Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• KRAS G12C INHIBITOR IN TREATING CANCERS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No.63/135,449, filed January 8, 2021, and U.S. Provisional Patent Application No.63/189,625, filed May 17, 2021, each of which is incorporated herein by reference in its entirety.
• FIELD The present disclosure provides uses for a KRAS G12C inhibitor, such as the compound of Formula I (AMG 510, sotorasib) in treating cancers, such as non-small cell lung cancer, in subjects with certain characteristics.
• BACKGROUND Lung cancer is the leading cause of cancer death, with more than 80% of all lung cancer cases classified as non-small cell lung cancer (NSCLC).
• NSCLC non-small cell lung cancer
• lung cancer small cell and non-small cell
• 2017 World Health Organization Statistics, 2018
• 2017 World Health Organization Statistics
• 2017 more than 250000, 470039, and 1225000 new cases of lung cancer were reported in North America, Europe, and Asia, respectively.
• the estimated number of deaths from lung cancer in 2018 was 173278 in North America, 387913 in Europe, and 1068862 in Asia (Globocan – Lung Cancer, 2018).
• KRAS Kirsten rat sarcoma viral oncogene homolog
• KRAS G12C mutation is present in approximately 13% of lung adenocarcinoma and has been identified as a putative oncogenic driver in this tumor type (AACR Project GENIE Consortium, 2017; Biernacka et al, 2016; Fernández-Medarde and Santos, 2011).
• the role of KRAS mutations in human cancers, including NSCLC, has been known for decades, but no inhibitors specifically targeting KRAS G12C mutations have been successfully developed until recently (McCormick, 2019).
• NSCLC National Comprehensive Cancer Network
• ESMO European Society for Medical Oncology
• no anticancer therapies are currently approved for the treatment of subjects with NSCLC that specifically target tumors that have the KRAS G12C mutation (Román et al, 2018; McCormick, 2016).
• Oncogenic KRAS mutations rarely occur concomitantly with other oncogenic mutations such as the epidermal growth factor receptor gene (EGFR), anaplastic lymphoma kinase gene (ALK), B-raf gene (BRAF); ROS proto-oncogene 1 (ROS1), or neurotrophic tyrosine kinase gene (NTRK) (Scheffler et al, 2019; Martorell et al, 2017; Gainor et al, 2013).
• EGFR epidermal growth factor receptor gene
• ALK anaplastic lymphoma kinase gene
• BRAF B-raf gene
• ROS1 ROS proto-oncogene 1
• NTRK neurotrophic tyrosine kinase gene
• PFS progression-free survival
• OS overall survival
• STK11 mutations have been observed at a high rate in NSCLC and even higher in KRAS mutated NSCLC; this co-mutation pattern has been associated with lower OS and resistance to immune checkpoint inhibitors (Scheffler et al, 2019; Ricciuti et al, 2020; Pavan et al, 2020; Tamiya et al, 2020; An et al, 2020; Uba et al, 2020).
• KEAP1 mutations have been associated with lower OS in NSCLC, while subjects with NSCLC harboring KEAP1 mutations are less sensitive to platinum-based treatments (Jeong et al, 2020; Tian et al, 2016; Solis et al, 2010; Arbour et al, 2018; Goeman et al., 2019).
• checkpoint inhibitors has changed the treatment paradigm for advanced cancers, such as NSCLC, most subjects do not respond to treatment.
• PD-L1 Programmed Death Ligand 1 emerged as an early biomarker to be tested in immunotherapy clinical trials.
• the subject has a PD-L1 tumor proportion score of less than 50%.
• the subject is positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• the subject is positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• the subject has no brain metastasis. In one embodiment, the subject has no bone metastasis.
• Figure 3 shows the objective response rate (ORR, %, non-responders/responders) by TP53/STK11/KEAP1 (data cutoff March 15, 2021).
• Figure 4 shows the objective response rate (ORR, %) by PD-L1 expression level groups by TPS ( ⁇ 1%, 1-49% and ⁇ 50%) overlaid by STK11 co-occurring mutations (data cutoff March 15, 2021).
• Wt wild type.
• Mut mutant.
• Figure 5 shows the objective response rate (ORR, %) by PD-L1 expression level groups by TPS ( ⁇ 1%, 1-49% and ⁇ 50%) overlaid by KEAP1 co-occurring mutations (data cutoff March 15, 2021).
• Figure 6 shows the objective response rate (ORR, %) by PD-L1 expression level groups by TPS ( ⁇ 1%, 1-49% and ⁇ 50%) overlaid by TP53 co-occurring mutations (data cutoff March 15, 2021).
• Figure 7 shows the progression free survival (PFS) by STK11 status (data cutoff March 15, 2021).
• Figure 8 shows the progression free survival (PFS) by KEAP1 status (data cutoff March 15, 2021).
• Embodiment 1 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a PD-L1 tumor proportion score, and (B) administering a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and has PD-L1 tumor proportion score of less than 50%.
• Embodiment 2 is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject has a PD-L1 tumor proportion score of less than 50%.
• Embodiment 3 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation and wherein the subject comprises cells that have a PD-L1 tumor proportion score of less than 50%.
• Embodiment 4 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and wherein the non-small cell lung cancer comprises cells that have a PD-L1 tumor proportion score of less than 50%.
• Embodiment 5 is a method of identifying a subject having non-small cell lung cancer as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a PD-L1 tumor proportion score, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation and a sample has a PD-L1 tumor proportion score of less than 50%.
• Embodiment 6 is a method of determining a treatment for a subject having non-small cell lung cancer, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a PD-L1 tumor proportion score, wherein the treatment determined for the subject comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation and a sample has a PD-L1 tumor proportion score of less than 50%.
• Embodiment 7 is the method according to any one of Embodiments 1-6, wherein the PD-L1 tumor proportion score is equal or more than 1% and less than 50%.
• Embodiment 8 is the method according to any one of Embodiments 1-6, wherein the PD-L1 tumor proportion score is less than 1%.
• Embodiment 9 is the method according any one of Embodiments 1-8, wherein the PD-L1 tumor proportion score is determined using an immunohistochemistry (IHC) test.
• Embodiment 10 is the method according to Embodiment 9, wherein the test is a PD-L1 IHC 22C3 pharmDx test.
• Embodiment 11 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a mutation of STK11, such as a loss-of- function mutation of STK11, and (B) administering a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 12 Provided herein as Embodiment 12, is the method according to Embodiment 11, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, and wherein in step (B) the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for mutation of STK11, such as a loss-of function mutation of STK11, and positive for a mutation of KEAP1, such as a loss-of function mutation of KEAP1.
• step (A) further comprises (iii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, and wherein in step (B) the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for mutation of STK11, such as a loss-of function mutation of STK11, and positive for
• Embodiment 13 Provided herein as Embodiment 13, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for a wild-type of KEAP1 and wherein in step (B) the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation of STK11, such as a loss-of function mutation of STK11, and positive for a wild-type of KEAP1.
• Embodiment 14 is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject is positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 15 is the method of Embodiment 14, wherein the subject is positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 16 is the method of Embodiment 14, wherein the subject is positive for a wild-type of KEAP1.
• Embodiment 17 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation and positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 18 is the method of Embodiment 17, wherein the subject further comprises cells that are positive for a wild-type of KEAP1.
• Embodiment 19 is the method of Embodiment 17, wherein the subject further comprises cells that are positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 20 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and positive for a mutation of STK11, such as a loss-of- function mutation of STK11.
• Embodiment 21 is the method of Embodiment 20, wherein the cancer further comprises cells that are positive for a wild-type of KEAP1.
• Embodiment 22 is the method of Embodiment 20, wherein the cancer further comprises cells that are positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 23 is a method of identifying a subject having non-small cell lung cancer as sensitive to treatment with a compound of Formula I Formula (I) acceptable salt thereof, comprising (i) assaying a sample obtained from the subj ation and (ii) assaying a sample obtained from the subject for a mutation of STK11, such as a loss-of-function mutation of STK11, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation and a sample is positive for a mutation of STK11, such as a loss-of- function mutation of STK11.
• Embodiment 24 is the method according to Embodiment 23, wherein the method further comprises (iii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of STK11, such as a loss-of function mutation of STK11, and a sample is positive for mutation of KEAP1, such as a loss-of function mutation of KEAP1.
• Embodiment 25 is the method according to Embodiment 23, wherein the method further comprises (iii) assaying a sample obtained from the subject for a wild-type of KEAP1, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of STK11, such as a loss-of function mutation of STK11, and a sample is positive for wild-type of KEAP1.
• Embodiment 26 is a method of determining a treatment for a subject having non-small cell lung cancer, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a mutation of STK11, such as a loss-of- function mutation of STK11, wherein the treatment determined for the subject comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation and a sample is positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 27 is the method according to Embodiment 26, wherein the method further comprises (iii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, wherein the treatment determined for the subject comprises administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of STK11, such as a loss-of-function mutation of STK11, and a sample is positive for a loss-of function mutation of KEAP1.
• Embodiment 28 is the method according to Embodiment 26, wherein the method further comprises (iii) assaying a sample obtained from the subject for a wild-type of KEAP1, wherein the treatment determined for the subject comprises administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of STK11, such as a loss-of-function mutation of STK11, and a sample is positive for a wild-type of KEAP1.
• Embodiment 29 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of- function mutation of KEAP1, and (B) administering a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 30 is the method according to Embodiment 29, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for a mutation of STK11, such as a loss-of-function mutation of STK11, and wherein in step (B) the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation of KEAP1, such as a loss-of function mutation of KEAP1, and positive for a mutation of STK11, such as a loss-of function mutation of STK11.
• Embodiment 31 Provided herein as Embodiment 31, wherein step (A) further comprises (iii) assaying a sample obtained from the subject for a wild-type of KEAP1 and wherein in step (B) the subject has non-small cell lung cancer that is positive for a KRAS G12C mutation, positive for a mutation of KEAP1, such as a loss-of function mutation of KEAP1, and positive for a wild-type of STK11.
• Embodiment 32 is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject is positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 33 is the method of Embodiment 32, wherein the subject is positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 34 is the method of Embodiment 32, wherein the subject is positive for a wild-type of STK11.
• Embodiment 35 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I Formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation and positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 36 is the method of Embodiment 35, wherein the subject further comprises cells that are positive for a wild-type of STK11.
• Embodiment 37 is the method of Embodiment 35, wherein the subject further comprises cells that are positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 38 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and positive for a mutation of KEAP1, such as a loss-of- function mutation of KEAP1.
• Embodiment 39 is the method of Embodiment 38, wherein the cancer further comprises cells that are positive for a wild-type of STK11.
• Embodiment 40 is the method of Embodiment 38, wherein the cancer further comprises cells that are positive for a mutation of STK11, such as a loss-of-function mutation of STK11.
• Embodiment 41 is a method of identifying a subject having non-small cell lung cancer as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation and a sample is positive for a mutation of KEAP1, such as a loss-of- function mutation of KEAP1.
• Embodiment 42 Provided herein as Embodiment 42 is the method according to Embodiment 41, wherein the method further comprises (iii) assaying a sample obtained from the subject for a mutation of STK11, such as a loss-of-function mutation of STK11, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of KEAP1, such as a loss-of function mutation of KEAP1, and a sample is positive for a mutation of STK11, such as a loss-of function mutation of STK11.
• a sample is positive for a KRAS G12C mutation
• a sample is positive for a mutation of KEAP1, such as a loss-of function mutation of KEAP1
• a sample is positive for a mutation of STK11, such as a loss-of function mutation of STK11.
• Embodiment 43 Provided herein as Embodiment 43 is the method according to Embodiment 41, wherein the method further comprises (iii) assaying a sample obtained from the subject for a wild-type of STK11, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of KEAP1, such as a loss-of function mutation of KEAP1, and a sample is positive for wild-type of STK11.
• Embodiment 44 is a method of determining a treatment for a subject having non-small cell lung cancer, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) assaying a sample obtained from the subject for a mutation of KEAP1, such as a loss-of- function mutation of KEAP1, wherein the treatment determined for the subject comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation and a sample is positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• Embodiment 45 is the method according to Embodiment 44, wherein the method further comprises (iii) assaying a sample obtained from the subject for a mutation of STK11, such as a loss-of-function mutation of STK11, wherein the treatment determined for the subject comprises administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, and a sample is positive for a mutation of STK11, such as a loss-of function mutation of STK11.
• Embodiment 46 is the method according to Embodiment 44, wherein the method further comprises (iii) assaying a sample obtained from the subject for a wild-type of STK11, wherein the treatment determined for the subject comprises administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when a sample is positive for a KRAS G12C mutation, a sample is positive for a mutation of KEAP1, such as a loss-of-function mutation of KEAP1, and a sample is positive for a wild-type of STK11.
• Embodiment 47 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has a brain metastasis, and (B) administering a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and wherein the subject has no brain metastasis.
• Embodiment 48 is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject has no brain metastasis.
• Embodiment 49 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation and wherein the subject has no brain metastasis.
• Embodiment 50 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and wherein the subject has no brain metastasis.
• Embodiment 51 is a method of identifying a subject having non-small cell lung cancer as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has a brain metastasis, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when the sample is positive for a KRAS G12C mutation and the subject has no brain metastasis.
• Embodiment 52 is a method of determining a treatment for a subject having non-small cell lung cancer, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has a brain metastasis, wherein the treatment determined for the subject comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when the sample is positive for a KRAS G12C mutation and the subject has no brain metastasis.
• Embodiment 53 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has a bone metastasis, and (B) administering a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and wherein the subject has no bone metastasis.
• Embodiment 54 is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject has no bone metastasis.
• Embodiment 55 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation and wherein the subject has no bone metastasis.
• Embodiment 56 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and wherein the subject has no bone metastasis.
• Embodiment 57 is a method of identifying a subject having non-small cell lung cancer as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has a bone metastasis, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when the sample is positive for a KRAS G12C mutation and the subject has no bone metastasis.
• Embodiment 58 is a method of determining a treatment for a subject having non-small cell lung cancer, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has a bone metastasis, wherein the treatment determined for the subject comprises administering of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when the sample is positive for a KRAS G12C mutation and the subject has no bone metastasis.
• Embodiment 59 is the method according to any one of Embodiments 5, 23, 41, 51, and 57, wherein the treatment comprises administering a total daily dose of 960 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof to the subject.
• Embodiment 60 is the method according to any one of Embodiments 6, 26, 44, and 58, wherein the treatment comprises administering a total daily dose of 960 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof to the subject.
• Embodiment 61 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising (A) (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has received a prior systemic platinum-based chemotherapy, and (B) administering a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject having non-small cell lung cancer that is positive for a KRAS G12C mutation and wherein the subject has not received a prior platinum-based chemotherapy.
• Embodiment 62 is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject has not received a prior systemic platinum-based chemotherapy.
• Embodiment 63 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject comprises cells that are positive for a KRAS G12C mutation and wherein the subject has not received a prior systemic platinum-based chemotherapy.
• Embodiment 64 is a method of treating non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer comprises cells that are positive for a KRAS G12C mutation and wherein the subject has not received a prior systemic platinum-based chemotherapy.
• Embodiment 65 is a method of identifying a subject having non-small cell lung cancer as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has received a prior systemic platinum-based chemotherapy, wherein the subject is identified as sensitive to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, when the sample is positive for a KRAS G12C mutation and the subject has not received a prior systemic platinum-based chemotherapy.
• Embodiment 66 is a method of determining a treatment for a subject having non-small cell lung cancer, comprising (i) assaying a sample obtained from the subject for a KRAS G12C mutation and (ii) determining whether the subject has received a prior systemic platinum-based chemotherapy, wherein the treatment determined for the subject comprises administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject, when the sample is positive for a KRAS G12C mutation and the subject has not received a prior systemic platinum-based chemotherapy.
• Embodiment 67 is the method according to Embodiment 65, wherein the treatment comprises administering a total daily dose of 960 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof to the subject.
• Embodiment 68 is the method according to Embodiment 66, wherein the treatment comprises administering a total daily dose of 960 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof to the subject.
• Additional Embodiments of the Disclosure Provided herein as Embodiment 69 is the method according to any one of Embodiments 61-68, wherein the subject has received at least one prior anticancer systemic therapy.
• Embodiment 70 is the method according to any one of Embodiments 1-60, wherein the subject has received at least one prior anticancer systemic therapy.
• Embodiment 71 is the method according to any one of Embodiments 1-70, wherein the subject has received one, two, or three prior systemic therapies.
• Embodiment 72 is the method according to any one of Embodiments 1-70, wherein the subject has received one prior anticancer systemic therapy.
• Embodiment 73 is the method according to any one of Embodiments 1-70, wherein the subject has received two prior anticancer systemic therapies.
• Embodiment 74 is the method according to Embodiments 1-70, wherein the subject as received three prior anticancer systemic therapies.
• Embodiment 75 is the method according to Embodiment 69 or Embodiment 70, wherein one prior anticancer systemic therapy is an anti-PD1 or anti-PD-L1 immunotherapy.
• Embodiment 76 is the method according to Embodiment 70, wherein one prior anticancer systemic therapy is a platinum-based chemotherapy.
• Embodiment 77 is the method according to any one of Embodiments 1-76, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer.
• Embodiment 78 is the method according to any one of Embodiments 1-77, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 1 or 0.
• Embodiment 79 is the method according to any one of Embodiments 1-78, wherein the subject is 18 years or older.
• Embodiment 80 is the method according to any one of Embodiments 1-79, wherein the compound is administered as a free base.
• Embodiment 81 is the method according to Embodiment 80, wherein the compound is administered as a crystalline form of the free base.
• Embodiment 82 is the method according to Embodiment 81, wherein the crystalline form is a crystalline anhydrous form.
• Embodiment 83 is the method according to Embodiment 82, wherein the crystalline anhydrous form is crystalline anhydrous Form I.
• Embodiment 84 is the method according to any one of Embodiments 1-83, wherein the compound is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.
• Embodiment 85 is the method according to Embodiment 84, wherein the pharmaceutical composition is a solid dosage form.
• Embodiment 86 is the method according to Embodiment 84 or embodiment 85, wherein the pharmaceutical composition is for oral administration.
• Embodiment 87 is the method according to any one of Embodiments 84-86, wherein the pharmaceutical composition is a tablet.
• Embodiment 88 is the method according to Embodiment 87, wherein the tablet comprises a fraction of the total daily dose of the compound of Formula I.
• Embodiment 89 is the method according to any one of Embodiments 1-87, wherein total daily dose of the compound is administered once daily.
• Embodiment 90 is the method according to any one of Embodiments 1-87, wherein the total daily dose of the compound is administered over two separate administrations at a dose of 480 mg each.
• Embodiment 91 is the method according to any one of Embodiments 1-90, wherein the treatment results in inducing or increasing tumor regression in the subject.
• Embodiment 92 is the method according to any one of Embodiments 1-90, wherein the treatment results in reducing tumor or cancer growth in the subject.
• Embodiment 93 is the method according to any one of Embodiments 1-90, wherein the treatment results in inducing or increasing death of cancer cells in the subject.
• the disclosure also includes embodiments encompassing one or more embodiments of one or more aspects combined.
• provided herein is also an embodiment that encompasses (i) the embodiments of the First Aspect of the disclosure or (ii) the embodiments of the Second Aspect of the disclosure. More specifically, the disclosure also encompasses an embodiment that recites (i) the characteristics of Embodiment 8 or (ii) the characteristics of Embodiment 14, or both.
• the disclosure provides an embodiment, wherein the embodiment is a method of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, (i) wherein the subject has a PD-L1 tumor proportion score of less than 1% or (ii) wherein the subject is positive for a mutation of STK11, such as a loss-of-function mutation of STK11; or both.
• the characteristics of the embodiments listed in the sections entitled “Additional Embodiments of the Disclosure” and “Additional Subpopulations” equally apply to any embodiments encompassing one or more embodiments of one or more aspects combined.
• Alternative Embodiment 1 is a method of treating KRAS G12C mutated non- small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject has a PD-L1 tumor proportion score of less than 50%.
• Alternative Embodiment 2 is the method according to Alternative Embodiment 1, wherein the PD-L1 tumor proportion score is equal or more than 1% and less than 50%.
• Alternative Embodiment 3 is the method according to Alternative Embodiment 1, wherein the PD-L1 tumor proportion score is less than 1%.
• Alternative Embodiment 4 is a method of treating KRAS G12C mutated non- small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the subject is positive for a loss-of-function mutation of STK11.
• Alternative Embodiment 5 is the method of Alternative Embodiment 4, wherein the subject is positive for a loss-of-function mutation of KEAP1.
• Alternative Embodiment 6 is the method of Alternative Embodiment 4, wherein the subject is positive for a wild-type of KEAP1.
• Alternative Embodiment 7 is a method of treating KRAS G12C mutated non- small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor proportion score of less than 50% or (ii) the subject is positive for a loss-of-function mutation of STK11.
• Alternative Embodiment 8 is a method of treating KRAS G12C mutated non- small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor proportion score of less than 50% and (ii) the subject is positive for a loss-of-function mutation of STK11.
• Alternative Embodiment 9 is a method of treating KRAS G12C mutated non- small cell lung cancer in a subject in need thereof, comprising administering to the subject a total daily dose of 960 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein (i) the subject has a PD-L1 tumor proportion score of less than 50%, (ii) the subject is positive for a loss-of-function mutation of STK11, or (iii) the subject has a PD-L1 tumor proportion score of less than 50% and the subject is positive for a loss-of-function mutation of STK11.
• Alternative Embodiment 10 is the method according to any one of Alternative Embodiments 7-9, wherein the PD-L1 tumor proportion score is equal or more than 1% and less than 50%.
• Alternative Embodiment 11 is the method according to any one of Alternative Embodiments 7-9, wherein the PD-L1 tumor proportion score is less than 1%.
• Alternative Embodiment 12 is the method of any one of Alternative Embodiments 7-11, wherein the subject is positive for a loss-of-function mutation of KEAP1.
• Alternative Embodiment 13 is the method of any one of Alternative Embodiments 7-11, wherein the subject is positive for a wild-type of KEAP1.
• Alternative Embodiment 14 is the method according to any one of Alternative Embodiments 1-13, wherein the subject has received no prior anticancer systemic therapy.
• Alternative Embodiment 15 is the method according to any one of Alternative Embodiments 1-13, wherein the subject has received at least one prior anticancer systemic therapy.
• Alternative Embodiment 16 is the method according to any one of Alternative Embodiments 1-13, wherein the subject has received one prior anticancer systemic therapy.
• Alternative Embodiment 17 is the method according to any one of Alternative Embodiments 1-13, wherein the subject has received two prior anticancer systemic therapies.
• Alternative Embodiment 18 is the method according to Alternative Embodiments 1-13, wherein the subject as received three prior anticancer systemic therapies.
• Alternative Embodiment 19 is the method according to Alternative Embodiment 15 or Alternative Embodiment 16, wherein the one prior anticancer systemic therapy is an anti-PD1 or anti-PD-L1 immunotherapy.
• Alternative Embodiment 20 is the method according to Alternative Embodiment 15 or Alternative Embodiment 16, wherein one prior anticancer systemic therapy is a platinum-based chemotherapy.
• Alternative Embodiment 21 is the method according to any one of Alternative Embodiments 1-20, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.
• Alternative Embodiment 22 is the method according to any one of Alternative Embodiments 1-20, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer.
• Alternative Embodiment 23 is the method according to any one of Alternative Embodiments 1-22, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 1 or 0.
• Alternative Embodiment 24 is the method according to any one of Alternative Embodiments 1-23, wherein the subject is 18 years or older.
• Alternative Embodiment 25 is the method according to any one of Alternative Embodiments 1-24, wherein the compound is administered as a free base.
• Alternative Embodiment 26 is the method according to any one of Alternative Embodiments 1-25, wherein the compound is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.
• Alternative Embodiment 27 is the method according to Alternative Embodiment 26, wherein the pharmaceutical composition is a solid dosage form.
• Alternative Embodiment 28 is the method according to Alternative Embodiment 26 or Alternative Embodiment 27, wherein the pharmaceutical composition is for oral administration.
• Alternative Embodiment 29 is the method according to any one of Alternative Embodiments 26-28, wherein the pharmaceutical composition is a tablet.
• Alternative Embodiment 30 is the method according to any one of Alternative Embodiments 1-29, wherein total daily dose of the compound is administered once daily.
• the Alternative Embodiments 1-29 may also be combined with one or more embodiments listed in the sections entitled “Additional Embodiments of the Disclosure” and “Additional Subpopulations.” Definitions The following definitions are provided to assist in understanding the scope of this disclosure.
• the term “anti PD1 or anti PD-L1 immunotherapy” as used herein refers to a treatment that comprises the administration of, for example, an programmed death receptor-1 (PD1) blocking antibody, such as pembrolizumab, or a programmed death ligand-1 (PD-L1) blocking antibody, such as atezolizumab.
• PD1 blocking antibody such as pembrolizumab
• PD-L1 blocking antibody such as atezolizumab.
• compound of Formula I refers to the compound described in the Section entitled “The Compound of Formula I and Phase 1 Clinical Trial Results” hereinbelow.
• the compound of Formula I (AMG 510, sotorasib, 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2- (propan-2-yl)pyridin-3-yl]-4-[(2S)-2- methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one) is disclosed in U.S.
• Patent No.10,519,146 (Example 41 (col.411-415) and Example 41-1 (col.469)), which Examples are specifically incorporated by reference herein in their entirety.
• U.S. Patent No.10,519,146 is incorporated by reference herein it its entirety.
• the term “crystalline anhydrous Form I” as used herein refers to the crystalline anhydrous Form I of the compound of Formula I as described in US 2020/00369662 A1, in particular paragraphs [0226]- [240] and [0346]-[0351] (Example 2), which are specifically incorporated by reference herein in their entirety.
• US 2020/00369662 A1 is incorporated by reference herein in its entirety.
• the compound of Formula I is characterized by a powder X-ray diffraction pattern comprising peaks at 9.0, 12.0, 12.6, and 19.0 ⁇ 0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 ⁇ .
• the compound of Formula I is characterized by a powder X-ray diffraction pattern comprising at least three, four, five, six, or seven peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0 ⁇ 0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 ⁇ .
• the compound of Formula I is characterized by a powder X-ray diffraction pattern comprising peaks at 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0 ⁇ 0.2 degrees 2 theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 ⁇ .
• the compound of Formula I is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset of about 293°C.
• the compound of Formula I is characterized by a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25 °C to about 275 °C.
• the compound of Formula I is characterized by 13 C solid state NMR (nuclear magnetic resonance) comprising at least three, four, five, six, or seven peaks selected from peaks at approximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm.
• the compound of Formula I is characterized by 13 C solid state NMR comprising peaks at approximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm.
• the compound of Formula I is characterized by 19 F solid state NMR comprising peaks at approximately -49, -60, -79, -90, -109, -120, -138, -150, -168, and - 179 ppm.
• the analytical characterizations described herein above were conducted as described in US 2020/00369662 A1 (see, e.g., paragraphs [0322]-[0328]).
• the term “loss-of-function mutation” as used herein refers to a mutation (e.g., a substitution, deletion, truncation, or frameshift mutation) that results in expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological activity or enzymatic activity), results in expression of only a fragment of the protein that no longer exhibits wild-type activity, or results in no expression of the wild-type protein.
• a loss-of-function mutation affecting the STK11 gene in a cell may result in the loss of expression of the STK11 protein, expression of only a fragment of the STK11 protein, or expression of the STK11 protein that exhibits diminished or no enzymatic activity (e.g., no serine/threonine kinase enzymatic activity) in the cancerous cell.
• enzymatic activity e.g., no serine/threonine kinase enzymatic activity
• a loss-of-function mutation affecting the KEAP1 gene in a cell may result in the loss of expression of the KEAP1 protein, expression of only a fragment of the KEAP1 protein, or expression of a KEAP1 protein that exhibits diminished or no activity (e.g., inability to interact with or activate Nuclear factor erythroid 2-related factor 2 (NRF2)) in the cell.
• pharmaceutically acceptable salt refers to a salt of the compound of Formula I that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-
• platinum-based chemotherapy refers to a chemotherapeutic treatment that comprises the administration of a compound comprising platinum.
• a compound used in platinum-based chemotherapy is cisplatin or carboplatin.
• cisplatin or carboplatin is used in combination with one or more compounds selected from paclitaxel (Taxol), albumin-bound paclitaxel (nab-paclitaxel, Abraxane), docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), etoposide (VP-16), and pemetrexed (Alimta).
• Paclitaxel Texol
• albumin-bound paclitaxel nab-paclitaxel, Abraxane
• docetaxel Taxotere
• gemcitabine Gamzar
• vinorelbine Navelbine
• etoposide VP-16
• pemetrexed Alimta
• platinum-based chemotherapies include, but are not limited to, oxaliplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate, picoplatin
• excipient refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation.
• excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
• subject refers to a human subject.
• Methods of Detecting KRAS, STK11, KEAP1, and TP53 Mutation Status Determining whether a tumor or cancer comprises a KRAS G12C, STK11, KEAP1 or TP53 mutation can be undertaken, for example, by assessing the nucleotide sequence encoding the KRAS, STK11, KEAP1, or TP53 protein, by assessing the amino acid sequence of the KRAS, STK11, KEAP1, or TP53 protein, or by assessing the characteristics of a putative KRAS, STK11, KEAP1, or TP53 mutant protein or any other suitable method known in the art.
• the nucleotide and protein sequence of wild-type human KRAS accesion No.
• BC010502 available at https://www.ncbi.nlm.nih.gov/nuccore/BC010502, accessed January 2020
• STK11 Gene ID: 6794; available at https://www.ncbi.nlm.nih.gov/gene/6794; accessed January 2020
• KEAP1 Gene ID: 9817; available at https://www.ncbi.nlm.nih.gov/gene/9817; accessed January 2020
• TP53 Gene ID: 7157; available at https://www.ncbi.nlm.nih.gov/gene/7157, accessed May 2021
• PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
• PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
• MASA mutant allele-specific PCR amplification
• primer extension reactions electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses.
• samples are evaluated for a mutation, such as the KRAS G12C mutation, by real-time PCR.
• fluorescent probes specific for a certain mutation such as the KRAS G12C mutation
• the probe binds and fluorescence is detected.
• the mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS, STK11, KEAP1, or TP53 gene. This technique will identify all possible mutations in the region sequenced. Methods for detecting a mutation in a KRAS, STK11, KEAP1, or TP53 protein are known by those of skill in the art.
• Methods for determining whether a tumor or cancer comprises a KRAS G12C, STK11, KEAP1, or TP53 mutation can use a variety of samples.
• the sample is taken from a subject having a tumor or cancer.
• the sample is a fresh tumor/cancer sample.
• the sample is a frozen tumor/cancer sample.
• the sample is a formalin-fixed paraffin-embedded (FFPE) sample.
• the sample is a circulating cell-free DNA and/or circulating tumor cell (CTC) sample.
• the sample is processed to a cell lysate.
• the sample is processed to DNA or RNA.
• the sample is acquired by resection, core needle biopsy (CNB), fine needle aspiration (FNA), collection of urine, or collection of hair follicles.
• a liquid biopsy test using whole blood or cerebral spinal fluid may be used to assess KRAS mutation status.
• a test approved by a regulatory authority such as the US Food and Drug Administration (FDA) is used to determine whether the subject has a KRAS G12C mutated non-small cell lung cancer or whether the tumor or tissue sample obtained from such subject contains cells with a KRAS G12C mutation.
• FDA US Food and Drug Administration
• the test is therascreen ® KRAS RGQ PCR Kit (Qiagen).
• the therascreen ® KRAS RGQ PCR Kit is a real-time qualitative PCR assay for the detection of 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene (G12A, G12D, G12R, G12C, G12S, G12V, and G13D) using the Rotor-Gene Q MDx 5plex HRM instrument.
• the kit is intended for use with DNA extracted from FFPE samples of NSCLC samples acquired by resection, CNB, or FNA.
• STK11 and KEAP1 mutation testing can be conducted with commercially available tests, such as the Resolution Bioscience Resolution ctDx Lung TM assay that includes 24 genes (including those actionable in NSCLC).
• Tissue samples may be tested using Tempus xT 648 panel.
• TP53 mutation testing can be conducted with commercially available tests, such as Foundation One, Tempus xT, Illumina TSO500, Guardant 360, or Guardant Omni.
• the cancer has been identified the cancer has been identified as having a KRAS G12C mutation.
• the cancer has been identified as having mutation of STK11, such as a loss-of-function mutation of STK11.
• the cancer has been identified as having a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• the cancer has been identified as having a wild-type STK11.
• the cancer has been identified as having a wild-type of KEAP1.
• the cancer has been identified as having mutation of STK11, such as a loss- of-function mutation of STK11 and a wild-type KEAP1. In one embodiment, the cancer has been identified as having mutation of STK11, such as a loss-of-function mutation of STK11 and a mutation of KEAP1, such as a loss-of-function mutation of KEAP1. In one embodiment, the cancer has been identified as having a wild-type of STK11 and a wild-type KEAP1. In one embodiment, the cancer has been identified as having a wild type of STK11 and a mutation of KEAP1, such as a loss-of-function mutation of KEAP1.
• PD-L1 expression can be determined by methods known in the art.
• PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, the FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for treatment with pembrolizumab.
• IHC in vitro diagnostic immunohistochemistry
• This is qualitative assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 PD-L1 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in FFPE samples, such as human non-small cell lung cancer tissue.
• TPS tumor proportion score
• FFPE paraffin- embedded
• PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca) that utilizes monoclonal rabbit anti- PD-L1, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-L1 clone SP142. Determination of PD-L1 status is indication-specific, and evaluation is based on either the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity or the percentage of PD-L1 expressing tumor cells (% TC) of any intensity.
• % IC proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells
• % TC percentage of PD-L1 expressing tumor cells
• a test approved by a regulatory authority such as the US Food and Drug Administration (FDA) is used to determine the PD-L1 TPS.
• the PD-L1 TPS is determined using an immunohistochemistry (IHC) test.
• the IHC test is the PD- L1 IHC 22C3 pharmDx test.
• the IHC test conducted with samples acquired by, for example, resection, CNB, or FNA.
• the subject has a PD-L1 TPS of less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In one embodiment the subject has a PD-L1 TPS of less than 50%, or less than 1%.
• the subject has a PD-L1 TPS of more than or equal to 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
• the subject has a PD-L1 TPS of less than or equal to 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In one embodiment the subject has a PD-L1 TPS of less than or equal to 50%, or less than or equal to 1%.
• the subject has a PD-L1 TPS of more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
• the subject has a PD- L1 TPS score a range bound by any of the values cited in the foregoing embodiments.
• the subject has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1%, less than or equal to 50% and more than 1%, less than or equal to 50% and more than or equal to 1%, or less than 50% and more than 1%.
• the subject has a PD-L1 TPS score in the range of less than 50% and more than or equal to 1%.
• the subject has a PD-L1 TPS score in the range of more than or equal to 0% and less than 1%.
• the subject has a PD-L1 TPS score in the range of more than 50% and less than or equal to 100%.
• brain metastasis may be diagnosed, for example, using Computerized Axial Tomography (CAT) Scan or Computerized Tomography (CT) with or without intravenous contrast agent and Magnetic Resonance Imaging (MRI) with or without intravenous contrast agent.
• CAT Computerized Axial Tomography
• CT Computerized Tomography
• MRI Magnetic Resonance Imaging
• the subject has an MRI of the brain performed within 28 days prior to treatment start. If MRI is contraindicated, then a CT with contrast agent is conducted.
• bone metastasis may be diagnosed, for example, using any one of X-ray, bone scan (bone scintigraphy), CT, MRI, Positron Emission Tomography (PET), and biopsy.
• Methods of Detecting Tumor Mutational Burden Methods to determine the tumor mutational burden (TMB) in a subject are known in the art.
• the TMB can be measured by a laboratory test that uses next-generation sequencing of tumor tissue, which looks broadly for a wide range of mutations.
• studies are now evaluating measuring TMB from circulating tumor DNA in the plasma, making it potentially possible to test TMB from blood in the future.
• TMB is reported as the number of mutations seen in a section of DNA and reported as mutations per megabase (mut/Mb). Cancers with a TMB of 10 mut/Mb or greater (called TMB-high) may be more likely to respond to drugs called immune checkpoint inhibitors that help activate the immune system to better recognize cancer cells (Fusco et al, 2021).
• TMB test used is a commercially available test, such as Foundation One, Tempus xT, Guardant Omni, and Illumina TSO500.
• Subpopulations Further provided herein are certain methods for treating a subject in need thereof, wherein the subject has certain characteristics in addition to the status regarding KRAS, STK11, KEAP1, TP53, PD- L1 TPS, or bone or brain metastases discussed herein above, or combinations thereof.
• the entry in the above table where Characteristic A reads “PD-L1 TPS is ⁇ 1%” and Characteristic B reads “positive for a loss of function mutation of STK11” represents the embodiments directed to methods of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof as disclosed in the various aspects of the invention above, wherein (i) the subject has a PD-L1 tumor proportion score of less than 1% or (ii) the subject is positive for a loss-of-function mutation of STK11 (A or B).
• the same entry also represents the embodiments directed to methods of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof as disclosed in the various aspects of the invention above, wherein (i) the subject has a PD-L1 tumor proportion score of less than 1% and (ii) the subject is positive for a loss-of-function mutation of STK11 (A and B).
• the same entry also represents the embodiments directed to methods of treating KRAS G12C mutated non-small cell lung cancer in a subject in need thereof as disclosed in the various aspects of the invention above, wherein (i) the subject has a PD-L1 tumor proportion score of less than 1%, (ii) the subject is positive for a loss-of-function mutation of STK11, or (iii) the subject has a PD-L1 tumor proportion score of less than 1% and the subject is positive for a loss-of-function mutation of STK11 (A or B or both).
• the following embodiments disclose certain additional characteristics of said subject. In one embodiment the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or all of the following additional characteristics.
• the subject has one of the following additional characteristics. In a certain embodiment the subject has two of the following additional characteristics. In a certain embodiment the subject has three of the following additional characteristics. In a certain embodiment the subject has five of the following additional characteristics. In a certain embodiment the subject has seven of the following additional characteristics. In a certain embodiment the subject has ten of the following additional characteristics. In a certain embodiment the subject has all of the following additional characteristics. In one embodiment the subject is a man. In another embodiment, the subject is a woman. In one embodiment the subject is 18 years or older. In one embodiment the subject has a pathologically documented, locally-advanced or metastatic malignancy with KRAS G12C mutation identified through molecular testing.
• the mutation was confirmed by central testing prior to treatment start.
• the subject has progressed after receiving anti-PD-1 or anti-PD-L1 immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy if actionable oncogenic driver mutations were identified (i.e., EGFR, ALK, and ROS1).
• actionable oncogenic driver mutations were identified (i.e., EGFR, ALK, and ROS1).
• the subject has not received more than 3 prior lines of therapy.
• an archived tumor tissue sample (formalin fixed, paraffin embedded [FFPE] sample collected within 5 years) is available, which was obtained from the subject.
• a pretreatment tumor biopsy sample is available, which was obtained from the subject.
• an additional biopsy sample taken from the subject at the time of tumor progression is available, provided the subject has lesions that can be feasibly biopsied.
• the subject has a measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 criteria (RECIST 1.1; Eisenhauer et al, 2009).
• the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of ⁇ 1 (Oken et al., 1982).
• the subject has an ECOG Performance Status of 1.
• the subject has a life expectancy of > 3 months.
• the subject has the ability to take oral medications.
• the subject has a QTc ⁇ 470 msec (based on average of screening triplicates). In one embodiment the subject has one, two or three of the following hematological laboratory assessments: an absolute neutrophil count (ANC) ⁇ 1.5 x 10 9 /L, a platelet count ⁇ 75 x 10 9 /L, a hemoglobin ⁇ 9 g/dL (90 g/L). In one embodiment the subject has an estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculation ⁇ 60 ml/min/1.73 m 2 .
• MDRD Modification of Diet in Renal Disease
• the subject has one, two, or three of the following hepatic laboratory assessments: aspartate aminotransferase (AST) ⁇ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ⁇ 5 x ULN), alanine aminotransferase (ALT) ⁇ 2.5 x ULN (if liver metastases are present, ⁇ 5 x ULN), total bilirubin ⁇ 1.5 x ULN ( ⁇ 2.0 x ULN for subjects with documented Gilbert’s syndrome or ⁇ 3.0 x ULN for subjects for whom the indirect bilirubin level suggests an extrahepatic source of elevation).
• AST aspartate aminotransferase
• UPN upper limit of normal
• ALT alanine aminotransferase
• ALT ⁇ 2.5 x ULN
• total bilirubin ⁇ 1.5 x ULN ( ⁇ 2.0 x ULN for subjects with documented Gilbert’s syndrome or ⁇ 3.0 x ULN for subjects
• the subject has a prothrombin time (PT) or partial thromboplastin time (PTT) ⁇ 1.5 x ULN, OR International normalized ratio (INR) ⁇ 1.5 or within target range if on prophylactic anticoagulation therapy.
• the subject has no active brain metastases from non-brain tumors.
• a subject who has had brain metastases resected or has received radiation therapy ending at least 4 weeks prior to treatment start is eligible for treatment if the subject meets all of the following criteria: residual neurological symptoms grade of less than 2; on stable doses of dexamethasone, if applicable; and follow-up MRI performed within 30 days showed no new lesions appearing.
• the subject has no history or presence of hematological malignancies unless curatively treated with no evidence of disease ⁇ 2 years.
• the subject has no myocardial infarction within 6 months of the start of treatment, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication.
• the subject has no gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis).
• GI gastrointestinal
• the subject as no active infection requiring IV antibiotics within 1 week of start of treatment.
• the subject has no hepatitis infection.
• the absence of a hepatitis infection in the subject is determined based on the following results: positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B); negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis B core antibody testing is not required for screening, however if this was done and was positive, then hepatitis B surface antibody [Anti-HBs] testing is necessary); undetectable anti-HBs in this setting would suggest unclear and possible infection, and needs exclusion); positive Hepatitis C virus antibody: Hepatitis C virus RNA by PCR is necessary - detectable Hepatitis C virus RNA suggests chronic hepatitis C.
• Hepatitis B Surface Antigen Hepatitis B Surface Antigen
• the subject has no known positive test for HIV.
• the subject is HIV negative.
• the subject has no unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to CTCAE version 5.0 grade 0 or 1.
• the subject is not subject to anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for a subject with breast cancer], or other investigational agent) within 28 days of treatment start.
• the subject concurrently is subjected to hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer.
• the subject does not have any radiotherapy related toxicity.
• the subject has not had major surgery within 28 days of treatment start.
• the subject is not a woman with a positive pregnancy test.
• the subject has not been administered a known cytochrome P450 (CYP) 3A4 sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to treatment start.
• the subject has not been administered a strong inducer of CYP3A4 (including herbal supplements such as St. John’s wort) within 14 days or 5 half-lives (whichever is longer) prior to treatment start.
• the subject has not had another malignancy within the past 2 years before start of treatment.
• the subject has not been submitted to prior treatment with a KRAS G12C inhibitor.
• a pharmaceutical composition comprising a compound of Formula I disclosed herein in combination with one or more pharmaceutically acceptable excipients and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V.
• the compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
• compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
• the pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension.
• the pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
• Patent No.10,519,146 is a novel, potent, and highly selective small molecule inhibitor that covalently binds to the KRAS protein with a G12C substitution (KRAS G12C ) and locks it in a guanine diphosphate (GDP)-bound, inactive state (see, e.g., U.S. Patent No.10,519,146).
• GDP guanine diphosphate
• the chemical name of the compound of Formula I is 6-fluoro-7- (2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2- enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one.
• the chemical structure is shown below.
• the compound of Formula I potently inhibits recombinant KRAS G12C but has minimal effect on wild type KRAS or other mutant versions of KRAS.
• the covalent, irreversible binding and inhibition of KRAS G12C by the compound of Formula I requires a reactive thiol group adjacent to the compound of Formula I binding pocket. This thiol is provided by the cysteine at KRAS position 12 (G12C), resulting in a precise interaction that is specific for KRAS G12C .
• the inhibitor contains a thiol-reactive portion that covalently modifies the cysteine residue and locks KRAS G12C in the inactive, GDP-bound conformation.
• KRAS KRAS with effectors such as rapidly accelerated fibrosarcoma (RAF), thereby preventing downstream proliferation and survival signaling, including the phosphorylation of extracellular signal regulated kinase (ERK)
• RAF rapidly accelerated fibrosarcoma
• ERK extracellular signal regulated kinase
• Treatment with the compound of Formula I impairs cell growth and induces apoptosis only in tumor cell lines and xenografts that have the KRAS G12C mutation (Canon et al, 2019).
• Blockade of KRAS G12C signaling by the compound of Formula I also enhances antigen presentation and inflammatory cytokine production in tumors to inflame the tumor microenvironment and drive anti-tumor immunity.
• the compound of Formula I represents an important advance for the treatment of subjects with KRAS G12C-mutated tumors, such as NSCLC.
• the compound of Formula I is subject of the ongoing clinical study entitled “A Phase 1/2, Open- label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 510 Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and AMG 510 Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreak 100)” (ClinicalTrials.gov identifier: NCT03600883, available at https://www.clinicaltrials.gov/ct2/show/NCT03600883, accessed January 2020).
• the primary objectives of the phase 1 portion of the study were to evaluate the safety and tolerability of the compound of Formula I and to estimate the maximum tolerated dose and/or a recommended phase 2 dose of sotorasib.
• the primary objective was to evaluate the objective response rate (ORR) for the compound of Formula I as monotherapy in subjects with KRAS G12C-mutated advanced solid tumors.
• ORR objective response rate
• Phase 1 Subjects in phase 1 were treated with the compound of Formula I as monotherapy at 180, 360, 720, and 960 mg once daily (QD).
• Certain results of the Phase 1 cohort of the CodeBreaK 100 trial (NCT03600883) have been published (Hong et al, 2020). Hong et al. discusses, inter alia, a set of 59 subjects with NSCLC, of which 53 (89.8%) had received prior anti-programmed cell death protein 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapies, and all 59 subjects had received prior platinum-based chemotherapy.
• PD-1 anti-programmed cell death protein 1
• PD-L1 anti-programmed death ligand 1
• Adequate renal laboratory assessments as follows: o Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculation ⁇ 60 ml/min/1.73 m 2 .
• Adequate hepatic laboratory assessments as follows: o Aspartate aminotransferase (AST) ⁇ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ⁇ 5 x ULN). o Alanine aminotransferase (ALT) ⁇ 2.5 x ULN (if liver metastases are present, ⁇ 5 x ULN).
• o Total bilirubin ⁇ 1.5 x ULN ( ⁇ 2.0 x ULN for subjects with documented Gilbert’s syndrome or ⁇ 3.0 x ULN for subjects for whom the indirect bilirubin level suggests an extrahepatic source of elevation).
• Adequate coagulation laboratory assessments as follows: o Prothrombin time (PT) or partial thromboplastin time (PTT) ⁇ 1.5 x ULN, OR International normalized ratio (INR) ⁇ 1.5 or within target range if on prophylactic anticoagulation therapy.
• PT Prothrombin time
• PTT partial thromboplastin time
• ISR International normalized ratio
• Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 were eligible if they meet all of the following criteria: o residual neurological symptoms grade of less than 2; o on stable doses of dexamethasone, if applicable; and o follow-up MRI performed within 30 days showed no new lesions appearing. • History or presence of hematological malignancies unless curatively treated with no evidence of disease ⁇ 2 years. • Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication.
• GI tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis).
• Active infection requiring IV antibiotics within 1 weeks of study enrollment (day 1).
• Exclusion of hepatitis infection based on the following results and/or criteria: o Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B).
• HepBsAg Positive Hepatitis B Surface Antigen
• Hepatitis B core antibody testing was not required for screening, however if this was done and was positive, then hepatitis B surface antibody [Anti-HBs] testing was necessary. Undetectable anti-HBs in this setting would suggest unclear and possible infection and needs exclusion).
• o Positive Hepatitis C virus antibody Hepatitis C virus RNA by PCR was necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C. • Known positive test for HIV.
• Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with breast cancer], or investigational agent) within 28 days of study day 1; concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer or breast cancer is permitted.
• Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity. • Currently enrolled in another investigational device or drug study, or less than 28 days since ending another investigational device or drug study(s) or receiving other investigational agent(s). • Other investigational procedures are excluded. • Major surgery within 28 days of study day 1.
• WOCBP childbearing potential
• accepted methods of highly effective birth control for women included sexual abstinence (refraining from heterosexual intercourse); vasectomy (women with a single male sexual partner) with testing showing there is no sperm in the semen; bilateral tubal ligation or occlusion; or intrauterine device.
• Acceptable methods of birth control for men included sexual abstinence (refraining from heterosexual intercourse); vasectomy with testing showing there is no sperm in the semen; bilateral tubal ligation or occlusion in the partner; or a condom (the female partner should also consider a form of birth control).
• Subject had known sensitivity to any of the products to be administered during dosing.
• Subject was not available for protocol-required study visits or procedures, to the best of the subject and investigator’s knowledge.
• Subject had any kind of disorder that, in the opinion of the investigator, may have compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures. • History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or physician would have posed a risk to subject safety or interfered with the study evaluation, procedures or completion. • Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator and the sponsor medical monitor.
• CYP cytochrome P450
• CYP3A4 including herbal supplements such as St. John’s wort
• FFPE paraffin embedded
• pretreatment tumor biopsy core needle or fine needle aspirates or excisional FFPE sample
• Tumor tissue was allowed to be submitted to the central laboratory either as FFPE blocks or unstained slides.
• KRAS G12C mutation testing was conducted using a therascreen ® KRAS RGQ PCR Kit (Qiagen). The kit is a real-time qualitative PCR assay performed on the Rotor-Gene Q MDx instrument for the detection of 7 somatic mutations in the human KRAS oncogene using DNA extracted from FFPE tissue.
• the mutations detected are: G12A, G12D, G12R, G12C, G12S, G12V, and G13D.
• PD-L1 testing was conducted at the central labs using the Dako PharmDx 22C3 immunohistochemistry FDA-approved kit according to the instructions for use. More specifically, immunohistochemical evaluation of programmed death-ligand 1 (PD-L1) expression on tumor cells was performed using the PD-L1 IHC 22C3 pharmDx assay on the BOND III automated staining system (Leica Microsystems), according to the manufacturer’s instructions for use (IFU). All slides were reviewed and scored by a board-certified pathologist trained to score the PD-L1 IHC 22C3 pharmDx assay.
• PD-L1 testing was conducted at the central labs using the Dako PharmDx 22C3 immunohistochemistry FDA-approved kit according to the instructions for use. More specifically, immunohistochemical evaluation of programmed death-ligand 1 (PD-L1) expression on
• the reporting of tumor cell PD-L1 expression (% tumor proportion score) and the test result (positive/negative) was conducted in accordance with established companion diagnostic guidelines by the Food and Drug Administration (FDA) for 22C3.
• Subject testing with the therascreen ® KRAS RGQ Assay and Dako PharmDx 22C3 took place at the NeoGenomics Central Testing Laboratory in Houston, Texas.
• STK11, KEAP1, and TP53 mutation testing was conducted using the Resolution Bioscience Resolution ctDx Lung TM assay that included 24 genes (including those actionable in NSCLC). Tissue samples were tested using Tempus xT 648 panel. Further, STK11 and KEAP1 mutation testing was also conducted using the Qiagen Comprehensive Cancer Panel (NGS).
• NGS Qiagen Comprehensive Cancer Panel
• STK11/KEAP1/TP53 co-mutation analysis determined mutational status from baseline tissue and/or plasma samples, and mutations include nonsense, missense, frameshift, or splice site mutations and insertion/deletions predicted to be loss-of- function, and excluded variants of unknown significance.
• Subjects with variant of uncertain significance (VUS) in STK11, KEAP1, or TP53 were not included in the corresponding comparisons of mutant versus wild-type for each gene. A subject with any qualifying variant was considered mutated for that gene, and otherwise wild type. Due to platform differences in report content, the filtering approach was customized to each platform.
• Tempus’ filtered molecular master file was processed to retain non- synonymous variants (including splice site mutations, deletions, frame shifts), rearrangements, and copy number variations (CNVs). Excluded variants were those not in COSMIC or dbSNP with either non- pathogenic status and allele frequency at least 0.40 or one of the following cases: uncertain significance, benign, likely benign or germline. Germline status was provided by Tempus, based on matched normal samples. Resolution Biosciences’ cfDNA NGS results were annotated using SnpEff v4.3t, and variants were further annotated with information from COSMIC (v92) and dbSNP (build 154) using SnpSift v4.3t.
• Variants were then filtered down to retain non-synonymous variants (including splice site mutations, deletions, frame shifts), ClinVar clinical significance of at least 4 (likely-pathogenic), indels, CNVs, and variants in at least 3 COSMIC samples. Excluded variants were those not in COSMIC or dbSNP with allele frequency at least 0.40 or ClinVar clinical significance of uncertain, benign or likely benign. Results Demographic and Baseline Characteristics As shown in Table 1.1 below, a total of 126 subjects with KRAS G12C-mutated locally advanced or metastatic NSCLC were enrolled in the phase 2 portion of the CodeBreaK 100 Trail and had received ⁇ 1 dose of the compound of Formula I as monotherapy (960 mg once daily).
• Median duration (range) of treatment with the compound of Formula I was 24.1 (1.0, 52.1) weeks, with 47.6% and 28.6% of subjects receiving ⁇ 6 and ⁇ 9 months of treatment, respectively.
• the median relative dose intensity was 100%.
• 81.7% were white and 50% were men.
• the median (range) age was 63.5 (37, 80) years.
• Most subjects had non-squamous NSCLC (99.2%) and stage IV disease at screening (96.0%).
• Per protocol eligibility criteria subjects had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (38 subjects [30.2%] and 88 subjects [69.8%], respectively).
• the median duration of treatment was 5.5 months (range, 0.2 to 17.8).
• Baseline characteristics are summarized in Table 1.2 and further detailed in Table 1.3.
• the median age was 63.5 years (range, 37 to 80), and 117 (92.9%) were current or former smokers.
• ORR is defined as the proportion of subjects with complete response or partial response and confirmation after at least 4 weeks.
• DCR is defined as the proportion of subjects with complete response or partial response with confirmation or stable disease ⁇ 5 weeks.
• DOR is defined as time from first evidence of complete response or partial response to disease progression or death due to any cause, among responders.
• Time to response is defined as time from the first dose of sotorasib until the first evidence of complete response or partial response, among responders.
• a Exact 95% CI was calculated using the Clopper Pearson method
• b Time to response and duration of response are calculated among confirmed responders N1.
• c 95% CIs are based on estimated variance for log-log transformation of the KM survival estimate.
• d Follow-up time is measured by reversing the status indicator for censored and events.
• the ORR was notably lower for subjects with brain metastasis compared with overall subject population (15.4% [4 of 26 subjects] versus 37.4% [46 of 123 subjects]). Bone Metastasis A trend to higher ORR was observed for subjects without bone metastasis compared to those with bone metastasis (41.5% [27 of 65 subjects] versus 32.8% [19 of 58 subjects]).
• PD-L1 Protein Expression Table 3 provides PD-L1 protein expression results obtained locally. A trend to higher ORR was observed in subjects with lower PD-L1 protein expression as measured by the tumor proportion score (TPS).
• the group with a PD-L1 TPS ⁇ 50% has a lower ORR compared to the overall response (26.5% [9 of 34 subjects] versus 37.4% [46 of 123 subjects]), whereas the group with a PD-L1 TPS of ⁇ 1% and the group with a PD-L1 TPS of ⁇ 1% and ⁇ 50% both have a higher ORR compared to the overall response (48.5% [16 of 33 subjects] and 40.9% [9 of 22 subjects] versus 37.4% [46 of 123 subjects]).
• the group with a PD-L1 TPS ⁇ 50% has a lower ORR compared to the overall response (22% [2 of 9 subjects] versus 42% [36 of 86 subjects]), whereas the group with a PD-L1 TPS of ⁇ 1% and the group a PD-L1 TPS of ⁇ 1% and ⁇ 50% both have a higher or similar ORR compared to the overall response (48% [21 of 44 subjects] and 39% [13 of 33 subjects] versus 42% [36 of 86 subjects]).
• STK11/KEAP1 co-mutation analysis determined mutational status from baseline tissue and/or plasma samples, and mutations include nonsense, missense, frameshift, or splice site mutations and insertion/deletions predicted to be loss-of-function, and excluded variants of unknown significance.
• co-occurring mutations refers to either or both of STK11 and KEAP1 have mutations that co-occur with the KRAS G12C mutation.
• STK11 and KEAP1 co-occurring mutations have been associated with lower overall survival (OS) in KRAS mutant NSCLC (see Background). While OS remains the gold standard in clinical studies, analyses to explore the association between ORR and survival have demonstrated patient-level and study-level associations between ORR, PFS, and OS (Blumenthal et al, 2015; Clarke et al, 2015). Against this backdrop it is notable that clinically meaningful ORRs were observed across STK11/KEAP1 co-occurring mutation profiles.
• the KEAP1 co-occurring loss-of-function mutation independent from the STK11 mutational status (loss-of-function or wild-type), demonstrated ORR of 20% (4 of 20 subjects). Further, it is especially notable that the STK11 co- occurring loss-of-function mutation, independent from the KEAP1 mutational status (loss-of-function or wild type), demonstrated a similar ORR when compared to the overall response in this subject population (40% [14 of 35 subjects] versus 39% [41 of 104 subjects], see also Figure 3).
• Figures 7 and 8 show the progression free survival (PFS) by STK11 and KEAP1 mutational status (data cutoff March 15, 2021).
• Table 3 Objective Response Rate Based on Central Review by Subgroup Table 3.
• EXAMPLE 2 A Phase 2, Multicenter, Open-label Study of Sotorasib (AMG 510) in Subjects with Stage IV NSCLC Whose Tumors Harbor a KRASG12C Mutation in Need of First- Line Treatment (CodeBreaK 201) Overall Design An open-label, multicenter phase 2 study to explore the anti-tumor effect of sotorasib monotherapy in subjects with metastatic non-small cell lung cancer (NSCLC) with KRAS p.G12C mutation whose tumors express ⁇ 1% programmed death-ligand 1 (PD-L1) and/or have a serine/threonine kinase 11 (STK11) mutation in need of first line treatment is set up.
• NSCLC metastatic non-small cell lung cancer
• P-L1 programmed death-ligand 1
• STK11 serine/threonine kinase 11
• Subjects are randomized in a 1:1 design for treatment with sotorasib at 960 mg orally (PO) daily (QD), stratified by known presence of STK11 mutation.
• the study is listed under ClinicalTrials.gov Identifier: NCT04933695 (see https://clinicaltrials.gov/ct2/show/NCT04933695; version of October 13, 2021; last accessed December 15, 2021).
• An independent Data Review Team (DRT) will monitor the study.
• a non-binding futility guideline based on Bayesian posterior probability will be used to facilitate termination in the event of inadequate efficacy.
• Subjects are treated until disease progression as confirmed by Blinded Independent Central Review (BICR), unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first.
• BICR Blinded Independent Central Review
• SFU safety follow-up
• LTFU long-term follow-up
• Subjects who discontinue sotorasib for reasons other than radiographic disease progression will have LTFU imaging for disease status until disease progression is documented radiographically per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, initiate a non study cancer treatment, withdrawal of consent, or end of study, whichever occurs first.
• Sotorasib tablets are administered PO QD with or without food for a treatment cycle of 21 days. Sotorasib tablets are formulated as PO, solid dosage form in a strength of 120 mg. The sotorasib dose used in the study is 960 mg per day. The total study duration for an individual subject is approximately 6 years: 28-day screening, 6 to 12 months on treatment and up to approximately 46 cycles, SFU, and 5 years of LTFU from the last subject enrolled.
• sotorasib with proton pump inhibitors (PPIs, such as omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, and dexlansoprazole), or H2RA (such as famotidine, ranitidine, cimetidine, nizatidine, roxatidine, and lafutidine) is prohibited. If treatment with an acid-reducing agent cannot be avoided, sotorasib should be administered 4 hours before or 10 hours after a local antacid, such as sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.
• PPIs proton pump inhibitors
• H2RA such as famotidine, ranitidine, cimetidine, nizatidine, roxatidine, and lafutidine
• the efficacy subgroup analysis will be performed for subjects with PD-L1 ⁇ 1%, STK11 co- mutation, and other co-occurring mutations of interest. For primary and final analyses, subgroups will be determined based on central data. Objectives and Endpoints O P K Study Population Subject inclusion criteria include the following: • Untreated stage IV (per American Joint Committee on Cancer (AJCC) v8, see Amin et al., 2017) NSCLC. o Subjects who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed greater than 12 months prior to the development of metastatic disease. • Pathologically documented, metastatic NSCLC with KRAS p.G12C mutation identified through molecular testing.
• KRAS p.G12C mutation must be performed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory or equivalent.
• Age 18 years.
• PD-L1 TPS score ⁇ 1% as determined by pharm Dx DAKO 22C3 or Ventana SP263 IHC. If subjects do not have PD-L1 TPS score ⁇ 1%, STK11 loss of function mutation as determined by NGS must be present. Subjects with PD-L1 TPS score ⁇ 1% may also have presence of STK11 mutation.
• Subjects must be willing to provide archived tumor tissue samples (formalin-fixed paraffin-embedded [FFPE] sample collected within 5 years) or willing to undergo pretreatment tumor biopsy.
• Subject has received prior treatment for metastatic NSCLC. Subjects who receive adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed greater than 12 months prior to the development of metastatic disease.
• Other Medical Conditions • History or presence of malignancy unless treated with curative intent and no evidence of disease ⁇ 3 years with the following exceptions: o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease o Adequately treated cervical carcinoma in situ without evidence of disease o Adequately treated breast ductal carcinoma in situ without evidence of disease o Prostatic intraepithelial neoplasia without evidence of prostate cancer o Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ • Spinal cord compression, active brain metastases and/or carcinomatous meningitis.
• Subjects who have had brain metastases resected or have received whole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to study day 1 are eligible if they meet all of the following criteria: o No residual neurological symptoms o No corticosteroid requirement to manage neurological symptoms o
• follow-up MRI performed within 30 days prior to enrollment shows no new lesions or enlarging lesion appearing o No single lesion larger than 10 mm • Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or cardiac arrythmia requiring medication.
• GI Gastrointestinal
• IV intravenous
• GI disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous (IV) alimentation, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis).
• Evidence of hepatitis infection based on the following results and/or criteria: o Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B).
• HepBsAg positive hepatitis B surface antigen
• Negative HepBsAg with a positive for hepatitis B core antibody hepatitis B core antibody testing is not required for screening, however if this is done and is positive, then hepatitis B surface antibody [Anti-HBs] testing is necessary.
• o Positive hepatitis C virus antibody Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA renders the subject ineligible.
• o Positive hepatitis B or C viral load if above antibody/antigen testing is not able to be obtained, obtain hepatitis B or C viral load.
• Prior/Concomitant Therapy Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 12 months. • Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity to grade 1 or better. • Received radiation therapy to the lung that is > 30 Gy within 6 months of first dose of trial treatment. • Previous treatment with a covalent KRAS p.G12C inhibitor.
• cytochrome P450 cytochrome P450
• P-gp substrates Use of known cytochrome P450 (CYP) 3A4 sensitive substrates or P-gp substrates, with a narrow therapeutic window, within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator and the medical monitor.
• Use of strong inducers of CYP3A4 including herbal supplements such as St. John's wort
• SEER Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 21 Regs Limited-Field Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2018 Sub (2000-2016) ⁇ Katrina/Rita Population Adjustment> - Linked To County Attributes - Total U.S., 1969-2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on the November 2018 submission. Accessed 10 February 2020. Tamiya Y, Zenke Y, Matsumoto S, et al.
• NSCLC KRAS–mutated non-small cell lung cancer

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  • 2022-01-07 US US18/270,581 patent/US20240091230A1/en active Pending
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