Combination of an anaplastic lymphoma kinase inhibitor and a cyclin dependent kinase inhibitor
Inventors
Wei, Ping • Weinrich, Scott Lawrence
Assignees
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Publication Number
US-12539304-B2
Publication Date
2026-02-03
Expiration Date
Abstract
This invention relates to combination therapies comprising an inhibitor of anaplastic lymphoma kinase (ALK) and, an inhibitor of cyclin dependent kinase 4 and 6 (CDK4/6 inhibitor) or an inhibitor of cyclin dependent kinase 2, 4 and 6 (CDK2/4/6 inhibitor), and associated methods of treatment, combinations, pharmaceutical compositions and uses thereof.
Core Innovation
The invention relates to treating lung cancer in a subject by administering an anaplastic lymphoma kinase (ALK) inhibitor together with a cyclin dependent kinase (CDK) inhibitor. The ALK inhibitor is lorlatinib, or a pharmaceutically acceptable salt thereof, and the CDK inhibitor is palbociclib or a CDK2, CDK4 and CDK6 (CDK2/4/6) inhibitor represented by 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(1-(methylsulfonyl)piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7 (8H)-one, or pharmaceutically acceptable salts.
The invention addresses the problem of cancer treatment effectiveness in the setting of ALK inhibitor resistance and aims to improve therapeutic outcomes when ALK inhibition is combined with CDK inhibition. The described preclinical evidence includes in vitro durability of response assays and in vivo xenograft studies. These studies show enhanced durability and/or tumor growth inhibition for the ALK inhibitor plus the CDK inhibitor combination versus monotherapy across ALK inhibitor-resistant NSCLC models.
The documented models include ALK inhibitor-resistant NSCLC, including cell lines with secondary ALK mutations such as G1269A and models exhibiting ALK-independent resistance, as well as patient-derived models. The reported efficacy metrics include increased durability of response, tumor growth inhibition, and tumor re-growth delay. The combination is also described as a synergistic combination.
Claims Coverage
The independent claims cover treatment of lung cancer using lorlatinib plus either palbociclib or a specific CDK2/4/6 inhibitor, a separately or together combination product defined by those drug components, and pharmaceutical compositions containing those drug components with pharmaceutically acceptable excipients. Across these claim sets, the core inventive features focus on the specific ALK inhibitor-CDK inhibitor pairing and the effective combined amounts.
Lorlatinib with palbociclib or a CDK2/4/6 inhibitor for lung cancer treatment
A method of treating lung cancer in a subject by administering an amount of an ALK inhibitor and an amount of a CDK inhibitor, wherein the CDK inhibitor is palbociclib or a CDK2/4/6 inhibitor which is 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(1-(methylsulfonyl)piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7 (8H)-one, and wherein the amounts together are effective in treating cancer, with the ALK inhibitor being lorlatinib or a pharmaceutically acceptable salt thereof.
Lorlatinib plus palbociclib with effective amounts
A method of treating lung cancer in a subject comprising administering an amount of lorlatinib, or a pharmaceutically acceptable salt thereof, and an amount of palbociclib, or a pharmaceutically acceptable salt thereof, wherein the amounts together are effective in treating cancer.
Lorlatinib plus a CDK2/4/6 inhibitor with effective amounts
A method of treating lung cancer in a subject comprising administering an amount of lorlatinib, or a pharmaceutically acceptable salt thereof, and an amount of 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(1-(methylsulfonyl)piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7 (8H)-one, or a pharmaceutically acceptable salt thereof, wherein the amounts together are effective in treating cancer.
Lorlatinib and CDK inhibitor combination
A combination comprising, separately or together, an ALK inhibitor and a CDK inhibitor, wherein the ALK inhibitor is lorlatinib, or a pharmaceutically acceptable salt thereof, and wherein the CDK inhibitor is palbociclib or 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(1-(methylsulfonyl)piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7 (8H)-one.
Pharmaceutical composition of lorlatinib, palbociclib, and excipient
A pharmaceutical composition comprising lorlatinib, or a pharmaceutically acceptable salt thereof, palbociclib, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Pharmaceutical composition of lorlatinib, a CDK2/4/6 inhibitor, and excipient
A pharmaceutical composition comprising lorlatinib, or a pharmaceutically acceptable salt thereof, 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(1-(methylsulfonyl)piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7 (8H)-one, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Overall, the independent claims primarily define treatment of lung cancer by administering lorlatinib with a CDK inhibitor, using effective combined amounts, where the CDK inhibitor is limited to palbociclib or the specified CDK2/4/6 inhibitor. The claim coverage further extends to separately or together combination products and to pharmaceutical compositions that include lorlatinib and the specified CDK inhibitor with pharmaceutically acceptable excipients.
Stated Advantages
Enhanced durability of response for the ALK inhibitor plus the CDK inhibitor combination versus monotherapy in ALK inhibitor-resistant NSCLC models.
Enhanced tumor growth inhibition for the ALK inhibitor plus the CDK inhibitor combination versus monotherapy.
Improved tumor re-growth delay for the ALK inhibitor plus the CDK inhibitor combination versus monotherapy.
The combination is characterized as a synergistic combination.
Documented Applications
Treating lung cancer in a subject using lorlatinib together with palbociclib or the specified CDK2/4/6 inhibitor.
Use of the lorlatinib and CDK inhibitor combination as a synergistic combination for lung cancer treatment in a subject.
Pharmaceutical compositions containing lorlatinib and palbociclib, and pharmaceutical compositions containing lorlatinib and the specified CDK2/4/6 inhibitor, each with at least one pharmaceutically acceptable excipient.
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