Methods of Treating Biliary Tract Cancer Using Anti-PD-L1 Antibodies in Combination with Chemotherapy

Abstract

The present disclosure relates to methods of treating biliary tract cancer (BTC) using anti-PD-L1 antibodies in combination with chemotherapy.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating biliary tract cancer (BTC) using anti-PD-L1 antibodies in combination with chemotherapy. [Background technology]

[0002] Biliary tract cancer (BTC), a heterogeneous group of malignant tumors including intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer, is typically diagnosed at an advanced stage where curative surgery is not feasible and has a poor prognosis (Non-Patent Document 1). Despite clinical trials evaluating several targeted therapies including cediranib, erlotinib, cetuximab, panitumumab, ramucirumab, and merestinib (Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6), the first-line standard treatment for advanced disease, gemcitabine and cisplatin chemotherapy, has remained unchanged for the past several decades and is associated with a median overall survival of 11.7 months and a survival rate of approximately 24 months of approximately 15% (Non-Patent Document 7), highlighting the need for new therapies (Non-Patent Document 8; Non-Patent Document 9).

[0003] In addressing the need for improved methods for the clinical management of BTC, the present disclosure provides methods comprising the administration of an anti-PD-L1 antibody in combination with chemotherapy, specifically gemcitabine and cisplatin chemotherapy, as a treatment for patients with advanced biliary tract cancer. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Valle et al., Lancet 397(10272):428-44,2021 [Non-Patent Document 2] Valle et al., 2015 [Non-Patent Document 3] Lee et al., 2012 [Non-Patent Document 4] Malka et al., 2014 [Non-Patent Document 5] Leone et al., 2016 [Non-Patent Document 6] Valle et al.,Lancet Oncol.22(10):1468-82,2021 [Non-Patent Document 7] Valle et al., 2010 [Non-Patent Document 8] Brindley et al., 2021 [Non-Patent Document 9] Boileve et al., 2021 Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides methods of treating biliary tract cancer (BTC) using anti-PD-L1 antibodies in combination with chemotherapy.

[0006] In one aspect, the disclosure herein provides a method of prolonging overall survival in a patient with biliary tract cancer (BTC), comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0007] In another aspect, the disclosure herein provides a method of prolonging progression-free survival in a patient with biliary tract cancer (BTC), comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0008] In a further aspect, the disclosure herein provides a method of treating a patient with biliary tract cancer (BTC), comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0009] These and other features and advantages of the present disclosure will be more fully understood from the following detailed description taken in conjunction with the appended claims, with the understanding that the claims are defined by the references made herein, and not by a specific discussion of the features and advantages described herein. [Brief description of the drawings]

[0010] [Figure 1] A CONSORT diagram is shown. [Diagram 2] TOPAZ-1 study design is shown. [Diagram 3] Durvalumab or placebo plus gemcitabine / cisplatin dosing schedules are shown. [Figure 4] Kaplan-Meier curves for overall survival and progression-free survival in the full analysis set are shown. CI stands for confidence interval, Durva+Gem+Cis stands for durvalumab plus gemcitabine and cisplatin, and Placebo+Gem+Cis stands for placebo plus gemcitabine and cisplatin. [Diagram 5] The Epanechnikov kernel smoothing hazard function is shown below. [Figure 6] Forest plots of overall survival and progression-free survival by subgroup for durvalumab versus placebo in the full analysis set. Circle size is proportional to the number of events observed. Race is defined as patients who identified as Asian or non-Asian without considering geography. Rest of World includes patients enrolled in Europe, North America, and South America. CI represents confidence interval, Durva+Gem+Cis represents durvalumab plus gemcitabine and cisplatin, ECOG = Eastern Cooperative Oncology Group, PD-L1 = programmed cell death ligand 1, Placebo+Gem+Cis represents placebo plus gemcitabine and cisplatin, TAP = tumor area positive (proportion of tumor and / or immune cells with PD-L1 staining at any intensity). [Figure 7]The primary endpoint of overall survival is shown. Overall survival was improved with the addition of durvalumab to gemcitabine and cisplatin. Median overall survival (95%CI) increased from 11.5 to 12.8 months. After 6 months, the difference between the durvalumab plus gemcitabine and cisplatin curve and the placebo plus gemcitabine and cisplatin curve increased; the difference continued to increase over time. The difference in overall survival increased from 6% at 12 months to 10% at 18 months to 15% at 24 months. [Figure 8] Subgroup analysis of overall survival is shown. The additive benefit of durvalumab over gemcitabine and cisplatin was observed across all subgroups. [Figure 9] Overall survival in subgroups according to PD-L1 expression is shown. The additive benefit of durvalumab over gemcitabine and cisplatin was observed across PD-L1 expression. [Figure 10] Tumor area positivity (TAP) scores using the Ventana PD-L1 (SP263) assay are shown. PD-L1 status was tracked on tumor and immune cells to determine the TAP score, which takes into account PD-L1 expression on both tumor and immune cells. The additive benefit of durvalumab over gemcitabine and cisplatin was observed regardless of PD-L1 expression. [Figure 11] Results are shown for the secondary endpoint of progression-free survival (PFS). Median PFS (95% CI) improved from 5.7 to 7.2 months with the addition of durvalumab to gemcitabine and cisplatin. [Figure 12]Results for the secondary endpoint of tumor response ((A) Objective Response Rate (ORR) and (B) DoR for tumor response for durvalumab + GemCis (durvalumab arm) and placebo + GemCis (placebo arm)) are shown. ORR improved from 18.7% in the placebo arm to 26.7% in the durvalumab arm. Median time to response was more rapid (1.6 months) in the durvalumab arm compared to 2.7 months in the placebo arm. More patients remained in response after 9 months (32.6% in the durvalumab arm compared to 25.3% in the placebo arm) and after 12 months (26.1% in the durvalumab arm compared to 15.0% in the placebo arm). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present disclosure relates to methods of treating patients with biliary tract cancer (BTC), comprising administering to the patient an anti-PD-L1 antibody in combination with chemotherapy. The disclosed treatment methods can result in substantial improvements in patient overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, and / or disease control rate.

[0012] The present disclosure also relates to an anti-PD-L1 antibody in combination with platinum-based chemotherapy and / or antimetabolite-based chemotherapy for the treatment of biliary tract cancer. In one embodiment, an anti-PD-L1 antibody in combination with gemcitabine and / or cisplatin for the treatment of biliary tract cancer is provided. In another embodiment, an anti-PD-L1 antibody in combination with platinum-based chemotherapy and / or antimetabolite-based chemotherapy for the treatment of biliary tract cancer is provided, wherein the treatment achieves a substantial improvement in the patient's overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, and / or disease control rate. In another embodiment, an anti-PD-L1 antibody in combination with gemcitabine and / or cisplatin for the treatment of biliary tract cancer is provided, wherein the treatment achieves a substantial improvement in the patient's overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, and / or disease control rate. In a further embodiment, the anti-PD-L1 is durvalumab.

[0013] The present disclosure also relates to the use of an anti-PD-L1 antibody in combination with platinum-based chemotherapy and / or antimetabolite-based chemotherapy in the manufacture of a medicament for treating biliary tract cancer. In one embodiment, an anti-PD-L1 antibody in combination with gemcitabine and / or cisplatin for use in treating biliary tract cancer is provided. In another embodiment, a use of an anti-PD-L1 antibody in combination with platinum-based chemotherapy and / or antimetabolite-based chemotherapy in the manufacture of a medicament for treating biliary tract cancer is provided, wherein the treatment provides a substantial improvement in the patient's overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, and / or disease control rate. In another embodiment, a use of an anti-PD-L1 antibody in combination with gemcitabine and / or cisplatin for use in the manufacture of a medicament for treating biliary tract cancer is provided, wherein the treatment provides a substantial improvement in the patient's overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, and / or disease control rate. In a further embodiment, the anti-PD-L1 is durvalumab.

[0014] It is to be understood that the specific aspects described herein are not limited to the specific embodiments presented and may vary. It will also be understood that the terminology used herein is for the purpose of describing the specific aspects only and is not intended to be limiting unless specifically defined herein. Furthermore, the specific embodiments disclosed herein can be combined with other embodiments disclosed herein without limitation, as will be recognized by those skilled in the art.

[0015] Unless otherwise defined, all scientific and technical terms used herein have the meanings commonly understood by those skilled in the art to which this disclosure belongs. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: 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). The following terms used herein have the meanings ascribed to them unless otherwise specified.

[0016] In this disclosure, "comprises," "comprising," "containing," "having," and the like, may have the meaning ascribed to them in U.S. patent law and may mean "includes," "including," and the like; "consisting essentially of" or "consisting essentially of" may likewise have the meaning ascribed to them in U.S. patent law and is open-ended, allowing for the presence of other things than are recited, but excluding prior art aspects, so long as the basic or novel characteristics of the recited items are not changed by the presence of other things than are recited.

[0017] Unless otherwise stated or clear from context, the term "or" as used herein is understood to be inclusive. Unless otherwise stated or clear from context, the terms "a," "an," and "the" as used herein are understood to be singular or plural.

[0018] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within normal tolerance in the art, for example, within 2 standard deviations of the mean. About can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term about.

[0019] Any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0020] Ranges provided herein are understood to be shorthand for all of the values ​​within that range. For example, the range of 1 to 50 is understood to include any number, combination of numbers, or subranges 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.

[0021] Provided herein is a method of increasing the objective response rate in BTC patients, comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0022] Also provided herein is a method of extending progression-free survival in a BTC patient, comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0023] Also provided herein is a method of treating a patient with BTC, comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0024] As used herein, "biliary tract cancer (BTC)" refers to any gastrointestinal cancer arising from the bile duct (cholangiocarcinoma), gallbladder, or ampulla of Vater (AoV).

[0025] In some embodiments, the biliary tract cancer is unresectable, locally advanced, and / or metastatic.

[0026] The term "unresectable" as used herein refers to a cancer or tumor that cannot be completely removed by surgery. The term "locally advanced" as used herein refers to a cancer that has grown outside the part of the body where it began but has not yet spread to other parts of the body (Stage 3). The term "metastatic" as used herein refers to a cancer that has spread from the part of the body where it began (primary site) to other parts of the body (Stage 4).

[0027] As used herein, "anti-PD-L1 antibody" refers to an antibody or antigen-binding fragment thereof that selectively binds to a PD-L1 polypeptide. Exemplary anti-PD-L1 antibodies are described, for example, in U.S. Patent No. 8,779,108 and U.S. Patent No. 9,493,565, which are incorporated herein by reference. In some embodiments, the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab. In other embodiments, the anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0028] The term "durvalumab" as used herein 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 (wherein durvalumab is referred to as "2.14H9OPT"), which is incorporated herein by reference in its entirety. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to complement components C1q and Fcγ receptors, which are responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Durvalumab can relieve PD-L1-mediated suppression of human T-cell activation in vitro and inhibits tumor growth in xenograft models via a T-cell-dependent mechanism.

[0029] The terms "treat", "treating", "treatment" and the like as generally used herein refer to alleviating, ameliorating, or slowing the progression of a disorder or disease and / or symptoms associated with the disorder or disease. Although not exclusive, it will be recognized that treating a disorder, disease, or condition does not require the complete elimination of the disorder, disease, or condition, or associated symptoms. In certain embodiments related to BTC, "treat", "treating", "treatment" may refer to achieving any one or combination of primary or secondary clinical endpoints.

[0030] The anti-PD-L1 antibodies may provide benefit to the patient while being administered 1-2 times every 3 or 4 weeks. In a further embodiment, the patient is administered additional subsequent doses. The subsequent doses may be administered at various time intervals depending on the patient's age, weight, clinical evaluation, tumor burden, and / or other factors, including the judgment of the attending physician.

[0031] In some embodiments, multiple doses of the anti-PD-L1 antibody are administered to the patient. In some embodiments, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, at least 15 doses, at least 26 doses, or more than at least 20 doses may be administered to the patient. In some embodiments, the anti-PD-L1 antibody is administered over a 2 week treatment period, over a 3 week treatment period, over a 4 week treatment period, over a 6 week treatment period, over an 8 week treatment period, over a 12 week treatment period, over a 24 week treatment period, over a 1 year treatment period, or over a more than 1 year treatment period.

[0032] In some embodiments, the interval between doses may be every 3 weeks (Q3W or q3w). In some embodiments, the interval between doses may be every 4 weeks (Q4W or q4w). In some embodiments, the interval between doses may be every 2 months.

[0033] In some embodiments, the anti-PD-L1 antibody is administered twice over a 21-day treatment cycle (i.e., a 3-week period), with the first dose administered on day 1 of the 21-day cycle and the second dose administered on day 8 of the 21-day cycle. In some embodiments, the treatment cycle may be repeated 1, 2, 3, 4, 5, 6, 7, or 8 times. In some embodiments, the anti-PD-L1 antibody is administered after completion of the last treatment cycle.

[0034] In some embodiments, the anti-PD-L1 antibody is administered following completion of chemotherapy treatment.

[0035] In some embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, which is a fixed dose of 1000-2000 mg. In some embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, which is a fixed dose of 1500 mg. In some embodiments, the patient is administered one or two doses of 1500 mg of anti-PD-L1 antibody every three or four weeks. In some embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, which is about 20 mg / kg. In some embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, which is about 20 mg / kg of anti-PD-L1 antibody every three or four weeks.

[0036] The amount of anti-PD-L1 antibody to be administered to a patient may be adjusted and may depend on various parameters, such as the patient's age, weight, clinical evaluation, tumor burden, and / or other factors, including the judgment of the attending physician.

[0037] In some embodiments, administration of an anti-PD-L1 antibody in accordance with the methods provided herein is via parenteral administration. For example, the anti-PD-L1 antibody can be administered by intravenous infusion or subcutaneous injection. In some embodiments, the administration is by intravenous infusion.

[0038] The treatment methods disclosed herein further comprise chemotherapy. In some embodiments, the chemotherapy comprises one or more platinum-based chemotherapeutic agents. In some embodiments, the one or more platinum-based chemotherapeutic agents are carboplatin, cisplatin, oxaliplatin, or a combination thereof. In some embodiments, the chemotherapy comprises one or more antimetabolite-based chemotherapeutic agents. In some embodiments, the one or more antimetabolite-based chemotherapeutic agents are gemcitabine. In some embodiments, the chemotherapy comprises one or more platinum-based chemotherapeutic agents in combination with one or more antimetabolite-based chemotherapeutic agents. In some embodiments, the chemotherapy comprises cisplatin and gemcitabine. In some embodiments, the patient is administered one or more doses of cisplatin, the dose being about 25 mg / m 2 In some embodiments, the patient is administered one or more doses of gemcitabine, the dose being about 1000 mg / m 2 It is.

[0039] In some embodiments, the anti-PD-L1 antibody is administered simultaneously with the chemotherapy. In some embodiments, the anti-PD-L1 antibody and the chemotherapy are administered within about 3 days of each other. In some embodiments, the anti-PD-L1 antibody and the chemotherapy are administered within about 2 days of each other. In some embodiments, the anti-PD-L1 antibody and the chemotherapy are administered within about 1 day of each other. In some embodiments, the anti-PD-L1 antibody and the chemotherapy are administered simultaneously (e.g., by simultaneous (same day) administration). In some embodiments, the anti-PD-L1 antibody is administered on day 1 of a chemotherapy treatment cycle. In some embodiments, a first dose of the anti-PD-L1 antibody and the chemotherapy are administered on day 1 of a 21 day treatment cycle, and a second dose of the anti-PD-L1 antibody is administered on day 8 of a 21 day treatment cycle.

[0040] In some embodiments, the observed toxicities of treatment with the anti-PD-L1 antibody and chemotherapy combination are similar to those typically seen with chemotherapy or immunotherapy alone.

[0041] In some embodiments, the patient has been previously treated for biliary tract cancer with surgery and / or adjuvant therapy and / or chemotherapy alone. In some embodiments, the patient has not been previously treated for biliary tract cancer. In some embodiments, the patient has been previously treated for biliary tract cancer, and the treatment was not with curative intent. In some embodiments, the patient has been previously treated for biliary tract cancer, and the treatment was with curative intent, but the patient has relapsed disease. In some embodiments, the patient has relapsed disease more than 2 months, 3, 4, 5, 6, 7, 8, 9, or more than 9 months after surgery with curative intent. In some embodiments, the patient has relapsed disease more than 2 months, 3, 4, 5, 6, 7, 8, 9, or more than 9 months after completion of adjuvant therapy.

[0042] In some embodiments, the treatment methods disclosed herein achieve an increase in PFS compared to placebo. In some embodiments, the methods achieve an increase in ORR compared to placebo. In some embodiments, the methods achieve an increase in OS versus placebo.

[0043] Overall survival (OS) refers to the time period starting from the date of treatment to death from any cause. OS may refer to overall survival within a period of, for example, 12 months, 18 months, 24 months, etc. Such periods may be identified, for example, by Kaplan-Meier estimation of overall survival at 24 months, as "OS24," which refers to the number (%) of patients alive at 24 months after the start of treatment.

[0044] Progression-free survival (PFS) refers to the time period starting from the date of treatment to the date of objective disease progression (RECIST 1.1) or death (from any cause in the absence of progression). In some embodiments, the method of the present disclosure achieves an extension of PFS. In some embodiments, the method achieves 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, up to about 5 years).

[0045] Objective response rate (ORR) refers to the number (%) of patients with at least one visit response of complete response (CR) or partial response (PR) by RECIST 1.1.

[0046] Duration of response (DoR) refers to the time from the date of first documented response to the first date of documented progression or death in the absence of disease progression (i.e., date of PFS event or censoring - date of first response + 1).

[0047] Disease control rate (DCR) refers to the proportion of best objective responses of CR, PR, or stable disease (SD) according to RECIST 1.1.

[0048] Patient-reported outcomes (PROs) are a type of clinical outcome assessment. PROs have been used to evaluate the efficacy of treatments in cancer clinical studies. PRO-related assessments are assessed using quality-of-life questionnaires. PROs use direct patient input to identify important symptomatic, functional, and health-related quality of life (HRQoL) burdens experienced by patients with advanced BTC. PRO endpoints are measured using the European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30) and the complementary EORTC-21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Questionnaire (QLQ-BIL21), Common Terminology Criteria for Patient-Reported Outcomes for Adverse Events (PRO CTCAE), Patient Global Impression of Severity (PGIS), and the EuroQoL 5-dimension, 5-level Health State Utility Index (EQ-5D-5L). These questionnaires provide an understanding of the overall impact of treatment benefits and toxicities from the patient's perspective, as well as aid in benefit / risk assessment. The EORTC QLQ-C30 and EORTC QLQ-BIL21 assess symptoms, effects, and the impact of treatment and disease states on HRQoL. EORTC scales include many important BTC signs and effects, such as abdominal pain, fatigue, pruritus, jaundice, loss of appetite, physical function, and insomnia.

[0049] The EORTC QLQ-C30 contains 30 items and assesses HRQoL / health status through nine multi-item scales: five functioning scales (i.e., physical, role, cognitive, emotional, and social), three symptom scales (i.e., fatigue, pain, and nausea and vomiting), and one health / QoL scale. It also includes six single-item symptom / impact scales: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.

[0050] The EORTC QLQ-BIL21 is used as a companion to the EORTC QLQ-C30. It consists of 21 questions: 18 items categorized into 5 scales: symptoms of pain (4 items), symptoms of fatigue (3 items), jaundice (3 items), symptoms of anxiety (4 items), and symptoms of feeding (4 items), plus 3 single-item assessments regarding procedural side effects, difficulties with drainage bags / tubes, and concerns about weight loss.

[0051] The PROs Common Terminology Criteria for Patient-Reported Outcomes Adverse Events (PRO CTCAE), Patient Global Impression of Severity (PGIS), and EuroQoL 5-dimension, 5-level Health State Utility Index (EQ-5D-5L) assess the benefits and risks of a treatment from the patient's perspective.

[0052] PRO-CTCAE evaluates tolerability from a patient perspective. PRO-CTCAE is an item-bank of symptoms. Six different symptomatic adverse events (AEs) are included in PRO-CTCAE.

[0053] The Patient Global Impression of Severity (PGIS) assesses how patients perceive the general severity of their cancer symptoms over the past 7 days. It is a single-item questionnaire in which patients select from response options ranging from "no symptoms" to "very severe."

[0054] The EQ-5D-5L is a questionnaire that provides a simple descriptive profile of health and a single index value for health status for economic evaluation (EuroQol Group, 2015). The EQ-5D-5L questionnaire contains five questions covering five dimensions of health (i.e., mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). Respondents also rate their health today using the EQ visual analog scale (VAS), ranging from 0 (worst imaginable health) to 100 (best imaginable health). EXAMPLES

[0055] Example 1: Efficacy of durvalumab in combination with chemotherapy for patients with first-line advanced biliary tract cancer (TOPAZ-1) overview This was a randomized, double-blind, placebo-controlled, multicenter, global, Phase III study in patients with previously untreated, unresectable, locally advanced, or metastatic BTC that determined the efficacy and safety of first-line treatment with durvalumab in combination with gemcitabine / cisplatin versus placebo in combination with gemcitabine / cisplatin. An overview of the study design is shown in Figure 2.

[0056] Approximately 672 patients with previously untreated, unresectable, locally advanced, or metastatic BTC will be randomized 1:1 to receive one of the following treatments (approximately 336 patients will be randomized to each arm):

[0057] Arm A: durvalumab plus gemcitabine / cisplatin combination therapy. Durvalumab 1500 mg via intravenous (IV) infusion q3w (cisplatin 25 mg / m2) until clinical progression or RECIST 1.1-defined radiological progression (PD) unless there is unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met. 2 and gemcitabine 1000mg / m 2(administered on days 1 and 8 of q3w, respectively) starting in cycle 1 for up to 8 cycles, followed by durvalumab 1500 mg q4w as monotherapy).

[0058] Arm B: Placebo plus gemcitabine / cisplatin. Placebo via IV infusion q3w (cisplatin 25 mg / m 2 and gemcitabine 1000mg / m 2 (administered on days 1 and 8 of q3w, respectively) starting in cycle 1 for up to 8 cycles, followed by placebo monotherapy q4w).

[0059] The primary objective of the study is to confirm the superiority of arm A compared with arm B in terms of overall survival (OS) in first-line advanced BTC patients.

[0060] Randomization will be stratified by disease status (initially unresectable vs. recurrent) and primary tumor site (intrahepatic vs. extrahepatic cholangiocarcinoma vs. gallbladder carcinoma).

[0061] Patients received cisplatin 25 mg / m via IV infusion q3w starting with cycle 1 for up to 8 cycles. 2 and gemcitabine 1000mg / m 2(administered on days 1 and 8 of q3w, respectively) plus durvalumab 1500 mg (arm A) or placebo (arm B). After completion of treatment with gemcitabine / cisplatin, patients will receive 1500 mg durvalumab (arm A) or placebo (arm B) via IV infusion q4w until clinical progression or RECIST 1.1-defined radiological PD, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met (Figure 3). (Note that if a patient's weight drops to <30 kg, the patient must receive a weight-based dose equivalent to 20 mg / kg durvalumab [or placebo] q3w or q4w, after consultation between the investigator and study physician, until weight improves to >30 kg, at which point the patient must begin receiving a fixed dose of durvalumab 1500 mg [or placebo] q3w or q4w.)

[0062] Objectives and Endpoints The primary endpoint of the proposed study is overall survival (OS), defined as the time from the date of randomization to death from any cause. OS is considered the most reliable cancer endpoint in this phase III study, supported by the US Food and Drug Administration and European Medicines Agency guidelines (US Food and Drug Administration, 2007; European Medicines Agency, 2012). OS is considered the most appropriate endpoint if the median overall survival (mOS) is <1 year in patients with advanced BTC receiving gemcitabine and cisplatin (Valle et al., 2010; Okusaka et al., 2010).

[0063] Secondary efficacy endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and patient-reported outcome (PRO) measures. All tumor-related endpoints will be assessed by site investigators according to RECIST 1.1; ORR and DoR will also be assessed by BICR according to RECIST 1.1 for IA-1.

[0064] The objectives and endpoints of the study are outlined in Table 1.

[0065] [Table 1]

[0066] [Table 2]

[0067] Study population The study population included patients aged ≥18 years with previously untreated, unresectable, locally advanced, or metastatic BTC (e.g., intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer). AoV cancer has a distinct genetic profile from other subtypes of BTC (Yachida et al., 2016). To minimize the diversity of the study population, AoV cancer patients were excluded from the study.

[0068] Each patient must meet all of the inclusion criteria for the study and not meet any of the exclusion criteria for the study to be randomized to the study intervention.

[0069] In this protocol, "enrolled" patients are defined as those who have signed an informed consent and received an enrollment number. "Randomized" patients are defined as those who have undergone randomization and received a randomization number.

[0070] Patients who do not meet the entry requirements will be screened as failures. Future approval of protocol deviations from recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be permitted.

[0071] Inclusion criteria Patients are eligible for inclusion in the study only if they meet all of the following inclusion criteria and none of the exclusion criteria.

[0072] Informed consent: 1. Be able to give signed informed consent, which includes compliance with the requirements and restrictions stated in the Informed Consent Form (ICF) and in this protocol. 2. Provide a signed and dated written ICF prior to any required study-specific procedures, sampling, and analyses. 3. Provide signed and dated written informed consent prior to collection of samples for optional genetic analysis.

[0073] age 4. ≥ 18 years of age at screening. For patients < 20 years of age enrolled in Japan, written informed consent must be obtained from the patient and / or their legal representative.

[0074] Patient types and disease characteristics 5. Histologically confirmed, unresectable, advanced, or metastatic adenocarcinoma of the biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma. 6. Patients with previously untreated disease are eligible if it is unresectable or metastatic at the time of initial diagnosis. 7. Patients with disease recurrence >6 months after intended curative surgery and >6 months after completion of adjuvant therapy (chemotherapy and / or radiation), if given, are eligible. 8.World Health Organization (WHO) / ECOG PS 0 or 1 at the time of enrollment. 9. At least one lesion is considered a RECIST 1.1 target lesion (TL) at baseline. 10. Including but not limited to, other anti-CTLA4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, which have not previously been subjected to immune-mediated therapy, excluding therapeutic anti-cancer vaccines. 11. Adequate organ and marrow function as defined below: Hemoglobin ≥ 9.0g / dL. Absolute neutrophil count ≥ 1.5 x 109 / L. ·Platelet count ≥100×109 / L. Serum bilirubin ≤ 2.0 × upper limit of normal (ULN); this does not apply to patients with confirmed Gilbert's syndrome. Any clinically significant biliary obstruction must be resolved prior to randomization. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; for patients with liver metastases, ALT and AST ≤ 5 × ULN Creatinine clearance (CL) >50mL / min calculated per 24-hour urine or by Cockcroft-Gault (using actual body weight): ·male · Creatinine CL (mL / min) = (body weight (kg) × (140-age)) / (72 × serum creatinine (mg / dL)) ·woman: · Creatinine CL (mL / min) = (body weight (kg) x (140-age) x 0.85) / (72 x serum creatinine (mg / dL)) 12. Patients must have a life expectancy of at least 12 weeks at the time of screening.

[0075] body weight 13. Weight >30kg.

[0076] sex 14. Male and / or female.

[0077] others Patients must provide a recent tumor biopsy or available archived unstained tumor tissue sample in sufficient quantity to permit analysis (done ≦3 years prior to screening). The tumor lesion to be used for biopsy must not be the tumor lesion used as a RECIST TL, as long as there are other lesions suitable for biopsy.

[0078] Patients with HBV infection (characterized by positive hepatitis B surface antigen [HBsAg] and / or anti-hepatitis B core antibody (anti-HBc) with detectable HBV deoxyribonucleic acid (DNA) [≥ 10 IU / mL or above the limit of detection at the local laboratory unit]) must receive antiviral therapy prior to randomization at the local implementation unit to ensure adequate viral suppression. Patients must be on antiviral therapy for the duration of the study and for 6 months after the last dose of study treatment. Patients testing positive for anti-HBc with undetectable HBV DNA (< 10 IU / mL or below the limit of detection at the local laboratory unit) should not require antiviral therapy unless HBV DNA exceeds 10 IU / mL or reaches the limit of detection at the local laboratory unit during the course of treatment. Patients with active coinfection with HBV and HCV as manifested by positive anti-HCV antibodies and patients with active coinfection with HBV and hepatitis D virus are not eligible.

[0079] Exclusion criteria Medical Conditions: Ampullary cancer.

[0080] History of allogeneic organ transplant.

[0081] Active or previously documented autoimmune disease or inflammatory disorder (inflammatory bowel disease (e.g., colitis or Crohn's disease), diverticulitis (excluding diverticulosis), systemic lupus erythematosus, sarcoidosis syndrome, or Wegener's syndrome (including granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, and others). The following are exceptions to this criterion:

[0082] Patients with vitiligo or alopecia.

[0083] Patients with stable hypothyroidism on hormone replacement (e.g., secondary to Hashimoto's syndrome).

[0084] Any chronic skin condition not requiring systemic treatment. Patients without active disease within the last 5 years may be included, but only after consultation with the study physician.

[0085] Patients with celiac disease controlled by diet alone.

[0086] Uncontrolled intercurrent illnesses (including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, uncontrolled cardiac arrhythmias, active interstitial lung disease (ILD), severe chronic gastrointestinal symptoms with diarrhea, or psychiatric / social circumstances that limit compliance with study requirements) that substantially increase the risk of incurring an AE or compromise the patient's ability to provide written informed consent.

[0087] History of another primary malignancy: (Other than malignancies treated with curative intent and with no known active disease ≥5 years prior to the first dose of investigational drug (IP) where the potential risk for recurrence is low).

[0088] Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease.

[0089] Adequately treated carcinoma in situ with no evidence of disease.

[0090] History of meningeal carcinomatosis.

[0091] History of active primary immunodeficiency. Active infection, such as tuberculosis (clinical evaluation including medical history, physical examination, and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (HIV 1 / 2 antibody positive).

[0092] Any unresolved toxicity of NCI Common Terminology Criteria for Adverse Events (CTCAE) grade ≧2 from prior anticancer therapy (excluding alopecia, vitiligo, and laboratory values ​​as defined in the inclusion criteria).

[0093] Patients with grade ≥2 neuropathy will be evaluated on an individual basis following consultation by a study physician.

[0094] Patients with irreversible toxicity (not reasonably expected to be exacerbated by treatment with durvalumab) may be included only after consultation with the study investigator.

[0095] Brain metastases or spinal cord compression (including asymptomatic, well-treated disease). Patients with suspected brain metastases at screening must have an MRI (preferred) or CT scan of the brain (each preferably with IV contrast) prior to study enrollment.

[0096] Known allergy or hypersensitivity to any of the study drugs or to any of the study drug excipients.

[0097] Previous Therapy / Concomitant Therapy Any concomitant chemotherapy, IP, biotherapy, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g. hormone replacement therapy) is acceptable.

[0098] Radiation therapy (including palliative radiation) is not permitted prior to the study, with the exception of radiation given in the adjuvant setting.

[0099] Receipt of a live attenuated vaccine within 30 days prior to the first dose of IP. Additionally, patients, if enrolled, may not receive a live vaccine while receiving IP for up to 30 days after the last dose of IP.

[0100] Major surgery (as defined by the investigator) within 28 days prior to the first dose of IP. However, minor surgery of solitary lesions with palliative intent is acceptable if performed more than 14 days prior to the first dose of IP.

[0101] Patients who have received previous immune-mediated therapy, including but not limited to other anti-PD-1, anti-PD-L1, or anti-CTLA-4.

[0102] Previous local treatment, e.g. radioembolization.

[0103] Current or previous use of immunosuppressant medications within 14 days prior to the first dose of durvalumab. The following are exceptions to this criterion:

[0104] Intranasal, inhaled, or topical steroids, or local steroid injections (eg, intra-articular injections).

[0105] Systemic corticosteroids at physiological doses not to exceed 10 mg / day of prednisone or its equivalent.

[0106] Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).

[0107] Previous / concurrent clinical research experience Participation in another clinical study involving IP administration within the last 3 months.

[0108] Previous IP assignments in this study.

[0109] Concurrent enrollment in another clinical study (unless it is an observational (non-interventional) clinical study or the follow-up period of an intervention study).

[0110] Previous randomization or treatment in a previous durvalumab clinical study, regardless of treatment arm assignment.

[0111] Other Exclusions Pregnant or lactating female patients, or male or female patients of reproductive potential who are not willing to use effective birth control, from screening through 180 days after the last dose of gemcitabine / cisplatin or 90 days after the last dose of durvalumab / placebo monotherapy.

[0112] The judgment by the investigator that a patient should not participate in a study if the patient is unlikely to comply with the procedures, restrictions, and requirements of the study.

[0113] Lifestyle Restrictions While patients were receiving IP, and for specified periods before, during and after the procedure, the following restrictions were imposed: Female patients of childbearing potential.

[0114] Female patients of childbearing potential who are not abstinent and who intend to be sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from screening through the total duration of drug treatment and the drug washout period (180 days after the last dose of gemcitabine / cisplatin or 90 days after the last dose of durvalumab / placebo monotherapy). Non-sterilized male partners of female patients of childbearing potential must use spermicide in addition to male condoms throughout this period. Discontinuation of birth control after this point must be discussed with the responsible physician. True abstinence is acceptable if consistent with the patient's preferred usual lifestyle. Cyclic abstinence, cyclic contraception, and withdrawal methods are not acceptable methods of contraception. Female patients must abstain from breastfeeding throughout this period.

[0115] Male patients with a female partner of childbearing potential.

[0116] Non-sterilized male partners who are not abstinent and who intend to be sexually active with female patients of childbearing potential must use spermicide in addition to male condoms from the time of screening and throughout the total duration of drug treatment and drug washout periods (180 days after the last dose of gemcitabine / cisplatin or 90 days after the last dose of durvalumab / placebo monotherapy). True abstinence is acceptable if consistent with the patient's preferred usual lifestyle. Cyclic abstinence, cyclic contraception, and withdrawal methods are not acceptable methods of contraception. Male patients must refrain from sperm donation throughout this period.

[0117] Additionally, female partners (of childbearing potential) of male patients must use highly effective contraception throughout this period.

[0118] A woman of childbearing potential is defined as a woman who has not been surgically sterilized (i.e., by bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) and is not postmenopausal.

[0119] A woman is considered postmenopausal if she has been amenorrhea for 12 months and has no alternative medical cause. The following age-specific requirements apply:

[0120] Women <50 years of age are considered postmenopausal if they have been amenorrhea for >12 months after cessation of exogenous hormone treatment and their luteinizing hormone and follicle-stimulating hormone levels are within the institutional postmenopausal range.

[0121] Women aged ≥50 years are considered postmenopausal if they are amenorrhea for ≥12 months after cessation of all exogenous hormone treatment, have radiation-induced menopause with last menstrual period >1 year ago, or have chemotherapy-induced menopause with last menstrual period >1 year ago.

[0122] Women who have been surgically sterilized (ie, bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) are eligible.

[0123] Highly effective contraceptive methods, defined as those that, when used consistently and correctly, have a low failure rate (i.e., <1% annually). Note that some methods are not considered highly effective (e.g., male or female condoms with or without spermicide; female caps, diaphragms, or sponges with or without spermicide; non-copper-containing intrauterine devices; progestogen-only oral hormonal contraceptive pills whose primary mechanism of action is not the inhibition of ovulation [excluding Serrazetta / Desogestrel, which are considered highly effective]; and triphasic combination oral contraceptives).

[0124] Serum levels of contraceptive hormones can be altered by concomitant use of other drugs, therefore, drug interactions must always be considered when prescribing hormonal sterilization methods; there may be a risk of contraceptive failure or other adverse effects.

[0125] For patients receiving gemcitabine / cisplatin (both arms), local prescribing information regarding contraception, time limits for that precaution, and any additional restrictions for these agents must be followed.

[0126] Combination therapy Investigators must be informed as soon as possible of any medications taken from the time of screening through the end of the clinical treatment phase of the study, including the 90-day follow-up period after the last dose of study drug.

[0127] Any medications or vaccines, including over-the-counter or prescription drugs, vitamins, and / or herbal supplements, that patients are receiving at the time of enrollment or receive during the study must be recorded along with the following: Reason for use: Dates of administration including start and end dates Dosage information including dose, unit, and frequency

[0128] Patients must be instructed not to take any medications, including over-the-counter products, without first consulting with the investigator.

[0129] Restricted, prohibited and permitted concomitant medications are listed in the table below. Also see Dosage Modifications and Toxicity Management Guidelines. For gemcitabine / cisplatin, see local prescribing information for warnings, precautions and contraindications.

[0130] [Table 3]

[0131] [Table 4]

[0132] [Table 5]

[0133] Other combination treatments Medications other than those listed above that are considered essential to the patient's safety and well-being may be given at the investigator's discretion and recorded in the appropriate section of the Case Report Form (CRF).

[0134] Rescue medicines As a result of immune-mediated adverse events (imAEs) that may potentially be experienced by patients with durvalumab, steroids and other immunosuppressive rescue medications must be made available to this patient population. Two products that fall into the immunosuppressant category are infliximab (e.g., for colitis) and mycophenolate (e.g., for hepatitis). These rescue medications must be receipted, controlled, and dispensed by an unblinded pharmacist and stored according to labeled storage conditions (with temperature deviations reported by the unblinded pharmacist accordingly). If required for use as a result of an imAE, the IVRS / IWRS will provide the unblinded pharmacist with the kit identification number to be assigned to the patient at that time. Blinded and unblinded access and notification will be managed using the IVRS / IWRS.

[0135] Dose Modification Dose delays are permitted for durvalumab (or placebo) therapy. However, dose reductions are not permitted for durvalumab (or placebo) therapy.

[0136] Investigators must follow local standard clinical practice regarding dose modifications for gemcitabine / cisplatin.

[0137] For gemcitabine / cisplatin, patients may delay and then resume dosing according to local standard clinical practice. If dosing must be delayed for reasons other than treatment-related toxicity, dosing will occur as soon as practicable. If chemotherapy is discontinued due to treatment-related toxicity, treatment with durvalumab / placebo may be continued at the investigator's discretion once toxicity is grade 2 or less; in that case, durvalumab / placebo monotherapy will be administered q4w.

[0138] During the first 8 cycles of durvalumab or placebo in combination with gemcitabine / cisplatin, if durvalumab or placebo must be discontinued due to durvalumab- or placebo-related toxicity, patients must complete a Treatment Interruption Visit and enter the follow-up period. Treatment with gemcitabine / cisplatin may be continued at the investigator's discretion during the follow-up period and must be reported as subsequent anticancer treatment in the eCRF. Subsequent anticancer treatment must be maintained until toxicity is grade 2 or less.

[0139] Suspension of treatment and withdrawal of subjects Discontinuation of study treatment An individual patient will not receive any further study treatment (durvalumab, placebo, or gemcitabine / cisplatin) if any of the following occurs in that patient:

[0140] Withdrawal of consent from further treatment with IP. Patients are free to discontinue treatment at any time without affecting further treatment. Patients who discontinue treatment are usually expected to continue participating in the study (e.g., for safety and survival follow-up) unless they explicitly withdraw consent for all further participation in any study procedures and evaluations.

[0141] Any AE that meets the criteria for discontinuation as defined in the Dose Modification and Toxicity Management Guidelines or as defined in the local prescribing information for gemcitabine / cisplatin. Note: Patients who permanently discontinue treatment with durvalumab or placebo for durvalumab / placebo-related toxicity must complete a Treatment Discontinuation Visit and enter the follow-up period. If this occurs while the patient is receiving SOC (e.g., cycles 1-8), treatment with gemcitabine / cisplatin may continue for the duration of the follow-up period at the investigator's discretion as described herein.

[0142] Pregnancy or intention to become pregnant. Non-compliance with the study protocol (e.g., refusal to adhere to scheduled visits) that, in the investigator's opinion, warranted withdrawal of treatment by IP.

[0143] Initiation of alternative anticancer treatments, including other agents under investigation.

[0144] Efficacy assessment This study will evaluate the primary endpoint of OS. Secondary efficacy endpoints of PFS, ORR, DoR, and DCR will be derived using investigator RECIST 1.1 assessment; ORR and DoR will also be assessed by BICR according to RECIST 1.1 for IA-1. PRO-related assessments will be assessed using quality of life questionnaires.

[0145] Baseline RECIST 1.1 assessment (selection of TL and floating target lesions) must be performed on images from a CT scan (preferred) or MRI scan (each, preferably with IV contrast) of the chest, abdomen (including whole liver and both adrenals), and pelvis obtained no earlier than 28 days prior to the date of randomization, and ideally as close as possible to and prior to the date of randomization. Additional dissections must be imaged based on individual patient signs and symptoms at baseline and follow-up. It is important to track the tumor assessment schedule as closely as possible. If an unscheduled assessment is performed (e.g., to investigate clinical signs / signs of progression), every attempt should be made to perform a subsequent assessment at the next regularly scheduled visit. Follow-up scans collected after RECIST 1.1-defined radiological PD should be performed preferably at the next (and no later than the next) scheduled imaging visit and no later than 4 weeks after the previous assessment of PD; this follow-up scan will be evaluated using the criteria outlined in Appendix A.

[0146] Survival assessment For patients not yet in long-term follow-up (i.e., all China cohort patients), survival assessments should be made every 2 months after treatment discontinuation. Patients who have discontinued treatment and are in long-term follow-up (after the first FA DCO) should continue to have survival assessments every 3 months during long-term follow-up. Survival information may be obtained via telephone contact with the patient or their family, or by contact with the patient's current physician. After treatment discontinuation, details of initial and subsequent cancer-related treatment will be collected.

[0147] In addition, patients on treatment or on survival follow-up will be contacted after DCO for interim, final (i.e., IA-1, IA-2, and FA), and additional exploratory long-term OS analyses to provide complete survival data. These contacts should usually be within 7 days of DCO.

[0148] Clinical Outcome Assessment Clinical outcome assessments are assessments of clinical outcomes made through reports by clinicians, patients, or non-clinical observers, or through performance-based assessments (FDA-NIH Biomarker Working Group, 2016). Clinical outcome assessments may be used in clinical studies to provide direct or indirect evidence of treatment benefit. PROs are a type of clinical outcome assessment. PROs are an umbrella term that refers to all outcomes and symptoms that are directly reported by patients. PROs can be important in evaluating the effectiveness of study treatments in clinical studies and aid in understanding benefit / risk assessments (Kluetz et al., 2018). The following PROs will be administered in this study: EORTC-QLQ-C30, EORTC-QLQ-BIL21, PRO-CTCAE, PGIS, and EQ-5D-5L. Each is described below. PROs will be translated into the language of the country in which they are administered, with the exception of PRO-CTCAE, which will only be administered in the language if a linguistically validated version is available.

[0149] EORTC QLQ-C30 and EORTC QLQ-BIL21 The EORTC-QLQ-C30 and EORTC QLQ-BIL21 are chosen to assess symptoms, effects, and the impact of treatment and disease states on HRQoL. The EORTC scales include many important BTC symptoms and effects, such as abdominal pain, fatigue, pruritus, jaundice, loss of appetite, physical function, and insomnia.

[0150] The EORTC QLQ-C30 contains 30 items and assesses HRQoL / health status through nine multi-item scales: five functioning scales (i.e., physical, role, cognitive, emotional, and social), three symptom scales (i.e., fatigue, pain, and nausea and vomiting), and one health / QoL scale. It also includes six single-item symptom / impact scales: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties (Aaronson et al., 1993).

[0151] The EORTC QLQ-BIL21 was developed to measure QoL in patients with BTC. It is used as a companion to the EORTC QLQ-C30. The EORTC QLQ-BIL21 consists of 21 questions: 18 items categorized into 5 scales, which are symptoms of pain (4 items), symptoms of fatigue (3 items), jaundice (3 items), symptoms of anxiety (4 items), and symptoms of feeding (4 items), plus 3 single-item assessments related to procedural side effects, difficulties with drainage bags / tubes, and concerns about weight loss.

[0152] The EORTC QLQ-BIL21 has evidence of content validity in patients with BTC. It was developed based on a literature review, in-depth patient interviews, and healthcare provider interviews specific to the BTC population (Friend et al., 2011). Its measurement properties have also been tested in BTC populations, including good evidence of internal consistency reliability, test-retest reliability (reproducibility), and construct validity (Kaup-Robberts et al., 2016).

[0153] PRO-CTCAE PRO-CTCAE includes addressing tolerability from a patient perspective. It was developed by the National Cancer Institute (NCI). It was developed with the recognition that collecting treatment-related symptom data directly from patients could improve accuracy and efficiency. It was based on findings from multiple studies demonstrating that physicians and nurses underestimate the occurrence, frequency, and severity associated with treatment compared to patients' assessments (Basch et al., 2009; Litwin et al., 1998; Sprangers and Aaronson, 1992). PRO-CTCAE is an item-bank of symptoms, and the items have undergone extensive qualitative review between experts and patients. To date, 78 symptoms of CTCAE have been identified as applicable for patient reporting, although not all items are administered in any one clinical study. Six different symptomatic AEs were selected for PRO-CTCAE based on the available safety reports of durvalumab and gemcitabine / cisplatin. Symptomatic AEs, which are not typically included in the EORTC, were prioritized by PRO-CTCAE to reduce patient burden as per published recommendations ( Trask et al., 2018 ). PRO-CTCAE will only be administered in languages ​​for which a linguistically validated version exists.

[0154] PGIS A PGIS item is included to assess how the patient perceives the overall severity of their cancer symptoms over the past 7 days. This is a single-item questionnaire in which patients select from response options ranging from "no symptoms" to "very severe."

[0155] EQ-5D-5L The EQ-5D-5L, developed by the EuroQoL Group, is a generic questionnaire that provides a simple descriptive profile of health and a single index value for health status for economic evaluation (EuroQol Group, 2015). The EQ-5D-5L questionnaire contains five questions covering five dimensions of health (i.e., mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). Respondents also rate their health today using the EQ visual analog scale (VAS), ranging from 0 (worst imaginable health) to 100 (best imaginable health).

[0156] Disease-specific tumor marker samples As part of the routine safety blood samples, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA-19-9) assessments will be performed. It is important to follow the assessment schedule as closely as possible. Elevations in CEA or CA-19-9 alone are not sufficient to declare progression and discontinue treatment.

[0157] Progression events must be defined by radiographic evidence of progression according to RECIST 1.1.

[0158] Further evaluation of CEA and CA-19-9 after radiological progression is at the discretion of the investigator according to local clinical practice.

[0159] Exploratory genetic testing The buffy coat layer obtained during plasma isolation may be retained and analyzed for germline mutations and / or for microsatellite instability (MSI) / tumor mutation burden (TMB) assessment in accordance with local regulations to more accurately identify tumor-specific mutations.

[0160] Biomarkers Tissue samples will be obtained from all patients screened.

[0161] Pretreatment tumor PD-L1 expression will be assessed (retrospectively) in all randomized patients. Data will be compared between arms to determine if baseline PD-L1 status is predictive and / or predictive of outcomes associated with Arm A vs. Arm B. Baseline tumor requirements are briefly described herein.

[0162] Based on tissue availability, additional exploratory biomarkers can be evaluated as described herein.

[0163] Results will allow biomarker data from other durvalumab studies to be pooled to assess biological response across endpoints and to compare results in monotherapy versus combination settings.

[0164] PD-L1 expression assessment The Ventana PD-L1 IHC assay will be used to determine PD-L1 status in tumor samples.

[0165] Exploratory biomarkers Blood and tumor samples will be obtained for exploratory biomarker analysis.

[0166] Baseline measurements and / or changes in measurements from baseline in samples during treatment will be correlated with outcome and / or drug treatment. Samples will be obtained from patients randomized to each treatment arm. Comparisons will be made between baseline measures to determine if a biomarker (or combination of markers) is predictive or predictive of outcome.

[0167] Microsatellite instability (MSI) and tumor mutation burden (TMB) Tumor tissue remaining after PD-L1 testing may be retrospectively analyzed for microsatellite instability (MSI) using next-generation sequencing (NGS)-based methods, such as whole exome sequencing (WES) or targeted NGS assays. MSI-H / MSS status and TMB will be determined based on MSI events or somatic variants detected in tumor sequence data and correlated with efficacy as an exploratory objective. Blood-based MSI or TMB testing may also be performed in cases of insufficient tissue material, failed tissue-based MSI testing, or for evaluation of blood-based MSI / TMB by clinical outcome and other biomarkers. Matched standard DNA obtained from the buffy coat layer collected during plasma isolation may be used to identify tumor-specific mutations for MSI / TMB evaluation. Incorporation of matched normal DNA in mutation analysis may also help to more accurately identify tumor-specific mutations in heterogeneous tumor cell populations, thereby reducing or preventing unintentional inclusion of standard inherited germline mutations in the final analysis or study report.

[0168] In cases where NGS-based MSI testing is not feasible or fails, MMR testing by IHC or similar methods will be performed.

[0169] Tumor microenvironment biomarkers Based on tissue availability, a panel of additional immune-related markers expressed in TILs or tumor cells may be assessed using immunohistochemistry (IHC), gene expression profiling, or other technically feasible methods. Markers of particular interest include, but are not limited to, CD8, FOXP3, CD68, CD3, CD73, NKp46, CXCL9, and LAG3.

[0170] Other tissue-based approaches may be performed, including but not limited to neoantigen prediction, T cell receptor clonality assessment, molecular profiling, and / or somatic variant detection methodologies. Note: This analysis will not be performed in China.

[0171] Whole Blood Gene Expression (PaxGene RNA) Whole blood samples will be obtained for RNA analysis. Total RNA will be prepared for quantification of RNA, microRNA, and / or other non-coding RNA using reverse transcription quantitative polymerase chain reaction, microarray, sequencing, or other techniques. The focus will likely be on expression of immunomodulatory genes. Correlation during treatment with baseline and / or outcome data will be completed for the selection of predictive candidate markers with the goal of identifying expression thresholds useful for identifying patients likely to benefit. These samples may also be used for other molecular analyses of features associated with immune response, such as, but not limited to, T cell receptor clonality and HLA type. Note: This sample will not be collected in China.

[0172] Soluble factors - plasma Blood samples will be collected at multiple time points for analysis of circulating factors such as circulating tumor deoxyribonucleic acid (ctDNA) in plasma. Analysis may include, but is not limited to, evaluation of baseline sensitivity mutations to treatment and correlation with clinical outcome, changes in ctDNA levels and variant frequency, and potentially minimal residual disease. Plasma may also be evaluated for relevant cytokines, chemokines, and other soluble biomarkers.

[0173] The buffy coat layer obtained during the plasma isolation process of the baseline sample may be retained and analyzed according to local regulations. DNA isolated from the buffy coat will be used as a patient-specific normal DNA standard to determine whether the mutations identified in the ctDNA or tumor mutation analysis are tumor-specific (somatic). Note: This analysis will not be performed in China.

[0174] Serum samples for biomarkers Serum will be obtained to investigate the expression of cytokines and chemokines, including but not limited to IFN-γ, interleukin 18, CXCL9, and CXCL10. Similarly, the concentration of a number of IC ligands, receptors, or other soluble factors may be evaluated. Proteins of special interest include CTLA-4, PD-1, PD-L1, B7-1, B7-2, and IL6R. In addition, the serum proteome may be investigated using mass spectrometry-based or similar techniques. Circulating exosomes may also be isolated from serum to assess exosomal RNA, DNA, and / or protein content. Note: This sample will not be collected in China.

[0175] Outcome measures for analysis statistical methods The primary objective of this study is to confirm the superiority of arm A compared with arm B in terms of OS in patients with advanced BTC.

[0176] The primary endpoint, OS, was defined as the time from the date of randomization to death from any cause. Secondary efficacy endpoints included progression-free survival (PFS), ORR, duration of response (DoR), disease control rate (DCR), and PRO measures.

[0177] The Full Analysis Set (FAS) will include all patients who were randomized. The FAS will be used for all efficacy analyses in which PROs are included. Treatment groups will be compared based on the study treatment to which they were randomized, regardless of the treatment they actually received. Patients who were randomized but did not continue to receive study treatment will be included in analyses with the treatment group to which they were randomized.

[0178] The OS improvement hypothesis will be tested if: Approximately 397 OS events occurred across Arm A and Arm B (59% mature) Interim Analysis 2 (IA-2); and Approximately 496 OS events occurred across arm A and arm B (74% mature) final analysis (FA).

[0179] The primary analysis of OS will be based on the log-rank test for the interim analysis and the Fleming-Harrington (FH)(0, 1) test for the final analysis. A sensitivity analysis using the log-rank test will also be performed at the final analysis. With a net mean OS hazard ratio (HR) of 0.745, approximately 496 OS events would provide 90% power to demonstrate statistical significance at the 4.20% level (using a two-sided log-rank test), allowing one interim analysis for clinical activity assessed by ORR and DoR, and one interim analysis for the initial test of superiority in improved OS in approximately 80% of the target events. The minimum treatment difference that could be statistically significant in FA is a mean HR of 0.833 using the log-rank test. Assuming a recruitment period of 21 months and a minimum follow-up period of 19 months, this analysis is expected to be performed approximately 40 months after the first patient is randomized. With the log-rank test for the second interim analysis and FH(0, 1) as the final analysis, the overall power is at least 86% under the various scenarios considered.

[0180] Two interim analyses and one FA are planned to evaluate efficacy: IA-1: The objective of IA-1 is to evaluate clinical activity. ORR and DoR will be summarized to support the initial enrollment of durvalumab when administered in combination with gemcitabine / cisplatin. Summaries will be performed for investigator assessment and for blinded independent central review (BICR) assessment according to RECIST 1.1. The planned data cut-off (DCO) for IA-1 will occur when at least 200 patients have had the opportunity to be followed for at least 32 weeks or the last patient has been randomized into the global cohort (whichever comes later). The analysis set will include all randomized patients with an opportunity for at least 32 weeks of follow-up at the time of the IA-1 DCO (i.e., randomized ≥ 32 weeks prior to the IA-1 DCO).

[0181] Based on enrollment prerequisites, this is expected to occur approximately 21 months after randomization of the first patient.

[0182] IA-2: The second interim analysis will test for early superiority of the durvalumab regimen compared to control. This analysis will be performed when approximately 397 OS events have been observed in the study (59% maturity or 80% informative fraction for the log-rank test) with 75% power. Based on enrollment prerequisites, this is expected to occur approximately 31 months after randomization of the first patient.

[0183] IA-2 will evaluate the efficacy of Arm A compared to Arm B with respect to OS (primary objective). OS will be analyzed using a stratified log-rank test (stratified by disease status and primary tumor location). Treatment effects will be estimated by HR, 95% confidence intervals (CI), and p-values.

[0184] A small alpha consumption of 0.001 (0.1%) will be assigned to IA-1. Strong control of the family-wise error rate (FWER) at the remaining 4.9% level (two-sided) across the studies of OS and PFS endpoints will be achieved by a combined approach of alpha allocation to OS analysis (IA-2 and FA) via alpha consumption functions and hierarchical testing procedures; i.e., PFS will be tested only if OS meets statistical significance in IA-2 or FA (Glimm et al., 2010). IA-2 will be performed for OS when approximately 397 of 496 expected OS events have occurred (i.e., 80% information fraction for the log-rank test). Using the Lan-DeMets consumption function that approximates the O'Brien-Fleming bounds, two-sided significance levels of 0.0238 and 0.0420 will be fitted to OS IA-2 and FA, respectively, using the log-rank test (Lan and DeMets, 1983). The significance level of the FH(0, 1) test in the final analysis will be determined based on the correlation between the intermediate and final data (Tsiatis, 1982).

[0185] PFS will be formally tested using the PFS information collected up to each DCO if OS meets statistical significance at DCO (IA-2 or FA). The significance level for PFS at IA-2 and FA will be derived based on an alpha consumption function approximating the Pocock bound, which tightly controls type I error at the 0.049 level (2-sided). Given that approximately 506 PFS events and 590 PFS events are available at the time of each PFS analysis, PFS testing will be performed at a 2-sided significance level of 0.0444 and 0.0236 at IA-2 and FA, respectively, based on the log-rank test. Since the timing of DCO will be determined based on the number of OS events, the nominal significance level for the PFS analysis may be adjusted for the actual information fraction for PFS at IA-2 compared to FA.

[0186] Safety data are summarized narratively and not formally analyzed.

[0187] Additional exploratory overall survival analyses will be performed using long-term follow-up survival data, which may be collected for up to approximately four years after the last patient randomization in the global cohort.

[0188] Analytical population The definition of the analysis sets for each outcome variable is described in Table 4 .

[0189] [Table 6]

[0190] AE adverse events; DoR duration of response; ORR objective response rate; OS overall survival; PFS progression-free survival; PK pharmacokinetics; PRO patient-reported outcomes.

[0191] Complete Analysis Set The FAS will include all patients who were randomized. The FAS will be used for all efficacy analyses in which PROs are included. Treatment groups will be compared based on the study treatment to which they were randomized, regardless of the treatment they actually received. Patients who were randomized but did not continue to receive study treatment will be included in analyses with the treatment group to which they were randomized.

[0192] The analysis for ORR will be based on patients in the FAS with measurable disease at baseline. The analysis for DoR will be based on patients in the FAS who achieved an objective response.

[0193] Safety Analysis Set The SAS will consist of all patients who received at least one dose of study treatment. Safety data will not be formally analyzed but will be summarized descriptively using the SAS according to treatment received; i.e., mistreated patients (e.g., patients randomized to treatment A but actually given treatment B) will be summarized according to the treatment actually received.

[0194] Pharmacokinetic Analysis Set All patients who received at least one dose of durvalumab according to the protocol for which any post-dose data are available and who do not violate or deviate from the protocol in a manner that would significantly affect the PK analysis will be included in the PK analysis set. The population will be defined by the study investigator, pharmacokineticist, and statistician prior to any analyses to be performed.

[0195] ADA Analysis Set The ADA analysis set will include all subjects with a non-missing baseline ADA and at least one non-missing post-baseline ADA result. All primary ADA analyses will be based on the ADA analysis set.

[0196] Safety assessment For change from baseline summaries of vital signs, laboratory data, ECG, and physical examination, baseline values ​​will be the most recent results obtained prior to the start of study treatment.

[0197] QTcF will be derived during the creation of the reporting database using the reported ECG values ​​(RR and QT) using the following formula: QTcF=QT / RR 1 / 3 where RR is seconds.

[0198] Corrected calcium products will be derived during generation of the reporting database using the following formula: Corrected calcium (mmol / L) = total calcium (mmol / L) + ([40-albumin (G / L)] × 0.02)

[0199] The denominator used for the laboratory summary only includes evaluable patients, ie, patients with sufficient data for a possible abnormality.

[0200] for example:

[0201] If the CTCAE criteria involve change from baseline, evaluable patients will have pre-dose and at least one post-dose value recorded.

[0202] If the CTCAE criteria do not consider change from baseline to be evaluable, patients only need to have post-one dose values ​​recorded.

[0203] For vital signs data, the denominator should include only patients for whom data was recorded.

[0204] Calculation or derivation of patient-reported outcome variables EORTC QLQ-C30 The EORTC QLQ-C30 consists of 30 questions that can be combined to yield five functioning scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea / vomiting), and a health / QoL scale. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 scoring manual (Fayers et al., 2001). Outcome variables consisting of scores from 0 to 100 will be derived for each of the symptom scales, each of the functioning scales, and the global health status scale in the EORTC QLQ-C30 according to the EORTC QLQ-C30 scoring manual. Higher scores on the global health status and functioning scales indicate better health status / functioning, whereas higher scores on the symptom scales represent greater symptom severity. For each subscale, if <50% of the subscale items are missing, the subscale score will be divided by the number of non-missing items and multiplied by the total number of items for the subscale (Fayers et al., 2001). If at least 50% of the items are missing, the subscale will be treated as missing. A single missing item will be treated as missing. Reasons for any missing questionnaires will be identified and recorded.

[0205] Definition of clinically meaningful change - visit response and best overall response The health / QoL scale includes two items derived from the EORTC QLQ-C30: “How would you rate your overall health during the past week?” (item 29) and “How would you rate your overall QoL during the past week?” (item 30). The definition of a clinically meaningful change in score compared to baseline will be assessed. A clinically meaningful change is defined as an absolute change in score from baseline of ≥10 on the scale derived from the EORTC QLQ-C30 (Osoba et al., 1998). For example, a clinically meaningful improvement in physical function (assessed by the EORTC QLQ-C30) is defined as an increase in score from baseline of ≥10, whereas a clinically meaningful deterioration is defined as a decrease in score from baseline of ≥10. At each post-baseline assessment, changes in health / QoL, symptoms, and function scores from baseline will be categorized as improved, unchanged, or worsened, as shown in Table 5.

[0206] [Table 7]

[0207] A patient's best overall response in symptoms, function, or health / QoL will be derived as the best response the patient achieved based on evaluable PRO data collected during the study period. The criteria in Table 6 will be used to assign best response in symptoms, function, or health / QoL.

[0208] [Table 8]

[0209] Time to deterioration of HRQoL or function Time to QoL or functional deterioration is defined as the time from the date of randomization to the date of the first clinically meaningful deterioration confirmed at a subsequent visit (if not the patient's last available assessment) or death (from any cause) in the absence of clinically meaningful deterioration, regardless of whether the patient discontinues study treatment or receives another anticancer treatment prior to health / QoL or functional deterioration. Death will be included as an event only if it occurs within 2 PRO assessment visits from the last available PRO assessment. Sensitivity analyses will be performed and deaths will be censored at the date of death.

[0210] Patients whose health / QoL or function (measured by EORTC QLQ-C30) did not show a clinically meaningful deterioration and who were alive at the time of analysis will be censored at the time of the last PRO assessment, where health / QoL or function can be assessed, or if health / QoL or function deteriorates or the patient dies after missing two or more PRO assessment visits, the patient will be censored at the time of the last PRO assessment, where health / QoL or function can be assessed before two missed visits.

[0211] Populations for analyses of health status / QoL or time to functional deterioration will include the subset of FAS with a baseline score ≧10.

[0212] Symptom improvement rate Symptom response (improved, worsened, and unchanged) by visit and best overall response will be presented by treatment group according to Table 6. Symptom improvement rate is defined as the number (%) of patients with a best overall score response of "improved" symptoms.

[0213] The denominator consisted of the subset of FAS with a baseline symptom score ≥10.

[0214] Health / QoL or functional improvement rate Health / QoL or function improvement rate is defined as the number (%) of patients with a best overall response of "improvement" in QoL or function.

[0215] The denominator consists of the subset of FAS with a baseline health / QoL or function score ≦90.

[0216] EORTC QLQ-BIL21 The QLQ-BIL21 is an EORTC-derived BTC-specific module that contains 21 questions to assess BTC symptoms. The module includes five multi-item domain scales and three single-item scales. For all items and scales, higher scores indicate increased symptomatology / more problems.

[0217] The scoring approach for the QLQ-BIL21 is in principle identical to that for the EORTC QLQ-C30 symptom scale / single items. Similar to the EORTC QLQ-C30 symptom scale, higher scores represent greater symptom severity.

[0218] Definition of clinically meaningful change - visit response and best overall response Changes in scores compared to baseline will be assessed. A clinically meaningful change will be defined as an absolute change in score from baseline of ≧10 for scales / items derived from QLQ-BIL21. For example, a clinically meaningful worsening or pain (assessed by QLQ-BIL21) will be defined as an increase in score from baseline of ≧10. At each post-baseline assessment, the change in symptom scores from baseline will be categorized as improved, unchanged, or worse, as shown in Table 7. The patient's best overall response in symptoms will be derived as the best response the patient achieved based on the evaluable PRO data collected during the study period. The criteria in Table 6 will be used to assign best response in symptom scores.

[0219] [Table 9]

[0220] Time to worsening of symptoms For each symptom scale / item in QLQ-BIL21, time to symptom worsening is defined as the time from randomization to the date of the first clinically meaningful symptom worsening confirmed at a subsequent visit (if not the patient's last available assessment) or death (from any cause) in the absence of clinically meaningful symptom worsening, regardless of whether the patient discontinues study treatment or receives another anticancer treatment prior to symptom worsening. Only deaths occurring within 2 PRO assessment visits from the last available PRO assessment will be included as events. Sensitivity analyses will be performed and deaths will be censored at the date of death.

[0221] Patients whose symptoms (measured by QLQ-BIL21) did not show clinically meaningful worsening and who were alive at the time of analysis will be censored at the time of the last PRO assessment, where symptoms can be assessed, or if symptoms progress or the patient dies after missing two or more PRO assessment visits, the patient will be censored at the time of the last PRO assessment, where symptoms can be assessed before two missed visits.

[0222] The population for analysis of time to symptom deterioration will include the subset of FAS with a baseline score ≦90.

[0223] EQ-5D-5L The EQ-5D-5L questionnaire includes six questions covering five dimensions of health (e.g., mobility, self-care, usual activities, pain / discomfort, and anxiety / depression) and a VAS. For each dimension, respondents choose which statement best describes their health that day from five possible options of increasing levels of severity (e.g., no problems, slight problems, moderate problems, severe problems, and incapacitating / extreme problems).

[0224] A unique EuroQoL 5-dimension (EQ-5D) health state (called the EQ-5D-5L profile) is reported as a 5-digit code of 3125 possible health states based on these responses. For example, state 11111 indicates no problems with respect to any of the five dimensions. This EQ-5D-5L profile will be converted into a weighted health state utility value, called the EQ-5D index, by fitting a country-specific formula to the profile, which represents the comparative value of the health state. The formula is based on a set of national assessments derived from the general population, with the base case being the UK Outlook. If the assessment set is not publicly available, the EQ-5D-5L profile will be converted into an EQ-5D index using the crosswalk algorithm (van Hout et al., 2012).

[0225] The evaluable population includes the subset of the FAS with a baseline EQ-5D-5L assessment.

[0226] PGIS PGIS data will be presented using summary and descriptive statistics. In addition, PGIS data will be further explored to support anchor-based analysis of clinically meaningful changes complemented by empirical cumulative distribution function and probability density function curves.

[0227] PRO-CTCAE PRO-CTCAE consists of nominal categories (e.g., in a questionnaire, “nothing” to “very severe” for some items).

[0228] Calculation or derivation of pharmacokinetic variables Population pharmacokinetic and exposure-response / safety analyses Population PK models will be developed using a nonlinear mixed-effects modeling approach. The effects of physiologically relevant patient characteristics (covariates) and disease on PK will be evaluated. The relationship between PK exposure and effects on safety and efficacy endpoints will be evaluated. Results of such analyses will be reported in separate reports. PK, demographic, safety, and efficacy data collected in this study may also be combined with similar data from other studies and explored using population PK and / or exposure-response / safety analyses.

[0229] Pharmacokinetic analysis Non-compartmental analysis will not be performed to calculate PK parameters due to sparse sampling. Durvalumab serum concentration data and summary statistics will be tabulated. Individual mean serum concentration-time profiles will be generated. Samples below the lower limit of quantification will be treated as missing in the summary statistics.

[0230] Immunogenicity analysis Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of patients developing detectable ADA to durvalumab. Immunogenicity titers and presence of neutralizing ADA will be reported for samples confirmed positive for the presence of ADA. The effect of immunogenicity on PK, efficacy, and safety will be evaluated if data permits.

[0231] Calculation or derivation of biomarker variables PD-L1 status, as defined in the secondary objectives, will be assessed for evaluable patients within each cohort.

[0232] Calculation or derivation of pharmacogenetic variables In the case of genetic data, only the date the patient gave consent to participate in the genetic study and the date the blood sample was taken from the patient will be recorded in the eCRF and in the database.

[0233] Primary endpoint: Overall survival OS in FAS will be analyzed using a stratified log-rank test, adjusting for disease status (initially unresectable or recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder carcinoma) in IA-2, and using a stratified FH(0, 1) test in FA. The effect in arm A versus arm B will be estimated by HR with its corresponding CI and p-value. Kaplan-Meier plots will be presented by treatment arm. A summary of the number and percentage of patients who died, those still alive and in follow-up, those lost to follow-up, and those who withdrew consent will be provided along with mOS by treatment.

[0234] Cox proportional hazards models will be used to estimate HRs and corresponding CIs based on long-term follow-up OS data. KM plots of overall survival will also be presented by treatment arm. Additional analyses may be performed if appropriate.

[0235] Sensitivity analysis The proportionality assumption will be assessed first by examining a plot of the complementary log-log(time to event) versus log(time) and, if this is unsettling, by fitting a time-dependent covariate to assess the extent to which this represents random variation. If a lack of proportionality is evident, the variation in treatment effect will be explained by showing piecewise HRs calculated over well-defined time periods. In such circumstances, the HRs can still be interpreted meaningfully as average HRs over time, unless there is extensive crossing of survival curves. If a lack of proportionality is found, this may be the result of a covarying unit treatment interaction, which will be explored. In addition, Kaplan-Meier (KM) curves will also aid in understanding the treatment benefit, along with landmark analyses (e.g., 1-year OS rates).

[0236] Attrition bias will be investigated by KM plots of time to censoring using OS data from the primary analysis, where the censoring indicator for the OS analysis is cancelled.

[0237] Cox proportional hazards modeling will be used to assess the effect of covariates on HR estimates. Models including treatment and stratification factors will be constructed to ensure that any output from Cox modeling is likely to be consistent with the results of stratified log-rank tests.

[0238] Also, using the approach of Gail and Simon, 1985, interactions between treatments and stratification factors will be tested to rule out any qualitative interactions.

[0239] At the time of FA, OS was adjusted for disease status (initially unresectable or recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder carcinoma) using a stratified log-rank test to ensure that any output from the stratified log-rank test is likely consistent with the FH(0,1) test method.

[0240] Delayed effects, i.e., delayed separation of survival curves, are expected in immunotherapy trials and have been noted in most IO+chemotherapy vs. chemotherapy phase 3 trials reported to date. The strategy of using the log-rank test at interim analyses and the FH(0, 1) test at final analyses provides robust statistical power and inference under various scenarios, including proportional hazards and delayed effects. The log-rank test is the most powerful approach in proportional hazard scenarios, and the FH(0, 1) is more powerful in delayed effect scenarios. In addition, at the time of final analyses, data maturity is high, and consequently, the weighting function of the FH(0, 1) test is stable.

[0241] Subgroup analysis Subgroup analyses will be performed comparing OS between Arm A vs. Arm B in the following subgroups of the FAS, including but not limited to: Gender (male vs. female) Age at randomization (<65 vs. ≥65 years) PD-L1 status Disease status (initially unresectable vs. recurrent) Primary tumor location (intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancer) Race (Asian vs. non-Asian)

[0242] Other baseline variables may also be evaluated if there is clinical justification or imbalances are observed between treatment arms. The purpose of the subgroup analysis is to evaluate the consistency of treatment effects across predictive and / or prognostic factors. Forest plots will be presented.

[0243] In addition, for each subgroup, HR (Arm A:Arm B) and 95% CI will be calculated from the with-treatment Cox proportional hazards model as the only covariate. These will be presented on a forest plot including the HR and 95% CI from the entire population.

[0244] No adjustments to significance levels were made for the subgroup and sensitivity analyses studies, as all of these analyses were considered to support the OS and PFS analyses.

[0245] Progression-free survival (PFS) The second PFS analysis will be based on programmatically derived RECIST 1.1 using investigator tumor assessment. The analysis will be performed in the FAS, adjusting for disease status and primary tumor location, using a stratified log-rank test. The effect of arm A versus arm B will be estimated by HR with its corresponding 95% CI and p-value.

[0246] Kaplan-Meier plots of PFS will be presented by treatment group. A summary of the number and percentage of patients experiencing PFS events and type of event (RECIST 1.1 or death) will be provided along with median PFS by treatment.

[0247] Sensitivity analysis If scans are not performed at the protocol scheduled time points, sensitivity analyses will be performed to evaluate possible assessment bias that may be introduced. The midpoint between the time of progression and the previous evaluable RECIST assessment will be analyzed using the log-rank test. For patients in whom death was treated as a PFS event, the date of death will be used to derive the PFS time used in the analysis. This approach has been shown to be robust even in highly asymmetric assessment schedules (Sun and Chen, 2010).

[0248] Attrition bias will be assessed by repeating the PFS analysis, but including actual PFS event times rather than censored times for patients who progressed or died in the absence of progression shortly after two or more non-evaluable tumor assessments. In addition, patients who receive subsequent treatment before progression or death will be censored at the time of their last evaluable assessment before subsequent treatment. This analysis will be supported by a Kaplan-Meier plot of time to censoring, where the censoring indicator for the PFS analysis is cancelled.

[0249] The proportionality assumption will be assessed first by examining a plot of the complementary log-log(time to event) versus log(time) and, if this is unsettling, by fitting a time-dependent covariate to assess the extent to which this represents random variation. If a lack of proportionality is evident, the variation in treatment effect will be explained by showing piecewise HRs calculated over well-defined time periods. In such circumstances, the HRs can still be interpreted meaningfully as average HRs over time, unless there is extensive crossing of survival curves. If a lack of proportionality is found, this may be the result of a covarying unit treatment interaction, which will be explored. In addition, Kaplan-Meier curves, along with landmark analyses (e.g., 1-year PFS rates), will also aid in understanding the treatment benefit.

[0250] Cox proportional hazards modeling will be used to assess the effect of covariates on HR estimates. Models including treatment and stratification factors will be constructed to ensure that any output from Cox modeling is likely to be consistent with the results of stratified log-rank tests.

[0251] Also, using the approach of Gail and Simon, 1985, interactions between treatments and stratification factors will be tested to rule out any qualitative interactions.

[0252] Further sensitivity analyses may be recorded in the SAP.

[0253] Subgroup analysis Subgroup analyses will be performed comparing PFS (according to RECIST 1.1 using investigator assessment) between Arm A and Arm B in subgroups of the FAS.

[0254] Objective response rate ORR will be based on programmatically derived RECIST using investigator tumor data. ORR will be compared between Arm A and Arm B using a stratified CMH test adjusting for the same factors as the primary endpoint (disease status and primary tumor location). Results of the analysis will be presented in terms of p-values. This analysis will be performed in the subset of patients in the FAS who had measurable disease at baseline.

[0255] A summary will be generated showing the number and percentage of patients with tumor response (CR / PR). All-visit response data will be tabulated for all patients (i.e., FAS). For each treatment arm, best overall response (BoR) will be summarized by n (%) for each category (CR, PR, SD, PD, and NE). Informal statistical analysis is planned for the BoR.

[0256] In IA-1, ORR assessment will be repeated for all randomized patients with an opportunity to be followed for at least 32 weeks, with tumor data assessed by BICR according to RECIST 1.1.

[0257] Duration of response KM plots of DoR based on investigator assessment of RECIST 1.1 will be presented, and median DoR will be summarized and calculated from the KM curves. Only patients with confirmed responses will be included in the summary table, and swimmer plots will be generated to clearly show the profile of each responding patient.

[0258] In IA-1, DoR assessment will be repeated for all randomized patients with an opportunity to be followed for at least 32 weeks, with tumor data assessed by BICR according to RECIST 1.1.

[0259] Disease control rate DCR, DCR-24w, and DCR-32w based on investigator assessment according to RECIST 1.1 will be summarized according to treatment arm (i.e. number [%] of patients).

[0260] Patient-reported outcomes EORTC QLQ-C30 The primary assessment of symptoms, effects, and HRQoL will focus on time to deterioration (TTD), which will be analyzed using the stratified log-rank test described for the PFS endpoint. Separate analyses will be performed for health / QoL, function (physical, role, cognitive, social, and emotional), multi-period symptoms (fatigue and pain), and single items (appetite loss and insomnia). The effect of durvalumab therapy versus placebo will be estimated by HR with its corresponding CI and p-value. Kaplan-Meier plots will be presented by treatment group. A summary of the number and percentage of patients with events and censored will be provided along with the median by treatment.

[0261] Additional analyses of HRQoL, impact, and symptoms will focus on comparing mean changes from baseline in health / QoL, function (physical, role, cognitive, social, and emotional), multi-period symptoms (fatigue and pain), and single-item (appetite loss and insomnia) scores between treatment groups. The analysis population for mean change in HRQoL, impact, or symptoms data will be the FAS and will include all randomized patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Changes from baseline will be derived using a mixed model repeated measures (MMRM) analysis of all post-baseline scores by visit. The model will include treatment, visit, and visit-by-treatment interactions as explanatory variables and baseline score as a covariate. Adjusted mean changes from baseline estimates according to treatment group and corresponding 95% CIs will be presented along with overall estimates of treatment differences, 95% CIs, and p-values.

[0262] Summary tables of visit responses by EORTC QLQ-C30 scale / item score (health / QoL, five functions, and total symptoms) and by visit (improved, worsened, and unchanged) will be presented by treatment group. In addition, summary tables of best overall response will be provided by treatment group for the following domains: health / QoL, function (physical, role, cognitive, social, and emotional), multi-phase symptoms (fatigue and pain), and single items (appetite loss and insomnia). The presence of symptoms, impact, and QoL / function improvement based on best overall response will be compared between treatment groups using logistic regression models adjusting for the same factors as the primary endpoint (disease status and primary tumor location). Odds ratios, p-values, and 95% CI will be visually presented in forest plots.

[0263] Finally, a summary of absolute and raw change from baseline for each EORTC QLQ-C30 scale / item will be reported by treatment group and by visit, and graphical displays may be presented as appropriate.

[0264] Additional supportive / exploratory analyses may be conducted.

[0265] EORTC QLQ-BIL21 The primary assessment of TTD described for the EORTC QLQ-C30 will be assessed for the single items of abdominal pain (item 42), pruritus (item 36), and jaundice (item 35) symptoms of the EORTC QLQ-BIL21.

[0266] For TTD in abdominal pain, pruritus, and jaundice, single items of EORTC QLQ-BIL21 will be presented using Kaplan-Meier plots and HRs with corresponding 95% CIs and p-values. Additionally, a summary of the number and percentage of patients experiencing clinically meaningful deterioration or death, as well as the median TTD will be provided by treatment group.

[0267] In addition, comparisons of mean changes from baseline using the MMRM described for EORTC QLQ-C30 will be repeated for EORTC QLQ-BIL21 abdominal pain, pruritus, and jaundice symptoms. All assumptions and outputs described for EORTC QLQ-C30 will apply.

[0268] Summary tables of visit responses by EORTC QLQ-BIL21 scale / item score and by visit (improved, worsened, and unchanged) will be presented by treatment group. In addition, summary tables of best overall response will be provided for abdominal pain, pruritus, and jaundice by treatment group. The presence of improvement based on best overall response will be compared between treatment groups using logistic regression models. Odds ratios, p-values, and 95% CI will be visually presented in forest plots.

[0269] As described for EORTC QLQ-C30, a summary of absolute and raw change from baseline for each EORTC QLQ-BIL21 scale / item will be reported by visit, by treatment group, and graphical displays may be presented as appropriate. This descriptive analysis will include EORTC QLQ-BIL21 item 49 ("To what extent were you bothered by side effects from the treatment?"), which assesses the patient's global impression of treatment tolerability, and will complement the exploratory findings of the PRO-CTCAE evaluation.

[0270] PRO-CTCAE PRO-CTCAE data will be presented using summary and descriptive statistics based on the FAS. EORTC QLQ-BIL21 item 49 ("To what extent were you bothered by side effects from the procedure?") descriptive statistics will complement the PRO-CTCAE survey results. See above section.

[0271] PGIS Responses on the PGIS will be summarized descriptively as the number of patients per category and corresponding percentages in the questionnaire at each visit by treatment group.

[0272] EQ-5D-5L Descriptive statistics will be calculated for each scheduled visit / study time point, by study arm, and in the aggregate. This will report the number of patients, the number of EQ-5D questionnaires completed at each visit, and the number and percentage responding to each EQ-5D-5L dimension. In addition, summary statistics (e.g., n, mean, median, SD, minimum, and maximum) will be reported for EQ-5D index scores and EQ-VAS scores, and changes from baseline for EQ-5D index scores and EQ-VAS scores.

[0273] Graphical plots of mean EQ-5D index scores and EQ-VAS scores, including associated 95% CIs, change from baseline and by time point in scheduled visits / studies may be generated. Additional analyses may be performed to support submission to payers, which will be outlined in a separate Payer Analysis Plan.

[0274] Example 2: A Global Phase 3 Study of the Efficacy of Durvalumab in Combination with Chemotherapy in Patients with Biliary Tract Cancer (BTC) patient Adults ≥18 years of age with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the biliary tract (including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder carcinoma) met the inclusion criteria. Eligible patients included those with previously untreated disease that was unresectable or metastatic at the time of initial diagnosis, and those with disease recurrence >6 months after intended curative surgery and >6 months after completion of adjuvant therapy. Other inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of ≥1, and no previous exposure to immune-mediated therapy. Patients were excluded if they had ampullary cancer, active or previously documented autoimmune or inflammatory disorders, or known allergies or hypersensitivities to any study treatment.

[0275] Study design and interventions TOPAZ-1 was a phase 3 randomized, double-blind, placebo-controlled global study. Patients were randomly assigned in a 1:1 ratio to receive durvalumab in combination with gemcitabine and cisplatin, or placebo in combination with gemcitabine and cisplatin. Randomization was stratified by disease status (initially unresectable vs. recurrent) and primary tumor location (intrahepatic vs. extrahepatic vs. gallbladder cancer).

[0276] Durvalumab or placebo in combination with gemcitabine and cisplatin was administered intravenously during 21-day cycles for up to eight cycles. Durvalumab 1500 mg or placebo was administered intravenously in combination with gemcitabine 1000 mg / m on day 1 of each cycle. 2 and cisplatin 25 mg / m 2(which were administered on days 1 and 8 of each cycle). After completion of gemcitabine and cisplatin, durvalumab 1500 mg or placebo monotherapy was administered once every 4 weeks until clinical or radiological (per RECIST v1.1) disease progression, or until unacceptable toxicity, withdrawal of consent, or any other discontinuation criteria were met. Patients who were clinically stable at the time of first disease progression could continue to receive study treatment at the discretion of the investigator and patient.

[0277] evaluation Tumor assessments were performed according to RECIST v1.1 using images obtained by computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis and were assessed according to investigator assessment. Adverse events were reported from the time of informed consent through 90 days after the last dose of study treatment; a causal relationship between reported adverse events and study treatment was investigator assessed. Other safety assessments included physical examination, laboratory findings, ECOG performance status, electrocardiogram, and vital signs. Health-related quality of life was assessed using the European Organisation for Research and Treatment of Cancer (EORTC)-30-item Core Quality of Life questionnaire, and the EORTC-21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life questionnaire. Patient-reported treatment tolerability was assessed using the Common Terminology Criteria for Patient-Reported Outcomes for adverse events.

[0278] Baseline tumor assessments were performed using images obtained ≦28 days prior to randomization. During the study period, tumor assessments were performed every 6 weeks (±1 week) for the first 24 weeks after randomization, and then every 8 weeks (±1 week) until radiological disease progression, followed by ≧1 additional follow-up scan. Survival assessments were performed every 2 months after treatment discontinuation. Patients on treatment or in survival follow-up were contacted after the data cutoff for the interim analysis to provide complete survival data. Freshly obtained tumor biopsy samples or archival samples taken ≦3 years prior to screening were obtained by image-guided core needle or by resection from all screened patients. Tissue samples were retrospectively evaluated for programmed cell death ligand 1 (PD-L1) expression by the Ventana PD-L1 (SP263) immunohistochemistry assay in all randomized patients using the tumor area positive (TAP) scoring method. "TAP" is the percentage of tumor and / or immune cells with PD-L1 staining at any intensity and may be used interchangeably with "TIP." A TAP score of ≥1% was defined as any intensity of PD-L1 staining in tumor cell membranes and / or tumor-associated immune cells covering ≥1% of the tumor area. A TAP score of <1% was defined as any intensity of PD-L1 staining in tumor cell membranes and / or tumor-associated immune cells covering <1% of the tumor area. The impact of PD-L1 expression on patient response and survival outcomes in durvalumab and placebo treatment groups was evaluated. MSI status was determined by Foundation Medicine, Inc. (described in US Food and Drug Administration, 2017) using data generated by the FoundationOne assay to analyze tumor tissue samples. Briefly, principal component analysis was used to analyze the length variability of 95 intronic homopolymeric repeat loci to assign samples a qualitative status of MSI-high or MSI-stable. Samples with low coverage (<250×median) were assigned an MSI-unknown status.

[0279] Objectives and Endpoints The primary objective was to assess overall survival, defined as the time between randomization and death from any cause, in the durvalumab versus placebo groups. Secondary endpoints included progression-free survival, objective response rate, duration of response, and disease control rate and efficacy according to PD-L1 expression according to RECIST v1.1 using investigator assessment in the durvalumab versus placebo groups. Progression-free survival is defined as the time from the date of randomization to the date of radiographic disease progression or death as defined by RECIST v1.1. Safety and tolerability of the durvalumab and placebo groups were assessed. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

[0280] statistical analysis Efficacy objectives were evaluated in the full analysis set, which included all randomized patients. The primary analysis of overall survival, testing the superiority of the durvalumab regimen compared with placebo, was analyzed using the log-rank test stratified by disease status (initially unresectable vs. recurrent) and primary tumor location (intrahepatic vs. extrahepatic vs. gallbladder cancer). This interim analysis was planned for approximately 397 of 496 deaths expected at the time of the final analysis to have occurred. This provided approximately 75% power to detect a significant difference in overall survival at a two-sided significance level of 0.0238 according to the Lan-DeMets approximation of the O'Brien Fleming alpha-spending function boundary. By the data cutoff date, 424 deaths had occurred, with an actual two-sided significance level of 0.03. Because a statistically significant improvement in overall survival in the durvalumab arm compared with the placebo arm was observed at the planned interim analysis, the key secondary endpoint of progression-free survival was formally evaluated at this interim analysis. The effect of durvalumab versus placebo for overall survival and progression-free survival was estimated by hazard ratios with 95% confidence intervals and two-sided P values. Progression-free survival in the durvalumab versus placebo treatment groups was tested using the log-rank test to derive a two-sided significance level of 0.0481 based on an alpha-spending function approximating the Pocock bound. No multiplicity adjustment was defined for other exploratory secondary endpoints; therefore, only estimates and 95% confidence intervals are provided. Confidence intervals for endpoints other than overall survival and progression-free survival were not adjusted for multiple comparisons and should not be used to infer clear treatment effects.

[0281] Objective response rates were compared between durvalumab and placebo treatment groups using the Cochran-Mantel-Haenszel test stratified by disease status (initially unresectable vs. recurrent) and primary tumor location (intrahepatic vs. extrahepatic vs. gallbladder). Safety was assessed in all patients who received at least one dose of study treatment, and data were summarized by descriptive statistics. All reported confidence intervals have not been adjusted for multiplicity and may not all be used to estimate effect.

[0282] The results of this planned interim analysis were reviewed by an independent data monitoring committee that concluded that the data met the pre-specified criteria for a statistically significant difference in the primary objective (overall survival) according to the statistical analysis plan with acceptable safety. Because the trial reached statistical significance for the primary objective based on this pre-specified interim analysis, the sponsor was not blinded and the results presented herein should be considered the final formal statistical analysis for overall survival. The TOPAZ-1 study is ongoing, which will allow for further exploratory follow-up overall survival analysis.

[0283] result Patients and Treatment During the study, 914 patients were enrolled at 105 sites in 17 countries. In total, 685 patients were randomized, 341 to the durvalumab group and 344 to the placebo group, with 338 and 342 patients receiving treatment, respectively (Figure 1). Patient demographics and disease characteristics were generally balanced between treatment groups (Tables 8-10). Representativeness of study participants in TOPAZ-1 is described in Table 11. As of the data cutoff date, the median (95% CI) duration of follow-up was 16.8 (14.8-17.7) months in the durvalumab group and 15.9 (14.9-16.9) months in the placebo group. In addition, 275 (81.4%) patients in the durvalumab group discontinued durvalumab and 322 (94.2%) patients in the placebo group discontinued placebo. In the full analysis set, the number of patients who received ≥1 subsequent regimen after discontinuation of anticancer treatment was 145 (42.5%) in the durvalumab group and 170 (49.4%) in the placebo group (Table 12).

[0284] [Table 10]

[0285] [Table 11]

[0286] [Table 12]

[0287] [Table 13]

[0288] [Table 14]

[0289] [Table 15]

[0290] [Table 16]

[0291] [Table 17]

[0292] First Objective At the time of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. Overall survival was significantly longer with durvalumab versus placebo (hazard ratio, 0.80; 95% CI, 0.66 to 0.97; P = .021). Median overall survival (95% CI) was 12.8 (11.1 to 14.0) months in the durvalumab group and 11.5 (10.1 to 12.5) months in the placebo-treated group (Figure 4A).

[0293] Estimated overall survival (95% CI) was 54.1% (48.4 to 59.4) for durvalumab and 48.0% (42.4 to 53.4) for placebo at 12 months, 35.1% (29.1 to 41.2) for durvalumab and 25.6% (19.9 to 31.7) for placebo at 18 months, and 24.9% (17.9 to 32.5) for durvalumab and 10.4% (4.7 to 18.8) for placebo at 24 months.

[0294] The Kaplan-Meier curves for overall survival separated at approximately 6 months of treatment, after which there was a clear and sustained separation of the survival curves in favor of durvalumab. The overall survival hazard ratio (95% CI) was 0.91 (0.66-1.26) up to 6 months and 0.74 (0.58-0.94) after 6 months. Furthermore, kernel smoothing estimates of the hazard function and associated log-log(time to event) versus log(time) plots confirmed departures from the proportional hazards assumption (Figure 5).

[0295] Second Objective The median (95% CI) progression-free survival was 7.2 (6.7-7.4) months with durvalumab and 5.7 (5.6-6.7) months with placebo (Fig. 4B). The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63-0.89; P = .001). The investigator-assessed confirmed objective response rate (the combined proportion of complete and partial responses in patients with measurable disease) was 26.7% in the durvalumab group (n = 341) and 18.7% in the placebo group (n = 343) (odds ratio, 1.60; 95% CI, 1.11-2.31). The number of patients who achieved a confirmed complete response was 7 (2.1%) with durvalumab and 2 (0.6%) with placebo, and the number of patients who achieved a confirmed partial response was 84 (24.6%) with durvalumab and 62 (18.1%) with placebo. The percentage of patients with a sustained response for ≥9 months was 32.6% with durvalumab and 25.3% with placebo. The percentage of patients with a sustained response for ≥12 months was 26.1% with durvalumab and 15.0% with placebo. Tumor responses are summarized in Table 13.

[0296] [Table 18]

[0297] The overall and progression-free survival benefits observed with durvalumab in combination with gemcitabine and cisplatin were generally consistent across the clinically relevant subgroups analyzed (Figures 6A and 6B). In patients with a PD-L1 tumor area positivity (TAP) score ≥1% (tumor area occupied by tumor and / or immune cells with PD-L1 staining of any intensity ≥1%), the hazard ratio for overall survival with durvalumab vs. placebo was 0.79 (95% CI, 0.61-1.00). In patients with a TAP score <1%, the hazard ratio for overall survival with durvalumab vs. placebo was 0.86 (95% CI, 0.60-1.23).

[0298] safety The safety analysis set included 680 patients who received ≥ 1 dose of durvalumab (n = 338) or placebo (n = 342). The median (range) duration of study treatment was 7.3 (0.1-24.5) months for durvalumab and 5.8 (0.2-21.5) months for placebo (Table 14).

[0299] [Table 19]

[0300] In the durvalumab group, the median (interquartile range) relative dose intensity of durvalumab, gemcitabine, and cisplatin was 100 (93.8-100), 93.8 (82.5-100), and 93.8 (83.3-100), respectively. In the placebo group, the median (interquartile range) relative dose intensity of placebo, gemcitabine, and cisplatin was 100 (95.0-100), 93.8 (82.2-100), and 93.8 (81.3-100), respectively.

[0301] Adverse events of any grade occurred in 336 (99.4%) patients in the durvalumab group and 338 (98.8%) patients in the placebo group (Table 15). Grade 3 / 4 adverse events occurred in 256 (75.7%) patients in the durvalumab group and 266 (77.8%) patients in the placebo group (Table 15). The discontinuation rate of any treatment component due to adverse events possibly related to treatment was 8.9% in the durvalumab group and 11.4% in the placebo group (Table 15). The number of deaths due to adverse events was 12 (3.6%) in the durvalumab group and 14 (4.1%) in the placebo group. Deaths due to treatment-related adverse events occurred in 2 (0.6%) patients in the durvalumab group and 1 (0.3%) patient in the placebo group (Table 15). The most common adverse events were anemia (48.2%), nausea (40.2%), constipation (32.0%), and neutropenia (31.7%) in the durvalumab group and anemia (44.7%), nausea (34.2%), and low neutrophil count (31.0%) in the placebo group (Table 16). Grade 3 or 4 treatment-related adverse events that occurred in ≥2% of patients in the durvalumab and placebo groups are listed in Table 17. The rate of immune-mediated adverse events was 12.7% in the durvalumab group and 4.7% in the placebo group. Grade 3 or 4 immune-mediated adverse events occurred in 2.4% of patients in the durvalumab group and 1.5% in the placebo group (Table 18).

[0302] [Table 20]

[0303] [Table 21]

[0304] [Table 22]

[0305] [Table 23]

[0306] [Table 24]

[0307] [Table 25]

[0308] In previously untreated advanced biliary tract cancer, durvalumab plus gemcitabine and cisplatin demonstrated statistically significant prolonged overall survival versus placebo plus gemcitabine and cisplatin. The large international patient population in TOPAZ-1 was representative of the general population of patients with advanced biliary tract cancer, with characteristics well balanced between treatment arms. The addition of durvalumab to chemotherapy benefited patients with tumors characterized by PD-L1 TAP ≥ 1% and TAP < 1%, demonstrating that PD-L1 status is of limited value in predicting clinical benefit from durvalumab plus chemotherapy in this patient population. Durvalumab plus chemotherapy was associated with a safety profile, with toxicities observed similar to those commonly seen with chemotherapy or immunotherapy alone. Durvalumab did not add any additional toxicity to that observed with chemotherapy in this double-blind trial, and the rates of grade 3 or 4 treatment-related adverse events were very similar between treatment arms. The phase 3 TOPAZ-1 trial met its primary objective of improving overall survival at a pre-planned interim analysis with durvalumab and chemotherapy while demonstrating manageable safety. Our global phase 3 trial demonstrated a statistically significant improvement in median overall survival with immunotherapy in advanced biliary tract cancer.

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[0310] Embodiment Embodiment 1: A method of treating a patient with biliary tract cancer (BTC), comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0311] Embodiment 2: A method of extending overall survival in a patient with biliary tract cancer (BTC), comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0312] Embodiment 3: A method of prolonging progression-free survival in a patient with biliary tract cancer (BTC), comprising treating the patient with an anti-PD-L1 antibody and chemotherapy.

[0313] Embodiment 4: An anti-PD-L1 antibody in combination with chemotherapy for use in the treatment of biliary tract cancer (BTC).

[0314] Embodiment 5: An anti-PD-L1 antibody in combination with chemotherapy for use in the treatment of biliary tract cancer (BTC) in a patient, wherein overall survival is prolonged in said patient.

[0315] Embodiment 6: An anti-PD-L1 antibody in combination with chemotherapy for use in the treatment of biliary tract cancer (BTC) in a patient, wherein progression-free survival is prolonged in said patient.

[0316] Embodiment 7: Use of an anti-PD-L1 antibody in combination with chemotherapy in the manufacture of a medicament for use in the treatment of biliary tract cancer (BTC).

[0317] Embodiment 8: Use of an anti-PD-L1 antibody in combination with chemotherapy in the manufacture of a medicament for use in the treatment of biliary tract cancer (BTC) in a patient, wherein overall survival is prolonged in said patient.

[0318] Embodiment 9: Use of an anti-PD-L1 antibody in combination with chemotherapy in the manufacture of a medicament for use in the treatment of biliary tract cancer (BTC) in a patient, wherein progression free survival is prolonged in said patient.

[0319] Embodiment 10: The method, combination for use, or use of any one of embodiments 1 to 9, wherein the chemotherapy comprises concomitant chemotherapy.

[0320] Embodiment 11: The method, combination for use, or use of any one of embodiments 1 to 10, wherein the chemotherapy comprises platinum-based chemotherapy and / or antimetabolite-based chemotherapy.

[0321] Embodiment 12: The method, combination for use, or use of embodiment 11, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

[0322] Embodiment 13: The method, combination for use, or use of embodiment 11 or embodiment 12, wherein the antimetabolite-based chemotherapy is gemcitabine.

[0323] Embodiment 14: The method, combination for use, or use of any one of embodiments 1 to 13, wherein the anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.

[0324] Embodiment 15: The method, combination for use, or use of any one of embodiments 1 to 14, wherein the anti-PD-L1 antibody and / or chemotherapy are administered intravenously.

[0325] Embodiment 16: The method, combination for use, or use of any one of embodiments 1 to 15, wherein the anti-PD-L1 antibody is administered to the patient every three weeks (Q3W).

[0326] Embodiment 17: The method, combination for use, or use of any one of embodiments 1 to 16, wherein the PD-L1 antibody and the dose of chemotherapy are administered simultaneously or sequentially.

[0327] Embodiment 18: The method, combination for use, or use of any one of embodiments 1 to 17, wherein the second dose of chemotherapy is administered 7 days after administration of the first dose of chemotherapy.

[0328] Embodiment 19: A treatment cycle lasting 21 days comprising: (a) the first dose of the anti-PD-L1 antibody and chemotherapy is administered on day 1 of the treatment cycle; (b) the second dose of chemotherapy is administered on day 8 of the treatment cycle; The method, combination for use, or use of any one of embodiments 1 to 18.

[0329] Embodiment 20: The method, combination for use, or use of embodiment 19, wherein the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, or 8 times.

[0330] Embodiment 21: The method, combination for use, or use of any one of embodiments 1 to 20, wherein the anti-PD-L1 antibody is administered after completion of chemotherapy treatment.

[0331] Embodiment 22: The method, combination for use, or use of any one of embodiments 19 to 21, wherein the anti-PD-L1 antibody is administered after completion of the last treatment cycle.

[0332] Embodiment 23: The method, combination for use, or use of embodiment 22, wherein the anti-PD-L1 antibody is administered once every four weeks (Q4W).

[0333] Embodiment 24: The method, combination for use, or use of any one of embodiments 1 to 23, wherein treatment with the human anti-PD-L1 antibody comprises administering 1000-2000 mg of anti-PD-L1 antibody.

[0334] Embodiment 25: The method, combination for use, or use of embodiment 24, wherein treatment with the human anti-PD-L1 antibody comprises administering 1500 mg of anti-PD-L1 antibody.

[0335] Embodiment 26: Chemotherapy treatment comprises gemcitabine 1000 mg / m 2 and cisplatin 25 mg / m 2 The method, combination for use, or use of any one of embodiments 1-25, comprising administering intravenously to a patient.

[0336] Embodiment 27: The method, combination for use, or use of any one of embodiments 1 to 26, wherein the biliary tract cancer is unresectable, locally advanced, or metastatic.

[0337] Embodiment 28: The method, combination for use, or use of any one of embodiments 1 to 27, wherein the patient has not been previously treated for BTC.

[0338] Embodiment 29: The method, combination for use, or use of any one of embodiments 1 to 28, wherein the patient has recurrent disease more than 6 months after intended curative surgery or more than 6 months after completion of adjuvant therapy.

[0339] Embodiment 30: The method, combination for use, or use of any one of embodiments 1 to 29, wherein the toxicity observed is similar to the toxicity commonly seen with chemotherapy or immunotherapy alone.

Claims

1. A method of extending overall survival in a patient with biliary tract cancer (BTC), comprising treating said patient with an anti-PD-L1 antibody and chemotherapy.

2. 10. The method of claim 1, wherein the chemotherapy comprises concomitant chemotherapy.

3. 3. The method of claim 1 or 2, wherein the chemotherapy comprises platinum-based chemotherapy and / or antimetabolite-based chemotherapy.

4. 4. The method of claim 3, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

5. 4. The method of claim 3, wherein the antimetabolite-based chemotherapy is gemcitabine.

6. The method of any one of claims 1 to 5, wherein the anti-PD-L1 antibody is durvalumab, avelumab, sugemalimab, or atezolizumab.

7. The method of any one of claims 1 to 6, wherein the anti-PD-L1 antibody and / or chemotherapy is administered intravenously.

8. The method of any one of claims 1 to 7, wherein the anti-PD-L1 antibody is administered to the patient every three weeks (Q3W).

9. The method of any one of claims 1 to 8, wherein the PD-L1 antibody and the dose of chemotherapy are administered simultaneously or sequentially.

10. The method of any one of claims 1 to 9, wherein the second dose of chemotherapy is administered 7 days after administration of the first dose of chemotherapy.

11. A treatment cycle lasting 21 days included: (a) the anti-PD-L1 antibody and the first dose of chemotherapy are administered on day 1 of the treatment cycle; (b) the second dose of chemotherapy is administered on day 8 of the treatment cycle; The method according to any one of claims 1 to 10.

12. 12. The method of claim 11, wherein the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, or 8 times.

13. The method of any one of claims 1 to 12, wherein the anti-PD-L1 antibody is administered after completion of the treatment with chemotherapy.

14. The method of any one of claims 11 to 13, wherein the anti-PD-L1 antibody is administered after completion of the last treatment cycle.

15. The method of claim 14, wherein the anti-PD-L1 antibody is administered once every four weeks (Q4W).

16. The method of any one of claims 1 to 15, wherein the treatment with the human anti-PD-L1 antibody comprises administering 1000 to 2000 mg of the anti-PD-L1 antibody.

17. 17. The method of claim 16, wherein the treatment with the human anti-PD-L1 antibody comprises administering 1500 mg of the anti-PD-L1 antibody.

18. Chemotherapy treatment consisted of gemcitabine 1000 mg / m ２ and cisplatin 25 mg / m ２ 18. The method of any one of claims 1 to 17, comprising intravenously administering to the patient

19. The method of any one of claims 1 to 18, wherein the biliary tract cancer is unresectable, locally advanced, or metastatic.

20. The method of any one of claims 1 to 19, wherein the patient has not been previously treated for BTC.

21. The method of any one of claims 1 to 20, wherein the patient has relapsed disease more than 6 months after intended curative surgery or more than 6 months after completion of adjuvant therapy.

22. The method of any one of claims 1 to 21, wherein the toxicity observed is similar to that typically seen with chemotherapy or immunotherapy alone.

23. A method of extending progression-free survival in a patient with biliary tract cancer (BTC), comprising treating said patient with an anti-PD-L1 antibody and chemotherapy.

24. 24. The method of claim 23, wherein the chemotherapy comprises concomitant chemotherapy.

25. 25. The method of claim 23 or 24, wherein the chemotherapy comprises platinum-based chemotherapy and / or antimetabolite-based chemotherapy.

26. 26. The method of claim 25, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

27. 26. The method of claim 25, wherein the antimetabolite-based chemotherapy is gemcitabine.

28. The method of any one of claims 23 to 27, wherein the anti-PD-L1 antibody is durvalumab, avelumab, sugemalimab, or atezolizumab.

29. The method of any one of claims 23 to 28, wherein the anti-PD-L1 antibody and / or chemotherapy is administered intravenously.

30. 30. The method of any one of claims 23-29, wherein the anti-PD-L1 antibody is administered to the patient every three weeks (Q3W).

31. The method of any one of claims 23 to 30, wherein the PD-L1 antibody and the dose of chemotherapy are administered simultaneously or sequentially.

32. The method of any one of claims 23 to 31, wherein the second dose of chemotherapy is administered 7 days after administration of the first dose of chemotherapy.

33. A treatment cycle lasting 21 days included: (a) the anti-PD-L1 antibody and the first dose of chemotherapy are administered on day 1 of the treatment cycle; (b) the second dose of chemotherapy is administered on day 8 of the treatment cycle; 33. The method according to any one of claims 23 to 32.

34. 12. The method of claim 11, wherein the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, or 8 times.

35. The method of any one of claims 23 to 33, wherein the anti-PD-L1 antibody is administered after completion of the treatment with chemotherapy.

36. The method of any one of claims 23 to 35, wherein the anti-PD-L1 antibody is administered after completion of the last treatment cycle.

37. 37. The method of claim 36, wherein the anti-PD-L1 antibody is administered once every four weeks (Q4W).

38. The method of any one of claims 32 to 37, wherein the treatment with the human anti-PD-L1 antibody comprises administering 1000 to 2000 mg of the anti-PD-L1 antibody.

39. 39. The method of claim 38, wherein the treatment with the human anti-PD-L1 antibody comprises administering 1500 mg of the anti-PD-L1 antibody.

40. Chemotherapy treatment consisted of gemcitabine 1000 mg / m ２ and cisplatin 25 mg / m ２ 40. The method of any one of claims 23 to 39, comprising intravenously administering to the patient.

41. The method of any one of claims 23 to 40, wherein the biliary tract cancer is unresectable, locally advanced, or metastatic.

42. The method of any one of claims 23 to 41, wherein the patient has not been previously treated for BTC.

43. The method of any one of claims 23 to 42, wherein the patient has relapsed disease more than 6 months after intended curative surgery or more than 6 months after completion of adjuvant therapy.

44. The method of any one of claims 23 to 43, wherein the toxicity observed is similar to that typically seen with chemotherapy or immunotherapy alone.

45. A method of treating a patient with biliary tract cancer (BTC), comprising treating said patient with an anti-PD-L1 antibody and chemotherapy.

46. 46. ​​The method of claim 45, wherein the chemotherapy comprises concomitant chemotherapy.

47. 47. The method of claim 45 or 46, wherein the chemotherapy comprises platinum-based chemotherapy and / or antimetabolite-based chemotherapy.

48. 48. The method of claim 47, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

49. 48. The method of claim 47, wherein the antimetabolite-based chemotherapy is gemcitabine.

50. 50. The method of any one of claims 45 to 49, wherein the anti-PD-L1 antibody is durvalumab, avelumab, sugemalimab, or atezolizumab.

51. The method of any one of claims 45 to 50, wherein the anti-PD-L1 antibody and / or chemotherapy is administered intravenously.

52. 52. The method of any one of claims 45-51, wherein the anti-PD-L1 antibody is administered to the patient every three weeks (Q3W).

53. The method of any one of claims 45 to 52, wherein the PD-L1 antibody and the dose of chemotherapy are administered simultaneously or sequentially.

54. 54. The method of any one of claims 45 to 53, wherein the second dose of chemotherapy is administered 7 days after administration of the first dose of chemotherapy.

55. A treatment cycle lasting 21 days included: (a) the anti-PD-L1 antibody and the first dose of chemotherapy are administered on day 1 of the treatment cycle; (b) the second dose of chemotherapy is administered on day 8 of the treatment cycle; 55. The method according to any one of claims 45 to 54.

56. 56. The method of claim 55, wherein the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, or 8 times.

57. The method of any one of claims 45 to 56, wherein the anti-PD-L1 antibody is administered after completion of the treatment with chemotherapy.

58. The method of any one of claims 45 to 57, wherein the anti-PD-L1 antibody is administered after completion of the last treatment cycle.

59. 59. The method of claim 58, wherein the anti-PD-L1 antibody is administered once every four weeks (Q4W).

60. The method of any one of claims 45 to 59, wherein the treatment with the human anti-PD-L1 antibody comprises administering 1000 to 2000 mg of the anti-PD-L1 antibody.

61. 61. The method of claim 60, wherein the treatment with the human anti-PD-L1 antibody comprises administering 1500 mg of the anti-PD-L1 antibody.

62. Chemotherapy treatment consisted of gemcitabine 1000 mg / m ２ and cisplatin 25 mg / m ２ 62. The method of any one of claims 45 to 61, comprising intravenously administering to the patient.

63. 63. The method of any one of claims 45 to 62, wherein the biliary tract cancer is unresectable, locally advanced, or metastatic.

64. The method of any one of claims 45 to 63, wherein the patient has not been previously treated for BTC.

65. 65. The method of any one of claims 45 to 64, wherein the patient has recurrent disease more than 6 months after intended curative surgery or more than 6 months after completion of adjuvant therapy.

66. 66. The method of any one of claims 45 to 65, wherein the toxicity observed is similar to that typically seen with chemotherapy or immunotherapy alone.

67. Anti-PD-L1 antibodies in combination with chemotherapy for the treatment of biliary tract cancer (BTC).

68. An anti-PD-L1 antibody in combination with chemotherapy for use in the treatment of biliary tract cancer (BTC) in a patient, wherein overall survival is extended in said patient.

69. An anti-PD-L1 antibody in combination with chemotherapy for use in a method of extending overall survival in patients with biliary tract cancer (BTC).

70. 1. An anti-PD-L1 antibody in combination with chemotherapy for use in the treatment of biliary tract cancer (BTC) in a patient, wherein progression-free survival is extended in said patient.

71. An anti-PD-L1 antibody in combination with chemotherapy for use in a method of extending progression-free survival in patients with biliary tract cancer (BTC).

72. Use of an anti-PD-L1 antibody in combination with chemotherapy in the manufacture of a medicament for use in the treatment of biliary tract cancer (BTC).

73. Use of an anti-PD-L1 antibody in combination with chemotherapy in the manufacture of a medicament for use in a method of extending overall survival in patients with biliary tract cancer (BTC).

74. Use of an anti-PD-L1 antibody in combination with chemotherapy in the manufacture of a medicament for use in a method of extending progression-free survival in patients with biliary tract cancer (BTC).

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