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Publication Number
US-12280055-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising a such compositions, kits comprising such compositions and methods of use therefor.
Core Innovation
The document describes combination therapies for treating KRas G12C-associated cancer by administering a therapeutically effective amount of adagrasib or a pharmaceutically acceptable salt thereof together with a SOS1 inhibitor or a pharmaceutically acceptable salt thereof. SOS1 is framed as a RAS GEF, and KRas G12C is framed as a covalent-binding target in the provided mechanistic context. The cancer types addressed include lung cancer; gastrointestinal cancer; genitourinary tract cancer; liver cancer; biliary tract cancer; bone cancer; nervous system cancer; gynecological cancer; hematologic cancer; skin cancer; and adrenal glands cancer.
The described combinations are stated to synergistically increase potency and/or efficacy relative to KRas G12C inhibitor monotherapy, with comparative clinical endpoints including overall survival and progression-free survival. The document also frames tumor-related outcomes such as tumor regression, tumor growth inhibition, and stable disease duration. The combination can optionally include a MEK inhibitor together with adagrasib and a SOS1 inhibitor.
The document further provides examples of SOS1 inhibitor compounds including MRTX0902 and BI1701963, and includes pharmaceutical compositions, kits, and methods of use associated with the combination therapy. Additional claim coverage is directed to inhibiting KRas G12C activity in a cell by contacting the cell with the adagrasib plus SOS1 inhibitor combination, and to increasing the sensitivity of a cancer cell to the KRas G12C inhibitor by administering the synergistic combination.
Claims Coverage
The provided claim set includes four independent claims. Across these independent claims, the inventive features consistently center on combining adagrasib with a SOS1 inhibitor, with one independent claim additionally reciting a MEK inhibitor, and two independent claims focusing on cellular activity and sensitivity rather than only subject-level treatment.
Adagrasib and SOS1 inhibitor combination for KRas G12C-associated cancer treatment
Administering to a subject a therapeutically effective amount of a combination of the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof and a SOS1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the cancer is a KRas G12C-associated cancer selected from lung cancer; gastrointestinal cancer; genitourinary tract cancer; liver cancer; biliary tract cancer; bone cancer; nervous system cancer; gynecological cancer; hematologic cancer; skin cancer; and adrenal glands cancer.
Triplet combination including adagrasib, SOS1 inhibitor, and MEK inhibitor
Administering to a subject a therapeutically effective amount of a combination comprising a KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof, a SOS1 inhibitor or a pharmaceutically acceptable salt thereof, and a MEK inhibitor or a pharmaceutically acceptable salt thereof for treating cancer.
Contacting a cell with adagrasib and SOS1 inhibitor to inhibit KRas G12C activity
Inhibiting KRas G12C activity in a cell by contacting the cell with an effective amount of a combination of the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof and a SOS1 inhibitor or a pharmaceutically acceptable salt thereof.
Increasing cancer cell sensitivity to KRas G12C inhibitor using synergistic SOS1
Increasing the sensitivity of a cancer cell to the KRas G12C inhibitor by administering to a subject undergoing KRas G12C treatment an effective amount of a combination comprising the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof and a SOS1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
Overall, the independent claims primarily cover treating KRas G12C-associated cancer by administering adagrasib in combination with a SOS1 inhibitor, with an optional extension to include a MEK inhibitor, and methods directed to cellular inhibition of KRas G12C activity and synergistic sensitization to the KRas G12C inhibitor.
Stated Advantages
Synergistically increases potency and/or efficacy of KRas G12C inhibitor therapy versus KRas G12C inhibitor monotherapy.
Improves clinical outcomes versus KRas G12C inhibitor monotherapy, including longer overall survival and longer progression-free survival.
Produces tumor regression and greater tumor growth inhibition versus KRas G12C inhibitor monotherapy.
Extends stable disease duration versus KRas G12C inhibitor monotherapy.
Documented Applications
Treating a subject with a KRas G12C-associated cancer using an adagrasib plus SOS1 inhibitor combination, optionally with an added MEK inhibitor.
Inhibiting KRas G12C activity in a cell by contacting the cell with an adagrasib plus SOS1 inhibitor combination.
Increasing the sensitivity of a cancer cell to the KRas G12C inhibitor by administering an adagrasib plus SOS1 inhibitor combination to a subject undergoing KRas G12C treatment.
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