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Therapeutic combination of a third-generation EGFR tyrosine kinase inhibitor and a raf inhibitor

A tyrosine kinase, EGFRT790M technology, applied in the field of treating cancer in human subjects, can solve the problem of incurable NSCLC

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 raf inhibitor
  • Therapeutic combination of a third-generation EGFR tyrosine kinase inhibitor and a raf inhibitor
  • Therapeutic combination of a third-generation EGFR tyrosine kinase inhibitor and a raf inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0152] Example 1: Short term viability assay: Compound B enhances the efficacy of EGF816 (Compound A)

[0153] The potential efficacy of adding a MAPK pathway inhibitor (eg compound B) to a third generation EGFR tyrosine kinase inhibitor (eg EGF816) in EGFR mutant NSCLC was assessed below. A panel of EGFR mutant NSCLC cell lines were treated with a fixed dose (300 nM) of EGF816 ("Compound A") or DMSO in combination with Compound B over a range of 10 doses for 5 days.

[0154] method

[0155] cell line:

[0156] PC9, HCC827, HCC4006, NCI-H1975 and MGH707 are all EGFR mutant NSCLC cell lines sensitive to EGF816. PC9, HCC827, HCC4006 and NCI-H1975 were obtained from the Cancer Cell Line Encyclopedia (CCLE) database. MGH707 was obtained from Massachusetts General Hospital. All cell lines were maintained in RMPI medium supplemented with 10% fetal calf serum.

[0157] Compound:

[0158] Both Compound A (EGF816) and Compound B were resuspended in DMSO at a concentration of 10...

example 2

[0163] Example 2: Long-Term Viability Assays Show that Combinations of Third Generation EGFR Tyrosine Kinase Inhibitors and Raf Inhibitors Slows the growth of drug-resistant cells.

[0164] The combination of Compound A and Compound B was further tested in a long-term drug combination growth assay. The same EGFR mutant NSCLC cell line used in Example 1 above was treated with EGF816 alone or in combination with Compound B over a range of 5 doses for 14 days as follows.

[0165] method

[0166] PC9 (6000 / well), HCC827 (4000 / well), HCC4006 (5000 / well), and MGH707 (5000 / well) cells were placed in a 96-well plate, and treated with EGF816 (300nM)+DMSO or Compound B was treated for two weeks at a dose range of (0.03, 0.1, 0.3, 1 and 3uM). Drugs are updated twice a week. Cell confluence was used as a surrogate indicator of cell number and was measured by incucyte zoom at t=0, 4, 7, 10 and 14 days of treatment.

[0167] result

[0168] As can be seen from Figure 2, compound B ...

example 3

[0171] Example 3: Phase Ib, Open Label EGF816 in Combination with Compound B in Patients with EGFR Mutant NSCLC Signature, dose escalation and / or dose expansion studies.

[0172] Patients eligible for this study were those with advanced EGFR-mutant NSCLC, a disease currently incurable by any therapy. In first-line, treatment-naïve patients, or patients with acquired EGFR T790M gatekeeper mutations, and / or patients not previously treated with third-generation EGFR TKIs, treatment with EGF816 (Compound A) as a single agent is expected to be effective for most patients with clinical benefit. However, all patients are expected to develop treatment resistance and eventual disease progression after a period of single-agent EGF816 treatment.

[0173] In the context of EGF816 treatment, Compound B is expected to be active in tumors where signaling from or upstream from BRAF, including activated RTK and Ras signaling, drives resistance or tumor cell persistence. As shown above, p...

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Abstract

This invention relates to a pharmaceutical combination comprising (a) a third generation EGFR tyrosine kinase inhibitor and (b) a Raf 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, particularly 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 Raf inhibitor, specifically N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4 -methylphenyl)-2-(trifluoromethyl)isonicotinamide, 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, in particular lung cancer (e.g. NSCLC); A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5377A61K31/55A61K45/06A61P35/00
CPCA61K45/06A61K31/5377A61K31/55A61P35/00A61K2300/00
Inventor S·穆迪L·佩特鲁泽利J·恩格尔曼
Owner NOVARTIS AG
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