Methods and combinations for treating cervical cancer

Abstract

This disclosure relates to methods, combinations, and uses for treating cervical cancer using anti-PD-L1 binding proteins or anti-PD-1 binding proteins and chemoradiotherapy.

Description

Technical Field

[0001] (Reference to Sequence Listing) This application includes a sequence listing, which is hereby incorporated by reference in its entirety. The sequence listing submitted here is included in an XML file entitled "B7H1-280-US-PSP_Sequence-Listing.xml" created on May 3, 2024 and is 15,863 bytes in size.

[0002] (Field of the Invention) The present disclosure relates to methods, combinations, and uses for treating cervical cancer using an anti-PD-1 binding protein or an anti-PD-L1 binding protein and chemoradiotherapy.

Background Art

[0003] Despite the introduction of PAP smears for early screening and prevention of cervical cancer in the 1950s, and more recently, HPV vaccination, cervical cancer remains the fourth most common cancer among women worldwide. Many women continue to be diagnosed with and die from this disease, with an estimated 528,000 new cases diagnosed and 266,000 deaths in 2012 (Ferlay et al., GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No.11 [serial online] 2013). North America has the third lowest incidence of cervical cancer. However, in the United States, 12,109 women were diagnosed with cervical cancer in 2011, and 4,092 died (Benard et al., "Vital signs: cervical cancer incidence, mortality, and screening - United States, 2007-2012," MMWR Morb.Mortal Wkly.Rep.63(44):1004-09(2014)). In contrast, in China, 98,900 women were diagnosed with cervical cancer in 2015, and 30,500 died from the disease (Chen et al., "Cancer statistics in China, 2015," CA Cancer J.Clin.66(2):115-32(2016)). Overall, the 5-year overall survival rate in this patient population remains low, at 58% for stage IIB, 35% for stage IIIA, and 16% for stage IVA (Ferlay et al., GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No.11 [serial online] 2013). The prevalence of cervical cancer varies significantly between developing and developed countries due to differences in access to treatment and preventive screening.

[0004] In addressing the need for improved methods and combinations for the clinical management of locally advanced cancer, this disclosure provides methods, combinations, and uses for the treatment of patients with locally advanced cervical cancer (LACC) using anti-PD-1 binding proteins or anti-PD-L1 binding proteins, with or without chemoradiotherapy. [Overview of the project]

[0005] This disclosure relates to methods, combinations, and uses for treating patients with cervical cancer, comprising administering an anti-PD-1 binding protein or an anti-PD-L1 binding protein to the patient, and in some embodiments, administering chemoradiotherapy. The disclosed methods, combinations, and uses for treatment can provide substantial improvements in the patient's progression-free survival (PFS), overall response rate (ORR), and / or overall survival (OS).

[0006] In one embodiment, the present disclosure provides a method for treating cervical cancer, comprising treating a patient with an anti-PD-1 binding protein or an anti-PD-L1 binding protein. In some embodiments, the method further comprises treating the patient with chemoradiotherapy. In some embodiments, the cervical cancer is locally advanced cervical cancer (LACC). In some embodiments, the patient has a tumor area positivity (TAP) score of ≥20% for PD-L1 expression.

[0007] In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, and semiprimab. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is an anti-PD-L1 antibody selected from durvalumab, avelumab, atezolizumab, and sugemalimab. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is a bispecific antibody, and the bispecific antibody is MEDI5752.

[0008] In some embodiments, chemoradiotherapy includes concurrent chemoradiotherapy. In some embodiments, chemoradiotherapy includes external beam radiation therapy and close-range radiation therapy. In some embodiments, chemoradiotherapy includes platinum-based chemotherapy. In some embodiments, platinum-based chemotherapy is cisplatin or carboplatin.

[0009] In some embodiments, treatment with an anti-PD-L1 antibody includes intravenous administration of 1500 mg of anti-PD-L1 antibody to the patient every four weeks (Q4W). In some embodiments, treatment with an anti-PD-L1 antibody includes intravenous administration of 1500 mg of anti-PD-L1 antibody to the patient every three weeks (Q3W). In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0010] In some embodiments, treatment with a bispecific antibody includes intravenous administration of 750 mg of the bispecific antibody to the patient every three weeks (Q3W). In some embodiments, treatment with a bispecific antibody includes intravenous administration of 500 mg or 750 mg of MEDI5752 to the patient every three weeks (Q3W).

[0011] In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein and chemoradiotherapy are administered simultaneously. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is administered after chemoradiotherapy.

[0012] In some embodiments, this method extends progression-free survival (PFS) in patients. In some embodiments, this method increases the overall response rate (ORR) in patients.

[0013] In one embodiment, the disclosure provides a combination for use in the treatment of cervical cancer in a patient, wherein the combination comprises an anti-PD-1 binding protein or an anti-PD-L1 binding protein. In some embodiments, the combination further comprises chemoradiotherapy. In some embodiments, the cervical cancer is locally advanced cervical cancer (LACC). In some embodiments, the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

[0014] In some embodiments of the combination for use, the anti-PD-1 binding protein or anti-PD-L1 binding protein is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, and semiprimab. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is an anti-PD-L1 antibody selected from durvalumab, avelumab, atezolizumab, and sugemalimab. In some embodiments, the anti-PD-1 binding protein is a bispecific antibody, and the bispecific antibody is MEDI5752.

[0015] In some embodiments of the combination for use, chemoradiotherapy includes concurrent chemoradiotherapy. In some embodiments, chemoradiotherapy includes external beam radiation therapy and close-range radiation therapy. In some embodiments, chemoradiotherapy includes platinum-based chemotherapy. In some embodiments, platinum-based chemotherapy is cisplatin or carboplatin.

[0016] In some embodiments of the combination for use, the combination involves administering 1500 mg of anti-PD-L1 antibody intravenously to the patient every four weeks (Q4W). In some embodiments of the combination for use, the combination involves administering 1500 mg of anti-PD-L1 antibody intravenously to the patient every three weeks (Q3W). In some embodiments of the combination for use, the anti-PD-L1 antibody is durvalumab.

[0017] In some embodiments of the combination for use, the combination therapy includes intravenous administration of 500 mg or 750 mg of a bispecific antibody to the patient every three weeks (Q3W). In some embodiments of the combination for use, the combination therapy includes intravenous administration of 500 mg or 750 mg of MEDI5752 to the patient every three weeks (Q3W).

[0018] In some embodiments of the combination for use, the anti-PD-1 binding protein or anti-PD-L1 binding protein and chemoradiotherapy are administered simultaneously. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is administered after chemoradiotherapy.

[0019] In some embodiments of the combination for use, the combination extends progression-free survival (PFS) in patients. In some embodiments of the combination for use, the combination increases the overall response rate (ORR) in patients.

[0020] In one embodiment, the present disclosure provides the use of an anti-PD-1 binding protein or an anti-PD-L1 binding protein for the manufacture of a pharmaceutical for the treatment of cervical cancer in a patient. In some embodiments, the pharmaceutical further comprises chemoradiotherapy. In some embodiments, the cervical cancer is locally advanced cervical cancer (LACC). In some embodiments, the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

[0021] In some embodiments of use, the anti-PD-1 binding protein or anti-PD-L1 binding protein is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, and semaprilumab. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is an anti-PD-L1 antibody selected from durvalumab, avelumab, atezolizumab, and sgezalimab. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is a bispecific antibody, and the bispecific antibody is MEDI5752.

[0022] In some embodiments of use, chemoradiotherapy includes concurrent chemoradiotherapy. In some embodiments, chemoradiotherapy includes external beam radiotherapy and brachytherapy. In some embodiments, chemoradiotherapy includes platinum-based chemotherapy. In some embodiments, the platinum-based chemotherapy is cisplatin or carboplatin.

[0023] In some embodiments of use, the treatment includes intravenous administration of 1500 mg of an anti-PD-L1 antibody to the patient every 4 weeks (Q4W). In some embodiments, the treatment includes intravenous administration of 1500 mg of an anti-PD-L1 antibody to the patient every 3 weeks (Q3W). In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0024] In some embodiments of use, the treatment includes intravenous administration of 500 mg or 750 mg of a bispecific antibody to the patient every 3 weeks (Q3W). In some embodiments, the bispecific antibody is MEDI5752.

[0025] In some embodiments of use, the anti-PD-1 binding protein or anti-PD-L1 binding protein, and chemoradiotherapy are administered simultaneously. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein is administered after chemoradiotherapy.

[0026] In some embodiments of use, the treatment prolongs the progression-free survival (PFS) in a patient. In some embodiments of use, the treatment increases the overall response rate (ORR) in a patient.

[0027] In one embodiment, the present disclosure provides a method of treating locally advanced cervical cancer (LACC) in a patient, the method comprising intravenous administration of 1500 mg of durvalumab to the patient every 4 weeks (Q4W), wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

[0028] In one embodiment, the present disclosure provides a method of treating locally advanced cervical cancer (LACC) in a patient, the method comprising intravenous administration of 500 mg or 750 mg of MEDI5752 to the patient every 3 weeks (Q3W), wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

[0029] In some embodiments of the methods disclosed herein, the method of any of claims 61 or 62 further comprises administration of chemoradiotherapy. In some embodiments, the chemoradiotherapy comprises concurrent chemoradiotherapy. In some embodiments, the chemoradiotherapy comprises external beam radiotherapy and brachytherapy. In some embodiments, the chemoradiotherapy comprises platinum-based chemotherapy. In some embodiments, the platinum-based chemotherapy is cisplatin or carboplatin.

[0030] In some embodiments of the methods disclosed herein, durvalumab or MEDI5752, and chemoradiotherapy are administered simultaneously. In some embodiments, durvalumab or MEDI5752 is administered after chemoradiotherapy.

[0031] In some embodiments of the methods disclosed herein, the method prolongs the progression-free survival (PFS) in a patient. In some embodiments of the methods disclosed herein, the method increases the overall response rate (ORR) in a patient.

[0032] In one embodiment, the present disclosure provides a combination of durvalumab and chemoradiotherapy for the treatment of locally advanced cervical cancer (LACC) in a patient, wherein 1500 mg of durvalumab is administered intravenously to the patient every four weeks (Q4W), and the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

[0033] In one embodiment, the present disclosure provides a combination of MEDI5752 and chemoradiotherapy for the treatment of locally advanced cervical cancer (LACC) in a patient, wherein 500 mg or 750 mg of MEDI5752 is administered intravenously to the patient every three weeks (Q3W), and the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

[0034] In some embodiments of the combinations disclosed herein, chemoradiotherapy includes concurrent chemoradiotherapy. In some embodiments of the combinations disclosed herein, chemoradiotherapy includes external beam radiation therapy and close-range radiation therapy. In some embodiments of the combinations disclosed herein, chemoradiotherapy includes platinum-based chemotherapy. In some embodiments of the combinations disclosed herein, platinum-based chemotherapy is cisplatin or carboplatin.

[0035] In some embodiments of the combinations disclosed herein, durvalumab or MEDI5752 is administered after chemoradiotherapy.

[0036] In some embodiments of the combinations disclosed herein, the combination extends progression-free survival (PFS) in patients. In some embodiments of the combinations disclosed herein, the combination increases the overall response rate (ORR) in patients. [Brief explanation of the drawing]

[0037] The accompanying drawings are included to provide a further understanding of the methods, combinations, and uses of this disclosure. The drawings illustrate one or more aspects of this disclosure and, together with the description, help to illustrate the principles and operation of this disclosure. [Figure 1] This shows the progression-free survival (PFS) of patients from the CALLA study. Progression-free survival is assessed according to RECIST 1.1 by the principal investigator, or by histopathological confirmation of local tumor progression, or by Kaplan-Meier plots (complete analysis set). CI = confidence interval, CRT = chemoradiotherapy, PFS = progression-free survival, RECIST = Response Evaluation Criteria in Solid Tumors. [Figure 2] The results from the post-hoc analysis of the CALLA study are shown. As the PD-L1 cutpoint increases, a PFS benefit was observed in patients with tumors (PD-L1 TAP ≥ 20%) who received durvalumab + CRT compared to placebo + CRT. [Figure 3] The results from the post-hoc analysis of the CALLA study are shown. In patients with tumors (PD-L1 TAP ≥ 20%) who received durvalumab + SoC CCRT (n=191) compared to placebo + SoC CCRT (n=178), a benefit in PFS was observed (hazard ratio, 0.62 [95% CI, 0.42~0.91]). CCRT = concurrent chemoradiotherapy. [Figure 4] In the durvalumab arm (n=277) compared to placebo (n=278), patients with lymph node-positive disease (stages IB2-IVA) showed a lower hazard ratio compared to the treatment-intent population (0.77 [95% CI, 0.58~1.03]), but patients with lymph node-negative disease (stages ≥III) did not show any PFS benefit with durvalumab (hazard ratio, 1.11 [95% CI, 0.65~1.91]). [Figure 5]In patients with tumors (PD-L1 TAP ≥ 20%), a lower hazard ratio was observed regardless of lymph node status (lymph node positive: durvalumab, n=138; placebo, n=141; hazard ratio, 0.66 [95% CI, 0.42-1.01]; lymph node negative: durvalumab, n=53; placebo, n=37; hazard ratio, 0.60 [95% CI, 0.26-1.41]). [Figure 6] This describes the trial design for the treatment of cervical cancer with MEDI5752. Borlustmig / placebo until clinical or radiological progression, or until 24 months. Thereafter, the decision on whether the patient is benefiting from treatment and whether other discontinuation criteria are met will be at the discretion of the principal investigator. Abbreviations: CCRT = concurrent chemoradiation therapy, ECOG = Eastern Cooperative Oncology Group, FIGO = The International Federation of Gynecologists and Obstetricians, IV = intravenous, N = number of participants randomized, PD-L1 = programmed death-ligand 1, R = randomization, SOC = standard of care, Q3W = every three weeks. [Figure 7] The predicted MEDI5752 concentration-time profile after IV infusion of MEDI5752 Q3W is shown, along with the predicted EC20, EC50, and EC90 for PD-1. [Figure 8] This shows the predicted MEDI5752 concentration-time profile after IV infusion of MEDI5752 Q3W, with predicted EC20 and EC90 for CTLA-4, EC20, and EC90PD-1. [Figure 9A]Figures 9A and 9C show peripheral blood T cell proliferation (CD4+ Ki67+) and T cell activation (ICOS expression on CD4 T cells) (Figure 9B), as measured by flow cytometry after MEDI5752 as monotherapy or in combination with chemotherapy. [Figure 9B] Figures 9A and 9C show peripheral blood T cell proliferation (CD4+ Ki67+) and T cell activation (ICOS expression on CD4 T cells) (Figure 9B), as measured by flow cytometry after MEDI5752 as monotherapy or in combination with chemotherapy. [Figure 9C] Figures 9A and 9C show peripheral blood T cell proliferation (CD4+ Ki67+) and T cell activation (ICOS expression on CD4 T cells) (Figure 9B), as measured by flow cytometry after MEDI5752 as monotherapy or in combination with chemotherapy. [Figure 10A] Figures 10A and 10C show the total number of proliferated T cell clones (Figure 10A) and the percentage of newly proliferated T cell clones (Figures 10B and 10C), as measured by T cell receptor sequencing (TCRseq) after MEDI5752 as monotherapy or in combination with chemotherapy. [Figure 10B] Figures 10A and 10C show the total number of proliferated T cell clones (Figure 10A) and the percentage of newly proliferated T cell clones (Figures 10B and 10C), as measured by T cell receptor sequencing (TCRseq) after MEDI5752 as monotherapy or in combination with chemotherapy. [Figure 10C] Figures 10A and 10C show the total number of proliferated T cell clones (Figure 10A) and the percentage of newly proliferated T cell clones (Figures 10B and 10C), as measured by T cell receptor sequencing (TCRseq) after MEDI5752 as monotherapy or in combination with chemotherapy. [Figure 11] This shows the percentage of free PD1 on CD4 T cells (PD1 receptor occupancy measured longitudinally by flow cytometry after MEDI5752 administration). [Figure 12] This shows the median duration of response for MEDI5752 monotherapy at various doses. [Figure 13] This study demonstrates the objective response of MEDI5752 monotherapy in a diverse range of IO-naive tumors across the MEDI5752 dose range. [Figure 14] This shows the mean pharmacokinetic profile of MEDI5752 Q3W after intravenous infusion. [Figure 15] This shows exposure (C trough) versus CD4 T cell proliferation after MEDI5752 treatment.

[0038] Those skilled in the art will understand that the elements in the figures are shown for simplification and clarity and are not necessarily drawn to scale. For example, the dimensions of some elements in the figures may be exaggerated relative to others to help improve the understanding of aspects of this disclosure. [Modes for carrying out the invention]

[0039] This disclosure relates to methods, combinations, and uses for treating patients with cervical cancer, comprising administering an anti-PD-1 binding protein or an anti-PD-L1 binding protein to the patient, and in some embodiments, administering chemoradiotherapy. The disclosed methods, combinations, and uses for treatment may provide substantial improvements in the patient's progression-free survival (PFS), overall response rate (ORR), and / or overall survival (OS).

[0040] Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art to the extent of this disclosure. The following references provide general definitions of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). Where used herein, the following terms have the meanings set forth below unless otherwise specified.

[0041] In this disclosure, “comprises,” “comprising,” “containing,” and “having,” etc., may have the meanings attributed to them in U.S. patent law, and “includes,” “including,” etc., and “consisting essentially of” or “consists essentially of” may have the meanings attributed to them in U.S. patent law, and is open-ended and allows for more than described existences, as long as the basic or novel features of the described are not altered by more than described existences, but excludes aspects of the prior art.

[0042] Unless otherwise specified or the context makes clear, the term “or” as used herein is understood to be inclusive. Unless otherwise specified or the context makes clear, the terms “a,” “an,” and “the” as used herein are understood to be singular or plural.

[0043] Unless otherwise stated or evident from the context, the term “about” as used herein is understood to mean within the normal tolerances in the art, for example, within two standard deviations of the mean. “About” can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise evident from the context, all numerical values ​​provided herein are modified by the term “about.”

[0044] Any composition, combination, method, or use provided herein may be combined with one or more other compositions, combinations, methods, and uses provided herein.

[0045] The ranges provided herein are understood to be abbreviated representations of all values ​​within that range. For example, the range 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0046] This specification provides methods, combinations, or uses for extending progression-free survival in patients with cervical cancer, comprising treating the patient with an anti-PD-1 binding protein or an anti-PD-L1 binding protein (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-PD-1 / CTLA-4 bispecific antibody). In some embodiments, the methods, combinations, or uses further include chemoradiotherapy. In some embodiments, the cervical cancer is locally advanced cervical cancer (LACC).

[0047] Furthermore, this specification also provides methods, combinations, or uses for increasing the overall response rate in patients with cervical cancer, comprising treating the patient with an anti-PD-1 binding protein or an anti-PD-L1 binding protein (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-PD-1 / CTLA-4 bispecific antibody). In some embodiments, the methods, combinations, or uses further include chemoradiotherapy. In some embodiments, the cervical cancer is locally advanced cervical cancer (LACC).

[0048] Furthermore, this specification also provides methods, combinations, or uses for treating patients with cervical cancer, comprising treating the patient with an anti-PD-1 binding protein or an anti-PD-L1 binding protein (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-PD-1 / CTLA-4 bispecific antibody). In some embodiments, the method further comprises chemoradiotherapy. In some embodiments, the cervical cancer is locally advanced cervical cancer (LACC).

[0049] In certain aspects of the methods, combinations, and uses disclosed herein, the patient has locally advanced cervical cancer with a tumor area positive (TAP) score of 20% or higher PD-L1 expression.

[0050] Programmed death ligand 1 (PD-L1) is part of a complex system of receptors and ligands involved in regulating T cell activation. Its normal function is to regulate the balance between T cell activation and resistance through interaction with its two receptors, programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1 or B7.1). PD-L1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system. PD-L1 is frequently expressed in a wide range of cancers.

[0051] Programmed Death-1 (PD-1) is a roughly 31 kD type I membrane protein member of the extended CD28 / CTLA-4 family of T cell regulators. PD-1 is expressed on activated T cells, B cells, and monocytes, where, after activation by binding to PD-L1 or PD-L2, it functions as a receptor involved in the downregulation of the immune system. This process is utilized in many tumors via PD-L1 overexpression, resulting in a suppressed immune response.

[0052] As used herein, the term “anti-PD-L1 binding protein” refers to a polypeptide, binding protein, antibody, or antigen-binding fragment thereof that selectively binds to a PD-L1 polypeptide. In some embodiments, the anti-PD-L1 binding protein may be an anti-PD-L1 antibody. Exemplary anti-PD-L1 antibodies are described, for example, in U.S. Patents 8,779,108 and 9,493,565 (which are incorporated herein by reference). In some embodiments, the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab. In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0053] As used herein, “durvalumab” refers to an antibody that selectively binds to PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors, as disclosed in U.S. Patent No. 9,493,565 (durvalumab is referred to as “2.14H9OPT”) (which is incorporated herein by reference in its entirety). The crystallizable fragment (Fc) domain of durvalumab has a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to the complement component C1q and the Fcγ receptor, which is involved in mediating antibody-dependent cell-mediated cytotoxicity (“ADCC”). Durvalumab can mitigate PD-L1-mediated suppression of human T cell activation in vitro and inhibit tumor growth in xenograft models via a T cell-dependent mechanism.

[0054] As used herein, the term “anti-PD-1 binding protein” refers to a polypeptide, binding protein, antibody, or antigen-binding fragment thereof that selectively binds to a PD-1 polypeptide. In some embodiments, the anti-PD-1 binding protein may be an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody may be pembrolizumab, nivolumab, or semiprimab.

[0055] In some embodiments, the anti-PD-1 binding protein may refer to a bispecific antibody that selectively binds to both the PD-1 polypeptide and a second target polypeptide. In some embodiments, the anti-PD-1 binding protein may refer to a bispecific antibody that targets both PD-1 and CTLA-4. In some embodiments, the bispecific antibody that targets both PD-1 and CTLA-4 is MEDI5752.

[0056] MEDI5752 is a monovalent bispecific antibody targeting PD-1 and CTLA-4. In some embodiments, the patient receives one or more doses of MEDI5752, which are fixed doses of 500 mg or 750 mg. In some embodiments, the patient receives 500 mg or 750 mg of MEDI5752 bispecific antibody every three weeks. See also International Publication 2017 / 193032, U.S. Patent Application Publication 2018 / 0022807, U.S. Patent No. 10,457,732, and U.S. Patent Application Publications 2020 / 0172622 and 2022 / 0251204 (each of these is incorporated herein by reference in whole).

[0057] As used herein, the term “MEDI5752” refers to an anti-PD-1 / CTLA-4 bispecific antibody comprising the light chain of SEQ ID NO: 1 and the heavy chain of SEQ ID NO: 2 (PD-1), and the light chain of SEQ ID NO: 3 and the heavy chain of SEQ ID NO: 4 (CTLA-4). MEDI5752 is disclosed in U.S. Patent No. 10,457,732 (which is incorporated herein by reference in its entirety) (see also Tables 1-4). MEDI5752 is also referred to herein as “Volrustomig.” Methods, combinations, and uses for treating cancer in a subject (e.g., a human subject) are provided, comprising administering an antibody (e.g., a bispecific antibody, monoclonal antibody, such as a chimeric antibody, a humanized antibody, or a human antibody) and its antigen-binding fragment to the subject. In some embodiments, PD-1 and CTLA-4 (e.g., human PD-1 and CTLA-4) antibodies and their antigen-binding fragments that can be used in the methods, combinations, and uses provided herein include MEDI5752, a monovalent, bispecific humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) having a crystallizable fragment (Fc) domain that is engineered to reduce Fc effector function and specifically binds to PD-1 and CTLA-4.

[0058] MEDI5752 was constructed on a DuetMab framework. The DuetMab design is described in Mazor et al., MAbs. 7(2):377-89 (2015) (the entire document is incorporated herein by reference). The DuetMab design incorporates a knob-into-hole (KIH) technique for heterodimerization of two different heavy chains, increasing the effectiveness of congeneral heavy- and light-chain pairing by replacing a native disulfide bond at one of the CH1-CL interfaces with an engineered disulfide bond.

[0059] The Fc domain of MEDI5752 harbors triple mutations (TM) (L234F, L235E, and P331S) designed to reduce Fc-mediated immunoeffector function (Oganesyan et al, Acta Crystallogr. D. Biol. Crystallogr. 64(Pt 6):700-04(2008)). MEDI5752 contains anti-PD-1 and anti-CTLA-4 Fab, an engineered interchain disulfide at the anti-CTLA-4 CH1-CL interface, and a knob-into-hole IgG1-TM Fc. MEDI5752 contains a knob mutation in the heavy chain containing a variable region that binds to CTLA-4 and a hole mutation in the heavy chain containing a variable region that binds to PD-1.

[0060] In some aspects of this disclosure, the bispecific antibodies or their antigen-binding fragments for use in the methods, combinations, and uses described herein specifically bind to human PD-1 and human CTLA-4 and include six CDRs of the listed MEDI5752 antibody, as provided in Table 1.

[0061] [Table 1] 1 The VH CDRs in Table 1 are determined according to Kabat.

[0062] [Table 2] 2 The VL CDR in Table 2 is determined according to Kabat.

[0063] In some aspects of this disclosure, the bispecific antibody or antigen-binding fragment thereof for use in the methods, combinations, and uses described herein specifically binds to human PD-1 and CTLA-4 and comprises a variable heavy chain (VH) and a variable light chain (VL) of the MEDI5752 antibody.

[0064] In some aspects of this disclosure, the bispecific antibodies or antigen-binding fragments for use in the methods, combinations, and uses described herein specifically bind to human PD-1 and CTLA-4 and include the heavy chain (HC) of the MEDI5752 antibody listed in Table 3.

[0065] [Table 3]

[0066] [Table 4]

[0067] Where used generally in this specification, terms such as “to treat,” “to treat,” and “to cure” mean reducing, improving, or delaying the progression of a disorder or disease and / or symptoms associated with the disorder or disease. It will be understood that treating a disorder, disease, or condition does not preclude the complete elimination of the disorder, disease, condition, or associated symptoms. In some aspects relating to locally advanced cervical cancer, “to treat,” “to treat,” and “to cure” may mean achieving one or a combination of primary or secondary clinical endpoints.

[0068] In some aspects of the methods, combinations, and uses disclosed herein, a patient has locally advanced cervical cancer with a tumor area positive (TAP) score of 20% or more of PD-L1 expression. PD-L1 expression can be measured by the tumor area positive (TAP) score using the Ventana PD-L1 (SP263) assay. As used herein, the “TAP score” is defined as a combination of tumor cell regions with PD-L1 expression and immune cell regions with PD-L1 expression. In some aspects, the “TAP 20%” score can be any intensity of PD-L1 staining in tumor cell membranes and tumor-associated immune cells covering 20% ​​or more of the tumor region.

[0069] Anti-PD-1 binding proteins or anti-PD-L1 binding proteins (e.g., anti-PD-L1 antibodies, anti-PD-1 antibodies, or anti-PD-1 / CTLA-4 bispecific antibodies) can be administered once every four weeks while providing benefits to the patient. In some embodiments, the patient may receive additional subsequent doses. These subsequent doses may be administered at various time intervals depending on other factors, including the patient's age, weight, clinical assessment, tumor burden, and / or the physician's judgment.

[0070] Anti-PD-1 binding proteins or anti-PD-L1 binding proteins (e.g., anti-PD-L1 antibodies, anti-PD-1 antibodies, or anti-PD-1 / CTLA-4 bispecific antibodies) can be administered once every three weeks while providing benefits to the patient. In some embodiments, the patient may receive additional subsequent doses. These subsequent doses may be administered at various time intervals depending on other factors, including the patient's age, weight, clinical assessment, tumor volume, and / or the physician's judgment.

[0071] In some embodiments, multiple doses of anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) are administered to the patient. In some embodiments, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least fifteen doses, at least 26 doses, or at least more than 20 doses may be administered to the patient. In some embodiments, anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) are administered over a period of two weeks, over a treatment period of four weeks, over a treatment period of six weeks, over a treatment period of eight weeks, over a treatment period of twelve weeks, over a treatment period of twenty-four weeks, over a treatment period of one year, or over a treatment period of more than one year.

[0072] In some embodiments, the interval between doses may be every four weeks (Q4W). In some embodiments, the interval between doses may be every two months.

[0073] In some embodiments, the interval between doses may be every three weeks (Q3W). In some embodiments, the interval between doses may be every two months.

[0074] In some embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, with a fixed dose of 1500 mg. In some embodiments, the patient is administered 1500 mg of anti-PD-L1 antibody every four weeks. In some embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, with a dose of approximately 20 mg / kg. In some embodiments, the patient is administered 20 mg / kg of anti-PD-L1 antibody every four weeks.

[0075] In some embodiments, the patient is administered one or more doses of anti-PD-1 / CTLA-4 bispecific antibody, with a fixed dose of 500 mg or 750 mg. In some embodiments, the patient is administered 500 mg or 750 mg of anti-PD-1 / CTLA-4 bispecific antibody every three weeks. In some embodiments, the patient is administered 500 mg or 750 mg of MEDI5752 every three weeks (Q3W). In some embodiments, the patient is administered one or more doses of anti-PD-1 / CTLA-4 bispecific antibody, with a fixed dose of 500 mg or 750 mg. In some embodiments, the patient is administered 500 mg or 750 mg of anti-PD-1 / CTLA-4 bispecific antibody every three weeks. In some embodiments, the patient is administered 500 mg or 500 mg of MEDI5752 every three weeks (Q3W).

[0076] In some embodiments, the administration of anti-PD-1 binding proteins or anti-PD-L1 binding proteins (e.g., anti-PD-L1 antibodies, anti-PD-1 antibodies, or anti-PD-1 / CTLA-4 bispecific antibodies) by the methods, combinations, and uses provided herein is by parenteral administration. For example, anti-PD-1 binding proteins or anti-PD-L1 binding proteins (e.g., anti-PD-L1 antibodies, anti-PD-1 antibodies, or anti-PD-1 / CTLA-4 bispecific antibodies) can be administered by intravenous infusion. In some embodiments, administration is by intravenous infusion.

[0077] The methods, combinations, and uses for treatment disclosed herein further include chemoradiation therapy (CRT) or chemoradiotherapy. In one embodiment, chemoradiotherapy includes concurrent chemoradiotherapy (CCRT). Concurrent chemoradiotherapy (concurrent chemoradiotherapy or CCRT) is performed in which both radiotherapy and chemotherapy are administered simultaneously (e.g., by simultaneous (same-day) administration) during a single stage. In some embodiments, chemoradiotherapy comprises one or more platinum-based chemotherapeutic agents. In some embodiments, one or more platinum-based chemotherapeutic agents are carboplatin, cisplatin, oxaliplatin, or a combination thereof. In some embodiments, chemoradiotherapy comprises cisplatin or carboplatin. In some embodiments, chemoradiotherapy comprises external beam radiation therapy and / or close-range radiation therapy.

[0078] In some embodiments, anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) is administered concurrently with chemoradiotherapy. In some embodiments, anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) and chemoradiotherapy are administered within approximately 3 days of each other. In some embodiments, anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) and chemoradiotherapy are administered within approximately 2 days of each other. In some embodiments, anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) and chemoradiotherapy are administered within approximately 1 day of each other. In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) and chemoradiotherapy are administered simultaneously (e.g., by simultaneous administration). In some embodiments, the anti-PD-1 binding protein or anti-PD-L1 binding protein (e.g., anti-PD-L1 antibody, anti-PD-1 antibody, or anti-PD-1 / CTLA-4 bispecific antibody) is administered on day 1 of cycle 1 of chemoradiotherapy.

[0079] In some embodiments, the methods, combinations, and uses for treatment disclosed herein result in an increase in progression-free survival (PFS) compared to placebo. In some embodiments, the methods, combinations, and uses result in an increase in objective response rate (ORR) compared to placebo. In some embodiments, the methods, combinations, and uses result in an increase in overall survival (OS) compared to placebo.

[0080] Overall survival (OS) refers to the time from the start of treatment to death from any cause. OS can refer to overall survival within a period such as 12 months, 18 months, or 24 months. Such a period can be specified, for example, as "OS24," which refers to the number (%) of patients who are alive at 24 months after the start of treatment, per Kaplan-Meier estimate of overall survival at 24 months.

[0081] Progression-free survival (PFS) is defined as the time from the date of treatment to the date of objective disease progression (RECIST 1.1) or death (by any cause if there is no progression). In some embodiments, the methods, combinations, and uses of the present disclosure result in an increase in PFS. In some embodiments, the methods, combinations, and uses of the present disclosure provide a PFS of at least 9 months to at least about 24 months (e.g., at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months, or more than 24 months, and up to about 5 years).

[0082] Objective response rate (ORR), according to RECIST 1.1, refers to the number (%) of patients who achieve a complete response (CR) or partial response (PR) at least once during their visit.

[0083] Cervical tumors are staged using the FIGO (2009) classification, the most widely used classification (Haie-Meder et al., "Cervical cancer: ESMO Clinical practice guidelines for diagnosis, treatment and follow-up," Ann.Oncol.21(5):v37-40(2010)), and are one of the most important prognostic factors (Marth et al., "ESMO Clinical practice guidelines for diagnosis, treatment and follow-up," Ann.Oncol.28(suppl_4):iv72-83(2017)). Cervical cancer is the only gynecological cancer that is clinically staged based on tumor size, involvement of the vagina or parauterine region, bladder / rectal enlargement, and distant metastasis. It requires examination under anesthesia, radiological imaging such as chest X-ray and IV renal pelvis imaging, or other diagnostic tools. CT can detect pathological lymph nodes, while MRI can determine tumor size, the degree of interstitial penetration, parauterine involvement, vaginal dilation, and uterine body dilation with high accuracy.

[0084] It should be understood that the specific embodiments described herein are not limited to the specific embodiments presented and may vary. It should also be understood that the terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting unless specifically defined herein. Furthermore, the specific embodiments disclosed herein may be combined with other embodiments disclosed herein without limitation, as will be recognized by those skilled in the art. [Examples]

[0085] The following embodiments illustrate specific aspects of the Disclosure and various uses thereof. They are provided for illustrative purposes only and should not be construed as limiting the scope of the Disclosure.

[0086] Example 1: Efficacy of durvalumab in combination with chemoradiotherapy in patients with locally advanced cervical cancer (LACC) Concurrent chemoradiotherapy (CCRT) has been the standard treatment for locally advanced cervical cancer (LACC) for over 20 years. However, 30%–40% of treated patients experience recurrence or progression within 5 years. Immune checkpoint inhibition improved outcomes in patients with metastatic / recurrent cervical cancer. We evaluated the benefits of adding durvalumab, a programmed cell death ligand 1 antibody, to and after CRT (chemoradiotherapy) for LACC. In Phase 3, a randomized trial ("CALLA Study"; Clinical Trial No.: NCT03830866) randomized (1:1) patients with previously untreated LACC (FIGO 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) to 105 hospital sites across 15 countries via an interactive web-based response system to receive either double-blind durvalumab (1500 mg intravenously every 4 weeks) or placebo with and after CRT (CRT compliance was monitored). The primary endpoint was progression-free survival (PFS), assessed by the investigator using RECIST v1.1 in the intention-to-treat (ITT) population.

[0087] [Table 5-1]

[0088] [Table 5-2]

[0089] A total of 770 women (durvalumab, n=385; placebo, n=385; 44% Hispanic, 39% Asian) were randomized. Durvalumab did not significantly improve PFS compared to placebo (hazard ratio for disease progression or death, 0.84; 95% CI, 0.65–1.08; P=0.174); 12-month PFS was 76.0% (293 / 385) in the durvalumab group and 73.3% (282 / 385) in the placebo group. Grade 3 or higher adverse events occurred in 51.7% (199 / 385) of patients receiving durvalumab compared to 51.0% (196 / 384) of patients receiving placebo.

[0090] Test design The randomized, double-blind CALLA study was conducted at 105 hospital sites in 15 countries. The CALLA trial protocol and all modifications were approved by the regional institutional review board or independent ethics committee at each study site. In conducting the trial, the Good Clinical Practice guidelines established by the International Conference on Harmonization and the ethical considerations detailed in the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines were followed. The study protocol is briefly described below and is registered as NCT03830866 in the ClinicalTrials database of the U.S. National Library of Medicine.

[0091] Treatment and duration of treatment: Durvalumab 1500 mg was administered intravenously (IV) at Q4W, starting on the day the patient initiated treatment (C1D1) and continuing until completion of planned treatment or progression of disease (PD). Placebo: A sterile solution of 0.9% wt / vol[w / v]) sodium chloride for injection is administered via IV infusion at Q4W, starting at C1D1 and continuing until completion of the planned treatment or PD. • Chemoradiotherapy: Cisplatin. 40 mg / m² 2 IV Q1W x 5 weeks.

[0092] Order of administration After randomization to receive durvalumab / placebo + SoC CCRT, patients received durvalumab / placebo via IV infusion over 1 hour (±5 minutes). Following durvalumab / placebo administration, SoC chemotherapy was performed via IV infusion, followed by radiotherapy on the same day. If there was insufficient time to administer cisplatin, it was administered within one calendar day of the durvalumab infusion. This provided flexibility in the timing of treatment regimen administration, allowing for radiotherapy and durvalumab / placebo to be administered on C1D1, cisplatin on C1D2, and similarly in subsequent cycles.

[0093] Cisplatin should only be administered on the day external beam radiation is scheduled. Radiation therapy can be administered before or after durvalumab and platinum-based drugs, and should be administered on the same day if possible. Cisplatin should not be administered on the day of close-range radiotherapy.

[0094] Regardless of the planned radiofractionation schedule, all patients were scheduled to receive five doses of cisplatin. An additional sixth dose of platinum chemotherapy may be administered at the discretion of the principal investigator.

[0095] Treatment with SoC CCRT was administered concurrently with durvalumab / placebo (i.e., initiated on day 1 of cycle 1). On days when both durvalumab / placebo and SoC CCRT were administered, durvalumab / placebo was administered first, followed by SoC chemotherapy.

[0096] Radiation therapy This protocol requires external beam radiation therapy (EBRT) with either whole-pelvic radiotherapy or wide-area radiotherapy. 3D conformal and intensity-modulated radiation therapy (IMRT) techniques, followed by low-dose-rate (LDR), pulsed-dose-rate (PDR), or high-dose-rate (HDR) close-range radiotherapy are permitted. 2D radiation is permitted only with prior approval from the PI of the study oncology and the study sponsor. All radiotherapy should ideally be completed within 56 days of commencement (59 days for compliance).

[0097] External beam radiation is delivered via conformal fields (3D conformal-to-orthogonal 4-field design: AP / PA, opposed lateral fields) or IMRT, including parauterine boost. For extended field radiation therapy (EFRT) encompassing pelvic and para-aortic lymph nodes (PALNs), 3D conformal planning can utilize a wide pelvic LN field to cover the PALN field. If the field size required to cover the target is larger than the maximum field size of the facility's linear accelerator for clinical use, it is recommended to use a two-isocenter technique for planning. The prescribed dose was 45 Gy (1.8 Gy / stroke for 25 strokes) unless simultaneous integrated boost (SIB) was used for macroscopic nodular disease using IMRT technique. In the case of SIB, total lymph node PTV boost was 50 Gy at 2 Gy / session, followed by sequential boost doses of 2 Gy per session for a total dose of 54–58 Gy, depending on the contribution of proximity irradiation and the location of lymph node or parauterine boost. In the case of conventional 3D conformal EBRT, the prescribed dose was 45 Gy (25 sessions at 1.8 Gy / session), with necessary parauterine boost and (optionally selected based on disease involvement) lymph node boost.

[0098] EBRT should be administered once daily, five times a week. For close-range radiotherapy, the prescribed dose was 27.5–30 Gy for HDR and 35–40 Gy for LDR or PDR, according to the facility protocol using image-guided close-range radiotherapy or point-based close-range radiotherapy. Image-guided close-range radiotherapy with 3D image-based acquisition and volumetric planning using CT or MRI was strongly encouraged.

[0099] patient Eligible patients were women aged 18 years or older with untreated, histologically confirmed cervical adenocarcinoma, squamous cell carcinoma, or adenosquamous cell carcinoma; FIGO 2009 stage IB2–IIB lymph node-positive or FIGO 2009 stage IIIA–IVA (any lymph node status); and no evidence of metastatic disease. A World Health Organization / US East Coast Clinical Trials Group performance status score of 0 or 1, as well as adequate organ and bone marrow function, were required for enrollment. Patients were required to have at least one lesion at baseline according to the Response Evaluation Criteria for Solid Tumors (RECIST) version 1 1.14. Surgical or image-based lymph node staging was acceptable, and pathological lymph node size was defined by a short-axis diameter of ≥10 mm in the axial plane.

[0100] Patients who had previously undergone a hysterectomy, or who were expected to undergo a hysterectomy as part of their initial cervical cancer treatment, were excluded. Prior exposure to immuno-mediated therapies for any indication, or concurrent use of chemotherapy, durvalumab, biologics, or hormone therapy for cancer, was not permitted. Written informed consent was obtained from the patient or their legal representative prior to participation.

[0101] Randomization and masking Patients were randomized in a 1:1 ratio to receive either durvalumab or placebo concurrently with and after SoC CRT. Randomization was performed by central assignment using an interactive web-based response system, stratified according to stage (FIGO stage IB2–IIB with lymph node positivity, stage ≥III with lymph node negativity, or stage ≥III with lymph node positivity) and global region (United States, Canada, European Union, South Korea, Japan, or other countries). After a patient was confirmed to be eligible for the trial, the principal investigator or delegator obtained a unique randomization number for the patient and treatment assignment via the interactive web-based response system. As patients became eligible for randomization, randomization codes were assigned sequentially within each tier. Blinded and open-label access was controlled via the interactive web-based response system. Principal investigators were not informed about the treatment assigned to each patient throughout the trial.

[0102] procedure The patient received intravenous durvalumab 1500 mg or placebo once every four weeks (Q4W) concurrently with and after SoC CRT for a total of 24 cycles. Chemoradiotherapy consisted of 45 Gy external beam radiation therapy five times a week, accompanied by cisplatin (40 mg / m²). 2 The treatment consisted of intravenous administration of durvalumab or carboplatin (area under the concentration-time curve) (once a week for 5 weeks, with an optional 6 doses), followed by image-guided near-field radiotherapy (high dose rate, 27.5-30 Gy, or low dose rate / pulsed dose rate, 35-40 Gy). To ensure the delivery of high-quality RT care, the Global RT Subcommittee reviewed and evaluated the care of each patient, and compliance at each site was confirmed using a feasibility questionnaire. Treatment was continued until the following conditions were met: maximum number of cycles; histopathological, clinical, or radiological progression; unacceptable toxicity; withdrawal of consent; or failure to comply with the study protocol justifying discontinuation. Delays in durvalumab administration were permitted to manage toxicity, but reductions were not. An independent data monitoring committee evaluated ongoing safety analyses using open-label safety data and made sponsor recommendations regarding the continuation, discontinuation, or modification of the study.

[0103] Disease progression was assessed by the principal investigator according to RECIST v1.1 or histopathological confirmation of local tumor progression. Baseline tumor assessment was performed 28 days prior to randomization. Radiological imaging of the tumor, pelvic examination, and (if necessary) biopsy for histopathological diagnosis of tumor progression were performed at week 20 and every 12 weeks thereafter for 164 weeks after randomization, and then every 24 weeks until progression or termination of the study. Images of the chest, abdomen, and pelvis were acquired by computed tomography (preferred) or magnetic resonance imaging, with or without intravenous contrast.

[0104] To assess survival, patients were contacted every three months after treatment discontinuation. Information was collected regarding the initial cancer therapy used after treatment discontinuation and subsequent cancer therapies.

[0105] Safety and tolerability were assessed through adverse events, laboratory findings, vital signs, and physical examination. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5). Immune-mediated adverse events were defined as adverse events of special interest (AESI) that were associated with durvalumab exposure, had no apparent alternative etiology, and were consistent with an immune-mediated mechanism of action. Patient-reported quality of life was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and the Cervical Cancer Module (QLQ-CX24).

[0106] Fresh or archived tumor biopsies (3 months of age or younger) were obtained at screening, and PD-L1 expression was measured pretreatment. PD-L1 expression was evaluated in a central laboratory assay using Ventana PD-L1 (SP263) (Ventana Medical Systems, Tucson, AZ, USA). PD-L1 expression was assessed according to a tumor area positivity (TAP) score, defined as the percentage of tumor areas (tumor and fibrous stroma) containing tumor cells with any intensity of membrane PD-L1 staining and tumor-associated immune cells with any pattern of PD-L1 staining of any intensity.

[0107] Definition of secondary endpoints The overall response rate (ORR) was defined as the proportion of patients whose all-visit response, as assessed by at least one investigator, was a complete response (CR) or a partial response (PR). The CR rate was defined as the proportion of patients with an all-visit response of CR. Confirmed ORR was defined as the proportion of patients whose at least one confirmed visit response was a CR or PR. The duration of response was defined as the time from the first recorded response (CR or PR) date to death without progression. For patients without progression, the duration of response was the censoring period for progression-free survival. Health-related quality of life was assessed by changes from baseline in the European Agency for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the EORTC Cervical Cancer 24 (CX24)-item module.

[0108] Summary of patient-reported research evaluations of quality of life Patient-reported quality of life was assessed using the EORTC QLQ-C30 and QLQ-CX24. The QLQ-C30 items are grouped into five functional scales, three symptom scales, five individual symptom items, and two overall health scales. The QLQ-CX24 is a 24-item complementary module to the QLQ-C30, specifically designed for use in cervical cancer. The items are grouped into three multi-item scales and six single-item scales. Questionnaires were given at baseline, and at weeks 2, 4, 8, 12, 16, and 20 from the first treatment cycle, then every 12 weeks up to week 164, every 24 weeks from weeks 165 to 260, and every 52 weeks thereafter. Results from QLQ-C30 and QLQ-CX24 were evaluated using a mixed model analysis of repeated measures of change from baseline score for all post-baseline visits, through the last scheduled visit in which at least 20 patients in each arm had a score. Treatment, visit, treatment vs. visit interaction, disease stage status, and domain were included as fixed category effects. Baseline Global Health Status / Quality of Life (GHS / QoL) scores and baseline GHS / QoL scores with visit interaction were included as covariates.

[0109] Outcome Progression-free survival (PFS) was the primary endpoint, defined as the time from the date of randomization to tumor progression or death from any cause. Overall survival was a key secondary endpoint, defined as the time from the date of randomization to death from any cause, regardless of whether the patient discontinued randomized therapy or received another anticancer therapy. Other secondary endpoints included PFS in pre-specified patient subgroups (e.g., FIGO stage, chemotherapy received, PD-L1 TAP ≥1% and ≥5%, lymph node status), objective response rate (ORR), duration of response, and health-related quality of life. Exploratory post-hoc analyses were also conducted to evaluate PFS in patients with tumors (PD-L1 TAP ≥20%).

[0110] Additional secondary endpoints, including 3-year PFS, overall survival in patients with PD-L1-high-expressing tumors, complete response rate, secondary malignancies, durvalumab blood concentration, and the presence of anti-durvalumab antibodies, will be reported at a later date.

[0111] statistical analysis Efficacy endpoints were analyzed in the intention-to-treat population (all randomized patients). The safety population (all patients who received at least one dose of durvalumab or placebo) was used for safety analysis. The primary endpoint of progression-free survival (PFS), the important secondary endpoint of overall survival, and the duration of response in patients with complete response were estimated using the Kaplan-Meier method. The effect of durvalumab versus placebo was determined by stratified log-rank tests adjusted for disease stage and global region, and the magnitude of the effect was summarized as hazard ratios and 95% confidence intervals (CIs) using stratified Cox proportional hazards models and Efron's tie-ranking method. Differences between arms in ORR were summarized as odds ratios using logistic regression models and relevant 95% CIs and p-values. Changes from baseline on the QLQ-C30 and QLQ-CX24 scales at each visit were analyzed using a mixed model of repeated measures. Adverse events observed up to 90 days after the last dose of the study treatment were collected and summarized.

[0112] result A total of 1040 patients were enrolled from 105 sites in 15 countries. A total of 770 patients were randomly assigned to receive either durvalumab (n=385) or placebo (n=385). Baseline patient demographics and disease characteristics were generally balanced across arms. The median age of patients was 49 years (interquartile range [IQR], 41–57). Of the patient population, 339 out of 770 (44.0%) were identified as Hispanic / Latino, and 300 out of 770 (39.0%) were Asian. CALLA was predominantly stage III (461 / 770 [59.9%]), and the majority of patients had a squamous epithelial tissue structure (642 / 770 [83.4%]). At baseline, 91.9% of patients had a PD-L1 TAP score of ≥1%, 79.4% had a TAP score of >5%, and the majority had lymph node metastases (pelvis, 62.7%; para-aortic, 7.0%; both, 4.0%).

[0113] The median follow-up period from randomization to data cutoff was 18.5 months (IQR, 13.2–21.5) for durvalumab and 18.4 months (13.2–23.7) for placebo. The median duration of treatment exposure was 15.8 months (IQR, 9.2–21.4) for durvalumab and 15.7 months (8.3–21.6) for placebo.

[0114] In the durvalumab and placebo groups, a total of 385 / 385 (100%) and 383 / 385 (99.5%) patients received CRT (Table 6). Most patients received 5 or 6 cycles of cisplatin / carboplatin (335 / 385 [87.0%] in the durvalumab group; 346 / 384 [90.1%] in the placebo group). External beam radiation therapy (EBRT) was completed according to protocol for 371 / 385 (96.4%) patients treated with durvalumab and 379 / 385 (98.4%) patients treated with placebo. Close-range radiotherapy was completed according to protocol for 363 / 385 (94.3%) and 360 / 385 (93.5%) patients. The median EBRT dose was 5400 (IQR, 5400–5800) cGy for the ITT population. Patients treated with durvalumab received a median of 4 (4–4) close-range radiotherapy sessions, while patients treated with placebo received 4 (4–5) close-range radiotherapy sessions. Both treatment groups were treated with close-range radiotherapy at 700 (600–700) cGy per session. The equivalent EQD2 dose was 8387 (8094–8649) cGy in patients treated with durvalumab and 8387 (8019–8714) cGy in patients treated with placebo. In the treatment-intent population, 42 / 215 (19.5%) and 57 / 230 (24.8%) of these variability in CRT delivery, as determined by the CALLA RT Steering Committee, were considered potentially clinically relevant to the durvalumab arm and placebo arm, respectively.

[0115] [Table 6]

[0116] [Table 7]

[0117] Following the site certification process for radiotherapy delivery, RT delivery was approved at almost all (123 / 133 [92.5%]) research sites. Patients received RT (EBRT + close-range radiotherapy) for a median of 56.0 (IQR, 51.0–60.0) days in the durvalumab arm and 55.0 (51.0–60.0) days in the placebo arm (Table 8). Most patients in the global dataset received intensity-modulated RT (627 / 717 [87.4%]) or three-dimensional conformal RT (88 / 717 [12.3%]), while one patient in the placebo arm received conventional two-dimensional RT (Table 9).

[0118] [Table 8]

[0119] [Table 9]

[0120] In the treatment-intent population, durvalumab did not significantly improve PFS compared to placebo (hazard ratio for disease progression or death, 0.84; 95% CI 0.65~1.08; P=0.174) (Figure 1). The 12-month and 24-month PFS for durvalumab versus placebo were 76.0% (293 / 385) vs. 73.3% (282 / 385) and 65.9% (254 / 385) vs. 62.1% (239 / 385), respectively. The upper limit of the 95% CI for the hazard ratio for disease progression or death was greater than 1 for all protocol-designated subgroups analyzed, including PD-L1 TAP ≥1% and ≥5% and pelvic and / or para-aortic lymph node metastases. Analysis of PFS by RT subgroup showed no statistically significant differences between treatment arms. Formal significance testing for overall survival was not performed according to a pre-specified multiple testing procedure. The hazard ratio for overall survival between durvalumab and placebo was 0.78 (95% CI, 0.55–1.10; nominal P=0.156). The confirmed and unconfirmed ORRs were 82.6% (318 / 385) in the durvalumab arm and 80.5% (310 / 385) in the placebo arm (odds ratio, 1.15 [95% CI, 0.80–1.66]). The proportion of patients with confirmed complete response was 42.9% (165 / 385) in the durvalumab arm and 40.3% (155 / 385) in the placebo arm. The median duration of response was not reached in either treatment arm. While local disease recurrence was similar between the two groups, numerically more patients in the placebo group experienced distal disease progression compared to durvalumab (Table 9).

[0121] A total of 371 patients in the durvalumab arm and 364 patients in the placebo arm had tumor samples evaluable for PD-L1 expression. A similar proportion of patients in each arm had tumors (PD-L1 TAP ≥ 1%) at baseline (durvalumab, 92.5% [356 / 385]; placebo, 91.4% [352 / 385]). In patients with PD-L1 TAP ≥ 1%, PFS was similar in the durvalumab arm compared to the placebo arm (hazard ratio, 0.84; 95% CI, 0.64–1.10; P=0.203).

[0122] An exploratory post-hoc analysis yielded unexpected and surprising results. A PFS benefit was observed in patients with tumors (PD-L1 TAP ≥ 20%) who received durvalumab (n=191) compared to placebo (n=178) (hazard ratio, 0.62 [95% CI, 0.42–0.91]) (Figure 3). In contrast, patients with PD-L1 TAP < 20% did not benefit from adding durvalumab to CRT (hazard ratio, 1.06 [95% CI, 0.74–1.53]). Furthermore, compared to the treatment intention population, a lower hazard ratio was observed in patients with lymph node-positive disease (stages IB2-IVA) in the placebo (n=278) vs. durvalumab arm (n=277) (0.77 [95% CI, 0.58-1.03]), but there was no PFS benefit from durvalumab in patients with lymph node-negative disease (stage ≥III) (hazard ratio, 1.11 [95% CI, 0.65-1.91]) (Figure 4). However, among patients with tumors (PD-L1 TAP ≥ 20%), a lower hazard ratio was observed regardless of lymph node status (lymph node positive: durvalumab, n=138; placebo, n=141; hazard ratio, 0.66 [95% CI, 0.42-1.01]; lymph node negative: durvalumab, n=53; placebo, n=37; hazard ratio, 0.60 [95% CI, 0.26-1.41]) (Figure 5).

[0123] Baseline compliance rates for both treatment arms combined were 92.1% (708 / 769) on the EORTC QLQ-C30 questionnaire and 91.4% (703 / 769) on the QLQ-CX24 questionnaire. The rates decreased over time, reaching 66.7% (166 / 249) and 66.3% (165 / 249) on day 1 of cycle 24, respectively, for both treatment arms combined. For the QLQ-C30 measure of overall health status / quality of life (positive scores indicate improvement), the adjusted mean change from baseline across all visits was 2.1 (95% CI, 0.5–3.6) and 2.8 (95% CI, 1.2–4.3) for the durvalumab and placebo arms, respectively, with an estimated mean difference of -0.7 points (95% CI, -2.8–1.3; P=0.487). For the QLQ-CX24 symptom experience (negative scores indicate improvement), the adjusted mean change from baseline across all visits was -7.6 (durvalumab 95% CI, -8.6–-6.7; placebo 95% CI, -8.5–-6.6; P=0.930) for both the durvalumab and placebo arms. No significant differences were observed between the Durvalumab arm and the placebo arm in symptom experience, role functioning, physical functioning, or quality of life.

[0124] Adverse events of any cause occurred in 379 / 385 (98.4%) of patients in the durvalumab arm and in 377 / 384 (98.2%) of patients in the placebo arm. Grade 3 or 4 adverse events occurred in 199 / 385 (51.7%) of patients who received durvalumab and in 196 / 384 (51.0%) of patients who received placebo. The most common grade 3 or 4 adverse events in both treatment arms were anemia, leukopenia, neutropenia, neutrophil count reduction, and lymphopenia. Immune-mediated adverse events occurred in 147 / 385 (38.2%) of patients who received durvalumab and in 91 / 384 (23.7%) of patients who received placebo. AESIs associated with durvalumab occurred in 237 out of 385 patients (61.6%) in the durvalumab arm and in 221 out of 384 patients (57.6%) in the placebo arm. The most common AESIs in the durvalumab arm were diarrhea, hypothyroid events, hyperthyroid events, and rash, while in the placebo arm they were diarrhea, rash, hypothyroid events, and colitis.

[0125] The most common treatment-related adverse events were nausea, anemia, and diarrhea. These occurred in 193 / 385 (50.1%), 159 / 385 (41.3%), and 147 / 385 (38.2%) patients receiving durvalumab, and in 184 / 384 (47.9%), 154 / 384 (40.1%), and 161 / 384 (41.9%) patients receiving placebo, respectively. Treatment-related adverse events leading to discontinuation of the study treatment occurred in 48 / 385 (12.5%) patients receiving durvalumab and in 37 / 384 (9.6%) patients receiving placebo. Six patients died from treatment-related adverse events: sepsis, urinary tract infection, hemorrhagic anemia, endocrine disorders, and pulmonary embolism (durvalumab arm; n=1 each), as well as pneumonia (placebo arm; n=1). Sepsis and endocrine disorders were thought to be likely caused by durvalumab, while the remaining events were attributed to CRT.

[0126] RT-related toxicities occurring within one year of the end of RT were experienced by 291 / 385 patients (75.6%; grade ≥3, 116 / 385 [30.2%]) in the durvalumab arm and by 287 / 384 patients (74.7%; grade ≥3, 106 / 384 [27.6%]) in the placebo arm. The most common RT-related toxicities of all grades were diarrhea, anemia, and nausea. These were reported in 124 / 385 patients (32.2%), 106 / 385 patients (27.5%), and 71 / 385 patients (18.4%) in the durvalumab arm, and in 135 / 384 patients (35.2%), 108 / 384 patients (28.1%), and 78 / 384 patients (20.3%) in the placebo arm, respectively. RT-related toxicities occurring more than one year after the end of RT were experienced by 37 / 385 patients (9.6%; grade ≥3, 7 / 385 [1.9%]) in the durvalumab arm and by 36 / 384 patients (9.4%; grade ≥3, 4 / 384 [1.0%]) in the placebo arm. In the durvalumab arm, the most common RT-related toxicities of all grades occurring more than one year after RT were rectal bleeding and radiation gastroenteritis, each reported in 5 / 385 patients (1.3%). In the placebo arm, the most common RT-related toxicities during this period were radiation proctitis (6 / 384 [1.6%]) and radiation cystitis (4 / 384 [1.0%]).

[0127] In the CALLA study, durvalumab in combination with CRT and durvalumab after CRT did not significantly improve PFS compared to CRT alone in patients with high-risk LACC. However, surprisingly, durvalumab, based on post-hoc analysis, conferred a PFS benefit in patients with PD-L1 TAP ≥20% expression, regardless of lymph node status. Safety was similar across treatment arms, with no new or unexpected toxicities occurring. The CALLA study demonstrated the potential for delivering high-quality overall RT, and RT delivery was not affected by the addition of durvalumab. The CALLA study highlights the importance of strong interdisciplinary collaboration and quality control strategies for achieving optimal CRT delivery.

[0128] [Table 10]

[0129] [Table 11]

[0130] Example 2: Phase 1 open-label dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and antitumor activity of MEDI5752 in subjects with advanced solid tumors. To evaluate the safety, tolerability, and early evidence of the efficacy of MEDI5752, administered as monotherapy or in combination with chemotherapy, in adult patients with advanced solid tumors, an initial phase 1 human, multicenter, open-label dose-escalation and dose-expansion study was conducted. The objective of this study was to provide a description of the safety profile, pharmacokinetics (PK), pharmacodynamics (PD), and early signs of antitumor effects. Participants were enrolled at approximately 50 sites worldwide. At the data cutoff date, a total of 178 participants with advanced solid tumors had received at least one dose of MEDI5752 monotherapy at one of 10 dose levels (1 each at 2.25 mg and 7.5 mg, 3 at 22.5 mg, 5 at 75 mg, 10 at 225 mg, 20 at 500 mg, 40 at 750 mg, 39 at 1500 mg, 34 at 2000 mg, and 7 at 2500 mg). The study included two phases: dose escalation and dose expansion (Figures 1A-1D). The dose escalation phase evaluated 10 dose levels to identify the maximum tolerated dose (MTD), optimal biological dose (OBD), or highest protocol-defined dose (HPDD).

[0131] The dose escalation consisted of 10 dose levels of MEDI5752 administered via IV infusion (dose levels 2.25, 7.5, 22.5, 75, 225, 500, 750, 1500, 2000, and 2500 mg). Once the OBD, MTD, or HPDD was determined, a specific cohort of up to 6 subjects with a glomerular filtration rate (GFR) of 30–45 mL / min could be explored within the OBD, MTD, or HPDD (i.e., the pharmacodynamic cohort). Up to approximately 111 subjects were enrolled in the dose escalation phase.

[0132] Once MTD, OBD, or HPDD was established during the dose escalation phase, the dose expansion phase was initiated. In the expanded cohort, only eligible metastatic patients who were immunotherapy-naive were enrolled.

[0133] The primary safety endpoints in the dose escalation phase were the assessment of the presence of AEs, SAEs, and DLTs, and the determination of the MTD, OBD, or HPDD of MEDI5752 not exceeding the MTD.

[0134] A total of 136 subjects were treated with MEDI5752. Table 5 shows the exposures and MEDI5752-related adverse events observed at selected MEDI5752 monotherapy and combination dose levels as of the data snapshot date.

[0135] [Table 12]

[0136] Dose-limiting toxicity (DLT) was reported in one patient each in the 2000 mg (grade 3 interstitial pneumonia and grade 1 myocarditis in the same patient population) and 2500 mg (grade 3 maculopapular rash) monotherapy cohorts. Two deaths were determined to be related to MEDI5752 treatment. One patient died from diabetic ketoacidosis and hyperthyroidism, and the other died from myocardial infarction.

[0137] A review of the benefit-risk profile in patients treated with MEDI5752 suggested that long-term administration at doses of 1500 mg or higher is not suitable for further development due to a high discontinuation rate, primarily caused by grade 3 / 4 hepatotoxicity.

[0138] In the dose-escalation and maximum tolerated dose (MTD) / optimal biological dose (OBD) cohorts, among 86 patients treated with MEDI5752 monotherapy, the overall objective response rate (ORR) (according to the RECIST version 1.1 for solid tumors) was 19.8% (17 / 86) in the evaluable response analysis set, regardless of dose, with one patient achieving a complete response (CR). In the five patients treated with 500 mg of MEDI5752 during dose escalation, two patients had a best overall response (BOR) or partial response (PR), two patients had stable disease (SD), and one patient had progressive disease (PD). In the eight patients treated with 750 mg of MEDI5752 during dose escalation, four patients had a BOR with SD, three had PD, and one patient was unevaluable. The median duration of response with MEDI5752 monotherapy was 17.5 months (Figure 12). MEDI5752 monotherapy also demonstrated sustained responses in a variety of IO-naive tumors across the MEDI5752 dose range (Figure 13).

[0139] At this initial stage of the human clinical trial, three subjects with relapsed / refractory cervical cancer were treated with MEDI5752 in a dose-escalation phase (one at 22.5 mg, one at 1500 mg, and one at 2000 mg). All three subjects achieved the best observed response, which resulted in disease stabilization.

[0140] The data suggested that MEDI5752 exhibited non-linear PK, possibly due to saturated target-mediated clearance at doses below 22.5 mg, and possibly also due to the potential influence of ADA on MEDI5752 clearance. The mean PK profile of MEDI5752 over the first 84 days is shown in Figure 14.

[0141] Pharmacodynamic data suggested that MEDI5752 administration resulted in a dose-dependent increase in CD4+ T cell proliferation, reaching a plateau at doses of 500 / 750 mg or higher (Figures 15 and 9A). At doses of >225 mg, MEDI5752 demonstrated sustained peripheral PD-1 receptor occupancy (>90%) (Figure 11). Pharmacodynamic data in monotherapy settings also suggested that MEDI5752 resulted in a dose-dependent increase in CD4+ T cell activation, with T cell proliferation reaching a plateau at doses of 500 / 750 mg or higher (Figures 9B and 10A-10B, respectively). Pharmacodynamic data in combination with chemotherapy agents showed that MEDI5752 at 750 mg and 1500 mg doses combined with chemotherapy resulted in a higher increase in CD4+ T cell proliferation on day 8 of cycle 1 and a higher percentage of newly proliferated T cell clones in cycle 2 compared to pembrolizumab combined with chemotherapy (Figures 9C and 10C, respectively).

[0142] Example 3: Efficacy of borulstomig (MEDI5752) in patients with cervical cancer There remains a significant unmet need for further treatment options for patients with cervical cancer. This is a phase III randomized, double-blind, placebo-controlled, multicenter international trial to explore the efficacy and safety of borulstomig in women with FIGO (2018) high-risk LACC who have not progressed after platinum-based CCRT.

[0143] The trial design aims to minimize potential risks to participants in this trial based on protocol inclusion and exclusion criteria, safety monitoring, TMG, and trial termination criteria. Specific intensive safety monitoring will be conducted.

[0144] Bolstomyg is being evaluated in patient populations with limited life expectancy due to lymph node metastasis. While other treatment options exist for such patients, Bolstomyg has the potential to offer an improved benefit-risk profile. Based on a review of the available safety data for Bolstomyg, its benefit-risk profile remains acceptable for continued investigation and is justified by the perceived benefits for patients with cancer.

[0145] [Table 13-1]

[0146] [Table 13-2]

[0147] Test design Approximately 1430 participants will be screened to randomize 1000 participants into two arms in a 1:1 ratio. Randomization will be stratified by PD-L1 expression (assessed by a central laboratory using the VENTANA PD-L1(SP263) assay (high PD-L1 expression vs. other)) and region (Asia vs. non-Asia). Arm A: 750 mg IV vorulstromig on day 1 of each 21-day cycle until disease progression or 24 months (n=500). Arm B: Placebo 750 mg IV on day 1 of each 21-day cycle until disease progression or 24 months (n=500).

[0148] Participants will receive their assigned treatment for up to 24 months, or until clinical or radiological progression as defined in RECIST 1.1, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. After 24 months, participants may continue treatment if, in the opinion of the principal investigator, the participant has benefited from the treatment and no other discontinuation criteria are met. Participants who discontinue treatment for reasons other than radiological disease progression will receive post-treatment follow-up imaging for their disease status until radiological disease progression, withdrawal of consent, inability to follow up, or death.

[0149] Scientific basis for test design This is a Phase III randomized, double-blind, placebo-controlled, multicenter international trial to explore the efficacy and safety of borulstomyg in women with FIGO (2018) high-risk lacytosis acute (LACC) that have not progressed after platinum-based CCRT. Borulstomyg (a monovalent, bispecific humanized IgG1 mAb that specifically binds to CTLA-4 and PD-1) will be administered after state-of-care (SOC) CCRT and compared to placebo after SOC CCRT in participants with high-risk LACC.

[0150] Concurrent chemoradiotherapy has been shown to induce immunogenic cell death. Cell death induced by radiation or CCRT enhances the immune system's ability to recognize and respond to tumors through enhanced antigen release and presentation. Furthermore, ionizing radiation triggers upmodulation of various pro-inflammatory signals and cytokines that play a crucial role in immunomodulatory pathways, resulting in improved anti-tumor immunity. Radiation also enhances the diversity of the T cell receptor repertoire of intratumor T cells.

[0151] Cytotoxic T lymphocyte antigen 4 is a negative regulator of T cell activation, and its inhibition enables a T cell response to cancer. Similarly, the PD-1 axis is involved in negative T cell regulation, and its inhibition leads to a restoration of T cell cytotoxicity against tumors. Recent studies have shown that tumor-specific CD8+ T cells express several inhibitory receptors (including CTLA-4, P-1, TIM-3, BTLA, and LAG3), and that their dual simultaneous blockade acts synergistically to make T cells more functional than single blockade (Huang et al. 2015).

[0152] Test group The target population for this trial is participants with FIGO (2018) stage IIIC-IVA cervical cancer (with lymph node positivity) who are not progressing on curative platinum-based CCRT. Prior approval (also known as protocol abandonment or exemption) of protocol deviations from recruitment and inclusion criteria is not permitted. Participants who do not meet the eligibility criteria will be dropped from screening.

[0153] Inclusion Criteria Participants are eligible to take the exam only if all of the following criteria apply.

[0154] age 1. Participants must be 18 years of age or older at the time of screening. For facilities planning to enroll pediatric participants, participants must be 15 years of age or older at the time of screening.

[0155] Participant types and disease characteristics 2. Participants must have histologically documented (lymph node positive) FIGO (2018) stage IIIC-IVA cervical cancer. Participants must have histologically confirmed cervical adenocarcinoma, cervical squamous cell carcinoma, or cervical adenosquamous cell carcinoma, and meet the following requirements: • Only participants with LN transfer are included. Confirmation of lymph node metastasis may be surgical, or by imaging studies (PET-CT, CT, or MRI) with pathological lymph node size defined by a short-axis diameter (axial plane) of ≥10 mm. • No evidence of metastatic disease (M0) 3. The initial staging procedures performed before initiating any component of curative treatment (CCRT) should include the following: • Pelvic MRI (preferred) or IV-enhanced CT; IV-enhanced CT of the chest / abdomen. PET-CT is recommended but not mandatory. Brain MRI (preferred) or IV-enhanced CT only if symptoms are present. • The above scans for the initial staging procedure must be performed at least 42 days before the first dose of CCRT. 4. WHO / ECOG performance status of 0 or 1 at registration and randomization. 5. Average life expectancy is 12 weeks or more. 6. Provision of pre-randomization FFPE tumor samples for evaluation of PD-L1 expression determined by central laboratory using the VENTANA PD-L1 (SP263) assay. Patients with unknown PD-L1 expression are not eligible for the study. The requirements for tumor samples are as follows: FFPE samples must be collected within 3 months of CCRT. 7. Participants must not have progressed after curative platinum-based CCRT, as demonstrated by the following imaging tests performed after completion of CCRT: baseline RECIST1.1 imaging at screening: IV-enhanced CT of the chest / abdomen, MRI (preferred) of the pelvis, or IV-enhanced CT. Participants must have completed SOC CCRT (EBRT + close-range radiotherapy + concurrent cisplatin) according to local clinical practice / guidelines and must not have progressed after CCRT. It is highly preferable that participants complete CCRT within 8 weeks. Participants should receive weekly cisplatin (40 mg / m²) as concurrent chemotherapy along with radiotherapy. 2Participants must have received 5-6 cycles of cisplatin. This must be completed within 1-28 days of the first dose of the trial intervention in the study (one cycle of chemotherapy is defined as 7 days). If a participant cannot tolerate toxicity, they must receive at least 4 cycles of cisplatin. Participants must complete screening within 28 days after CCRT. The platinum chemotherapy regimen must be cisplatin monotherapy, and the last dose of chemotherapy must be administered before or concurrently with the last dose of radiation. Consolidation chemotherapy after radiation is not permitted. Sufficient bone marrow reserve and organ function within 7 days prior to randomization / treatment.

[0156] Dose level: A fixed dose of 500 mg or 750 mg of bolustomig (MEDI5752) is administered during Q3W.

[0157] Route of administration: IV

[0158] Regimen and duration: One IV infusion on day 1 of each 21-day cycle (Q3W). Administered as an IV infusion over 1 hour (±10 minutes).

[0159] Duration of treatment: Participants in both the borulstomig (750 mg and 500 mg) group and the placebo group will receive their assigned treatment for up to 24 months, or until clinical or RECIST 1.1 defined radiological progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. After 24 months, participants may continue treatment with borulstomig if, in the opinion of the principal investigator, the participant has benefited from the treatment and no other discontinuation criteria are met.

[0160] Effectiveness evaluation Imaging for tumor evaluation Tumor assessment will use images from pelvic MRI (preferred) or IV-enhanced CT and chest / abdomen (including the entire liver and both adrenal glands) IV-enhanced CT (PET-CT is additionally recommended but not required) collected during screening / baseline and at regular (follow-up) intervals during the intervention period. Other areas involved in the disease should be further imaged at screening based on known metastatic sites or individual participant signs and symptoms. The imaging modalities used for baseline tumor assessment (pelvic MRI [preferred] or IV-enhanced CT and chest / abdomen IV-enhanced CT [PET-CT of the pelvis and chest / abdomen is additionally recommended but not required]; MRI (preferred) or IV-enhanced CT (only if symptoms are present) should, if possible, be consistent across the entire trial and at each subsequent follow-up assessment. It is important to adhere as strictly as possible to the tumor assessment schedule for randomization / first dose (see SoA).

[0161] Screening / baseline imaging results must be obtained within 28 days of randomization, and ideally, as close to, and before, the start of the study intervention. Study treatment will continue until completion of the planned therapy (up to 24 months), clinical or radiological progression as defined by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met.

[0162] Scans / tumor assessments will be performed every 12 ± 1 weeks (relative to the randomization date) up to 158 weeks (relative to the randomization date) until radiological progression as defined in RECIST 1.1 + additional follow-up scans, and then every 24 ± 2 weeks thereafter (relative to the randomization date). Participants who discontinue treatment for reasons other than radiological disease progression will receive post-treatment follow-up imaging assessments of their disease status until radiological disease progression, withdrawal of consent, inability to follow up, or death.

[0163] If an unscheduled assessment is conducted, for example, to investigate clinical signs / symptoms of progression, and the participant has not progressed, all attempts should be made to conduct a follow-up assessment at the next scheduled visit.

[0164] Baseline imaging assessments using RECIST 1.1 identify TLs (defined as measurable) and NTLs. Intra-trial imaging assesses the baseline-selected TLs and NTLs, as well as the NLs (non-linear lesions) at which they appear. This allows for the determination of follow-up TL responses, NTL lesion responses, the presence of apparent NLs, and overall time-point responses (CR, PR, SD, disease progression, or NE).

[0165] Central scan reading Images, including scans taken during unscheduled visits, will be continuously collected and sent to an AstraZeneca-designated iCRO ​​for quality control and storage. Digital copies of all original scans must be stored at the principal investigator's site as source documents. Electronic transfer of images from the site to the iCRO ​​is strongly encouraged. BICR of images will be performed at AstraZeneca's discretion. The results of these independent reviews will not be communicated to the principal investigator, and the results of the principal investigator's tumor assessment will not be shared with the central evaluator.

[0166] Time until secondary progression or death Following the initial objective progression, participants' subsequent progression will be recorded every 12 weeks according to local standard practice by the principal investigator, until a secondary progression event occurs after the initiation of subsequent anticancer therapy.

[0167] Prior evaluation of subsequent chemotherapy: In subsequent progression assessments, if subsequent chemotherapy has not been initiated, subsequent progression is evaluated against primary objective RECIST 1.1 progression. Furthermore, the reasons for not initiating subsequent chemotherapy are recorded.

[0168] Evaluation after initiation of subsequent chemotherapy: If subsequent chemotherapy is initiated at the time of PFS2 evaluation, secondary progression is evaluated with respect to the last tumor assessment prior to the initiation of subsequent chemotherapy.

[0169] The principal investigator's opinion on the progression of the disease (progressive or non-progressive) is recorded, and if a progressive disease is recorded, the type of progression is also recorded.

[0170] overall survival Survival assessments will be conducted every 12 weeks after safety follow-up visits at 30 and 90 days after discontinuation of treatment. Survival information may be obtained through telephone contact with participants, their families, their current physicians, or from local death registries. Note: Survival confirmation contacts will be made after the data cut-off date (DCO) for analysis (these contacts should generally be made within 7 days of the DCO date). If a participant is confirmed to be alive, or if the date of death is after the DCO date, these participants will be terminated on the DCO date.

[0171] Clinical Outcome Assessment (COA) A COA is a discretionary assessment that can be influenced by a person's choices, judgments, or motivations, and can support either direct or indirect evidence of therapeutic benefit. Patient-reported outcome assessment is a type of COA and is a general term referring to all outcomes and symptoms directly reported by participants. Patient-reported outcomes are important in assessing the effectiveness and tolerability of trial interventions in clinical trials and are helpful in understanding benefit / risk assessments (Kluetz et al. 2018).

[0172] The PRO rating scale used in this study is as follows: • EORTC IL172 (QLQ-C30 function subscale + HRQoL item) • EORTC IL:QLQ-CX24 ·EQ-5D-5L · PGI-C · PGI-S PGI-TT • PRO-CTCAE ·PROMIS physical function 8c

[0173] Patient-reported outcome scales are used according to the State of Assessment (SoA). PRO scales are completed by participants if a linguistically valid version is available in the language of the participant's country of residence.

[0174] Determination of sample size Approximately 1430 participants will be enrolled, and approximately 1000 participants will be randomized in a 1:1 ratio to receive either vorulstromig or placebo. Of the approximately 1000 participants randomized to the trial, approximately 500 will be included in the PD-L1 high-expression population analysis set. The primary analysis of PFS will be planned to be performed in the PD-L1 high-expression population analysis set. A secondary objective of the trial will be to analyze PFS in the FAS (Focused Assessment System).

[0175] The primary (final) PFS analysis for superiority will be performed when approximately 162 PFS events occur across the borulstomig and placebo treatment arms (approximately 32% maturity) in the analysis set of the PD-L1 high-expression population. If the true PFS HR is 0.60 in this population, the analysis will provide 90% power to demonstrate statistical significance for PFS at a 5% two-sided significance level. This means that, assuming exponentially distributed PFS, the proportion of participants with no progression at year 2 will increase by approximately 14%, from 58% in placebo to 72%. This analysis is estimated to be performed approximately 40 months after the initial participant randomization.

[0176] The analysis of PFS in FAS is performed at the time of the primary PFS analysis. It is estimated that approximately 342 PFS events occur in FAS. If the true PFS HR is 0.70 in this population, the analysis provides at least 90% power to demonstrate statistical significance for PFS at a 5% two-sided significance level. This means that, assuming PFS is exponentially distributed, the proportion of participants experiencing PFS at year 2 increases by approximately 10%, from 58% in placebo to 68%.

[0177] Assuming a true OS HR of 0.60 in the PD-L1 high-expression population analysis set, the trial is also sized to provide at least 90% power for the OS endpoint in the Bolstomig vs. placebo comparison, assuming a two-sided significance level that allows two interim analyses to be performed at approximately 45% (at PFS analysis) and 75% of the target events. This means that if OS is exponentially distributed, the 3-year OS rate increases by approximately 10%, from 72% in placebo to 82%.

[0178] Intermediate / final analyses of OS in the FAS are performed at the time of each intermediate / final analysis of OS in the PD-L1 high-expression population analysis set. At the time of the final OS analysis in the PD-L1 high-expression population analysis set, it is estimated that approximately 343 OS events will occur in all randomized participants. If the true OS HR for this population is 0.70, the analysis will provide at least 90% power to demonstrate statistical significance for OS at a two-sided significance level, allowing for two intermediate analyses performed at the time of the two OS intermediate analyses in the PD-L1 high-expression population analysis set. This means that if OS is exponentially distributed, the 3-year OS rate will increase by approximately 7%, from 72% in placebo to 82%.

[0179] [Table 14]

[0180] statistical analysis General Considerations The primary objective of this trial is to evaluate the efficacy of borulstomig compared to placebo in terms of PFS, which will be assessed by investigator-reported tumor assessment and histopathological confirmation of local tumor progression in a PD-L1 high-expression population analysis set. An important secondary objective is to evaluate the efficacy of borulstomig compared to placebo in terms of PFS in the FAS, OS in the PD-L1 high-expression analysis set, and OS in the FAS.

[0181] The primary endpoint of PFS is tested once. The secondary endpoint of OS is tested at two intermediate and final time points. The alpha level assigned to OS is controlled at the intermediate and final time points separately for each population using the Lan-DeMet (Lan and DeMet 1983) consumption function. The consumption function approximates the O'Brien-Fleming approach, and the alpha assigned at the intermediate time points depends on the proportion of information available at the time of analysis.

[0182] PFS analysis will be performed when PFS reaches approximately 162 events (maturity 32%) in the PD-L1 high-expression population analysis set. This is estimated to occur approximately 40 months after the initial participants were randomized.

[0183] Overall survival in the PD-L1 high-expression population analysis set will be tested using two IAs and one FA as described below: The first OS IA is planned to be performed at the time of the final PFS analysis. Approximately 73 OS events (15% maturity or 45% information fraction) are expected to be observed in the PD-L1 high-expression population analysis set. The second OS IA is planned to be performed when approximately 121 OS events (maturity 24% or information fraction 75%) are observed in the PD-L1 high-expression population analysis set, which is expected to occur approximately 56 months after the initial participants were randomized. The final OS analysis will be conducted when approximately 162 OS events (maturity level 32%) have been observed, which is expected to occur approximately 72 months after the initial participants were randomized.

[0184] In FAS, the IA / FA of OS is performed at each IA / FA time point for OS in the PD-L1 high-expression population analysis set.

[0185] The primary PFS analysis is based on RECIST 1.1, programmatically derived using the investigator's tumor assessment or histopathological confirmation of local tumor progression. PFS and OS are analyzed using a stratified log-rank test with treatment as a fixed effect, adjusted for the randomization stratification variable. The randomization stratification variable in the statistical model is based on the values ​​entered into the IRT at randomization (even if these values ​​are subsequently found to be inaccurate). If there are insufficient events per stratification, stratification is pooled according to a pre-specified pooling strategy. HR and its corresponding CI are estimated from a stratified Cox proportional hazards model, and stratification is the same as the randomization stratification variable from the IRT.

[0186] Efficacy data will be compiled and analyzed based on ITT (Intention-to-Take) criteria, and treatment arms will be compared based on the randomized treatment, regardless of the treatment actually received. Patients who were randomized but did not subsequently receive the study treatment will be included in the FAS (Functional Analysis) population.

[0187] Safety and tolerability data are presented descriptively and not formally analyzed unless otherwise specified. Data are presented for each treatment group using a safety analysis set.

[0188] Depending on the extent of the impact, summaries of data related to civil crises, natural disasters, or public health crises may be generated.

[0189] Calculation or derivation of tumor response variables Principal Investigator's Assessment Based on RECIST 1.1: All RECIST 1.1 assessments, whether planned or not, are included in the calculation. This also applies regardless of whether the participant discontinues the trial intervention or receives another anti-cancer therapy.

[0190] At each visit, participants are programmatically assigned a RECIST 1.1 visit-time response (CR, PR, SD, PD, or NE) based on their disease status compared to baseline and previous assessments. Tumor response endpoints (PFS, ORR, and DoR) are then derived from scan-day and overall visit-time responses.

[0191] BICR: Radiologic scans for BICR are performed against a PD-L1 high-expression population analysis set or an ITT analysis set to confirm the robustness of PFS as assessed by the principal investigator. All images are collected centrally. Diagnostic imaging scans are reviewed by two independent radiologists using RECIST 1.1 and determined as necessary. For each participant, BICR defines the total visit response data (CR, PR, SD, PD, or NE) and relevant scan dates for each time point (i.e., for visits where response or progression is identified / not identified). If a participant has a tumor assessment that cannot be assessed, the participant is assigned a visit response of NE (in which case, the response is assigned as disease progression unless there is evidence of progression). The PFS endpoint is then derived from the scan dates and total visit responses.

[0192] Primary endpoints Progression-free survival Progression-free survival is defined as the time from the date of randomization to tumor progression or death due to any cause, regardless of whether the participant discontinues therapy, receives another anticancer therapy, or experiences clinical progression before RECIST 1.1 progression. However, if a participant progresses or dies immediately after missing two or more consecutive visits, the participant will be terminated at the final evaluation date (when physical examination for RECIST 1.1 evaluation and response evaluation was available). The analysis includes all participants with high PD-L1 expression.

[0193] The PFS period is derived based on the scan / evaluation date, not the visit date.

[0194] RECIST 1.1 assessments contributing to specific hospital visits may be performed on different days.

[0195] The following rules apply: • For the investigator's assessment, the progression date will be determined based on the earliest RECIST 1.1 assessment / scan date of the component indicating progression. • If a participant is discontinued based on PFS, they will be discontinued on the most recent scan date that contributes to a specific overall visit-time evaluation.

[0196] Secondary endpoints Progression-free survival Progression-free survival is defined as the time from the date of randomization to tumor progression or death due to any cause, regardless of whether the participant discontinues therapy, receives another anticancer therapy, or experiences clinical progression before RECIST 1.1 progression. However, if a participant progresses or dies immediately after missing two or more consecutive visits, the participant will be terminated at the final evaluation date (when physical examination for RECIST 1.1 evaluation and response evaluation was evaluable). The analysis will include all participants with high PD-L1 expression or the ITT analysis set.

[0197] PFS time is based on the scan / evaluation date, not the visit date. RECIST 1.1 evaluations contributing to a specific visit may be performed on different days.

[0198] overall survival Overall survival is defined as the time from randomization to death from any cause. Comparisons include all randomized participants with high PD-L1 or ITT analysis sets, regardless of whether the participant discontinued the study intervention or received another anticancer therapy.

[0199] At 36 months, Kaplan-Meier plots are presented for each treatment group in the overall survival (OS) assessment.

[0200] Any participant whose death was not discovered at the time of analysis will be terminated based on the last recorded date on which the participant was known to be alive.

[0201] Objective response rate and complete response rate Objective response rate is defined as the percentage of evaluable patients whose response at visit was CR or PR as assessed by the principal investigator. Complete response rate is defined as the disappearance of all target and non-target lesions. Duration of response is defined as the time from the first detection of CR to the objective disease progression date, according to RECIST 1.1.

[0202] The analysis includes all randomized participants with high PD-L1 expression who have a measurable disease at baseline / a assessable disease at baseline, or an ITT analysis set.

[0203] Data obtained up to the point of progression, or the last evaluable assessment in the absence of progression, are included in the ORR assessment. Participants who discontinued randomized treatment without progression received subsequent chemotherapy and are then included as non-responders in the ORR (note that palliative radiotherapy is not considered subsequent chemotherapy for the purposes of this analysis). Participants without an evaluable post-baseline assessment are included as non-responders. Participants without a baseline assessment are also included as non-responders unless they had a complete response (CR) at their first post-baseline assessment (unconfirmed response) and this was confirmed at a subsequent assessment (confirmed response).

[0204] ORR uses all scans, whether scheduled or not, based on data from the principal investigator at the regional site.

[0205] Incidence of advanced or secondary malignant tumors The incidence of local progression, distant disease progression, and secondary malignancies is defined as the number and proportion of participants who develop local progression, distant disease recurrence, or secondary malignancies.

[0206] The comparison includes all participants in the ITT analysis set. All events are included, regardless of whether participants discontinued subsequent therapy or did not attend follow-up appointments.

[0207] Time to first subsequent therapy or time to death (TFST) TFST is defined as the time from randomization to the initiation of the first subsequent anticancer therapy after discontinuation of randomized treatment or death from any cause. The analysis includes all randomized participants with high PD-L1 expression or ITT analysis sets.

[0208] Time until secondary progression or death The time to secondary progression or death is defined as the time from randomization to the earlier of the progression event or death after the first subsequent therapy (following the progression assessed by the initial investigator). The date of secondary progression is recorded by the investigator in the eCRF and defined according to local standard clinical practice.

[0209] The analysis includes all randomized participants with high PD-L1 expression or ITT analysis sets. All events are included, regardless of whether participants discontinued subsequent therapy or failed to attend appointments.

[0210] Time to secondary progression or death is analyzed using the same methodology specified for PFS. The effect of vorulstomig versus placebo is estimated by its corresponding CI and p-value, along with the hazard ratio (HR). Kaplan-Meier plots are presented for each treatment group.

[0211] Tertiary / Exploratory Endpoints safety Safety and tolerability will be evaluated with respect to adverse events (AEs), clinical laboratory tests, vital signs, and ECG. Furthermore, additional evaluations will be conducted for the following pre-specified AE categories (bleeding, ISR, thrombocytopenia, neurological events, hypersensitivity) and the pre-specified safety category of new onset or exacerbation of diabetes. Exposure to the study intervention will be documented.

[0212] The purpose of analyzing safety data is to assess general safety objectives, as evaluated in scenarios where the trial intervention is not terminated prematurely.

[0213] Pharmacokinetics and pharmacodynamics Details of PK, population PK, pharmacodynamics, PK / pharmacodynamic relationships, and / or exposure response / safety analysis are provided in the SAP. Population PK analysis and pharmacodynamic analysis are presented separately from the main CSR.

[0214] biomarkers The status of biomarkers is assessed for participants in each treatment group according to pre-specified criteria (which may be detailed in the SAP). Exploratory biomarker analyses may be documented in separate analytical plans and reported outside the CSR in separate reports. The results of these biomarker assessments are reported in the CSR itself, as an addendum, or separately in scientific reports or publications. The results of these biomarker assessments may be pooled with biomarker data from other trials involving trial interventions to generate hypotheses to be tested in future research.

[0215] Any claim or statement containing “or” between one or more members of a group is considered satisfied unless otherwise indicated or is evident from the context, if one, two or more, or all of the group members are present in, used in, or related to a given product or process. This disclosure includes embodiments in which exactly one member of a group is present in, used in, or otherwise related to a given product or process. This disclosure also includes embodiments in which two or more, or all of the group members are present in, used in, or related to a given product or process.

[0216] Furthermore, this disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim can be modified to include one or more limitations found in any other claim dependent on the same basic claim. If elements are presented as a list, for example in Markush group form, each subgroup of elements is also disclosed, and any element can be removed from the group.

[0217] In general, whereever this disclosure or any aspect thereof is referred to as containing certain elements and / or features, it should be understood that certain aspects of this disclosure or any aspect thereof consists of or is essentially such elements and / or features. For simplicity, these aspects are not specifically described herein.

[0218] All patents and publications referenced herein are incorporated herein by reference to the same extent as each independent patent and publication is specifically and individually indicated as being incorporated by reference. No citation or specification of any reference in any section of this application should be construed as an acknowledgment that such reference is available as prior art to this disclosure.

Claims

1. A method for treating cervical cancer, comprising treating a patient with an anti-PD-1 binding protein or an anti-PD-L1 binding protein.

2. The method according to claim 1, further comprising treating the patient with chemoradiotherapy.

3. The method according to either claim 1 or 2, wherein the cervical cancer is locally advanced cervical cancer (LACC).

4. The method according to any one of claims 1 to 3, wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

5. The method according to any one of claims 1 to 4, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, and semiprimab.

6. The method according to any one of claims 1 to 4, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is an anti-PD-L1 antibody selected from durvalumab, avelumab, atezolizumab, and sugemalimab.

7. The method according to any one of claims 1 to 4, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is a bispecific antibody, and the bispecific antibody is MEDI5752.

8. The method according to any one of claims 1 to 7, wherein the chemoradiotherapy includes concurrent chemoradiotherapy.

9. The method according to any one of claims 1 to 8, wherein the chemoradiotherapy includes external beam radiation therapy and near-field radiation therapy.

10. The method according to any one of claims 1 to 9, wherein the chemoradiotherapy includes platinum-based chemotherapy.

11. The method according to claim 10, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

12. The method according to any one of claims 5 to 11, wherein the treatment with the anti-PD-L1 antibody comprises administering 1,500 mg of the anti-PD-L1 antibody intravenously to the patient every four weeks (Q4W).

13. The method according to any one of claims 5 to 11, wherein the treatment with the anti-PD-L1 antibody comprises administering 1,500 mg of the anti-PD-L1 antibody intravenously to the patient every three weeks (Q3W).

14. The method according to claim 12 or 13, wherein the anti-PD-L1 antibody is durvalumab.

15. The method according to any one of claims 7 to 11, wherein the treatment with the bispecific antibody comprises administering 750 mg of the bispecific antibody intravenously to the patient every three weeks (Q3W).

16. The method according to any one of claims 7 to 11, wherein the treatment with the bispecific antibody comprises administering 500 mg or 750 mg of MEDI5752 intravenously to the patient every three weeks (Q3W).

17. The method according to any one of claims 2 to 16, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein and the chemoradiotherapy are administered simultaneously.

18. The method according to any one of claims 2 to 16, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is administered after the chemoradiotherapy.

19. The method according to any one of claims 1 to 18, wherein the method extends progression-free survival (PFS) in the patient.

20. The method according to any one of claims 1 to 18, wherein the method increases the overall response rate (ORR) in the patient.

21. A combination for use in the treatment of cervical cancer in patients, comprising an anti-PD-1 binding protein or an anti-PD-L1 binding protein.

22. The combination for use according to claim 21, wherein the combination further comprises chemoradiotherapy.

23. The combination for use according to either claim 21 or 22, wherein the cervical cancer is locally advanced cervical cancer (LACC).

24. The combination for use according to any one of claims 21 to 23, wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

25. The combination for use according to any one of claims 21 to 24, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, and semiprimab.

26. The combination for use according to any one of claims 21 to 24, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is an anti-PD-L1 antibody selected from durvalumab, avelumab, atezolizumab, and sugemalimab.

27. The combination for use according to any one of claims 21 to 24, wherein the anti-PD-1 binding protein is a bispecific antibody, and the bispecific antibody is MEDI5752.

28. The combination for use according to any one of claims 22 to 27, wherein the chemoradiotherapy includes concurrent chemoradiotherapy.

29. The combination for use according to any one of claims 22 to 28, wherein the chemoradiotherapy includes external beam radiation therapy and close-range radiation therapy.

30. The combination for use according to any one of claims 22 to 28, wherein the chemoradiotherapy comprises platinum-based chemotherapy.

31. The combination for use according to claim 30, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

32. The combination for use according to any one of claims 26 or 28-31, wherein the combination comprises administering 1500 mg of the anti-PD-L1 antibody intravenously to the patient every four weeks (Q4W).

33. The combination for use according to claim 26 or any one of claims 28-31, wherein the combination comprises administering 1500 mg of the anti-PD-L1 antibody intravenously to the patient every three weeks (Q3W).

34. The combination for use according to any one of claims 32 of claim 33, wherein the anti-PD-L1 antibody is durvalumab.

35. The combination therapy for use according to any one of claims 27 to 31, comprising administering 500 mg or 750 mg of the bispecific antibody intravenously to the patient every three weeks (Q3W).

36. The combination for use according to any one of claims 27 to 31, wherein the combination therapy comprises administering 500 mg or 750 mg of MEDI5752 intravenously to the patient every three weeks (Q3W).

37. The combination for use according to any one of claims 22 to 36, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein and the chemoradiotherapy are administered simultaneously.

38. The combination for use according to any one of claims 22 to 36, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is administered after the chemoradiotherapy.

39. The combination for use according to any one of claims 21 to 38, wherein the combination extends progression-free survival (PFS) in the patient.

40. The combination for use according to any one of claims 21 to 38, wherein the combination increases the overall response rate (ORR) in the patient.

41. Use of anti-PD-1 binding protein or anti-PD-L1 binding protein for the manufacture of pharmaceuticals for the treatment of cervical cancer in patients.

42. The use according to claim 41, wherein the pharmaceutical further comprises chemoradiotherapy.

43. The use according to either claim 41 or 42, wherein the cervical cancer is locally advanced cervical cancer (LACC).

44. The use according to any one of claims 41 to 43, wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

45. The use according to any one of claims 41 to 44, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, and semiprimab.

46. The use according to any one of claims 41 to 44, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is an anti-PD-L1 antibody selected from durvalumab, avelumab, atezolizumab, and sugemalimab.

47. The use according to any one of claims 41 to 44, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is a bispecific antibody, and the bispecific antibody is MEDI5752.

48. The use according to any one of claims 42 to 47, wherein the chemoradiotherapy includes concurrent chemoradiotherapy.

49. The use according to any one of claims 42 to 48, wherein the chemoradiotherapy includes external beam radiation therapy and close-range radiation therapy.

50. The use according to any one of claims 42 to 49, wherein the chemoradiotherapy includes platinum-based chemotherapy.

51. The use according to claim 50, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

52. The use according to any one of claims 46 to 51, wherein the treatment comprises administering 1500 mg of the anti-PD-L1 antibody intravenously to the patient every four weeks (Q4W).

53. The use according to any one of claims 46 to 51, wherein the treatment comprises administering 1500 mg of the anti-PD-L1 antibody intravenously to the patient every three weeks (Q3W).

54. The use according to claim 52 or 53, wherein the anti-PD-L1 antibody is durvalumab.

55. The use according to any one of claims 47 to 51, wherein the treatment comprises administering 500 mg or 750 mg of a bispecific antibody intravenously to the patient every three weeks (Q3W).

56. The use according to claim 55, wherein the bispecific antibody is MEDI5752.

57. The use according to any one of claims 42 to 56, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein and the chemoradiotherapy are administered simultaneously.

58. The use according to any one of claims 42 to 56, wherein the anti-PD-1 binding protein or the anti-PD-L1 binding protein is administered after the chemoradiotherapy.

59. The use according to any one of claims 41 to 58, wherein the treatment extends progression-free survival (PFS) in the patient.

60. The use according to any one of claims 41 to 58, wherein the treatment increases the overall response rate (ORR) in the patient.

61. A method for treating locally advanced cervical cancer (LACC) in a patient, comprising administering 1500 mg of durvalumab intravenously to the patient every four weeks (Q4W), wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

62. A method for treating locally advanced cervical cancer (LACC) in a patient, comprising administering 500 mg or 750 mg of MEDI5752 intravenously to the patient every three weeks (Q3W), wherein the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

63. The method according to either claim 61 or 62, further comprising administering chemoradiotherapy.

64. The method according to claim 63, wherein the chemoradiotherapy includes simultaneous chemoradiotherapy.

65. The method according to claim 63 or 64, wherein the chemoradiotherapy includes external beam radiation therapy and near-field radiation therapy.

66. The method according to any one of claims 63 to 65, wherein the chemoradiotherapy includes platinum-based chemotherapy.

67. The method according to claim 66, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

68. The method according to any one of claims 63 to 67, wherein durvalumab or MEDI5752 and the chemoradiotherapy are administered simultaneously.

69. The method according to any one of claims 63 to 67, wherein durvalumab or MEDI5752 is administered after the chemoradiotherapy.

70. The method according to any one of claims 61 to 69, wherein the method extends progression-free survival (PFS) in the patient.

71. The method according to any one of claims 61 to 69, wherein the method increases the overall response rate (ORR) in the patient.

72. A combination of durvalumab and chemoradiotherapy for the treatment of locally advanced cervical cancer (LACC) in a patient, wherein 1500 mg of durvalumab is administered intravenously to the patient every four weeks (Q4W), and the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

73. A combination of MEDI5752 and chemoradiotherapy for the treatment of locally advanced cervical cancer (LACC) in a patient, wherein 500 mg or 750 mg of MEDI5752 is administered intravenously to the patient every three weeks (Q3W), and the patient has a tumor area positive (TAP) score of ≥20% for PD-L1 expression.

74. The combination according to claim 72 or 73, wherein the chemoradiotherapy includes simultaneous chemoradiotherapy.

75. The combination according to any one of claims 72 to 74, wherein the chemoradiotherapy includes external beam radiation therapy and close-range radiation therapy.

76. The combination according to any one of claims 72 to 75, wherein the chemoradiotherapy includes platinum-based chemotherapy.

77. The combination according to claim 76, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

78. The combination according to any one of claims 72, 73, or 75-77, wherein durvalumab or MEDI5752 is administered after the chemoradiotherapy.

79. The combination according to any one of claims 72 to 78, wherein the combination extends progression-free survival (PFS) in the patient.

80. The combination according to any one of claims 72 to 78, wherein the combination increases the overall response rate (ORR) in the patient.

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