Therapeutic combination of a third generation EGFR tyrosine kinase inhibitor and a cyclin d kinase inhibitor

A tyrosine kinase, EGFRT790M technology, applied in the field of cancer treatment of human subjects), can solve the problem of NSCLC can not be cured

Inactive Publication Date: 2020-04-10
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the efficacy of EGFR TKIs, since NSCLC, specifically EGFR-mutant NSCLC, remains incurable, there is still a need to continue to develop new treatment options for the disease

Method used

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  • Therapeutic combination of a third generation EGFR tyrosine kinase inhibitor and a cyclin d kinase inhibitor
  • Therapeutic combination of a third generation EGFR tyrosine kinase inhibitor and a cyclin d kinase inhibitor
  • Therapeutic combination of a third generation EGFR tyrosine kinase inhibitor and a cyclin d kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0146] Example 1: Mechanistic Combination Studies to Demonstrate Target Activity and Combinatorial Effects of Compounds on Proximal Biomarkers.

[0147] This experiment was performed to test the combined effect of Compound A (EGF816) and Compound B (LEE011) on EGFR mutant NSCLC cell lines and to demonstrate that the observed anti-proliferative synergy was determined by mechanistic analysis of proximal readouts. Target efficacy driven.

[0148] Several EGFR mutant NSCLC cell lines were treated with combinations of EGF816 and LEE011 at different concentrations as follows for 72 hours. NCI-H1975 (with mutation L858R, T790M), PC-14 (with mutation ex 19del or exon 19 deletion), HCC827 (with mutation ex19del) and HCC4006 (with mutation ex19del) cells in RPMI-1640 growth medium ( ATCC, catalog number 20-2001), and suspended with 10% fetal bovine serum (GIBCO, catalog number F4135) in a humidified 5% CO2 incubator at 37°C. For mechanistic studies, for HCC827, NCI-H1975, HCC4006, a...

example 2

[0160] Example 2: Long-term viability study: Combination of EGFRi plus CDK4 / 6i slows down the viability of EGFR-mutant NSCLC cells regrowth.

[0161] PC9 (3,000 / well), HCC827 (10,000 / well), HCC4006 (5000 / well) and MGH707 (5000 / well) cells were seeded into 96-well plates, and treated with EGF816 (300nM) alone or with LEE011 (1000nM) combined treatment for four weeks. Drugs are updated twice a week. Cell confluency was used as a surrogate indicator of cell number and was measured by incucyte zoom (Essen Biosciences) at the beginning of treatment and twice weekly thereafter (2x).

[0162] Single-agent treatment with EGF816 resulted in varying degrees of apoptosis and cell cycle arrest in the four EGFR-mutant NSCLC cell lines tested (PC9, HCC827, HCC4006, and MGH707), although in all cases, by the end of the four-week treatment time course These cells were then able to begin to slowly re-grow in the presence of EGFRi. To test whether the regrowth was mediated by residual ac...

example 3

[0163] Example 3: In vivo efficacy studies of Compound A and Compound B alone or in combination

[0164] Combination activity with co-treatment with Compound B and Compound A was observed in vivo in a patient-derived xenograft model harboring EGFR mutations, L858R and T790M, as described below ( Figure 4 ).

[0165] tumor cell culture

[0166] NCI-H1975 cells were grown to mid-log phase in RPMI 1640 medium containing the following: 10% fetal bovine serum, 2 mM glutamine, 100 units / mL penicillin G sodium, 25 μg / mL gentamicin, and 100 μg / mL streptomycin sulfate. The tumor cells were incubated at 37°C in 5% CO 2 and 95% air in tissue culture flasks in a humidified incubator.

[0167] In vivo implantation and tumor growth

[0168] NCI-H1975 cells for implantation into mice were harvested in log phase and resuspended in 50% Matrigel TM (BD Biosciences) in cold PBS. Inject 1 x 107 cells (0.2 mL of cell suspension) subcutaneously into the right flank of each mouse. Whe...

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Abstract

This invention relates to a pharmaceutical combination comprising (a) a third generation EGFR tyrosine kinase inhibitor and (b) a cyclin D kinase 4 / 6 (CDK4 / 6) inhibitor, particularly for use in the treatment of a cancer, particularly a lung cancer. This invention also relates to uses of such a combination for the preparation of a medicament for the treatment of a cancer; methods of treating a cancer in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combination; pharmaceutical compositions comprising such combination and commercial packages thereto.

Description

technical field [0001] The present invention relates to methods of treating cancer, such as lung cancer, and in particular non-small cell lung cancer (NSCLC), in a human subject, and to drug combinations useful in such treatment. In particular, the present invention provides a pharmaceutical combination comprising (a) a third generation EGFR tyrosine kinase inhibitor (TKI), specifically (R,E)-N-(7-chloro-1-( 1-(4-(Dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide , or a pharmaceutically acceptable salt thereof, and (b) a cyclin D kinase 4 / 6 (CDK4 / 6) inhibitor, specifically 7-cyclopentyl-2-(5-piperazin-1-yl-pyridine -2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, or a pharmaceutically acceptable salt thereof. Also provided are such combinations for use in the treatment of cancer, in particular lung cancer (e.g. NSCLC); the use of such combinations for the manufacture of a medicament for the treatment of cancer, i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/55A61K31/519A61K45/06A61P35/00
CPCA61K45/06A61K31/519A61K31/55A61P35/00A61K2300/00
Inventor S·穆迪I·穆尔福德J·芭蕾蒂娜
Owner NOVARTIS AG
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