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EP-4736884-A1 - TREATMENT COMBINATION, AND USE THEREOF AND TREATMENT METHOD

EP4736884A1EP 4736884 A1EP4736884 A1EP 4736884A1EP-4736884-A1

Abstract

The present disclosure relates to a therapeutic combination, and the use thereof and a treatment method. Specifically, the present disclosure relates to a pharmaceutical composition of an immunoconjugate and an anti-human PD-1 antibody or an antigen-binding fragment thereof, a kit, a treatment combination and the use thereof, and a method for treating cancer in a patient.

Inventors

  • GE, Junyou
  • CHARTASH, ELLIOT
  • TOKER, Sarper
  • POEHLEIN, Christian
  • MORENO, BIANCA HOMET
  • JIN, XIAOPING
  • DIAO, Yina
  • YANG, JIACHENG
  • FU, Yujie
  • QIAO, Zhijiao
  • CHEN, LIHUA
  • ZHOU, Yiting
  • AKALA, Omobolaji

Assignees

  • Merck Sharp & Dohme LLC
  • Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. A method of treating a cancer in a patient, comprising administering to the patient: (a) an anti-human PD-1 antibody or antigen binding fragment thereof; and (b) an immunoconjugate of Formula (I): wherein: Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10, wherein the amounts of (a) and (b) are together effective to treat ovarian cancer, cervical cancer, prostate cancer, or urothelial cancer.
  2. The method of claim 1, wherein n is from 6 to 8.
  3. The method of claim 1 or 2, wherein the antibody that binds to Trop-2 comprises: (i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and (ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.
  4. The method of any one of claims 1-3, wherein the antibody that binds to Trop-2 comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38.
  5. The method of any one of claims 1-4, wherein the antibody that binds to Trop-2 comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36.
  6. The method of any one of claims 1-5, wherein the antibody that binds to Trop-2 is sacituzumab.
  7. The method of any one of claims 1-6, wherein the immunoconjugate of Formula (I) is administered to the patient at a dose from 1.0 mg/kg to 6.0 mg/kg.
  8. The method of any one of claims 1-7, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab and pembrolizumab.
  9. The method of claim 8, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.
  10. The method of any one of claims 1-9, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is administered to the patient at a dose of 50 mg to 500 mg.
  11. The method of any one of claims 1-10, wherein the immunoconjugate of Formula (I) and the anti-human PD-1 antibody or antigen binding fragment thereof are each administered in three-week cycles, and each are administered on Day 1 of each three-week cycle.
  12. The method of any one of claims 1-10, wherein the immunoconjugate of Formula (I) and the anti-human PD-1 antibody or antigen binding fragment thereof are each administered in six-week cycles, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is administered on Day 1 of each six-week cycle, and the immunoconjugate of Formula (I) is administered on Days 1, 15, and 29 of each six-week cycle.
  13. The method of claim 11, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 3 mg/kg.
  14. The method according to claim 11, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 4 mg/kg.
  15. The method according to claim 11, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 5 mg/kg.
  16. The method according to claim 12, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 3 mg/kg.
  17. The method according to claim 12, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 4 mg/kg.
  18. The method according to claim 12, wherein the anti-human PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg, and the immunoconjugate of Formula (I) is administered at a dose of about 5 mg/kg.
  19. The method of any one of claims 11-18, wherein the number of cycles is from 1-4.
  20. The method of any one of claims 1-19, further comprising administering to the patient an additional anticancer agent.

Description

The present application is based on and claims priority to the PCT application with application number PCT/CN2023/105367, filed on June 30, 2023, and the Chinese application with application number 202410821906.3, filed on June 24, 2024. The content of the PCT application is hereby incorporated into the present application in its entirety. TECHNICAL FIELD The present disclosure relates to a therapeutic combination, and use and treatment method thereof. Specifically, the present disclosure relates to a therapeutic combination, which comprises an antibody or antigen-binding fragment thereof capable of binding to programmed cell death protein 1 (PD-1), and an immunoconjugate. The present disclosure also relates to a combination therapy for treating cancer. BACKGROUND OF THE DISCLOSURE PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and up-regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells. Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues. In large sample sets of e.g., ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment. Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma, and to correlate with poor prognosis in renal cancer. Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor. Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers. Immune therapies targeting the PD-1 axis include monoclonal antibodies directed to the PD-1 receptor (KEYTRUDA™ (pembrolizumab), Merck and Co., Inc., Kenilworth, NJ, USA and OPDIVO™ (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ, USA) and also those that bind to the PD-L1 ligand (MPDL3280A; TECENTRIQ™ (atezolizumab), Genentech, San Francisco, CA, USA). Both therapeutic approaches have demonstrated anti-tumor effects in numerous cancer types. It has been proposed that the efficacy of such antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents. Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein involved in calcium signal transduction, and is expressed in multiple tumor types. Trop-2 is expressed in normal trophoblasts and allows for trophoblast cell growth, migration, and proliferation. Trop-2 has been implicated in several cell signaling pathways, including intracellular calcium transduction, MAPK signaling pathway, RAF, NF-κB, and Cyclin D/E among others. It has been shown that Trop-2 is upregulated in cancer cells when compared to normal cell counterparts. This increased expression has been seen in many different tumor types including breast cancer, colon cancer, non-small cell lung cancer (NSCLC), esophageal squamous cell cancer, thyroid cancer, and hepatobiliary cancers, raising the possibility of Trop-2 as a tumor agnostic biomarker. The reason for Trop-2 upregulation in cancer cells is unclear; however it is postulated that Trop-2 has critical regulatory effects on cellular proliferation and invasion, meaning that overexpression would lead to selective tumor progression. In fact, preclinical data suggests that Trop-2 overexpression stimulates tumor growth while Trop-2 knock-down inhibits tumor growth. In breast cancer specifically, elevated Trop-2 expression has been associated with worse survival. Trop-2 gene expression has been detected in all breast cancer subtypes with higher levels noted in HR+/HER2-, and triple negative breast cancer (TNBC) compared to HER2+ disease. Genomic analyses of TNBC also identified Trop-2 as an attractive candidate for targeted therapy, and led to further investigation of Trop-2 as a new therapeutic target. The success of targeting Trop-2 via antibody-drug conjugates (ADCs) in metastatic breast cancer (MBC), and urothelial cancer and ongoing trials in NSCLC have established Trop-2 targeting as a valid and fruitful strategy, and several Trop-2-targeted therapeutics have recently been developed for clinical use, such as anti-Trop-2 antibodies and Trop-2-targeted ADCs. Subsequently, multiple early-phase clinical trials have demonstrated good safety profiles, and clinical benefit associated with Trop-2-based ADCs across multiple tumor types. This includes clinical benefit