JPWO2019202527A5

JPWO2019202527A5 -

Info

Publication number: JPWO2019202527A5
Application number: JP2020556794A
Authority: JP
Publication date: 2022-04-19
Anticipated expiration: 2039-04-17

Description

The present invention includes the following embodiments.
[1]
A compound that is nazartinib or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of metastases in patients, said metastases being selected from central nervous system (CNS) metastases, brain metastases and soft membrane metastases. , Optionally, the metastasis is the result of a primary lesion such as non-small cell lung cancer (NSCLC), particularly NSCLC with an EGFR mutation (Exon 19 deletion or Exon 21 (L858R) substitution).
[2]
Nazartinib is a compound for use according to the above [1], which is a form of the mesylate.
[3]
The compound for use according to [1] or [2] above, wherein the patient is a patient with locally advanced or metastatic non-small cell lung cancer (NSCLC).
[4]
The NSCLC is a compound for use according to any one of the above [1] to [3], which has an EGFR activation mutation.
[5]
The compound for use according to [4] above, wherein the EGFR activation mutation is an L858R mutation.
[6]
The compound for use according to the above [4] or [5], wherein the EGFR activation mutation is an ex19del mutation.
[7]
The compound for use according to any one of the above [1] to [6], wherein the patient is an NSCLC patient who has progressively developed brain metastasis, CNS metastasis and / or pial metastasis.
[8]
The compound for use according to any one of [1] to [7] above, wherein the patient's progression-free survival (PFS) is improved relative to PFS obtained after treatment with, for example, erlotinib or gefitinib.
[9]
The compound for use according to any of the above [1] to [8], wherein the overall survival (OS) of the patient is improved, for example, with respect to the OS obtained after treatment with erlotinib or gefitinib.
[10]
The compound for use according to any one of [1] to [9] above, wherein the overall response rate (ORR) of the patient is improved with respect to the ORR obtained after treatment with, for example, erlotinib or gefitinib.
[11]
Use according to any of [1] to [10] above, wherein the exacerbation-free period (TPP) in the CNS or brain is increased compared to the TPP in the CNS or brain by administration / treatment of, for example, erlotinib, gefitinib or osimertinib. Compound for.
[12]
The compound for use according to any of the above [1] to [11], wherein the CNS or brain ORR is increased compared to, for example, CNS ORR by treatment with erlotinib, gefitinib or osimertinib.
[13]
The compound for use according to any one of [1] to [12] above, wherein the CNS or brain response period (DoR) is increased compared to, for example, CNS or brain DoR by treatment with erlotinib, gefitinib or osimertinib.
[14]
Nazartinib is a compound for use according to any one of the above [1] to [13], which is used as a monotherapy.
[15]
Nazartinib or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of central nervous system (CNS) metastases, including brain metastases, in first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). The cancer is nazartinib or a pharmaceutically acceptable salt thereof having an EGFR mutation (eg, exon 19 deletion or exon 21 (L858R) substitution).
[16]
Nazartinib for use according to [15] above, which is used as part of monotherapy (single agent for the treatment of NSCLC) or combination therapy for the treatment of NSCLC.
[17]
The use according to any of the above [1] to [16], which is administered daily, preferably once daily, in a total dose selected from the range of about 50 to about 200 mg (eg, about 150 mg). Nazartinib for.
[18]
A method of treating patients with NSCLC that provides a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof to patients preliminarily determined to have an exon 19 deletion or an exon 21 (L858R) substituted EGFR mutation. A method comprising the step of selectively administering.
[19]
A method of treating patients with NSCLC
(A) A step of determining or determining that the patient has an exon 19 deletion or an exon 21 (L858R) substituted EGFR mutation;
(B) The step of administering to the patient a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof.
How to include.
[20]
A method of treating a patient with NSCLC, the step of selecting the patient for treatment based on the prior determination that the patient has an exon 19 deletion or an exon 21 (L858R) substituted EGFR mutation. And a step of administering to the patient a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof.
[21]
The method according to any one of [18] to [20] above, wherein the patient has a metastasis selected from central nervous system (CNS) metastasis, brain metastasis and pia mater metastasis.
[22]
The method according to any one of [18] to [21] above, wherein the therapeutically effective amount is selected from the range of about 50 to about 200 mg (for example, about 150 mg) and is preferably administered once a day. ..
[23]
A compound that is nazartinib or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of metastases in patients, said metastases being selected from central nervous system (CNS) metastases, brain metastases and soft membrane metastases. , Optionally, the metastasis is the result of a primary lesion such as non-small cell lung cancer (NSCLC), in particular the patient has NSCLC with an EGFR mutation (Exon 19 deletion or Exon 21 (L858R) replacement). A compound that has been previously determined to have.

Claims

A pharmaceutical composition comprising nazartinib or a compound which is a pharmaceutically acceptable salt thereof for the treatment or prevention of metastasis in a patient, wherein the metastasis is central nervous system (CNS) metastasis, brain metastasis and soft membrane metastasis. Selected from, and optionally, the metastasis is the result of a primary lesion such as non-small cell lung cancer (NSCLC), particularly NSCLC with an EGFR mutation (exon 19 deletion or exon 21 ( L858R ) replacement). Things .

The pharmaceutical composition according to claim 1, wherein nazartinib is in the form of its mesylate.

The pharmaceutical composition according to claim 1 or 2, wherein the patient is a patient having locally advanced or metastatic non-small cell lung cancer (NSCLC).

The pharmaceutical composition according to any one of claims 1 to 3, wherein the NSCLC has an EGFR activation mutation.

The pharmaceutical composition according to claim 4, wherein the EGFR activation mutation is an L858R mutation.

The pharmaceutical composition according to claim 4 or 5, wherein the EGFR activation mutation is an ex19del mutation.

The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient is an NSCLC patient who has progressively developed brain metastasis, CNS metastasis and / or pial metastasis.

The pharmaceutical composition according to any one of claims 1 to 7, wherein the progression-free survival (PFS) of the patient is improved with respect to PFS obtained after treatment with, for example, erlotinib or gefitinib.

The pharmaceutical composition according to any one of claims 1 to 8, wherein the overall survival (OS) of the patient is improved, for example, with respect to the OS obtained after treatment with erlotinib or gefitinib.

The pharmaceutical composition according to any one of claims 1 to 9, wherein the overall response rate (ORR) of the patient is improved with respect to the ORR obtained after treatment with, for example, erlotinib or gefitinib.

The pharmaceutical composition according to any one of claims 1 to 10, wherein the exacerbation-free period (TPP) in the CNS or the brain is increased as compared with the TPP in the CNS or the brain by administration / treatment of erlotinib, gefitinib or osimertinib, for example. Things .

The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS or brain ORR is increased compared to, for example, CNS ORR by treatment with erlotinib, gefitinib or osimertinib.

The pharmaceutical composition according to any one of claims 1 to 12, wherein the CNS or brain response period (DoR) is increased as compared with, for example, CNS or brain DoR by treatment with erlotinib, gefitinib or osimertinib.

The pharmaceutical composition according to any one of claims 1 to 13, wherein nazartinib is used as a monotherapy.

A drug comprising nazartinib or a pharmaceutically acceptable salt thereof for treating or preventing central nervous system (CNS) metastases, including brain metastases, in first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). The composition , wherein the cancer has an EGFR mutation (eg, exon 19 deletion or exon 21 (L858R) substitution).

25. The pharmaceutical composition of claim 15, wherein nazartinib is used as part of monotherapy (single agent for the treatment of NSCLC) or combination therapy for the treatment of NSCLC.

13. Pharmaceutical composition .

A pharmaceutical composition comprising a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof for treating a patient with NSCLC prior to having an exon 19 deletion or an exon 21 (L858R) substituted EGFR mutation. A pharmaceutical composition that is selectively administered to a patient determined to be.

A pharmaceutical composition comprising a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof for use in a method of treating a patient with NSCLC, said method.
(A) A step of determining or determining that the patient has an exon 19 deletion or an exon 21 (L858R) substituted EGFR mutation;
(B) A pharmaceutical composition comprising the step of administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof .

A pharmaceutical composition comprising a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof for use in a method of treating a patient with NSCLC, wherein the patient is deficient in exon 19. Includes steps to select for treatment based on prior determination of loss or possession of the Exon 21 (L858R) substituted EGFR mutation and a therapeutically effective amount of nazartinib or a pharmaceutically acceptable salt thereof for said patient. A pharmaceutical composition comprising the step of administering the pharmaceutical composition .

The pharmaceutical composition according to any one of claims 18 to 20, wherein the patient has a metastasis selected from central nervous system (CNS) metastasis, brain metastasis and pial metastasis.

The pharmaceutical composition according to any one of claims 18 to 21, wherein the therapeutically effective amount is selected from the range of about 50 to about 200 mg (for example, about 150 mg) and is preferably administered once a day. Things .

A pharmaceutical composition comprising nazartinib or a compound which is a pharmaceutically acceptable salt thereof for the treatment or prevention of metastasis in a patient, wherein the metastasis is central nervous system (CNS) metastasis, brain metastasis and soft membrane metastasis. Selected from, and optionally, the metastasis is the result of a primary lesion such as non-small cell lung cancer (NSCLC), in particular the patient has an EGFR mutation (exon 19 deletion or exon 21 (L858R) replacement). A pharmaceutical composition previously determined to have NSCLC.