Toripalimab-tpzi (Monograph)

Brand name: Loqtorzi
Drug class: Antineoplastic Agents

Introduction

Toripalimab-tpzi, a programmed death receptor-1 (PD-1)- blocking antibody, is an antineoplastic agent.

Uses for Toripalimab-tpzi

Toripalimab-tpzi has the following uses:

Toripalimab-tpzi is used in combination with cisplatin and gemcitabine for first-line treatment of adults with metastatic or with recurrent locally advanced nasopharyngeal carcinoma (NPC).

Toripalimab-tpzi is also used as a single agent for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after a platinum-containing chemotherapy.

Toripalimab-tpzi Dosage and Administration

General

Toripalimab-tpzi is available in the following dosage form(s) and strength(s):

240 mg/6 mL (40 mg/mL) solution in a single-dose vial for dilution and IV infusion.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Dilute required volume of toripalimab in a 100 mL or 250 mL infusion bag containing 0.9% sodium chloride injection to provide a final concentration between 1 mg/mL to 3 mg/mL. See Full Prescribing Information for additional instructions on preparation of infusion solution.
Recommended dosage when used in combination with cisplatin and gemcitabine for first-line treatment of nasopharyngeal carcinoma: 240 mg IV every three weeks.
Recommended dosage when used as a single agent for treatment of recurrent nasopharyngeal carcinoma: 3 mg/kg IV every two weeks.
Administer diluted solution via infusion pump.
First Infusion: Infuse over at least 60 minutes.
Subsequent Infusions: If no infusion-related reactions occurred during the first infusion, subsequent infusions may be administered over 30 minutes.
When administered on the same day as chemotherapy, administer toripalimab prior to chemotherapy.
See Full Prescribing Information for recommended dosage modifications for adverse reactions.

Cautions for Toripalimab-tpzi

Contraindications

None

Warnings/Precautions

Severe and Fatal Immune-mediated Adverse Reactions

Toripalimab is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed in the prescribing information 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 and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor 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 toripalimab depending on severity. In general, if toripalimab requires interruption or discontinuation, administer systemic corticosteroid therapy (1 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.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-mediated Pneumonitis

Toripalimab (used in combination with cisplatin and gemcitabine or as single agent therapy) can cause immune-mediated pneumonitis. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 2.1% (3/146) of patients receiving toripalimab-tpzi in combination with cisplatin and gemcitabine, including Grade 2 (1.4%) adverse reactions. Pneumonitis resolved in 67% (2/3) of these patients.

Immune-mediated pneumonitis occurred in 2.6% (22/851) of patients receiving toripalimab-tpzi as single agent therapy, including fatal (0.2%), Grade 3 (0.7%), and Grade 2 (1.1%) adverse reactions. Systemic corticosteroids were required in 82% (18/22) of patients. Pneumonitis led to permanent discontinuation of toripalimab in 1.2% (10/851) of patients. Pneumonitis resolved in 23% (5/22) of these patients.

Immune-mediated Colitis

Toripalimab can cause immune-mediated colitis, which may present 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 occurred in 0.4% (3/851) of patients receiving toripalimab-tpzi as single agent therapy, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. Colitis resolved in all 3 patients.

Hepatotoxicity and Immune-mediated Hepatitis

Toripalimab in combination with cisplatin and gemcitabine can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (1/146) of patients receiving such combination therapy; the patient experienced a Grade 3 (0.7%) adverse reaction which required treatment with systemic corticosteroids.

Toripalimab as single agent therapy can also cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 3.3% (28/851) of patients receiving toripalimab-tpzi, including Grade 4 (0.8%), Grade 3 (2.1%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of the drug in 1.1% of patients and withholding of therapy in 0.8% of patients. Hepatitis resolved in 54% (15/28) of these patients.

Immune-mediated Adrenal Insufficiency

Toripalimab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue toripalimab depending on severity. Adrenal insufficiency occurred in 0.5% (4/851) of patients receiving toripalimab-tpzi as single agent therapy, including Grade 2 (0.4%) and Grade 1 (0.1%) adverse reactions. Systemic corticosteroids were required in 75% (3/4) of the patients and 0.1% (1/851) of patients required interruption of therapy. In the one patient in whom toripalimab was withheld, the drug was reinitiated after symptom improvement.

Immune-mediated Hypophysitis

Toripalimab can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effects such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue toripalimab depending on severity.

Hypophysitis occurred in 0.4% (3/851) of patients receiving toripalimab-tpzi as single agent therapy, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. All three patients received systemic corticosteroids. Hypophysitis led to permanent discontinuation of toripalimab in 0.1% (1/851) of patients and withholding of therapy in 0.1% (1/851) of patients. The one patient in whom toripalimab was withheld reinitiated therapy.

Immune-mediated Thyroid Disorders

Toripalimab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue therapy depending on severity.

Thyroiditis occurred in 2.1% (3/146) of patients receiving toripalimab-tpzi in combination with cisplatin and gemcitabine, including Grade 2 (1.4%). Three patients required thyroid hormone replacement therapy. Thyroiditis resolved in one of the 3 patients. Hyperthyroidism occurred in 1.4% (2/146) of patients receiving toripalimab in combination with cisplatin and gemcitabine. Hyperthyroidism resolved in these 2 patients. Hypothyroidism occurred in 30% (44/146) of patients receiving toripalimab-tpzi in combination with cisplatin and gemcitabine, including Grade 2 (24%) and Grade 1 (6%). Eighty percent of the 44 patients required thyroid hormone replacement therapy. Toripalimab was withheld in 2.1% (3/146) of the patients. Of the 3 patients in whom toripalimab was withheld, 2 patients reinitiated therapy.

Thyroiditis occurred in 0.6% (5/851) of patients receiving toripalimab as single agent therapy, including Grade 2 (0.1%). Two of these 5 patients received systemic corticosteroids and 2 required thyroid hormone replacement therapy. Thyroiditis resolved in 2 of the 5 patients. Hyperthyroidism occurred in 7% (55/851) of patients receiving toripalimab-tpzi, including Grade 2 (1.9%). Hyperthyroidism resolved in 85% (47/55) of the patients. Hypothyroidism occurred in 15% (128/851) of patients receiving toripalimab-tpzi, including Grade 2 (8%); 63% of these patients required thyroid hormone replacement therapy. Toripalimab was withheld in 0.5% of patients. Of the 4 patients in whom toripalimab was withheld, 3 patients reinitiated therapy.

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. Withhold or permanently discontinue toripalimab depending on severity. Diabetes mellitus occurred in 0.9% (8/851) of patients receiving toripalimab-tpzi as single agent therapy, including Grade 4 (0.1%), Grade 3 (0.7%), and Grade 2 (0.1%). Diabetes mellitus led to permanent discontinuation in 0.4% of patients, and 6 of the 8 (75%) patients with diabetes mellitus required long-term insulin therapy.

Immune-mediated Nephritis with Renal Dysfunction

Immune-mediated nephritis occurred in 0.7% (1/146) of patients receiving toripalimab-tpzi in combination with cisplatin and gemcitabine. The one patient with immune-mediated nephritis (Grade 4) required systemic corticosteroids and nephritis led to discontinuation of therapy. Nephritis resolved in this patient.

Immune-mediated nephritis occurred in 0.5% (4/851) of patients receiving toripalimab-tpzi as single agent therapy, including Grade 3 (0.5%) adverse reactions. Nephritis resolved in 75% (3/4) of these patients.

Immune-mediated Dermatologic Adverse Reactions

Toripalimab 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/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue toripalimab depending on severity.

Immune-mediated dermatologic adverse reactions occurred in 8% (12/146) of patients receiving toripalimab-tpzi in combination with cisplatin and gemcitabine, including Grade 3 (3.4%) and Grade 2 (1.4%) adverse reactions. Systemic corticosteroids were required in 25% (3/12) of the patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of toripalimab in 2.1% (3) of patients and resolved in 92% (11/12) of these patients.

Immune-mediated dermatologic adverse reactions occurred in 4% (34/851) of patients receiving toripalimab-tpzi as single agent therapy, including Grade 3 (0.4%) and Grade 2 (1.4%) adverse reactions. Immune-mediated dermatologic adverse reactions led to withholding of toripalimab in 0.4% (3) of the patients. Systemic corticosteroids were required in 12% (4/34) of the patients. Immune-mediated dermatologic adverse reactions resolved in 71% (24/34) of these patients.

Other Immune-mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received toripalimab-tpzi or were reported with the use of other PD1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular:Myocarditis, pericarditis, vasculitis, pericardial effusion.

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, including 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:Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue:Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica, dermatomyositis.

Endocrine:Hypoparathyroidism.

Hematologic/Immune:Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-related Reactions

Toripalimab-tpzi can cause severe or life-threatening infusion-related reactions including hypersensitivity and anaphylaxis.

Infusion-related reactions have been reported in 4.1% of patients receiving toripalimab-tpzi in combination with cisplatin and gemcitabine, including Grade 2 (0.7%) reactions.

Infusion-related reactions occurred in 2% of 851 patients receiving toripalimab-tpzi as single agent, including Grade 3 (0.1%) and Grade 2 (0.6%). Toripalimab was withheld for one Grade 3 infusion related reaction.

Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue toripalimab.

Complications of Allogeneic HSCT

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. 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/PD-L1 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/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-fetal Toxicity

Based on its mechanism of action, toripalimab can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with toripalimab and for 4 months after the last dose.

Specific Populations

Pregnancy

Based on its mechanism of action, toripalimab can cause fetal harm when administered to a pregnant woman. There are no available data on the use of toripalimab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus and result in fetal death. Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, toripalimab can potentially be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of toripalimab in human milk or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local GI exposure and limited systemic exposure in the breastfed child to toripalimab are unknown. Because of the potential for serious adverse reactions in breastfed children, advise lactating women not to breastfeed during treatment with toripalimab and for 4 months after the last dose.

Females and Males of Reproductive Potential

Toripalimab can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to initiating toripalimab.

Advise females of reproductive potential to use effective contraception during treatment with toripalimab and for 4 months after the last dose.

Pediatric Use

The safety and effectiveness of toripalimab-tpzi have not been established in pediatric patients.

Geriatric Use

Of the 146 patients with nasopharyngeal carcinoma (NPC) who were treated with toripalimab-tpzi in combination with cisplatin and gemcitabine, 7 (4.8%) were 65 years of age or older; there were no patients 75 years of age and older. Clinical studies of toripalimab-tpzi in combination with cisplatin and gemcitabine did not include a sufficient number of patients 65 years of age and older with NPC to determine whether they respond differently from younger patients.

Of the 851 patients with tumor types including nasopharyngeal carcinoma or other types of tumors from the safety pool treated with toripalimab-tpzi as a single agent, 171 (20%) patients were 65 years or older and 13 (1.5%) patients were 75 years and older. No overall differences in safety were observed between elderly patients and younger patients

Of the 190 patients with NPC treated with toripalimab-tpzi as single agent, 10 (5%) patients were 65 years or older; there were no patients 75 years and older. Clinical studies of toripalimab-tpzi did not include sufficient numbers of patients 65 years of age and older with NPC to determine whether they respond differently from younger patients.

Common Adverse Effects

Toripalimab-tpzi in combination with cisplatin and gemcitabine: The most common adverse reactions (≥ 20%) are nausea, vomiting, decreased appetite, constipation, hypothyroidism, rash, pyrexia, diarrhea, peripheral neuropathy, cough, musculoskeletal pain, upper respiratory infection, insomnia, dizziness, and malaise.
Toripalimab-tpzi as a single agent: The most common adverse reactions (≥ 20%) are fatigue, hypothyroidism and musculoskeletal pain.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Toripalimab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of toripalimab. These reactions may include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reaction, or other immune-mediated adverse reactions.
Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath.
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding.
Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus.
Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN.
Advise patients that other immune-mediated adverse reactions can occur and may involve any organ system. Advise patients to contact their healthcare provider immediately for any new or worsening signs or symptoms.
Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection.
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.
Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications.
Advise females of reproductive potential that toripalimab can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with toripalimab and for 4 months after the last dose.
Advise women not to breastfeed during treatment with toripalimab and for 4 months after the last dose.
Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.