IMFINZI™ (durvalumab) Granted Breakthrough Therapy Designation by US FDA for Patients with Locally Advanced Unresectable Non-Small Cell Lung Cancer

AstraZeneca and MedImmune, its global biologics research and development arm, today announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for IMFINZI™ (durvalumab), an anti-PD-L1 monoclonal antibody, being investigated for the treatment of patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation therapy.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “For patients who have not progressed following chemoradiation therapy the only current option is active monitoring. Unfortunately, for the majority of patients, their cancer will progress to metastatic disease, typically within 12 months. IMFINZI is the first immuno-oncology medicine to show a clinically significant benefit in this earlier, non-metastatic setting, so following Breakthrough Designation we hope to bring it to patients as soon as possible.”

The Breakthrough Therapy Designation is designed to expedite the development and regulatory review of new medicines that are intended to treat a serious condition and that have shown encouraging early clinical results, which demonstrate substantial improvement on a clinically significant endpoint over available therapies and when there is significant unmet medical need. Use of durvalumab in patients with locally advanced, unresectable NSCLC is not yet FDA-approved.

The Breakthrough Therapy Designation for durvalumab was granted on the basis of interim results from the Phase III PACIFIC trial, a randomized, double-blinded, placebo-controlled multi-center trial of durvalumab as sequential treatment in patients with locally-advanced, unresectable (Stage III) NSCLC who had not progressed following standard platinum-based chemotherapy concurrent with radiation therapy. This achievement is the fourth Breakthrough Therapy Designation AstraZeneca has received from the FDA for medicines in Oncology over the past three years and the second for durvalumab. In May 2017, AstraZeneca received accelerated approval from the FDA for IMFINZI for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery. IMFINZI is approved under the FDA’s accelerated approval pathway, based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Data from the PACIFIC trial have been submitted for presentation at a forthcoming medical meeting.

Durvalumab is also being tested in for the treatment of NSCLC in the adjuvant setting in the ADJUVANT Phase III trial. In the Stage IV 1st-line setting for patients with advanced NSCLC, durvalumab as monotherapy and in combination with tremelimumab, an anti-CTLA-4 monoclonal antibody, is being tested in the MYSTIC, NEPTUNE and PEARL Phase III trials. The POSEIDON trial is evaluating durvalumab with and without tremelimumab in combination with chemotherapy.

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI™ (durvalumab).

Monitor patients for clinical signs and symptoms of immune-mediated pneumonitis, hepatitis, colitis or diarrhea, endocrinopathies, nephritis, rash or dermatitis, other immune-mediated adverse reactions, and infection. Please refer to the full Prescribing Information for important dose management information specific to adverse reactions.

Immune-Mediated Pneumonitis

In the combined safety database (n=1414), immune-mediated pneumonitis occurred in 32 patients (2.3%), including 1 fatal case (0.1%) and 6 Grade 3–4 cases (0.4%). In Study 1 (n=182), 1 patient (0.5%) died from immune-mediated pneumonitis. Monitor patients for signs and symptoms of pneumonitis and evaluate with radiographic imaging when suspected. Administer corticosteroids for ≥Grade 2 pneumonitis. Withhold IMFINZI for Grade 2 pneumonitis; permanently discontinue for Grade 3–4 pneumonitis.

Immune-Mediated Hepatitis

In the combined safety database (n=1414), immune-mediated hepatitis occurred in 16 patients (1.1%), including 1 fatal case (<0.1%) and 9 Grade 3 cases (0.6%). Grade 3–4 elevations in ALT occurred in 40/1342 patients (3.0%), AST in 58/1336 patients (4.3%), and total bilirubin in 37/1341 patients (2.8%). In Study 1 (n=182), 1 patient (0.5%) died from immune-mediated hepatitis, and 2 patients (1.1%) experienced immune-mediated hepatitis, including 1 Grade 3 case (0.5%). Monitor patients for abnormal liver tests in each cycle during treatment with IMFINZI. Administer corticosteroids and withhold IMFINZI for Grade 2–3 ALT or AST >3–5X ULN or ≤8X ULN or total bilirubin >1.5–3X ULN or ≤5X ULN. Permanently discontinue IMFINZI in patients with Grade 3 ALT or AST >8X ULN or total bilirubin >5X ULN, or in patients with concurrent ALT or AST >3X ULN and total bilirubin >2X ULN with no other cause.

Immune-Mediated Colitis

In the combined safety database (n=1414), immune-mediated colitis or diarrhea occurred in 18 patients (1.3%), including 1 Grade 4 case (<0.1%) and 4 Grade 3 cases (0.3%). In Study 1 (n=182), 23 patients (12.6%) experienced colitis or diarrhea, including 2 Grade 3–4 cases (1.1%). Monitor patients for signs and symptoms of colitis or diarrhea. Administer corticosteroids for ≥Grade 2 colitis or diarrhea. Withhold IMFINZI for Grade 2 colitis or diarrhea; permanently discontinue for Grade 3–4 colitis or diarrhea.

Immune-Mediated Endocrinopathies

• Immune-mediated thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism have occurred with IMFINZI. Monitor patients for clinical signs and symptoms of endocrinopathies. For Grade 2–4 endocrinopathies (except hypothyroidism) withhold dose until clinically stable and offer symptomatic management for hyperthyroidism. For Grade 2–4 hypothyroidism, initiate thyroid hormone replacement as needed
• Thyroid disorders— In the combined safety database (n=1414), immune-mediated hypothyroidism and hyperthyroidism occurred in 136 patients (9.6%) and 81 patients (5.7%), respectively. Thyroiditis occurred in 10 patients (0.7%), including 1 Grade 3 case (<0.1%) in a patient who had a myocardial infarction. In 9 patients with thyroiditis, transient hyperthyroidism preceded hypothyroidism. Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in five of these patients. In Study 1 (n=182), Grade 1–2 hypothyroidism or thyroiditis occurred in 10 patients (5.5%). Grade 1–2 hyperthyroidism or thyroiditis leading to hyperthyroidism occurred in 9 patients (4.9%). Monitor patients for abnormal thyroid function tests prior to and periodically during treatment
• Immune-mediated adrenal insufficiency—In the combined safety database (n=1414), immune-mediated adrenal insufficiency occurred in 13 patients (0.9%), including 2 Grade 3 cases (0.1%). In Study 1 (n=182), Grade 1 adrenal insufficiency occurred in 1 patient (0.5%). Administer corticosteroids and hormone replacement as clinically indicated
• Type 1 diabetes mellitus—In the combined safety database (n=1414), new onset type 1 diabetes mellitus without an alternative etiology occurred in 1 patient (<0.1%). For type 1 diabetes mellitus, initiate insulin as indicated and withhold IMFINZI until clinically stable
• Hypophysitis—In the combined safety database (n=1414), hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in 1 patient (<0.1%). Administer corticosteroids and hormone replacement as clinically indicated

Other Immune-Mediated Adverse Reactions

• IMFINZI has caused immune-mediated rash. Other immune-related adverse reactions, including aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, nephritis, and ocular inflammatory toxicity including uveitis and keratitis, have occurred in ≤1.0% of patients treated with IMFINZI
• Immune-mediated rash or dermatitis—In the combined safety database (n=1414), immune-mediated rash or dermatitis occurred in 220 patients (15.6%) and 4 patients (0.3%) developed vitiligo. In Study 1 (n=182), 20 patients (11.0%) developed rash, including 1 Grade 3 case (0.5%). Patients should be monitored for signs and symptoms of rash or dermatitis. Administer corticosteroids if indicated. Withhold IMFINZI for Grade 3 rash or dermatitis or Grade 2 rash or dermatitis lasting >1 week. Permanently discontinue IMFINZI in patients with Grade 4 rash or dermatitis
• Immune thrombocytopenic purpura—In the combined safety database (n=1414), 1 fatal case (<0.1%) of immune thrombocytopenic purpura occurred. Monitor patients for signs and symptoms of immune thrombocytopenic purpura
• Nephritis—In the combined safety database (n=1414), immune-mediated nephritis occurred in 3 patients (0.2%), including 2 Grade 3 cases (0.1%). Monitor patients for abnormal renal function tests prior to and during each cycle of IMFINZI. Administer corticosteroids for ≥Grade 2 nephritis (creatinine >1.5X ULN). Withhold IMFINZI for Grade 2 nephritis; permanently discontinue for ≥Grade 3 nephritis (creatinine >3X ULN)

Infection

Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis, occurred in patients receiving IMFINZI. In the combined safety database (n=1414), infections occurred in 531 patients (37.6%). In Study 1 (n=182), infections occurred in 54 patients (29.7%). 11 patients (6.0%) experienced Grade 3–4 infection and 5 patients (2.7%) were experiencing infection at the time of death. 8 patients (4.4%) experienced urinary tract infection, the most common ≥Grade 3 infection. Monitor patients for signs and symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Withhold IMFINZI for ≥Grade 3 infection.

Infusion-Related Reactions

In the combined safety database (n=1414), severe infusion-related reactions occurred in 26 patients (1.8%). In Study 1 (n=182), infusion-related reactions occurred in 3 patients (1.6%). There were 5 Grade 3 (0.4%) and no Grade 4 or 5 reactions. Patients should be monitored for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1–2 infusion-related reactions and permanently discontinue for Grade 3–4 infusion-related reactions.

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. There are no data on the use of IMFINZI in pregnant women. Advise pregnant women of the potential risk to a fetus and advise women of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI.

Nursing Mothers

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 a lactating woman not to breastfeed during treatment and for at least 3 months after the last dose.

Most Common Adverse Reactions

• The most common adverse reactions (≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions (≥3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration
• Adverse reactions leading to discontinuation of IMFINZI occurred in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each)

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Please see complete Prescribing Information including Patient Information.

NOTES TO EDITORS

About PACIFIC

The PACIFIC trial is a randomized, double-blinded, placebo-controlled multi-center trial of durvalumab as sequential treatment in unselected patients with locally advanced, unresectable (Stage III) NSCLC, who have not progressed following platinum-based chemotherapy concurrent with radiation therapy.

The trial is being conducted in 235 centers across 26 countries, including the US, Canada, Europe, South and Central America, Japan, Korea, Taiwan, South Africa and Australia. The primary endpoints of the trial are PFS and OS, and secondary endpoints include landmark PFS and OS, objective response rate and duration of response.

About IMFINZI™ (durvalumab)

IMFINZI™ (durvalumab, previously known as MEDI4736) is a human monoclonal antibody directed against PD-L1, which blocks the interaction of PD-L1 with PD-1 and CD80.

Durvalumab continues to be studied in multiple monotherapy trials and combination trials with tremelimumab and other potential new medicines in Immuno-Oncology. Durvalumab is being assessed in Phase III trials as a monotherapy in various stages of non-small cell lung cancer (NSCLC), in small-cell lung cancer (SCLC), in urothelial cancer and in head and neck squamous cell carcinoma (HNSCC). The combination of durvalumab and tremelimumab is being assessed in Phase III trials in urothelial cancer, NSCLC, SCLC and HNSCC and in Phase I/II trials in hepatocellular carcinoma and hematological malignancies.

About Locally Advanced (Stage III) NSCLC

Stage III lung cancer is divided into two stages (IIIA and IIIB), which are defined by how much the cancer has spread locally and the possibility of surgery. This differentiates it from Stage IV disease, when the cancer has metastasized to other organs.

Stage III lung cancer represents approximately one-third of non-small cell lung cancer incidence and is estimated to affect over 43,000 patients in the United States. About half of these patients have tumors that are unresectable. The current standard of care is chemotherapy and radiation followed by active surveillance to monitor for progression. The prognosis remains poor and long-term survival rates are low.

About AstraZeneca in NSCLC

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths and more than breast, prostate and colorectal cancers combined.

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of non-small cell lung cancer (NSCLC) across all stages of disease and lines of therapy. We aim to address unmet needs of patients with EGFR-mutated tumors as a genetic driver of disease, which occur in 10% to 15% of NSCLC patients in the US and Europe and 30% to 40% of NSCLC patients in Asia, with our approved medicines IRESSA and TAGRISSO and ongoing FLAURA and ADAURA trials. Our extensive late-stage Immuno-Oncology program focuses on 75% to 80% of patients with NSCLC without a known genetic mutation. Our portfolio includes IMFINZI (durvalumab), an anti-PD-L1 monoclonal antibody, which is in development as monotherapy (ADJUVANT, PACIFIC, MYSTIC, PEARL and ARCTIC trials) and in combination with tremelimumab, an anti-CTLA-4 monoclonal antibody (MYSTIC, NEPTUNE and POSEIDON trials).

About AstraZeneca’s approach to Immuno-Oncology (IO)

Immuno-Oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumors. At AstraZeneca and MedImmune, our biologics research and development arm, our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumor immune suppression. We believe that IO-based therapies will offer the potential for life-changing cancer treatments for the vast majority of patients.

We are pursuing a comprehensive clinical trial program that includes durvalumab (anti-PD-L1) monotherapy and in combination with tremelimumab (anti-CTLA-4) in multiple tumor types, stages of disease, and lines of therapy, 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 our IO portfolio with small targeted molecules from across our oncology pipeline, and with those of our research partners, may provide new treatment options across a broad range of tumors.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology; Respiratory, Cardiovascular & Metabolic Diseases; and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three global R&D centers, with additional sites in Cambridge, UK, and Mountain View, Ca. For more information, please visit www.medimmune.com.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas – Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

US-12590 Last Updated 7/17

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