or its pharmaceutically acceptable salt is administered twice daily. In one embodiment, the dose of the compound of formula I or its pharmaceutically acceptable salt is selected from the group consisting of: about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0317] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately, or sequentially in combination with pembrolizumab to treat KRAS G12C mutant advanced NSCLC, wherein pembrolizumab is administered intravenously at 200 mg once every three weeks. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0318] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg. On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Abemaciclib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC. In another embodiment, the CDK4 / CDK6 inhibitor is Abemaciclib, wherein Abemaciclib is administered at 150 mg BID. In another embodiment, the CDK4 / CDK6 inhibitor is palbociclib. In another embodiment, the CDK4 / CDK6 inhibitor is ribociclib. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0319] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg to a patient in need thereof, simultaneously, separately, or sequentially in combination with abemaciclib, to treat KRAS G12C mutant advanced NSCLC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0320] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with an EGFR inhibitor or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg. On the other hand, disclosed herein is a method for treating KRASG12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately or sequentially in combination with erlotinib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC. In another embodiment, the EGFR inhibitor is erlotinib, wherein erlotinib is administered 150 mg once daily. In another embodiment, the EGFR inhibitor is afatinib. In another embodiment, the EGFR inhibitor is gefitinib. In another embodiment, the EGFR inhibitor is cetuximab. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0321] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg to a patient in need thereof, simultaneously, separately, or sequentially in combination with erlotinib, to treat KRAS G12C mutant advanced NSCLC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0322] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg to a patient in need thereof, simultaneously, separately, or sequentially in combination with cetuximab, to treat KRAS G12C mutant advanced CRC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0323] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg. On the other hand, disclosed herein is a method for treating KRASG12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC or CRC. In another embodiment, the ERK inhibitor is Temuterkib, wherein Temuterkib is administered 400 mg twice daily. In another embodiment, the ERK inhibitor is LTT462. In another embodiment, the ERK inhibitor is KO-947. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0324] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg to a patient in need thereof, simultaneously, separately, or sequentially in combination with Temuterkib, to treat KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0325] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof in a dose of between about 50 mg and about 200 mg simultaneously, separately, or sequentially in combination with a platinum agent. In another embodiment, the platinum agent is cisplatin. In another embodiment, the platinum agent is carboplatin. In another embodiment, the platinum agent is oxaliplatin. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0326] On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, for simultaneous, separate or sequential administration in combination with an antifolate, for treating KRAS G12C mutant cancer. In another embodiment, the antifolate is pemetrexed. In one embodiment, a dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, a dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg.

[0327] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and an Aurora A inhibitor or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid: 2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC. In another embodiment, the Aurora A inhibitor is an aminopyridine compound or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is an Aurora A selective inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is alisertib as described in WO 2008 / 063525. In another embodiment, the Aurora A inhibitor is a pan-Aurora inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is tozasertib as described in WO 2004 / 000833. In another embodiment, the Aurora A inhibitor is danusertib as described in WO 2005 / 005427. In another embodiment, the Aurora A inhibitor is (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:

[0328]

[0329] or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt is an amine salt. An example of an amine salt is an NH3 amine salt. Another example of an amine salt is a 2-methylpropane-2-amine salt.

[0330] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt having the following structure:

[0331]

[0332] In another aspect, disclosed herein is a method for treating a KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt having the following structure:

[0333]

[0334] In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0335] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof in a dose of between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid: 2-methylpropan-2-amine (1:1) salt to treat KRASG12C mutant advanced NSCLC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg.

[0336] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately, or sequentially in combination with TNO155 at a dose between about 50 mg and about 200 mg, to treat KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the SHP2 inhibitor is a type I SHP2 inhibitor or a type II SHP2 inhibitor. In another embodiment, the type I SHP2 inhibitor is PHPS1 or GS-493, or a pharmaceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is NSC-87877 or NSC-117199, or a pharmaceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is cefsulodin, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is JAB-3068 or JAB-3312, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RMC-4550 or RMC-4630, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is SHP099, SHP244, SHP389, SHP394 or TNO155, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RG-6433 or RLY-1971, or a pharmaceutically acceptable salt thereof. On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and RMC-4630. In another aspect, disclosed herein is a method of treating a KRASG12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I at a dose between about 50 mg and about 200 mg, or a pharmaceutically acceptable salt thereof, and JAB-3068. In another embodiment, the SHP2 inhibitor is BBP-398, IACS-15509 or IACS-13909, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is X37, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is SH3809, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is HBI-2376, or a pharmaceutically acceptable salt thereof.In another embodiment, the SHP2 inhibitor is ETS-001, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is PCC0208023, or a pharmaceutically acceptable salt thereof. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0337] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg to a patient in need thereof, simultaneously, separately, or sequentially in combination with TNO155, to treat KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0338] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, administering a dose of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof, simultaneously, separately or sequentially in combination with a second therapeutic agent.

[0339] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating KRAS G12C mutant cancer, wherein a dose of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of: a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof, an EGFR inhibitor or a pharmaceutically acceptable salt thereof, an ERK inhibitor or a pharmaceutically acceptable salt thereof, a platinum agent or a pharmaceutically acceptable salt thereof, an antifolate or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, and one or more of a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0340] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a PD-1 or PD-L1 inhibitor at a dose of about 50 mg and about 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, for the treatment of KRAS G12C mutant cancer. In another embodiment, the PD-1 or PD-L1 inhibitor is pembrolizumab, which is administered (or administered) 200 mg once every three weeks. In another embodiment, the PD-1 or PD-L1 inhibitor is nivolumab. In another embodiment, the PD-1 or PD-L1 inhibitor is cemiplizumab. In another embodiment, the PD-1 or PD-L1 inhibitor is sindilimab. In another embodiment, the PD-1 or PD-L1 inhibitor is atezolizumab. In another embodiment, the PD-1 or PD-L1 inhibitor is avelumab. In another embodiment, the PD-1 or PD-L1 inhibitor is durvalumab. In another embodiment, the PD-1 or PD-L1 inhibitor is lodapilimab. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0341] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab to treat advanced NSCLC of the KRAS G12C mutant type, wherein pembrolizumab is administered intravenously at 200 mg once every three weeks. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0342] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In one embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In one embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0343] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy. In one embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In one embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0344] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab at a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, the patient in need is treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time. In one embodiment, the patient in need has received at least one treatment, which includes a previous KRASG12C inhibitor. In another embodiment, the tumor proportion score (TPS) status of the patient in need is 0% to 49%. In another embodiment, the tumor proportion score (TPS) status of the KRAS G12C mutant advanced NSCLC is 0% to 49%. In one embodiment, the tumor proportion score (TPS) status of the patient in need is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is 1% to 49%. In one embodiment, the tumor proportion score (TPS) status of a patient in need is greater than or equal to 50%. In one embodiment, the tumor proportion score (TPS) status of KRAS G12C mutant advanced NSCLC is greater than or equal to 50%.

[0345] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 150 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time.

[0346] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time.

[0347] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered (or administered) on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, cisplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time.

[0348] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 150 mg of a compound of formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / min, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0349] On the other hand, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In one embodiment, patients in need are treated with KRAS G12Ci, PD-1 or PD-L1 therapy for the first time.

[0350] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, which is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of about 50 mg of a compound of formula I or a pharmaceutically acceptable salt thereof to treat KRAS G12C mutant advanced NSCLC. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or administered) once every three weeks with an area under the curve (AUC) of 5 mg / ml / min, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, pembrolizumab is administered for up to thirty-five cycles. In one embodiment, carboplatin is administered for up to four cycles. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0351] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and cisplatin, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and cisplatin is administered for up to four cycles, and then a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, to treat KRAS G12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, the patient in need is a KRAS G12Ci, PD-1 or PD-L1 therapy-naive patient.

[0352] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially with pembrolizumab, pemetrexed and cisplatin, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and cisplatin is administered for up to four cycles, and then a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially with pembrolizumab and pemetrexed, to treat KRAS G12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, the patient in need is a KRAS G12Ci, PD-1 or PD-L1 therapy-naive patient.

[0353] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and cisplatin at a dose of about 50 mg, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and cisplatin is administered for up to four cycles, and then a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab and pemetrexed at a dose of about 150 mg to treat KRAS G12C mutant advanced NSCLC, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, cisplatin is administered (or administered) 75 mg / m2 once every three weeks. In one embodiment, pemetrexed and cisplatin are administered on the same day. In one embodiment, the patient in need is a KRAS G12Ci, PD-1 or PD-L1 therapy-naive patient.

[0354] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 150 mg, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and carboplatin is administered for up to four cycles, followed by administration of a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg simultaneously, separately or sequentially in combination with pembrolizumab and pemetrexed to a patient in need thereof, to treat advanced NSCLC of the KRAS G12C mutant type, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or applied) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0355] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 100 mg, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and carboplatin is administered for up to four cycles, followed by administration of a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg simultaneously, separately or sequentially in combination with pembrolizumab and pemetrexed to a patient in need thereof for the treatment of advanced NSCLC with KRAS G12C mutation, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or applied) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0356] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab, pemetrexed and carboplatin at a dose of 50 mg, wherein the combination of the compound of formula I or a pharmaceutically acceptable salt thereof, pembrolizumab, pemetrexed and carboplatin is administered for up to four cycles, followed by administration of a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of about 150 mg simultaneously, separately or sequentially in combination with pembrolizumab and pemetrexed to a patient in need thereof, to treat advanced NSCLC of the KRAS G12C mutant type, wherein pembrolizumab is administered for up to an additional thirty-one cycles. In one embodiment, pembrolizumab is administered (or administered) 200 mg once every three weeks. In one embodiment, pemetrexed is administered (or administered) 500 mg / m2 once every three weeks. In one embodiment, carboplatin is administered (or applied) once every three weeks with an area under the curve (AUC) of 5 mg / ml / minute, with a maximum dose of 750 mg. In one embodiment, pemetrexed and carboplatin are administered on the same day. In one embodiment, patients in need are treated for the first time with KRAS G12Ci, PD-1 or PD-L1 therapy.

[0357] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg. In another embodiment, the CDK4 / CDK6 inhibitor is abemaciclib, wherein abemaciclib is administered at 150 mg BID. In another embodiment, the CDK4 / CDK6 inhibitor is palbociclib. In another embodiment, the CDK4 / CDK6 inhibitor is reboxiclib. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0358] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with abemaciclib at a dose between about 50 mg and about 200 mg to treat advanced NSCLC with KRAS G12C mutants. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0359] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with an EGFR inhibitor or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg. In another embodiment, the EGFR inhibitor is erlotinib, wherein erlotinib is administered 150 mg once daily. In another embodiment, the EGFR inhibitor is afatinib. In another embodiment, the EGFR inhibitor is gefitinib. In another embodiment, the EGFR inhibitor is cetuximab. In one embodiment, a dose of a compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, a dose of a compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of a compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0360] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with erlotinib at a dose between about 50 mg and about 200 mg to treat advanced NSCLC with KRAS G12C mutants. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0361] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with cetuximab at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced CRC. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0362] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg. In another embodiment, the ERK inhibitor is Temuterkib, wherein Temuterkib is administered 400 mg twice daily. In another embodiment, the ERK inhibitor is LTT462. In another embodiment, the ERK inhibitor is KO-947. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0363] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with Temuterkib at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0364] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with a platinum agent at a dose between about 50 mg and about 200 mg. In another embodiment, the platinum agent is cisplatin. In another embodiment, the platinum agent is carboplatin. In another embodiment, the platinum agent is oxaliplatin. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0365] On the other hand, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need at a dose of between about 50 mg and about 200 mg, for simultaneous, separate or sequential administration in combination with an antifolate, for the treatment of KRAS G12C mutant cancer. In another embodiment, the antifolate is pemetrexed. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg.

[0366] In another aspect, disclosed herein is a use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a dose of between about 50 mg and about 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof and an Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to a patient in need thereof. In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of between about 50 mg and about 200 mg simultaneously, separately or sequentially in combination with (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC. In another embodiment, the Aurora A inhibitor is an aminopyridine compound or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is an Aurora A selective inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is alisertib as described in WO 2008 / 063525. In another embodiment, the Aurora A inhibitor is a pan-Aurora inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is tauzasertib as described in WO 2004 / 000833. In another embodiment, the Aurora A inhibitor is danasertib as described in WO 2005 / 005427. In another embodiment, the Aurora A inhibitor is (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0367] In another aspect, disclosed herein is a use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid: 2-methylpropan-2-amine (1:1) salt to treat KRAS G12C mutant advanced NSCLC. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0368] In another aspect, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof between about 50 mg and about 200 mg, and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof are administered to a patient in need thereof. In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof simultaneously, separately, or sequentially in combination with TNO155 at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the SHP2 inhibitor is a type I SHP2 inhibitor or a type II SHP2 inhibitor. In another embodiment, the type I SHP2 inhibitor is PHPS1 or GS-493, or a pharmaceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is NSC-87877 or NSC-117199, or a pharmaceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is cefsulodin, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is JAB-3068 or JAB-3312, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RMC-4550 or RMC-4630, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is SHP099, SHP244, SHP389, SHP394 or TNO155, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RG-6433 or RLY-1971, or a pharmaceutically acceptable salt thereof. On the other hand, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg, and RMC-4630. In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need thereof a compound of Formula I at a dose between about 50 mg and about 200 mg, or a pharmaceutically acceptable salt thereof, and JAB-3068. In another embodiment, the SHP2 inhibitor is BBP-398, IACS-15509 or IACS-13909, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is X37, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is SH3809, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is HBI-2376, or a pharmaceutically acceptable salt thereof.In another embodiment, the SHP2 inhibitor is ETS-001, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is PCC0208023, or a pharmaceutically acceptable salt thereof. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0369] In another aspect, disclosed herein is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof simultaneously, separately or sequentially in combination with TNO155 at a dose between about 50 mg and about 200 mg to treat KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0370] Example

[0371] Example 1

[0372] Antitumor growth activity in the H358 lung cancer xenograft mouse model

[0373] The purpose of this study was to determine the antitumor activity of the compound of formula I in a lung cancer H358 mouse xenograft model. H358 lung tumor cells (10 x 10 6 ) were implanted subcutaneously into the hind legs of nude female mice (Taconic Biosciences). Four mice were used in each group for efficacy studies. When the tumor size reached approximately 300 mg, the test compound or vehicle (20% The animals were treated with 25 mM phosphate, pH 2.0 in 0.2 ml volume, once or twice daily for 28 days. Tumor growth and body weight were monitored over time to assess efficacy and toxicity signs. The results are summarized in Table 1. Under the twice daily dosing regimen, at a dose of 30 mg / kg, the compound of formula I was observed to cause tumor regression of 67.68% to 72.14%. Throughout the study, no significant weight loss was observed with the compound.

[0374] Table 1: Anti-tumor growth activity in the H358 lung cancer xenograft mouse model

[0375]

[0376] Example 2

[0377] Antitumor growth activity in other lung cancer models, as well as colorectal, pancreatic, bladder, and esophageal cancer models

[0378] In addition to the H358 xenograft model, the compounds of Formula I were tested at various doses in other xenograft or patient-derived xenograft (PDX) models of lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, and esophageal cancer. For the xenograft models of H1373, HCC44, MiaPaca-2, SW1463, SW837, KYSE-410, and UM-UC-3, 5-10 x 10 6 Cells were mixed with 1:1 matrix gel (total volume of 0.2mL) and implanted into the hind legs of nude mice by subcutaneous injection. Four mice were usually used in each group for efficacy studies. When the tumor size reached about 200-300mg, treatment was started by oral (gavage) test compound or vehicle (20% Captisol, 25mM phosphate, pH2.0) volume 0.2mL. Tumor growth and body weight were monitored over time to evaluate efficacy and toxicity signs. For the EL3187 PDX model, the frozen vials containing tumor fragments were thawed in a 37°C water bath. The tumor fragments were transferred to a 50mL Falcon tube, and ice-cold DMEM medium was slowly added to the tube to a total volume of 35mL. The tumor fragments were then centrifuged at 30x g for 2 minutes at 4°C and the supernatant was aspirated. This washing step was repeated twice and the tumor fragments were resuspended in 10 mL of DMEM for implantation into athymic Foxn1 nude mice (Envigo RMS, Inc., Mount Comfort, Indiana). Once the tumor volume reached 800 to 1000 mm 3 The animals were sacrificed and the tumors were harvested using sterile techniques. Fresh tumors were cut into 10 to 15 mm 3 The tumor fragments were placed in cold Gibco hibernate medium. Tumor fragments were implanted subcutaneously into the animals using a 10 g trocar. When the tumor size reached 200 to 300 mm 3 At 4 pm, animals were randomized into groups for compound treatment.

[0379] The anti-tumor growth or regression activity of the compounds of formula I is summarized in Table 2. Among the models listed in Table 2, EL3187 is a patient-derived xenograft (PDX) model, and all other models are tumor xenograft models. As shown in Table 2, the compounds of formula I exhibited dose-dependent anti-tumor activity in all models, indicating that the compounds of formula I are active against cancers with KRasG12C mutations, including lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, and esophageal cancer.

[0380] Table 2: Anti-tumor growth activity of compounds of Formula I in lung cancer, colorectal cancer, pancreatic cancer, bladder cancer and esophageal cancer xenograft or PDX models.

[0381]

[0382] Example 3

[0383] Study of the Compound of Formula I in Patients with Advanced Solid Tumors with KRAS G12C Mutations

[0384] Study NCT04956640 is a first-in-human, multicenter, open-label, Phase 1a / 1b study designed to evaluate the safety, tolerability, and preliminary efficacy of an oral compound of Formula I. The compound of Formula I is being evaluated as monotherapy and as part of combination therapy in patients with KRAS G12C mutant advanced solid tumor types, including but not limited to NSCLC and CRC.

[0385] NCT04956640 includes a Phase 1a dose escalation (Part A of NCT04956640, see Table 3), followed by a Phase 1b dose expansion (Parts B to E of NCT04956640, see Table 4). In the Phase 1a dose escalation phase, the Formula I monotherapy cohort (see Table 3) will recruit any eligible patient with advanced solid tumors with KRAS G12C mutations. The Phase 1b dose expansion phase will include 12 cohorts (see Table 4) to further evaluate safety and clinical activity.

[0386] KRAS G12C mutations will be identified by standard of care testing, as routinely performed at each participating site using material collected prior to patient consent for this trial. Molecular testing for enrollment is required to be performed in a laboratory accredited under the Clinical Laboratory Improvement Amendments (CLIA), International Organization for Standardization / International Electrotechnical Commission (ISO / IEC), College of American Pathologists (CAP), or similar certification.

[0387] Table 3: NCT04956640 Phase 1a dose escalation

[0388]

[0389] Abbreviations: BID = twice daily; DL = dose level; PO = oral; PK = pharmacokinetics; QD = once daily; SRC = safety review committee

[0390] aBased on the totality of safety, PK / pharmacodynamics, and efficacy data, the SRC may consider a lower or intermediate dose DL, as well as an alternative dosing schedule (i.e., QD). Higher dose levels may be supported by clinical safety established at lower dose levels.

[0391] Table 4: NCT04956640 Phase 1b dose expansion

[0392]

[0393]

[0394]

[0395] Abbreviations: BID = twice daily; CRC = colorectal cancer; ERK = extracellular signal-regulated kinase; IV = intravenous; NSCLC = non-small cell lung cancer; PO = oral; QD = once daily; QW = once weekly; Q3W = once every 3 weeks.

[0396] a Based on the totality of safety, PK / pharmacodynamics, and efficacy data, the SRC may consider a lower or intermediate dose DL, as well as an alternative dosing schedule (i.e., QD). Higher dose levels may be supported by clinical safety established at lower dose levels.

[0397] Eligibility Criteria:

[0398] Inclusion Criteria

[0399] Each patient must meet all of the following inclusion criteria to be eligible to participate in the NCT04956640 study:

[0400] 1 Each patient must be ≥18 years old when signing the informed consent form.

[0401] 2 Patients were eligible if they had measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

[0402] 3 Patients must have disease with evidence of a KRASG12C mutation in tumor tissue or circulating tumor deoxyribonucleic acid (DNA) as determined by molecular testing routinely performed by a CLIA, ISO / IEC, College of American Pathologists (CAP), or other similarly certified laboratory. For the dose-escalation backfill cohort and Cohort E1, NSCLC patients who have progressed on a prior KRASG12C inhibitor must have a KRASG12C mutation confirmed in a blood or tumor tissue sample collected after discontinuation of the prior KRASG12C inhibitor.

[0403] 4 Each patient must have a histologically or cytologically confirmed diagnosis of locally advanced, unresectable and / or metastatic cancer and meet the criteria for the specific cohort:

[0404] a) Phase 1a dose escalation:

[0405] The patient must be an appropriate candidate for the experimental therapy, including palliative measures

[0406] The palliative measure is no longer valid or is considered by researchers to be inappropriate or unsafe.

[0407] b) Phase 1b dose expansion cohort B (NSCLC):

[0408] Patients must not have known targetable oncogenic driver mutations or alterations in genes such as EGFR, ALK, BRAF (V600E), MET (exon 14), ROS1, RET, or NTRK1 / 2 / 3.

[0409] Patients must be appropriate candidates for the experimental therapy, progressing on, being intolerant of, or experiencing adverse reactions to immunotherapy or platinum-based therapy.

[0410] to) or ineligible, and where palliative measures are no longer effective or the investigator deems them inappropriate or unsafe. If the investigator deems the existing standard of care inappropriate or unsafe, the rationale for its inappropriateness must be provided and documented in the case report form (CRF). In addition, if the investigator deems the patient intolerant to standard care, medication information, toxicity, and grade must be documented in the CRF.

[0411] · Specific criteria for cohort B9 only

[0412] Histologically or cytologically confirmed stage IIIB-IIIC or IV NSCLC, previously untreated in the advanced / metastatic setting, and not amenable to radical surgery or radiation therapy. Staging will be performed according to the American Joint Committee on Cancer (AJCC) staging system (8th edition). The histology of the tumor must be predominantly non-squamous. Squamous cell and / or mixed small cell / non-small cell histology is not permitted.

[0413] Patients may have received up to one 21-day cycle of pembrolizumab plus pemetrexed and cisplatin or carboplatin at doses as defined for Cohort B9 in Table 4. This therapy must have been started within 21 days (+14 days) prior to enrollment.

[0414] · Specific criteria for cohort B8 only

[0415] Patients must have at least 1 untreated, active brain metastasis, defined as new and / or growing lesions of at least 5 mm in diameter, without any subsequent local therapy prior to starting study treatment, and without associated neurological symptoms requiring urgent intervention with locoregional therapy. Patients with leptomeningeal disease are ineligible. Prophylactic anticonvulsants are permitted provided that participants have been on a stable dose for ≥14 days prior to Cycle 1 Day 1 (C1DI), but patients taking enzyme-inducing anticonvulsant drugs must have discontinued that therapy with a washout period equal to 5 half-lives of the drug.

[0416] The remaining Part B cohort

[0417] Patients must be suitable candidates for study treatment following progression, intolerance or ineligibility on immunotherapy and platinum-based therapy. Progression, intolerance or ineligibility on immunotherapy is not eligible for patients in Cohort B4.

[0418] c) Phase 1b dose expansion cohort C (CRC):

[0419] Patients must be appropriate candidates for the experimental therapy and must have received prior cytotoxic chemotherapy containing a fluoropyrimidine, oxaliplatin, and irinotecan for the treatment of advanced or metastatic CRC for which palliative measures were no longer effective or were considered inappropriate or unsafe by the investigator.

[0420] For Cohort C2, patients were enrolled only if, in the investigator's judgment, they were suitable for initiation of cetuximab at the standard dose of cetuximab in the cetuximab package insert.

[0421] d) Phase 1b dose expansion cohort D (solid tumors other than NSCLC and CRC):

[0422] Patients must have histologically or cytologically confirmed recurrent / metastatic, unresectable solid tumors (excluding NSCLC and CRC) with a KRASG12C mutation.

[0423] Patients must be appropriate candidates for the experimental therapy for whom palliative measures are no longer effective or are considered by the investigator to be inappropriate or unsafe.

[0424] e) Phase 1b dose expansion cohort E (NSCLC):

[0425] Patients must have progressed on a KRAS G12C inhibitor.

[0426] Patients must be appropriate candidates for the experimental therapy for whom palliative measures are no longer effective or are considered by the investigator to be inappropriate or unsafe.

[0427] f) Phase 1b dose expansion cohort F (pancreatic cancer):

[0428] Patients must have histologically or cytologically confirmed recurrent / metastatic, unresectable pancreatic cancer with a KRAS G12C mutation.

[0429] Patients must be appropriate candidates for the experimental therapy for whom palliative measures are no longer effective or are considered by the investigator to be inappropriate or unsafe.

[0430] g) Phase 1b dose optimization part G (NSCLC)

[0431] Patients must not have other validated oncogenic drivers in NSCLC if known, for example, altered activity in genes such as: EGFR, ALK, BRAF (V600E), MET (exon 14), ROS1, RET, or NTRK1 / 2 / 3.

[0432] Patients must have histologically or cytologically confirmed stage IIIB-IIC or IV NSCLC who have not been previously treated in the advanced / metastatic setting and are not suitable for radical surgery or radiation therapy. Staging will be performed according to the AJCC staging system (8th edition).

[0433] Prior to administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof, the patient may have received up to one previous cycle of pembrolizumab. The one previous cycle of pembrolizumab must have been completed within no more than 35 days prior to administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0434] Patients may have PD-L1 positive (TPS ≥ 1%) tumors as determined by IHC using the anti-PD-L1 antibody clone 22C3 in a local or sponsor-designated laboratory with CLIA, ISO / IEC, CAP or other similar certification in accordance with local guidelines (including but not limited to appropriate IVDR compliance).

[0435] 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6): 649-655).

[0436] 6 Have adequate organ function, as defined in Table 5 below:

[0437] Table 5:

[0438]

[0439]

[0440] Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; -GCSF = granulocyte colony-stimulating factor; -TBL = total bilirubin; -ULN = upper limit of normal.

[0441] NOTE: Transfusions to increase the patient's hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet participation criteria were not permitted within 14 days prior to participation. If the patient received transfusions, erythropoietin, or G-CSF therapy >14 days prior to participation, the blood criteria listed above must be met after the 14-day window and prior to participation.

[0442] 7 Each patient must have discontinued all previous cancer treatments, and any AEs (except alopecia and grade 2 neuropathy) must have resolved, and all clinically significant toxicities from previous local therapy, surgery, radiotherapy, or systemic anticancer therapy must have decreased to ≤ grade 1 or previous baseline. Patients with persistent secretory diseases that have not resolved due to previous treatment but are receiving appropriate replacement therapy (such as thyroid, adrenal or pituitary, or pancreas) are allowed to participate.

[0443] For Cohort B9 only: Participants who have experienced treatment-related toxicities related to one cycle of pembrolizumab plus pemetrexed with cisplatin or carboplatin (except immune-related toxicities outlined in Exclusion Criterion 24) may be enrolled if the investigator determines that these toxicities do not need to resolve at study entry and the participant remains an appropriate candidate for study treatment.

[0444] 8 Each patient must have discontinued previous treatment, as defined in Table 6 below:

[0445] Table 6:

[0446]

[0447] 9 Each patient must be able to swallow the capsule.

[0448] 10 Each patient must agree to and comply with male or female contraceptive measures consistent with local regulations on contraceptive methods for clinical research participants.

[0449] 11 Women of childbearing potential (WOCBP) patients were required to have a documented negative serum or urine pregnancy test within 7 days prior to participation.

[0450] 12 Each patient must have a life expectancy of ≥12 weeks.

[0451] 13 All patients were reliable, willing to be available during the study, and willing to comply with study procedures.

[0452] 14 Each patient must be able to provide signed informed consent.

[0453] Exclusion criteria

[0454] Patients who meet any of the following criteria are not eligible to participate in the LOXO-RAS-20001 study:

[0455] 1Diseases suitable for local therapy with curative intent.

[0456] 2. Have active fungal, bacterial, and / or untreated viral infection, including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis.

[0457] Note: For queue B4, queue B9 and section G only:

[0458] a) HIV-infected patients must be receiving antiretroviral therapy (ART) and their HIV infection / disease must be well controlled, specifically defined as:

[0459] Each patient receiving ART must have >350 cells / mm at screening 3 CD4+ T cell count.

[0460] Each patient receiving ART must achieve and maintain viral suppression, defined as a confirmed HIV RNA level of less than 50 copies / mL or the lower limit of acceptance (below the limit of detection) using a locally available test at the time of screening and for at least 12 weeks prior to screening.

[0461] Each patient receiving ART must be on a stable regimen with no medication or dose changes for at least 4 weeks prior to study entry (Day 1).

[0462] All HIV-infected patients with a history of Kaposi sarcoma and / or multicentric Castleman's disease were excluded.

[0463] b) Each HBsAg-positive patient is eligible if he / she has received at least 4 weeks of HBV antiviral treatment and has an undetectable HBV viral load before randomization.

[0464] Notice : Each patient maintained antiviral therapy during the study intervention and followed local guidelines for HBV antiviral therapy after the study intervention.

[0465] Hepatitis B screening tests are not needed unless:

[0466] Known history of HBV infection

[0467] Designated by the local health department

[0468] c) Each patient with a history of HCV infection is eligible if the HCV viral load is undetectable at screening.

[0469] Notice : Each patient must complete curative antiviral treatment at least 4 weeks before randomization.

[0470] Hepatitis C screening tests are not needed unless:

[0471] Known history of HCV infection

[0472] Designated by the local health department

[0473] 3. Patients have serious pre-existing diseases that, in the investigator's judgment, will exclude participation in this study, including interstitial lung disease (ILD), severe dyspnea at rest, or the need for oxygen therapy.

[0474] 4. Patients with clinically significant active cardiovascular disease, unstable angina or a history of myocardial infarction within 6 months prior to the planned start of treatment with a compound of Formula I, or a QT interval (QTcF) ≥ 470 milliseconds calculated using the Fridericia formula (QTcF) on the screening electrocardiogram (ECG) during consecutive days of assessment.

[0475] 5 Patients had a second active primary malignancy or had been diagnosed and / or treated for other malignancies within 3 years prior to enrollment, except for basal cell carcinoma of the skin that had been radically treated, non-metastatic prostate cancer that had been treated with observation only, squamous cell carcinoma of the skin, and / or in situ cervical cancer and / or breast cancer that had been radically resected.

[0476] 6 All patients except patients in cohort B8: Patients with symptomatic central nervous system (CNS) malignancies or metastatic cancer or carcinomatous meningitis. Patients who have been treated for CNS cancer metastases are eligible for this study if they are not currently receiving corticosteroids at a dose greater than 10 mg / day of prednisone / prednisolone (or equivalent), their disease is asymptomatic and imaging is stable for at least 30 days, and they have completed CNS-directed treatment (including radiation therapy and / or surgery) ≥28 days before the first dose of study intervention. Symptoms and imaging studies show stable disease (i.e., repeat imaging shows no signs of disease progression for ≥28 days). Clinically stable within 14 days before randomization, without the need for steroid therapy. Prophylactic use of anticonvulsants is allowed if the patient has been stable on anticonvulsants for ≥14 days before C1D1, but subjects taking enzyme-inducing antiepileptic drugs must discontinue such treatment with a washout period equal to 5 half-lives of the drug.

[0477] Previous / concomitant treatment

[0478] 7 Each patient must not have received any prior treatment with a KRAS G12C small molecule inhibitor, but such prior treatment is allowed in the following cases:

[0479] a) Phase 1a dose escalation backfill cohort (NSCLC only)

[0480] b) Queue E1

[0481] c) Queue B4

[0482] 8 Patients who have been treated with known strong inhibitors or inducers of cytochrome P450 (CYP) 3A (such as ketoconazole and rifampicin) are not eligible for inclusion in cohorts B2, B3, B5 / C1 unless the strong inhibitor or inducer of CYP3A has been discontinued (or switched to another drug) and a washout period of at least 5 half-lives has been performed before starting the study drug. Patients who are receiving drugs with a risk of QTc prolongation are not eligible to participate in cohorts B7 and C3.

[0483] 9 For patients who have received prior immunotherapy, the following patients will be excluded from Cohort B4, Cohort B9, and Part G:

[0484] a) Experience of grade 3 immune-related toxicity or any immune-related toxicity leading to permanent discontinuation of previous anti-PD-1, anti-PD-L1 or other immunotherapy

[0485] b) Grade ≤3 immune-related adverse events (irAEs) that did not recover to Grade 1 after the use of corticosteroids during previous immunotherapy, excluding endocrine disorders. Patients with previous endocrine adverse events are allowed to be included if they are asymptomatic, considered clinically stable, and maintain appropriate replacement therapy.

[0486] c) Any level:

[0487] i. Ocular irAEs,

[0488] ii. Severe neurological irAEs (such as Guillain-Barré syndrome, myasthenia gravis, encephalitis), or

[0489] iii. Severe cardiovascular irAE (such as myocarditis).

[0490] d) Requires immunosuppressants in addition to corticosteroids for management of irAEs, or currently requires a maintenance dose of ≥10 mg of prednisone / prednisolone (or equivalent) per day for irAEs.

[0491] 10 Exclude from Cohort B4, Cohort B9 and Section G each patient with any of the following:

[0492] a) Active autoimmune disease requiring systemic anti-autoimmune therapy (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered a form of systemic therapy and is permitted.

[0493] b).

[0494] c) Received live vaccines within 30 days before the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella / zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG)

[0495] Guérin, BCG) and typhoid vaccine. Seasonal influenza vaccines for injection are generally inactivated virus vaccines and are permitted; however, intranasal influenza vaccines are live attenuated vaccines and are therefore not permitted.

[0496] d) Have received allogeneic tissue / solid organ transplantation.

[0497] e) Severe hypersensitivity reaction (≥Grade 3) to pembrolizumab and / or any of its excipients.

[0498] f) received lung radiation therapy > 30 Gy within 6 months of the first administration of the compound of formula I.

[0499] Note: For Cohort B9 and Section G only:

[0500] g) Patients received prior systemic therapy (chemotherapy, immunotherapy, or biologic therapy) for advanced or metastatic disease, except for Cohort B9 participants as permitted in Inclusion Criteria 4. Patients receiving adjuvant or neoadjuvant therapy were eligible if the last dose of systemic therapy was completed at least 6 months prior to inclusion.

[0501] For patients receiving immunotherapy in the neoadjuvant or adjuvant setting, recurrence / flare-up of metastatic disease should occur at least 6 months after the last dose.

[0502] Note: Only for queue B9

[0503] h) Patients should not stop taking NSAIDs for 2 days before pemetrexed administration (5 days for long-acting NSAIDs), on the day of administration, and 2 days after administration.

[0504] i) The patient is unable or unwilling to take folic acid, dexamethasone or vitamin B12 supplements.

[0505] j) The patient has known hypersensitivity to carboplatin, cisplatin or any of the excipients of pemetrexed.

[0506] Other exclusions

[0507] 11 Patients who are pregnant, breastfeeding, or anticipate pregnancy or childbirth during the expected duration of the trial (from the screening visit to 180 days after the last dose of study drug).

[0508] 12 patients with known allergic reactions to components of the study treatment.

[0509] For Cohort B4, Cohort B9 and Part G only, patients with a history of (non-infectious) pneumonitis / interstitial lung disease requiring treatment with steroids, or patients with current pneumonitis / interstitial lung disease.

[0510] The patient had previously participated in another cohort of this study.

[0511] Table 7 shows the preliminary NCT04956640 Phase 1a clinical pharmacokinetic data.

[0512] Table 7:

[0513]

[0514] N represents the number of patients. b For 14 patients c For 11 patients.

[0515] The dose of 200 mg BID has been supported by the Phase 1a clinical safety of NCT04956640 established at a lower dose level. 200 mg BID is supported by the clearance of DLT at 150 mg BID. 150 mg BID is supported by the clearance of DLT at 100 mg BID. 100 mg BID is supported by the clearance of DLT at 50 mg BID. Higher dose levels may be supported by clinical safety established at lower dose levels.

[0516] Table 8 presents preliminary NCT04956640 Phase 1a clinical response data including intra-patient dose escalation.

[0517] Table 8:

[0518]

[0519]

[0520] + Eleven patients with scan data available. * 5 patients with scan data available.

[0521] Table 9 presents preliminary NCT04956640 Phase 1a clinical response data by response.

[0522] Table 9:

[0523]

[0524] Tables 10, 11 and 12 respectively show the preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4 and Phase 1b Cohort C2 data for adverse events occurring during treatment with the compound of Formula I or a pharmaceutically acceptable salt thereof at the starting dose as of January 2023.

[0525] Tables 10A and 11A present data as of April 2023 for adverse events occurring during treatment with a starting dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for the Phase 1a and Phase 1b Cohorts B4 of preliminary NCT04956640, respectively.

[0526] Table 10: Preliminary NCT04956640 Phase 1a data for adverse events arising from treatment with the starting dose of a compound of Formula I or a pharmaceutically acceptable salt thereof

[0527]

[0528] As shown in Table 10 above, no serious TEAEs related to the compound of Formula I or its pharmaceutically acceptable salts were observed in patients in Phase 1a. As shown in Table 10 above, no fatal TEAEs related to the compound of Formula I or its pharmaceutically acceptable salts were observed in patients in Phase 1a.

[0529] Table 10A: Preliminary NCT04956640 Phase 1a data for adverse events arising from treatment with the starting dose of a compound of Formula I or a pharmaceutically acceptable salt thereof

[0530]

[0531]

[0532] Table 11: Preliminary NCT04956640 Phase 1b Cohort B4 data for adverse events arising from treatment with the starting dose of a compound of Formula I or a pharmaceutically acceptable salt thereof

[0533]

[0534] As shown in Table 11 above, no patients in Phase 1b Cohort B4 experienced TEAEs related to the compound of Formula I or fatal TEAEs related to pembrolizumab.

[0535] Table 11A: Preliminary NCT04956640 Phase 1b Cohort B4 Data for Adverse Events Emerging from Starting Dose of Compound of Formula I

[0536]

[0537] Table 12: Preliminary NCT04956640 Phase 1b Cohort C2 Data for Adverse Events Emerging from Treatment with Starting Dose of Formula I Compound

[0538]

[0539] As shown in Table 12 above, no serious TEAEs related to the compound of Formula I were observed in patients in Phase 1b Cohort C2. As shown in Table 12 above, no serious TEAEs related to cetuximab were observed in patients in Phase 1b Cohort C2. As shown in Table 12 above, no fatal TEAEs were observed in patients in Phase 1b Cohort C2.

[0540] As shown in Tables 10-12 above, as of January 2023, 4 patients in Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 experienced TEAEs of Grade 3 or above. No DLT was observed and the MTD was not reached.

[0541] As of January 2023, 1 patient in Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 had a dose reduction due to a TRAE. As of January 2023, 1 patient in Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 had a permanent discontinuation due to a TRAE.

[0542] Tables 13, 14, and 15 present the preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 data as of January 2023, respectively, by starting dose of Formula I compound and severity of TRAEs.

[0543] Table 13: Preliminary NCT04956640 Phase 1a data of TRAEs by starting dose and severity of compound of Formula I,

[0544]

[0545] As shown in Table 13 above, no patients in Phase 1a experienced Grade 4 or 5 TEAEs related to the compound of Formula I.

[0546] Table 14: Preliminary NCT04956640 Phase 1b Cohort B4 Data for TRAEs by Starting Dose and Severity of Compound of Formula I

[0547]

[0548]

[0549] As shown in Table 14 above, no Grade 5 TEAEs occurred in Phase 1b Cohort B4 patients. No DLTs were observed in Phase 1b Cohort B4 patients. In Phase 1b Cohort B4 patients, delayed AST / ALT ratio increases were observed at 150 mg BID. In Phase 1b Cohort B4 patients, no dose reductions occurred at 50 mg and 100 mg BID. One discontinuation due to a TRAE occurred at 50 mg BID.

[0550] Table 15: Preliminary NCT04956640 Phase 1b Cohort C2 Data for TRAEs by Starting Dose and Severity of Formula I Compound

[0551]

[0552] As shown in Table 15 above, no patients in Phase 1b Cohort C2 experienced Grade 4 or 5 TEAEs. At 100 mg BID, 1 DLT was observed in a Phase 1b Cohort C2 patient, Grade 3 ALT / AST ratio increase. 10% of Phase 1b Cohort C2 patients had their dose of the compound of Formula I reduced due to TRAEs. No Phase 1b Cohort C2 patient permanently discontinued due to TRAEs.

[0553] Seven patients in Phase 1a, Phase 1b Cohort B4, or Phase 1b Cohort C2 discontinued their previous KRAS G12C inhibitors due to toxicity. The TRAE grade of these seven patients due to taking the compound of Formula I was less than Grade 2. Currently, all seven patients are still continuing treatment.

[0554] Tables 16, 17, and 18 present preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 data as of January 2023 for best overall response, objective response rate, and disease control rate by starting dose of the compound of Formula I, respectively. Table 16A presents preliminary NCT04956640 Phase 1a data for best overall response, objective response rate, and disease control rate by tumor type for starting dose of the compound of Formula I. Table 16B presents preliminary NCT04956640 Phase 1a data for best overall response, objective response rate, and disease control rate of the compound of Formula I in NSCLC patients with or without prior KRAS G12C inhibitors.

[0555] Table 16: Preliminary NCT04956640 Phase 1a data for best overall response, objective response rate, and disease control rate by starting dose of Formula I compound

[0556]

[0557]

[0558] As shown in Table 16 above, remissions have been observed at each starting dose level of the compound of Formula I: 50 mg BID, 100 mg BID, 150 mg BID, and 200 mg BID.

[0559] Table 16A: Preliminary NCT04956640 Phase 1a Data for Best Overall Response, Objective Response Rate, and Disease Control Rate by Tumor Type for Starting Dose of Formula I Compound

[0560]

[0561] Other tumor types included biliary cancer, bile duct cancer, chondrosarcoma, distal CBD cancer, duodenal cancer, jejunal adenocarcinoma, large cell neuroendocrine lung cancer, nasal malignant melanoma, ovarian tumor, salivary gland-like cystic carcinoma, small bowel tumor, tracheal basaloid squamous cell carcinoma, and upper tract urothelial carcinoma.

[0562] Table 16B: NSCLC patients (Pt) receiving or not receiving a compound of Formula I with or without prior KRAS G12C inhibitors

[0563]

[0564]

[0565] Table 17: Preliminary NCT04956640 Phase 1b Cohort B4 Data for Best Overall Response, Objective Response Rate, and Disease Control Rate by Starting Dose of Formula I Compound

[0566]

[0567] As shown in Table 17 above, responses have been observed at the starting dose levels of the compound of Formula I: 100 mg BID and 150 mg BID.

[0568] Table 18: Preliminary NCT04956640 Phase 1b Cohort C2 Data for Best Overall Response, Objective Response Rate, and Disease Control Rate by Starting Dose of Formula I Compound

[0569]

[0570] As shown in Table 18 above, responses have been observed at two starting dose levels of the compound of Formula I: 100 mg BID and 150 mg BID.

[0571] Tables 19, 20, and 21 present preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 data as of January 2023, respectively, summarized by duration of response at starting dose of Formula I compound.

[0572] Table 19: Preliminary NCT04956640 Phase 1a data summarized by duration of response of Formula I compound at starting dose

[0573]

[0574] 1 Estimates are based on the Kaplan–Meier method, with 95% confidence intervals calculated using the Brookmeyer and Crowley method.

[0575] The median treatment duration for patients in phase 1a was 3.8 months.

[0576] Table 20: Preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 Data as of January 2023 for TRAEs by Starting Dose of Formula I and Severity

[0577]

[0578] The median treatment duration for patients in Phase 1b Cohort B4 was 2.5 months.

[0579] Table 21: Preliminary NCT04956640 Phase 1b Cohort C2 Data Summary of Duration of Response by Starting Dose of Formula I Compound

[0580]

[0581] Tables 22, 23, and 24 present the preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 data as of January 2023, respectively, for the time to remission by starting dose of Formula I compound.

[0582] Table 22: Preliminary NCT04956640 Phase 1a data on time to remission by starting dose of Formula I compound

[0583]

[0584] As shown in Table 22 above, the median time to remission for Phase 1a patients was 1.4 months.

[0585] Table 23: Preliminary NCT04956640 Phase 1b Cohort B4 Data on Time to Remission by Starting Dose of Formula I Compound

[0586]

[0587] As shown in Table 23 above, the median time to remission for patients in Phase 1b Cohort B4 was 1.4 months.

[0588] Table 24: Preliminary NCT04956640 Phase 1b Cohort C2 Data on Time to Remission by Starting Dose of Formula I Compound

[0589]

[0590] As shown in Table 24 above, the median time to remission for patients in Phase 1b cohort C2 was 1.3 months.

[0591] The median time to remission for patients in Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 was 1.4 months. At a median follow-up of 4.2 months, 55% of patients in Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 remained on treatment. 100% of patients in Phase 1b Cohort B4 remained on treatment.

[0592] Tables 25, 26, and 27 present the preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 data as of January 2023 by starting dose of Formula I compound, prior KRAS inhibitor ("KRASG12Ci"), % change from baseline, and best response, respectively.

[0593] Table 25: Preliminary NCT049566401a Phase Data by Starting Dose of Formula I Compound, Prior KRAS Inhibitor ("KRAS G12Ci"), % Change from Baseline, and Best Response

[0594]

[0595]

[0596]

[0597] 2If the patient has received at least one KRAS G12Ci treatment, fill in "Y". If the patient has not received prior KRAS G12Ci treatment, leave blank.

[0598] One patient discontinued treatment before the first postbaseline assessment and is not included in Table 25. Two patients had postbaseline assessments, but not all target lesions were assessed at the time of data extraction and are not included in Table 25.

[0599] As shown in Table 25 above, Phase 1a patients who received prior KRAS G12Ci experienced PD, stable SD, and confirmed PR. The median treatment duration for Phase 1a patients was 3.8 months.

[0600] Table 26: Preliminary NCT049566401b Phase Cohort B4 Data by Starting Dose of Formula I Compound, Prior KRAS Inhibitor ("KRAS G12Ci"), % Change from Baseline, and Best Response

[0601]

[0602]

[0603] The median treatment duration for patients in the Phase 1b cohort B4 was 2.5 months.

[0604] Table 27: Preliminary NCT049566401b Phase Cohort C2 Data by Starting Dose of Formula I Compound, Prior KRAS Inhibitor ("KRAS G12Ci"), % Change from Baseline, and Best Response

[0605]

[0606] The median treatment duration for patients in the Phase 1b cohort C2 was 1.8 months.

[0607] Tables 28, 29, and 30 present preliminary NCT04956640 Phase 1a, Phase 1b Cohort B4, and Phase 1b Cohort C2 data as of January 2023, respectively, by starting dose of Formula I compound, prior KRAS inhibitor ("KRASG12Ci"), time, and parameter (wherein the parameter identifies the condition experienced at the corresponding time).

[0608] Table 28: Preliminary NCT049566401a Phase Data by Starting Dose of Formula I Compound, Prior KRAS Inhibitor ("KRAS G12Ci"), Time, and Parameter (Where the Parameter Identifies the Condition Experienced at the Corresponding Time)

[0609]

[0610]

[0611]

[0612]

[0613]

[0614] Table 29: Preliminary NCT04956640 Phase 1b Cohort B4 Data by Starting Dose of Formula I Compound, Prior KRAS Inhibitor ("KRAS G12Ci"), Time, and Parameter (Where the Parameter Identifies the Condition Experienced at the Corresponding Time)

[0615]

[0616] Table 30: Preliminary NCT04956640 Phase 1b Cohort C2 Data by Starting Dose of Formula I Compound, Prior KRAS Inhibitor ("KRAS G12Ci"), Time, and Parameter (Where the Parameter Identifies the Condition Experienced at the Corresponding Time)

[0617]

[0618] Tables 31 and 32 show the preliminary NCT04956640 Phase 1a and Phase 1b Cohort B4 data as of April 2023, respectively, by treatment duration at starting dose of Formula I compound.

[0619] Table 31: Preliminary NCT04956640 Phase 1a Data as of April 2023 by Treatment Duration of Formula I Compound by Starting Dose

[0620]

[0621]

[0622] Table 32: Preliminary NCT04956640 Cohort B4 Data as of April 2023 by Treatment Duration of Formula I Compound by Starting Dose

[0623]

[0624]

[0625] In summary, the compound of formula I was well tolerated by patients in phase 1a. The compound of formula I showed preliminary efficacy in patients in phase 1a at different dose levels and in a variety of tumor types.

[0626] The safety profile of Phase 1b Cohort B4 patients and Phase 1b Cohort C2 patients was surprisingly promising. The safety profile of Phase 1b Cohort B4 patients at 50 mg BID and 100 mg BID was noteworthy for low immune-related AEs, and 3 Phase 1b Cohort B4 patients received more than 4 months of treatment.

[0627] Embodiment 1. A method for treating KRAS G12C mutant cancer, comprising:

[0628] A dose of between about 50 mg and about 200 mg of a compound of formula I is administered to a patient in need of such treatment:

[0629]

[0630] or a pharmaceutically acceptable salt thereof.

[0631] Embodiment 2. The method according to embodiment 1, wherein the dosage of the compound of formula I is between about 50 mg and about 200 mg.

[0632] Embodiment 3. The method according to embodiment 1, wherein the dosage is a maximum daily dose selected from the group consisting of: 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg and 800 mg.

[0633] Embodiment 4. The method of embodiment 2, wherein the maximum daily dose is about 50 mg.

[0634] Embodiment 5. The method of embodiment 2, wherein the maximum daily dose is about 100 mg.

[0635] Embodiment 6. The method of embodiment 2, wherein the maximum daily dose is about 200 mg.

[0636] Embodiment 7. The method of embodiment 2, wherein the maximum daily dose is about 300 mg.

[0637] Embodiment 8. The method of embodiment 2, wherein the maximum daily dose is about 400 mg.

[0638] Embodiment 8-1. A method of treating a KRAS G12C mutant cancer comprising administering to a patient in need of such treatment a compound of Formula I at a dose between about 50 mg and about 200 mg.

[0639] Embodiment 9. A method according to any one of embodiments 1-8, wherein the KRAS G12C mutant cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer and esophageal cancer.

[0640] Embodiment 10. A method according to any one of Embodiments 1-9, wherein the KRAS G12C mutant cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer.

[0641] Embodiment 11. A method according t...

Claims

1. A method for treating KRAS G12C mutant cancer, comprising: A dose of between about 50 mg and about 200 mg of a compound of formula I is administered to a patient in need of such treatment: or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the compound is administered.

3. The method of claim 1, wherein the dose administered is a maximum daily dose selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, and about 800 mg.

4. The method of claim 3, wherein the maximum daily dose is about 50 mg.

5. The method of claim 3, wherein the maximum daily dose is about 100 mg.

6. The method of claim 3, wherein the maximum daily dose is about 200 mg.

7. The method of claim 3, wherein the maximum daily dose is about 300 mg.

8. The method of claim 3, wherein the maximum daily dose is about 400 mg.

9. The method of any one of claims 1-8, wherein the KRAS G12C mutant cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, and esophageal cancer.

10. The method of any one of claims 1-9, wherein the KRAS G12C mutant cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer.

11. The method of any one of claims 1-10, wherein the KRAS G12C mutant cancer is non-small cell lung cancer or colorectal cancer.

12. The method of any one of claims 1-9, wherein the KRAS G12C mutant cancer is non-small cell lung cancer.

13. The method of any one of claims 1-9, wherein the KRAS G12C mutant cancer is pancreatic cancer.

14. The method of any one of claims 1-9, wherein the KRAS G12C mutant cancer is colorectal cancer.

15. The method according to any one of claims 1 to 11, wherein the dose is administered to the patient at least once daily.

16. The method of claim 15, wherein the dose is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

17. The method of any one of claims 1 to 16, wherein the dose is in a capsule.

18. The method of claim 17, wherein the capsule contains about 25 mg or about 50 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

19. The method according to any one of claims 1 to 16, wherein the dose is administered to the patient at least twice daily.

20. The method according to any one of claims 1 to 18, wherein the dose is administered to the patient at least twice daily at a dose of about 50 mg.

21. The method according to any one of claims 1 to 18, wherein the dose is administered to the patient at least twice daily at a dose of about 100 mg.

22. The method according to any one of claims 1 to 18, wherein the dose is administered to the patient at least twice daily at a dose of about 150 mg.

23. The method according to any one of claims 1 to 18, wherein the dose is administered to the patient at least twice daily at a dose of about 200 mg.

24. The method according to any one of claims 1 to 23, comprising: Monitor patients for dose-limiting toxicities (DLTs); as well as If the patient exhibits a DLT, a second dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

25. The method of claim 24, wherein the first dose is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

26. The method of claim 24 or 25, wherein the second dose is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and about 150 mg.

27. The method of claim 24, wherein the second dose is reduced by 50 mg compared to the first dose.

28. The method of any one of claims 24 to 27, wherein the second dose is selected from the group consisting of about 50 mg, about 100 mg, and about 150 mg.

29. The method of any one of claims 24 to 28, wherein the DLTs include treatment-emergent adverse events and clinically significant determinations.

30. The method of any one of claims 24 to 29, wherein the DLT occurs within the first 21 days of administration of the first dose.

31. The method according to any one of claims 24 to 30, further comprising the steps of: (a) monitoring the patient for DLT after administering to the patient in need of such treatment a second dose of a compound of Formula I or a pharmaceutically acceptable salt thereof selected from the group consisting of about 50 mg, about 100 mg, and about 150 mg; and (b) if the patient exhibits DLT, administering a third dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the third dose is reduced compared to the second dose.

32. The method of claim 31, wherein the DLTs include treatment-emergent adverse events and clinically significant determinations.

33. The method of claim 31, wherein the DLT occurs within the first 21 days of administering the second dose.

34. The method of claim 32 or 33, wherein the adverse events occurring during the treatment are grade 3 or above.

35. The method of any one of claims 32 to 34, wherein the treatment-emergent adverse event is Grade 4.

36. The method of any one of claims 32 to 35, wherein the third dose is reduced by 50 mg compared to the second dose.

37. A method for treating KRAS G12C mutant cancer, comprising: A compound of Formula I in a dosage of between about 50 mg and about 200 mg is administered to a patient in need thereof in combination, simultaneously, separately or sequentially with a second therapeutic agent: or a pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein the second therapeutic agent is selected from one or more of the group consisting of a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof, an EGFR inhibitor or a pharmaceutically acceptable salt thereof, an ERK inhibitor or a pharmaceutically acceptable salt thereof, a platinum agent or a pharmaceutically acceptable salt thereof, an antifolate or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

39. The method of claim 38, wherein the PD-1 or PD-L1 inhibitor is pembrolizumab.

40. The method of claim 38, wherein the platinum agent is cisplatin.

41. The method of claim 38, wherein the platinum agent is carboplatin.

42. The method of claim 38, wherein the antifolate is pemetrexed.

43. A method for treating KRAS G12C mutant cancer, comprising: A compound of Formula I at a dose of between about 50 mg and about 200 mg is administered to a patient in need thereof simultaneously, separately or sequentially in combination with pembrolizumab: or a pharmaceutically acceptable salt thereof, to treat KRAS G12C mutant advanced NSCLC.

44. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: The invention relates to a method for preparing a medicament for treating KRAS G12C mutant cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose between about 50 mg and about 200 mg.

45. The use according to claim 44, wherein the dose is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg.

46. ​​Use of a compound of formula I or a pharmaceutically acceptable salt thereof: The invention relates to a method for treating KRAS G12C mutant cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a first dose selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg; Monitor patients for DLTs; and If the patient exhibits a DLT, a second dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered, wherein the second dose is reduced compared to the first dose.

47. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: The invention relates to a method for manufacturing a medicament for treating KRAS G12C mutant cancer, wherein a dose of between about 50 mg and about 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the KRAS G12C mutant cancer is KRAS G12C mutant advanced NSCLC.

48. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: A dosage of between about 50 mg and about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in simultaneous, separate or sequential combination with a second therapeutic agent.

49. The use according to claim 48, wherein the second therapeutic agent is selected from the group consisting of: a PD-1 inhibitor or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharmaceutically acceptable salt thereof, an EGFR inhibitor or a pharmaceutically acceptable salt thereof, an ERK inhibitor or a pharmaceutically acceptable salt thereof, a platinum agent or a pharmaceutically acceptable salt thereof, an antifolate or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, and one or more of a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

50. The use according to claim 49, wherein the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is a reduced dose selected from the group consisting of about 50 mg, about 100 mg and about 150 mg.

51. The use of claim 50, wherein the reduced dose is about 50 mg.

52. The use of claim 50, wherein the reduced dose is about 100 mg.

53. The use of claim 50, wherein the reduced dose is about 150 mg.

54. Compounds of formula I: or a pharmaceutically acceptable salt thereof for use in treating KRAS G12C mutant cancer, wherein the dose of the compound administered is between about 50 mg and about 200 mg.

55. The compound for use according to claim 54, wherein the compound is administered at a dose of about 150 mg.

56. The compound for use according to claim 54, wherein the compound is administered at a dose of about 100 mg.

57. The compound for use according to claim 54, wherein the compound is administered to a patient in need thereof in a dose of between about 50 mg and about 200 mg in combination, either simultaneously, separately or sequentially, with a second therapeutic agent.

58. A compound for use according to claim 54, wherein: (b) administering to the patient a first dose of the compound selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg; (b) monitoring patients for DLT; and (c) If the patient exhibits a DLT, administering a second dose of the compound that is reduced compared to the first dose.

59. The compound for use according to claim 58, wherein the first dose is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg and about 200 mg.

60. The compound for use according to claims 58 to 59, wherein the second dose is selected from the group consisting of about 50 mg, about 100 mg and about 150 mg.

61. A method for treating KRAS G12C mutant cancer, comprising: A dose of between about 50 mg and 200 mg of a compound of formula I is administered to a patient in need thereof: or a pharmaceutically acceptable salt thereof, wherein the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer.

62. Compounds of formula I: or a pharmaceutically acceptable salt thereof for use in treating KRAS G12C mutant pancreatic cancer, wherein the dose of the compound administered is between about 50 mg and about 200 mg.

63. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: A method for treating KRAS G12C mutant cancer by administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose between about 50 mg and about 200 mg to a patient in need thereof, wherein the KRAS G12C mutant cancer is KRAS G12C mutant pancreatic cancer.

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