Positive results from the TOPAZ-1 Phase III trial showed AstraZeneca’s IMFINZI® (durvalumab) in combination with standard-of-care chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy alone as a 1st-line treatment for patients with advanced biliary tract cancer (BTC). These results will be presented on January 21 at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. BTC is a group of rare and aggressive cancers that occur in the bile ducts and gallbladder. Approximately 50,000 people in the US, Europe and Japan and about 210,000 people worldwide are diagnosed with BTC each year.These patients have a poor prognosis, with approximately 5% to 15% of all patients with BTC surviving five years. Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator in the TOPAZ-1 Phase III trial, said: “After minimal progress for more than a decade in advanced biliary tract cancer, the TOPAZ-1 results are a tremendous advance for our patients, showing a clear survival benefit for IMFINZI added to chemotherapy compared to standard of care with a remarkable safety profile. This combination will provide a desperately needed and potentially practice-changing new treatment option in a setting where the current prognosis is devastating.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “The results from the TOPAZ-1 trial challenge treatment expectations in advanced biliary tract cancer and provide compelling evidence that longer-term survival is possible. Overall survival improves over time with an estimated one in four patients on IMFINZI plus chemotherapy alive at two years compared to one in ten on chemotherapy alone. This is a potential new standard of care for patients in this setting and we remain committed to making advances in gastrointestinal cancers with high unmet need.” In a predefined interim analysis, patients treated with IMFINZI in combination with standard-of-care chemotherapy experienced a 20% reduction in the risk of death versus chemotherapy alone (based on a hazard ratio [HR] of 0.80; 95% confidence interval [CI], 0.66-0.97; 2-sided p=0.021). Median OS was 12.8 months versus 11.5 for chemotherapy. An estimated 25% of patients were still alive at two years versus 10% for chemotherapy. Results also showed a 25% reduction in the risk of disease progression or death with IMFINZI plus chemotherapy (HR, 0.75; 95% CI, 0.64-0.89; 2-sided p=0.001). Median PFS was 7.2 months for the combination versus 5.7 for chemotherapy. Patients treated with IMFINZI plus chemotherapy achieved an objective response rate (ORR) of 26.7% versus an ORR of 18.7% for patients treated with chemotherapy alone. Summary of efficacy resultsi:
IMFINZI +
chemotherapy
(n=341)
Placebo +
chemotherapy
(n=344)
OSii,iii
Percentage of patients with event
58.1
65.7
Median OS (95% CI) (in months)
12.8 (11.1, 14.0)
11.5 (10.1, 12.5)
HR (95% CI)
2-sided p-value
0.80 (0.66, 0.97)
0.021
OS rate at 18 months (95% CI) (%)
35.1 (29.1, 41.2)
25.6 (19.9, 31.7)
OS rate at 24 months (95% CI) (%)
24.9 (17.9, 32.5)
10.4 (4.7, 18.8)
PFSiv,v
Percentage of patients with event
80.9
86.3
Median PFS (95% CI) (in months)
7.2 (6.7, 7.4)
5.7 (5.6, 6.7)
HR (95% CI)
2-sided p-value
0.75 (0.64, 0.89)
0.001
ORR (%)
26.7
18.7
i.
Analysis was done at 62% maturity in OS data.
ii.
Investigator-assessed OS data cut-off date was 11 August 2021.
iii.
Median follow-up in censored patients at DCO: 13.7 months (range 0.4-27.2) for IMFINZI plus chemotherapy, 12.6 months (range 0.7-26.0) for chemotherapy alone.
iv.
Investigator-assessed PFS data cut-off date was 11 August 2021.
v.
Median follow-up in censored patients at DCO: 9.2 months (range 0.0-24.0) for IMFINZI plus chemotherapy, 6.9 months (range 0.0-20.4) for chemotherapy alone. IMFINZI plus chemotherapy did not increase the discontinuation rate due to adverse events (AEs) compared to chemotherapy alone. Grade 3 or 4 treatment-related AEs were experienced by 62.7% of patients treated with IMFINZI and chemotherapy, and by 64.9% of patients receiving chemotherapy alone. Treatment-related AEs led to discontinuation in 8.9% of patients treated with the IMFINZI combination versus 11.4% of patients receiving chemotherapy. In December 2020, IMFINZI was granted Orphan Drug Designation in the US for the treatment of BTC. In October 2021, an Independent Data Monitoring Committee recommended the TOPAZ-1 Phase III trial to be unblinded at an interim analysis due to clear evidence of efficacy for IMFINZI plus chemotherapy. There are no contraindications for IMFINZI® (durvalumab).
Immune-Mediated Adverse Reactions
Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Other Immune-Mediated Adverse Reactions
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies. Infusion-Related Reactions
IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions. Complications of Allogeneic HSCT after IMFINZI
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI. Lactation
There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for at least 3 months after the last dose. In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy
The safety and effectiveness of IMFINZI have not been established in pediatric patients. The primary endpoint was OS and key secondary endpoints included progression-free survival, objective response rate and safety. The trial was conducted in 105 centres across 17 countries including in the US, Europe, South America and several countries in Asia including South Korea, Thailand, Japan and China.
About IMFINZI® (durvalumab)
IMFINZI is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses. IMFINZI is also approved for previously treated patients with advanced bladder cancer in several countries. Since the first approval in May 2017, more than 100,000 patients have been treated with IMFINZI. As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, liver cancer, BTC, esophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer and other solid tumors. About AstraZeneca Support Programs
AstraZeneca strives to ensure that appropriate patients and their oncologists have access to IMFINZI and relevant support resources. These include educational resources, an Oncology Nurse Educator program and affordability and reimbursement programs, such as Access 360™. Additionally, AstraZeneca has launched Lighthouse, a program that provides support to patients during any immune-mediated adverse events they may encounter during treatment, through medically trained Lighthouse Advocates. The program aims to make patients’ treatment experience as comfortable as possible. About AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumors. The Company’s Immuno-Oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome anti-tumor immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumor types. The Company is pursuing a comprehensive clinical-trial program that includes IMFINZI as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumor types, stages of disease and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.
In addition, the ability to combine the IO portfolio with radiation, chemotherapy and targeted small molecules from across AstraZeneca’s Oncology pipeline and from research partners, may provide new treatment options across a broad range of tumors. About AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.
The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. References
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US-61053 Last Updated 1/22