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EP-4735002-A1 - TREATMENT METHODS FOR SUBJECTS WITH NON-SMALL CELL LUNG CANCER HAVING AN ABERRATION IN EGFR

EP4735002A1EP 4735002 A1EP4735002 A1EP 4735002A1EP-4735002-A1

Abstract

A method of treating a subject with a cancer having at least one aberration in EGFR, whereby the subject is administered (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (also known as zipalertinib and as TAS6417) or a pharmaceutically acceptable salt thereof, to a subject who has previously been treated with a molecularly targeted therapeutic. The molecularly targeted therapeutic may be an EGFR-targeting therapeutic other than Compound (1) or a non-EGFR-targeting therapeutic. The method may optionally involve administering to the subject an additional therapeutic agent.

Inventors

  • JONES, JEFFERY
  • HAYASHI, KOHEI
  • AOYAGI, YOSHIMI
  • WACHECK, VOLKER

Assignees

  • Taiho Pharmaceutical Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A method of treating a subject with a cancer having at least one aberration in EGFR, the method comprising: administering to the subject an effective amount of (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, wherein the subject has previously been treated with a systemic treatment which is at least one selected from the group consisting of a chemotherapeutic agent and a molecularly targeted therapeutic.
  2. 2. The method of claim 1, wherein the cancer is at least one selected from the group consisting of locally advanced and has metastasized to a brain of the subject.
  3. 3. The method of claim 1, wherein the cancer is locally advanced.
  4. 4. The method of any one of claims 1 to 3, wherein the cancer is unresectable.
  5. 5. The method of any one of claims 1 to 3, wherein the at least one aberration in EGFR is an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.
  6. 6. The method of claim 5, wherein the at least one aberration in EGFR is an EGFR mutation in exon 20.
  7. 7. The method of any one of claims 1 to 3, wherein the at least one aberration in EGFR is an EGFR exon 20 insertion mutation.
  8. 8. The method of claim 7, wherein the EGFR exon 20 insertion mutation is at least one selected from the group consisting of D770_N771insX, V769_D770insX, H773_V774insX, P772_H773insX, N771_P772insX, A763_Y764insX, V774_C775insX, D761_E762insX, A763_Y764insTLA, Y764_V765insHH, A767_S768insASV, S768dupSVD, A767_S768insX, S768_V769insX, Y764_V765insX, V765_M766insX, A763_Y764insFQEA, A767_S768insTLA, S768_V769insVAS, S768_V769insAWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770insGE, V769_D770delInsDGEL, D770_N771insSVD, D770_N771insNPG, D770_N771insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_N771insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insNPH, D770_N77 tins SVP, D770_N771insSVQ, D770_N771insMATP, D770_N771insG, D770_N771insY, D770_N771insGF, D770_N771insGT, delD770insGY, N771_P772insH, N771_P772insN, delN771insGY, delN771insGF, N771delinsGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773insDPH, P772_H773insDNP, P772_H773insQV, P772_H773insTPH, P772_H773insN, P772_H773insV, P772_H773insNP, P772_H773insNPH, H773_V774insH, H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG, H773_V774insGH, H773_V774insAH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV.
  9. 9. The method of any one of claims 1 to 3, wherein from about 10 to about 500 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
  10. 10. The method of any one of claims 1 to 3, wherein from about 30 to about 300 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8- yljacrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.
  11. 11. The method of any one of claims 1 to 3, wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice per day (BID).
  12. 12. The method of any one of claims 1 to 3, wherein (S)-N-(4-amino-6-methyl-5- (quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject every day of a treatment cycle lasting 21 days.
  13. 13. The method of any one of claims 1 to 3, wherein lOOmg of (S)-N-(4-amino-6- methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or its pharmaceutically acceptable salt there is administered to the subject twice daily(BID), every day of a treatment cycle lasting 21 days.
  14. 14. The method of any one of claims 1 to 3, further comprising administering to the subject an effective amount of an additional therapeutic agent.
  15. 15. The method of claim 14, wherein the additional therapeutic agent is at least one selected from the group consisting of a chemotherapeutic agent, a tyrosine kinase inhibitor, and an immunotherapeutic agent.
  16. 16. The method of any one of claims 1 to 3, wherein the systemic treatment is a systemic treatment with a molecularly targeted therapeutic selected from the group consisting of an EGFR-targeting therapeutic other than Compound (1) and a non-EGFR-targeting therapeutic.
  17. 17. The method of claim 16, wherein the EGFR-targeting therapeutic other than Compound (1) is at least one selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, lazertinib, sunvozertinib, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rociletinib, vandetanib, lapatinib, duligotuzumab, panitumumab, zalutumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imgatuzumab, matuzumab, and nimotuzumab.
  18. 18. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is osimertinib.
  19. 19. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is mobocertinib.
  20. 20. The method of claim 17, wherein the EGFR-targeting therapeutic other than Compound (1) is afatinib.

Description

TITLE OF THE INVENTION TREATMENT METHODS FOR SUBJECTS WITH NON-SMALL CELL LUNG CANCER HAVING AN ABERRATION IN EGER CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Applications No. 63/523,518, 63/523,572, both filed June 27, 2023, and 63/650,590, filed May 22, 2024, each of which is incorporated by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION FIELD OF THE INVENTION [0001] The present invention relates to methods of treating cancers harboring an aberration in EGFR. DESCRIPTION OF THE RELATED ART [0002] In patients with advanced or metastatic NSCLC harboring epiderma! growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations, current lung cancer treatment guidelines recommend standard platinum-based chemotherapy to treat patients in the front- line setting. This regimen is preferred due to low response rates against EGFR ex20ins mutation patients with single agent fust-, second-, and third-generation EGFR-tyrosine kinase inhibitors (TKI). See National Comprehensive Cancer Network. NCCN guidelines. Non-small cell lung cancer version 3.2022. J Natl Compr Cane Netw. 2022;20:497-530. Real world evidence analysis of overall survival (OS) and progression-free survival (PFS) outcomes indicate that patients having advanced NSCLC with EGFR ex20ins mutations have better outcomes with front-line platinum-based chemotherapy as compared to standard EGFR TKIs. However, outcomes for these patients remain poor regardless of treatment in subsequent lines of therapy. See Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer. 2021; 162: 154-161. Further, imm uno-oncology therapy does not appear to offer the same benefit in patients with NSCLC harboring EGFR ex20ins mutations, as would be expected in patients with advanced NSCLC without actionable mutations. See Remon J, Hendriks LEL, Cardona AF, Besse B. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treat Rev. 2020;90: 102105; Minchom A, Viteri S, Bazhenova L, et al. Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy. Lung Cancer. 2022;168:74-82. [0003] Despite recent accelerated/conditional approvals for amivantamab (US, EU, and Canada) and mobocertinib (US and China) for EGFR ex20ins patients for whom platinumbased chemotherapy failed to treat their locally advanced or metastatic disease, there continues to be an unmet medical need for tolerable and effective treatment options specifically targeting EGFR ex20ins mutations, particularly in the front-line treatment setting. Further, because of the narrow therapeutic window between inhibition of EGFR ex20ins and wild-type (WT) EGFR, currently available EGFR ex20ins-specific TKIs such as mobocertinib cause frequent rash and diarrhea. Amivantamab, a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (MET), requires intravenous administration and causes frequent infusion reactions (IRRs). While more effective for some patients, amivantamab treatment is associated with adverse events including rash, infusion- related reactions, infected skin around the nail, muscle and joint pain, shortness of breath, nausea, fatigue, swelling of hands, ankles, feet, face, or the entire body, sores in the mouth, cough, constipation, vomiting, and changes in certain blood tests (e.g., decreased albumin levels, increased glucose levels, increased liver enzymes) and has the further disadvantage of requiring intravenous administration. [0004] Hence, despite recent progress in the development of EGFR ex20ins-targeting therapies, there remains a significant need for novel agents that will maximize clinical efficacy while achieving a more favorable safety profile. [0005] In view of the forgoing, there exists a need for new treatment methods in patients with cancers harboring having an aberration in EGFR, particularly those in patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations. SUMMARY OF THE INVENTION [0006] Zipalertinib (CLN-081/TAS6417) is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations (including ex20ins) and increased selectivity for ex20ins versus wild-type (WT) EGFR. In cell-based assays using genetically engineered cell lines, zipalertinib potently inhibited intracellular phosphorylation of mutant EGFRs, including EGFRs harboring a wide spectrum of ex20ins mutations. Its inhibitory activity is more potent against mutant EGFRs than that against WT EGFR, and zipalertinib exerts significant antitumor activity in vivo against cancer xenografts harboring EGFR ex20ins mutations. See Udagawa H, Hasako S, Ohashi A, et al. TAS6417/CLN-081 is a pan- mutation-s