Finding Durvalumab

The late Nobel Prize-winning geneticist Barbara McClintock once said: “If you know you are on the right track, then nobody can turn you off.” It’s that sentiment—combined with data and steely perseverance—that has propelled durvalumab to the cancer immunotherapy stage, despite some early reticence about its potential therapeutic promise.

In February 2016, the US Food and Drug Administration (FDA) granted Breakthrough Therapy designation (BTD) for durvalumab, MedImmune and AstraZeneca’s investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1), for the treatment of patients with metastatic urothelial carcinoma whose tumor has progressed during or after one standard platinum-based regimen.

In December 2016, the FDA accepted the Biologics License Application (BLA) for durvalumab and accelerated approval followed on Monday, May 1, 2017. Durvalumab was 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. Patients should be monitored for immune-mediated adverse reactions including pneumonitis, hepatitis, colitis, endocrinopathies (including adrenal insufficiency, hypophysitis, or Type 1 diabetes mellitus), nephritis, rash, thrombocytopenic purpura, infection, infusion-related reactions, or embryo-fetal toxicity. 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). Eight patients (4.4%) who were treated with IMFINZI experienced Grade 5 adverse events of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. IMFINZI was discontinued for adverse reactions in 3.3% of patients. See below for important safety information.  

While the pathway to approval appears swift and straightforward, the story of durvalumab began nearly a decade ago.

The early story of durvalumab
“The history of durvalumab really starts with our focus on the unmet need in many cancers; and every chapter in its progression shows the culmination of grit, determination and scientific discoveries, ultimately showing that we were indeed on the right track, and nothing was going to deter us,” reflected Dr. David Berman, Head of Oncology Innovative Medicines unit and Senior Vice President, MedImmune.

Laying the foundation
Ten years ago, the cancer immunotherapy community was still gaining in reputation — and many people were dubious about how and if it would move forward. Slowly, emerging data began to demonstrate promise, initially with therapies against CTLA-4 — an immune checkpoint preventing T-cell activation — and then with therapies targeting against PD-L1 — an immune checkpoint that provides escape for tumor cells and triggers apoptosis (or cell death) on activated T cells.

Durvalumab demonstrated activity in vitro and then in in vivo testing. These data, and the belief in the promise of immunotherapy for long-term survival benefit, were the groundwork for MedImmune’s commitment to developing durvalumab and to building a strong cancer immunotherapy portfolio, even against a backdrop of uncertainty in the scientific community.

“Molecules, like ideas, begin as rough outlines with a lot of risk,” Berman added. “You have an ultimate goal but never know exactly what their final shape will be. Despite numerous challenges, we had one simple policy that allowed us to overcome any challenge — follow the science. We never gave up, and now we are pleased to have durvalumab as the backbone of our broad cancer immunotherapy investigational portfolio.”

That policy paid off when our researchers started the first trial of durvalumab called Study 1108 — a multisite trial of nearly 1,000 patients across 16 tumor types. We identified activity in multiple tumors, including in metastatic UC, where the early clinical data led to BTD.

Right track, right molecule, right time
Urothelial bladder cancers arise from the epithelium of the bladder and are the sixth most common form of cancer in the US. It is estimated that in 2017, approximately 79,000 Americans will be diagnosed with bladder cancer, and almost 17,000 will die from this disease. The existing standard of care is systemic platinum-based chemotherapy—introduced nearly 30 years ago—and while other treatments are available, patients still need more options.

A look to the future
The story has only just begun for durvalumab as MedImmune and AstraZeneca’s first biologic approval in oncology. Today, we have more than 30 ongoing cancer immunotherapy trials with durvalumab as monotherapy or in combination with other molecules.  

“Now, it’s really about more than the success of one molecule,” Berman noted. “We’re inspired, and we have a laser focus on developing more immunotherapies to help patients with cancer.”

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, and other immune-mediated adverse reactions. 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. 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 accompanying complete Prescribing Information including Patient Information.

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