IMJUDO® (tremelimumab) in Combination With IMFINZI® (durvalumab) Approved in the US for Patients With Unresectable Liver Cancer
AstraZeneca has received FDA approval for IMJUDO (tremelimumab) in combination with IMFINZI (durvalumab) to treat adults with unresectable hepatocellular carcinoma (HCC). This combination therapy demonstrated a 22% reduced risk of death compared to sorafenib, based on Phase III HIMALAYA trial results. The novel STRIDE regimen includes a single dose of IMJUDO followed by IMFINZI every four weeks. An estimated 31% of patients treated with the combination were alive after three years. The approval underscores AstraZeneca's commitment to advancing cancer treatment options.
- FDA approval for IMJUDO in combination with IMFINZI for treating unresectable HCC.
- 22% reduction in death risk compared to sorafenib based on HIMALAYA trial results.
- 31% of patients alive after three years with the combination therapy.
- Safety concerns related to immune-mediated adverse reactions, including potential severe outcomes.
Approval based on HIMALAYA Phase III trial results which showed single priming dose of IMJUDO added to IMFINZI reduced risk of death by
The approval by the
Liver cancer is the third-leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide.3,4 It is the fastest rising cause of cancer-related deaths in the US, with approximately 36,000 new diagnoses each year.5,6
The safety profiles of the combination of IMJUDO added to IMFINZI and for IMFINZI alone were consistent with the known profiles of each medicine, and no new safety signals were identified.
Regulatory applications for IMJUDO in combination with IMFINZI are currently under review in
IMPORTANT SAFETY INFORMATION
There are no contraindications for IMFINZI® (durvalumab) or IMJUDO® (tremelimumab-actl).
Severe and Fatal 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 clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. 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 and IMJUDO depending on severity. See USPI Dosing and Administration for specific details. In general, if combination of IMFINZI and IMJUDO 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.
Immune-Mediated Pneumonitis
IMFINZI in combination with IMJUDO can cause immune-mediated pneumonitis, which may be fatal. Immune‑mediated pneumonitis occurred in
Immune-Mediated Colitis
IMFINZI in combination with IMJUDO can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune‑mediated colitis or diarrhea occurred in
Immune-Mediated Hepatitis
IMFINZI in combination with IMJUDO can cause immune-mediated hepatitis, which may be fatal. Immune‑mediated hepatitis occurred in
Immune-Mediated Endocrinopathies
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Adrenal Insufficiency: IMFINZI in combination with IMJUDO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in
1.5% (6/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3% ) adverse reactions. -
Hypophysitis: IMFINZI in combination with IMJUDO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Immune-mediated hypophysitis/hypopituitarism occurred in
1% (4/388) of patients receiving IMFINZI and IMJUDO. -
Thyroid Disorders (Thyroiditis, Hyperthyroidism, and Hypothyroidism): IMFINZI in combination with IMJUDO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.
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Immune-mediated thyroiditis occurred in
1.5% (6/388) of patients receiving IMFINZI and IMJUDO. -
Immune-mediated hyperthyroidism occurred in
4.6% (18/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3% ) adverse reactions. -
Immune-mediated hypothyroidism occurred in
11% (42/388) of patients receiving IMFINZI and IMJUDO.
-
Immune-mediated thyroiditis occurred in
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Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Two patients
0.5% (2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.
Immune-Mediated Nephritis with Renal Dysfunction
IMFINZI in combination with IMJUDO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in
Immune-Mediated Dermatology Reactions
IMFINZI in combination with IMJUDO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 and CTLA-4 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in
Immune-Mediated Pancreatitis
IMFINZI in combination with IMJUDO can cause immune-mediated pancreatitis. Immune-mediated pancreatitis occurred in
Other Immune-Mediated Adverse Reactions
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than
- Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
- Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
- Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
- Gastrointestinal: Gastritis, duodenitis.
- Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.
- Endocrine: Hypoparathyroidism.
- Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.
Infusion-Related Reactions
IMFINZI and IMJUDO 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 and IMJUDO based on the severity. See USPI 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 10 (
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, both IMFINZI and IMJUDO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and IMJUDO and advise them to use effective contraception during treatment with IMFINZI and IMJUDO and for 3 months after the last dose of IMFINZI and IMJUDO.
Lactation
There is no information regarding the presence of either IMFINZI or IMJUDO in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI and IMJUDO, advise women not to breastfeed during treatment and for 3 months after the last dose.
Adverse Reactions
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In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO, the most common adverse reactions (occurring in ≥
20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. -
In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO, serious adverse reactions occurred in
41% of patients. Serious adverse reactions in >1% of patients included hemorrhage (6% ), diarrhea (4% ), sepsis (2.1% ), pneumonia (2.1% ), rash (1.5% ), vomiting (1.3% ), acute kidney injury (1.3% ), and anemia (1.3% ). Fatal adverse reactions occurred in8% of patients who received IMJUDO in combination with durvalumab, including death (1% ), hemorrhage intracranial (0.5% ), cardiac arrest (0.5% ), pneumonitis (0.5% ), hepatic failure (0.5% ), and immune-mediated hepatitis (0.5% ). Permanent discontinuation of treatment regimen due to an adverse reaction occurred in14% of patients.
The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients.
Indication:
IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).
IMPORTANT PRODUCT INFORMATION
IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis and renal dysfunction, immune-mediated dermatologic reactions, immune-mediated pancreatitis, and solid organ transplant rejection. IMFINZI and IMJUDO can cause severe or life-threatening infusion-related reactions. 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/PD-L1 blocking antibody.
Advise women not to become pregnant or breastfeed during treatment with IMFINZI and IMJUDO and for 3 months after the last dose.
Serious adverse reactions in >
The most common adverse reactions (occurring in ≥
The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients.
Please see Full Prescribing Information including Medication Guide for IMFINZI and IMJUDO.
Notes
Liver cancer
About
More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.8 A critical unmet need exists for patients with HCC who face limited treatment options.8 The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC.8
HIMALAYA
HIMALAYA was a randomized, open-label, multicenter, global Phase III trial of IMFINZI monotherapy and a regimen comprising a single priming dose of IMJUDO 300mg added to IMFINZI 1500mg followed by IMFINZI every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.
The trial included a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue).
The trial was conducted in 181 centers across 16 countries, including in the US,
IMFINZI
IMFINZI® (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.
IMFINZI was recently approved to treat patients with advanced biliary tract cancer in the US based on results from the TOPAZ-1 Phase III trial. It is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy and is the global standard of care in this setting based on the PACIFIC Phase III trial.
IMFINZI is also approved in the US, EU,
IMFINZI is also approved for previously treated patients with advanced bladder cancer in several countries.
Since the first approval in
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, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer, and other solid tumors.
IMFINZI combinations have also demonstrated clinical benefit in metastatic NSCLC in the POSEIDON Phase III trial.
IMJUDO
IMJUDO® (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). IMJUDO blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.
Beyond HIMALAYA, IMJUDO is being tested in combination with IMFINZI across multiple tumor types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE).
IMJUDO is also under review by global regulatory authorities in combination with IMFINZI and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON Phase III trial, which showed the addition of a short course of IMJUDO to IMFINZI plus chemotherapy improved both overall and progression-free survival compared to chemotherapy alone.
Within this program, the Company is committed to improving outcomes in gastric, liver, biliary tract, esophageal, pancreatic, and colorectal cancers.
IMFINZI is being assessed in combinations in esophageal and gastric cancers in an extensive development program spanning early to late-stage disease across settings.
The Company aims to understand the potential of fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Fam-trastuzumab deruxtecan-nxki is jointly developed and commercialized by
Olaparib is a first-in-class PARP inhibitor with a broad and advanced clinical trial program across multiple GI tumor types including pancreatic and colorectal cancers. Olaparib is developed and commercialized in collaboration with Merck & Co., Inc., known as MSD outside the US and
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 evasion of the anti-tumor immune response.
The Company is pursuing a comprehensive clinical trial program that includes IMFINZI as a single treatment and in combination with IMJUDO 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.
The Company's focus is on some of the most challenging cancers. It is through persistent innovation that
About
References
- Imfinzi and Imjudo US prescribing information; 2022.
- Abou-Alfa, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1-12.
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ASCO. Liver Cancer: View All Pages. Available at: https://www.cancer.net/cancer-types/liver-cancer/view-all. Accessed
October 2022 . -
WHO. Liver Cancer Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf. Accessed
October 2022 . - Rawla, P, et al. Update in global trends and aetiology of hepatocellular carcinoma. Contemp Oncol (Pozn). 2018; 22(3): 141–150.
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CDC . Liver Cancer. Available at: https://www.cdc.gov/cancer/liver/index.htm. Accessed:October 2022 . - Tarao K, et al. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases—meta‐analytic assessment. Cancer Med. 2019;8(3):1054-1065.
- Colagrande S, et al. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645-7659.
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WHO. World Cancer Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/39-All-cancers-fact-sheet.pdf. Accessed
October 2022 .
US-66853 Last Updated 10/22
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