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CN-121986118-A - Anti-PD-1 based treatment before and after surgery

CN121986118ACN 121986118 ACN121986118 ACN 121986118ACN-121986118-A

Abstract

The present disclosure relates to the treatment of solid cancers, such as breast, colon and lung cancer, in particular non-small cell lung cancer (NSCLC), in a human subject using an anti-PD-1 antibody as monotherapy or as a combination therapy with, for example, chemotherapy and/or surgery. The treatment provided may be a combination of pre-operative tirelimumab with chemotherapy, with different doses of tirelimumab used in the post-operative adjuvant stage. The administration regimen may include administration of 200 mg anti-PD-1 antibody (e.g., tirelimumab) (e.g., every three weeks), followed by tumor resection, followed by administration of 400 mg of the anti-PD-1 antibody (e.g., every six weeks). Furthermore, the chemotherapy may be platinum-based (e.g., carboplatin and/or cisplatin), and may further include pemetrexed (e.g., for non-squamous cancers) or paclitaxel (e.g., for squamous cancers).

Inventors

  • ZHENG WENJUAN
  • WANG RUIHUA
  • ZHANG QIUYANG

Assignees

  • 广州百济神州生物制药有限公司

Dates

Publication Date
20260505
Application Date
20241011
Priority Date
20231012

Claims (20)

  1. 1. A method of treating cancer in a subject in need thereof, wherein the cancer is a surgically resectable solid cancer, the method comprising: (a) Parenterally administering a first dose of an anti-PD-1 antibody or antigen-binding fragment thereof to the subject during a first treatment period, wherein the first dose of the anti-PD-1 antibody is 200 mg, once every three weeks, and wherein the anti-PD-1 antibody comprises: (i) V H CDR1、V H CDR2 and V H CDR3 comprising the amino acid sequences as set forth in SEQ ID NOS: 31, 32 and 33, and (Ii) V L CDR1、V L CDR2 and V L CDR3 comprising the amino acid sequences as set forth in SEQ ID NOs 34, 35 and 36; (b) And parenterally administering a second dose of the anti-PD-1 antibody or antigen-binding fragment thereof to the subject during a second treatment period following (ii), wherein the second dose of the anti-PD-1 antibody is 400 mg every 6 weeks.
  2. 2. The method of claim 1, wherein the cancer is an early stage cancer.
  3. 3. The method of claim 1, wherein the cancer is a stage II or stage IIIA cancer.
  4. 4. The method of claim 1, wherein the cancer is not locally advanced or metastatic.
  5. 5. The method of claim 1, wherein the cancer is breast cancer, colon cancer, or lung cancer.
  6. 6. The method of claim 5, wherein the cancer is non-small cell lung cancer (NSCLC).
  7. 7. The method of claim 6, wherein the cancer is squamous cell carcinoma.
  8. 8. The method of claim 6, wherein the cancer is non-squamous cell carcinoma.
  9. 9. The method of any one of claims 5-8, wherein the cancer is stage II or stage IIIA.
  10. 10. The method of any one of claims 5-9, wherein the cancer is not locally advanced or metastatic.
  11. 11. The method of any one of claims 1-10, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID No. 24 and the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID No. 26.
  12. 12. The method of claim 11, wherein the anti-PD-1 antibody comprises an IgG constant region comprising the amino acid sequence of SEQ ID No. 88.
  13. 13. The method of any one of claims 1-12, wherein the anti-PD-1 antibody is administered intravenously, optionally wherein the administration is by IV infusion.
  14. 14. The method of any one of claims 1-13, wherein the subject has not previously received treatment for the cancer or the treatment is first line therapy.
  15. 15. The method of any one of claims 1-13, wherein the subject has not been previously treated with chemotherapy, radiation therapy, and/or immunotherapy.
  16. 16. The method of any one of claims 1-13, wherein the treatment is two-wire therapy.
  17. 17. The method of any one of claims 1-16, wherein the first treatment period comprises 3 or 4 cycles, each cycle being three weeks.
  18. 18. The method of any one of claims 1-17, wherein the second treatment period comprises less than or equal to 8 cycles, each cycle being six weeks.
  19. 19. The method of any one of claims 1-17, wherein the second treatment period comprises at least 8 cycles, each cycle being six weeks.
  20. 20. The method of any one of claims 1-19, wherein the second treatment period begins within 8 weeks after the surgical resection.

Description

Anti-PD-1 based treatment before and after surgery Technical Field Disclosed herein is a method for preventing solid tumors, such as breast cancer, colon cancer and lung cancer (e.g., non-small cell lung cancer), delaying progression of solid tumors, or treating solid tumors in a subject in need thereof, comprising administering an antibody or fragment thereof that binds to anti-PD-1 as described herein (particularly using the administration doses and regimens described herein), optionally in combination with chemotherapy. Reference to electronic sequence Listing The contents of the electronic sequence listing (BEIG _109_00_us_seqlist_st 26.Xml; size: 130,386 bytes; and date of creation: 2023, 8, 11 days) are incorporated herein by reference in their entirety. Background Programmed death ligand 1 (PD-L1; also known as CD274 and B7-H1) is thought to play an important role in immune regulation and maintenance of peripheral tolerance. Immune checkpoint therapies targeting PD-L1 or its receptor PD-1 have achieved breakthrough improvements in clinical response in a variety of human cancer types (see, e.g., brahmer et al, N Engl J Med, 366: 2455-2465 (2012); robert et al, N Engl J Med, 372:320-330 (2015); topalian et al, N Engl J Med, 366:2443-2454 (2012); wolchok et al, N Engl J Med, 369:122-133 (2013)). Tirelimumab (Tislelizumab, also known as BGB a 317) is a humanized immunoglobulin G4 (IgG 4) variant monoclonal antibody against PD-1, which was developed for the treatment of human malignancies in various organs and tissues. Tirelimumab binds with high specificity and affinity to the extracellular domain of human PD-1 and competitively blocks the binding of PD-L1 and programmed death ligand-2 (PD-L2). Unlike other PD-1 inhibitors, tirelimumab was specifically engineered to remove Fc and hinge regions in order to minimize fcγ receptor binding on macrophages, which can reduce potential negative interactions. Management of early and late solid tumors is a significant challenge and often consists of a combination of surgical, radiation therapy and systemic therapy approaches. However, pre-operative treatment, with or without adjuvant therapy, presents a significant risk of morbidity and potential complications. For example, in the case of non-small cell lung cancer (NSCLC), although surgery is considered a first line of choice, only 25% -30% of NSCLCs are suitable for potentially curative resections. Moreover, despite optimal surgical management, resected NSCLC has a 5-year survival rate ranging from 73% in pathological stage Ia to 25% in pathological stage IIIa (LE CHEVALIER, t., 2010.Annals of Oncology, 21, pages vii196-vii 198). Thus, only a small fraction of patients with newly diagnosed lung tumors can undergo curative surgery, and many of the patients have a high risk of postoperative recurrence. Treatment with chemotherapy and/or immunotherapy in the form of checkpoint inhibitors targeting the PD-1/PD-L1 axis (neoadjuvant (neoadjuvant)) may be incorporated into the care of patients with early solid tumors. The best timing of neoadjuvant and adjuvant immunotherapy treatments is still unclear. (Owen D. Et al J Thorac Dis. 2 months in 2018; 10 (journal 3): S404-S411). In the case of NSCLC, the disease-free survival (DFS) benefit of targeted immunotherapy cannot be translated into the total survival (OS) benefit for patients with cancer-driven gene mutations. For patients without lung cancer driving gene mutations, chemotherapy has reached plateau in terms of increased efficacy and survival. (Bai, r. Et al 2020.Frontiers in Oncology, 10, page 575472). Accordingly, there is a long-felt unmet need in the art for effective treatment of solid tumors (such as breast cancer, colon cancer, and non-small cell lung cancer). In particular, there is a need to improve the longevity, survival and response to treatment of patients suffering from early stage surgical disease. Disclosure of Invention In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, wherein the cancer is a surgically resectable solid cancer, the method comprising: (i) Parenterally administering a first dose of an anti-PD-1 antibody or antigen-binding fragment thereof to the subject during a first treatment period, wherein the first dose of the anti-PD-1 antibody is 200 mg (e.g., once every three weeks); (ii) Surgical excision of the cancer in the subject after (i), and (Iii) During a second treatment period following (ii), a second dose of the anti-PD-1 antibody or antigen-binding fragment thereof is parenterally administered to the subject, wherein the second dose of the anti-PD-1 antibody is 400 mg (e.g., once every 6 weeks). In some aspects, the tumor lesion is measured by CT scan or X-ray prior to treatment, and then measured at the time of surgery after 200 mg. In some aspects, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: VH CDR1, VH CDR2 and VH CDR3 comprising the amino acid