Loqtorzi Drug Information

Generic name: TORIPALIMAB-TPZI

Programmed Death Receptor-1 Blocking Antibody [EPC]

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Uses of Loqtorzi

First-line Treatment of Metastatic or Recurrent, Locally Advanced NPC with Cisplatin and Gemcitabine LOQTORZI is indicated, in combination with cisplatin and gemcitabine, for the first-line treatment of adults with metastatic or with recurrent, locally advanced nasopharyngeal carcinoma (NPC).

Previously Treated Unresectable or Metastatic NPC LOQTORZI is indicated, 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.

Dosage & Administration of Loqtorzi

Recommended Dosage

The recommended dosages of LOQTORZI are provided in Table 1. Administer as recommended. Table 1: Recommended Dosage

Dosage Modifications

No dose reductions of LOQTORZI are recommended. In general, withhold LOQTORZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue LOQTORZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.

Dosage modifications for LOQTORZI for adverse reactions that require management different from these general guidelines are summarized in Table 2. Table 2: Recommended Dosage Modifications for

Preparation and Administration Preparation for Intravenous Infusion Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.

Withdraw the required volume of LOQTORZI and inject slowly into a 100 mL or 250 mL infusion bag containing 0.9% Sodium Chloride Injection, USP. Mix diluted solution by gentle inversion. Do not shake.

The final concentration of the diluted solution should be between 1 mg/mL to 3 mg/mL. Discard any unused portion left in the vial. Storage of Diluted Solution for Infusion LOQTORZI does not contain a preservative.

If the diluted solution is not administered immediately, store either: At room temperature, 20°C to 25°C (68°F to 77°F), for no more than 8 hours from the time of dilution to the completion of the infusion. Discard diluted solution stored at room temperature after 8 hours. Or Refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution to the completion of the infusion.

If refrigerated, allow the diluted solution to come to room temperature prior to administration. Discard the refrigerated diluted solution after 24 hours. Do not freeze.

Administration Administer diluted solution intravenously via an infusion pump using an in-line aseptic filter (0.2 or 0.22 micron). 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.

Do not co-administer other drugs through the same intravenous line. When administered on the same day as chemotherapy, LOQTORZI should be administered prior to chemotherapy. Refer to the Prescribing Information for cisplatin and gemcitabine for recommended dosing information.

Table 1: Recommended Dosage
Indication	Recommended Dosage of LOQTORZI	Duration of Treatment
First-line NPC	240 mg every three weeks	Until disease progression, unacceptable toxicity, or up to 24 months.
Recurrent NPC	3 mg/kg every two weeks	Until disease progression or unacceptable toxicity.

Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity Based on National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0	Dose Modification
ALT=alanine aminotransferase, AST=aspartate aminotransferase, DRESS=drug rash with eosinophilia and systemic symptoms, SJS=Stevens Johnson syndrome, TEN=toxic epidermal necrolysis, ULN=upper limit of normal
Immune-Related Adverse Reactions [see Warnings and Precautions (5.1) ]
Pneumonitis	Grade 2	Withhold Resume LOQTORZI in patients with complete or partial resolution to Grade 0-1 after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
Pneumonitis	Grades 3 or 4	Permanently discontinue
Colitis	Grade 2 or 3	Withhold
Colitis	Grade 4	Permanently discontinue
Hepatitis with no tumor involvement of the liver	AST/ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN	Withhold
Hepatitis with no tumor involvement of the liver	AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue LOQTORZI based on recommendations for hepatitis with no liver involvement.	Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN	Withhold
	Baseline AST or ALT is above the ULN and increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Endocrinopathies	Grades 3 or 4	Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal Dysfunction	Grade 2 or 3 increased blood creatinine	Withhold
Nephritis with Renal Dysfunction	Grade 4 increased blood creatinine	Permanently discontinue
Exfoliative Dermatologic Conditions	Suspected SJS, TEN, or DRESS	Withhold
Exfoliative Dermatologic Conditions	Confirmed SJS, TEN, or DRESS	Permanently discontinue
Myocarditis	Grades 2, 3, or 4	Permanently discontinue
Neurological toxicities	Grade 2	Withhold
Neurological toxicities	Grade 3-4	Permanently discontinue
Other Adverse Reactions
Infusion-related reactions [see Warnings and Precautions (5.2) ]	Grade 1 or 2	Interrupt or slow the rate of infusion
	Grade 3 or 4	Stop infusion Permanently discontinue

Side Effects of Loqtorzi

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to LOQTORZI at a dose of 240 mg every 3 weeks in combination with up to 6 cycles of cisplatin and gemcitabine, followed by LOQTORZI 240 mg IV every 3 weeks, in 146 patients with NPC enrolled in a randomized, double-blind, placebo-controlled trial (JUPITER-02). The most common adverse reactions (≥ %).

The data described in the WARNINGS AND PRECAUTIONS section also reflects exposure to LOQTORZI as a single agent at a dose of 3 mg/kg IV every 2 weeks in 851 patients enrolled in 12 trials: one randomized, active-controlled trial and 11 open-label, non-randomized trials. The tumor types included nasopharyngeal carcinoma n= months or more. First-line Treatment of Metastatic or Recurrent, Locally Advanced Nasopharyngeal Carcinoma (NPC) The safety of LOQTORZI in combination with cisplatin and gemcitabine was evaluated in JUPITER-02.

Key eligibility criteria were recurrent locally advanced or metastatic nasopharyngeal carcinoma (NPC) not previously treated with systemic chemotherapy for recurrent or metastatic disease. Patients with recurrent NPC after treatment with curative intent were required to have an interval of at least 6 months between the last dose of radiotherapy or chemotherapy and recurrence. Among patients who received LOQTORZI, 73% were exposed for 6 months or longer and 54% were exposed for greater than one year.

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) was Approximately 59% of patients had received at least one prior systemic therapy for locally advanced disease and 60% had received prior radiation therapy. Serious adverse reactions occurred in 43% of patients receiving LOQTORZI in combination with cisplatin and gemcitabine. Of the patients who received LOQTORZI in combination with cisplatin and gemcitabine, there were three fatal adverse reactions (2.1%) one due to epistaxis; one due to intracranial hemorrhage associated with immune-related thrombocytopenia and coagulopathy; and one due to pneumonia.

Permanent discontinuation of LOQTORZI, when given in combination with cisplatin and gemcitabine, due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of % of patients. Table 3 summarizes the adverse reactions in JUPITER-02.

Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Recurrent, Locally Advanced or Metastatic NPC Who Received LOQTORZI in Combination with Cisplatin and Gemcitabine in JUPITER-02 0 Previously Treated, Unresectable or Metastatic Nasopharyngeal Carcinoma (NPC) The safety of LOQTORZI was evaluated in POLARIS-02. Eligible patients had previously treated unresectable or metastatic NPC. Patients received LOQTORZI 3 mg/kg every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity.

Serious adverse reactions occurred in 24% of patients who received LOQTORZI. Dosage interruptions due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥1% were pneumonia ( %).

Table 5 summarizes the adverse reactions in POLARIS-02.

Table 3: Adverse Reactions (≥ 10%) in Patients with Recurrent, Locally Advanced or Metastatic NPC Who Received LOQTORZI in Combination with Cisplatin and Gemcitabine in JUPITER-02
Adverse Reaction NCI CTCAE v5.0.	LOQTORZI Cisplatin/Gemcitabine N = 146		Placebo Cisplatin/Gemcitabine N = 143
Adverse Reaction NCI CTCAE v5.0.	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal Disorders
Nausea	71	1.4	84	2.8
Vomiting	68	2.1	66	2.1
Constipation	39	0	46	0
Diarrhea	31	1.4	23	0
Stomatitis Includes mouth ulceration, stomatitis, and radiation stomatitis.	12	0	8	0.7
Metabolism and Nutrition Disorders
Decreased appetite	55	0.7	63	0
Endocrine Disorders
Hypothyroidism Includes hypothyroidism, tri-iodothyronine decreased, tri-iodothyronine free decreased, and thyroiditis.	38	0.7	17	0
Skin Disorders
Rash Includes acneiform dermatitis, allergic dermatitis, catheter-site rash, dermatitis, drug eruption, eczema, erythema, macule, maculopapular rash, palmar-plantar erythrodysesthesia syndrome, papule, pruritic rash, rash, and urticaria.	36	3.4	28	2.8
Pruritus	17	0	8	0
General Disorders
Pyrexia	32	1.4	24	0.7
Malaise	21	0.7	20	0
Fatigue Includes asthenia and fatigue.	19	0.7	22	2.1
Nervous System Disorders
Peripheral neuropathy Includes hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.	30	0	31	0.7
Dizziness	21	0	22	0.7
Headache	18	0	23	0.7
Respiratory, Thoracic and Mediastinal Disorders
Cough Includes cough and productive cough.	26	0	27	0
Musculoskeletal Disorders
Musculoskeletal pain Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, pain in jaw.	25	0	25	0.7
Infections
Upper respiratory infection Includes acute sinusitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection.	23	3.4	13	2.8
Pneumonia Includes aspiration pneumonia and pneumonia	18	11	7	3.5
Psychiatric Disorders
Insomnia	23	0	17	0
Vascular Disorders
Epistaxis	10	1.3	13	2.8
Hypertension Includes blood pressure increased, blood pressure systolic increased, hypertension, and hypertensive crisis.	10	6	6	4.2

Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Recurrent, Locally Advanced or Metastatic NPC Who Received LOQTORZI in Combination with Cisplatin and Gemcitabine in JUPITER-02
Laboratory Abnormalities Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: LOQTORZI/chemotherapy (range: 139 to 146 patients) and placebo/chemotherapy (range: 136 to 143 patients).	LOQTORZI Cisplatin/Gemcitabine		Placebo Cisplatin/Gemcitabine
	All Grades Graded per NCI CTCAE v5.0; AKP=alkaline phosphatase. ALT=alanine aminotransferase. AST=aspartate aminotransferase. (%)	Grade 3 or 4 (%)	All Grades (%)	Grades 3 or 4 (%)
Hematology
Decreased hemoglobin	94	50	97	38
Decreased neutrophils	91	58	95	63
Decreased lymphocytes	88	57	88	49
Decreased platelets	71	33	66	31
Chemistry
Decreased magnesium	78	4.2	77	8
Decreased sodium	63	9	62	6
Increased alanine aminotransferase	58	6	50	3.5
Increased aspartate aminotransferase	58	2.7	53	4.9
Decreased albumin	49	0	48	0
Decreased calcium	45	3.5	46	4.2
Increased lactate dehydrogenase	42	0	35	0
Increased calcium	39	0	35	0.7
Decreased potassium	40	10	39	8
Increased creatinine	39	0.7	41	0
Increased alkaline phosphatase	27	0	27	0
Decreased glucose	23	1.4	16	0

Table 5: Adverse Reactions (≥10%) in Patients with Previously Treated, Unresectable or Metastatic NPC Who Received LOQTORZI in POLARIS-02
Adverse Reaction Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.	LOQTORZI N=190
	All Grades (%)	Grade 3 or 4 (%)
Endocrine Disorders
Hypothyroidism Includes hypothyroidism, thyroiditis, tri-iodothyronine decreased, and tri-iodothyronine free decreased	27	0
General Disorders
Fatigue Includes fatigue and asthenia	22	2.6
Pyrexia	16	0
Respiratory Disorders
Cough Includes cough and productive cough.	20	0
Musculoskeletal Disorders
Musculoskeletal Pain Includes musculoskeletal pain and myalgia.	18	1.1
Metabolism and Nutrition
Decreased Appetite	13	1.1
Gastrointestinal Disorders
Constipation	11	0
Skin and Subcutaneous Disorders
Pruritus	11	0
Rash Includes dermatitis allergic, eczema, and rash.	11	0
Investigations
Weight Decreased	11	0

Table 6: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Previously Treated, Unresectable or Metastatic NPC Who Received LOQTORZI in POLARIS-02
	LOQTORZI
	All Grades (%) Toxicity graded per NCI CTCAE v4.03. The denominator used to calculate the rate varied from 141 to 186 based on the number of patients with a baseline value and at least one post-treatment value.	Grade 3 or 4 (%)
Chemistry
Decreased albumin	38	0.5
Decreased sodium	35	11
Decreased phosphate	32	3.2
Increased aspartate aminotransferase	30	3.8
Decreased calcium	29	0.5
Increased alkaline phosphatase	28	2.2
Increased triglyceride	26	1.1
Increased glucose	24	1.1
Increased alanine aminotransferase	23	1.6
Hematology
Decreased lymphocytes	52	9
Decreased hemoglobin	43	6

Warnings & Cautions for Loqtorzi

Severe and Fatal Immune-Mediated Adverse Reactions LOQTORZI 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 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 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 LOQTORZI depending on severity. In general, if LOQTORZI 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 LOQTORZI in Combination with Cisplatin and Gemcitabine LOQTORZI in combination with cisplatin and gemcitabine 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. Pneumonitis resolved in 67% (2/3) of these patients.

LOQTORZI as a Single-Agent LOQTORZI can cause immune-mediated pneumonitis. Systemic corticosteroids were required in 82% (18/22) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of LOQTORZI in 1.2% (10/851) of patients.

Pneumonitis resolved in 23% (5/22) of these patients. Immune-Mediated Colitis LOQTORZI 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. Colitis resolved in all 3 patients. The patient with immune-mediated hepatitis required systemic corticosteroids.

Hepatitis led to permanent discontinuation of LOQTORZI in 1.1% of patients and withholding of LOQTORZI in 0.8% of patients. Hepatitis resolved in 54% (15/28) of these patients. Immune-Mediated Endocrinopathies Adrenal Insufficiency LOQTORZI can cause primary or secondary adrenal insufficiency.

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Systemic corticosteroids were required in 75% (3/4) of the patients with adrenal insufficiency. Adrenal insufficiency led to withholding of LOQTORZI in 0.1% (1/851) of patients.

In the one patient in whom LOQTORZI was withheld, LOQTORZI was reinitiated after symptom improvement. Hypophysitis LOQTORZI 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. All three patients received systemic corticosteroids.

Thyroid Disorders LOQTORZI 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. 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 LOQTORZI in combination with cisplatin and gemcitabine. Hyperthyroidism resolved in these 2 patients. Eighty percent of the 44 patients required thyroid hormone replacement therapy.

LOQTORZI was withheld in 2.1% (3/146) of the patients. Of the 3 patients in whom LOQTORZI was withheld, 2 patients reinitiated LOQTORZI. Two of these 5 patients received systemic corticosteroids and 2 required thyroid hormone replacement therapy.

Thyroiditis resolved in 2 of the 5 patients. Hyperthyroidism resolved in 85% (47/55) of the patients. Sixty three percent of the 128 patients required thyroid hormone replacement therapy.

LOQTORZI was withheld in 0.5% of patients. 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.

Diabetes mellitus led to permanent discontinuation in 0.4% of patients. Six of the 8 (75%) patients with diabetes mellitus required long-term insulin therapy. Immune-mediated nephritis occurred in 0.7% (1/146) of patients receiving LOQTORZI.

The one patient with immune-mediated nephritis (Grade 4) required systemic corticosteroids and nephritis led to discontinuation of LOQTORZI. Nephritis resolved in this patient. Nephritis resolved in 75% (3/4) of these patients.

Immune-Mediated Dermatologic Adverse Reactions LOQTORZI 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.

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 LOQTORZI in 2.1% of patients. Immune-mediated dermatologic adverse reactions resolved in 92% (11/12) of these patients.

Immune-mediated dermatologic adverse reactions led to withholding of LOQTORZI in 0.4% of the patients. Systemic corticosteroids were required in 12% (4/34) of the patients with immune-mediated dermatologic adverse reactions. 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 LOQTORZI 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, other transplant (including corneal graft) rejection. Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurrence of either two or all three adverse reactions

Infusion-Related Reactions LOQTORZI can cause severe or life-threatening infusion-related reactions including hypersensitivity and anaphylaxis. LOQTORZI in Combination with Cisplatin and Gemcitabine Infusion-related reactions have been reported in 4.1% of patients receiving LOQTORZI in combination with cisplatin and gemcitabine, including Grade 2 (0.7%) reactions. LOQTORZI 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 LOQTORZI.

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, LOQTORZI 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 LOQTORZI and for 4 months after the last dose.

Pregnancy Safety for Loqtorzi

Pregnancy Risk Summary Based on its mechanism of action, LOQTORZI can cause fetal harm when administered to a pregnant woman. There are no available data on the use of LOQTORZI 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 (see Data ).

Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, LOQTORZI 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 respectively.

Data Animal Data Animal reproduction studies have not been conducted with LOQTORZI to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering LOQTORZI during pregnancy could include increased rates of abortion or stillbirth.

As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to toripalimab-tpzi may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Pediatric Use of Loqtorzi

Pediatric Use The safety and effectiveness of LOQTORZI have not been established in pediatric patients.

Clinical Studies of Loqtorzi

First-line Treatment of Metastatic or Recurrent, Locally Advanced NPC with Cisplatin and Gemcitabine The efficacy of LOQTORZI in combination with cisplatin and gemcitabine was investigated in JUPITER-02 (NCT03581786), a randomized, multicenter, single region, double-blind, placebo-controlled trial in 289 patients with metastatic or recurrent, locally advanced NPC who had not received previous systemic chemotherapy for recurrent or metastatic disease. Patients with recurrent NPC after treatment with curative intent were required to have an interval of at least 6 months between the last dose of radiotherapy or chemotherapy and recurrence. Patients with autoimmune disease, other than stable hypothyroidism or Type I diabetes, and patients who required systemic immunosuppression were ineligible.

Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 versus 1) and disease stage (recurrent versus metastatic). Treatment with LOQTORZI or placebo continued until disease progression per RECIST v1.1, unacceptable toxicity, or a maximum of 2 years. Administration of LOQTORZI was permitted beyond radiographic progression if the patient was deriving benefit as assessed by the investigator.

Tumor assessments were performed every 6 weeks for the first 12 months and every 9 weeks thereafter. The main efficacy outcome measure was Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS) according to RECIST v1.1. Additional efficacy outcome measures include BIRC-assessed overall response rate (ORR) and overall survival (OS).

Eighty-six percent of patients had metastatic disease at study entry. Histological subtypes of NPC included 98% non-keratinizing, 1% keratinizing squamous cell carcinoma, and 1% did not have the subtype identified. Efficacy results of the pre-specified interim analysis of PFS and final analysis of OS are summarized in Table 7 and Figure 1 below.

The trial demonstrated statistically significant improvements in BIRC-assessed PFS, ORR and OS for patients randomized to LOQTORZI in combination with cisplatin/gemcitabine compared to cisplatin and gemcitabine with placebo. Table 7: Efficacy Results in JUPITER-02 Figure 1 Kaplan-Meier Curves of Overall Survival for JUPITER-02 Figure 1

Previously Treated Unresectable or Metastatic NPC

The efficacy of LOQTORZI was investigated in POLARIS-02 (NCT 02915432), an open-label, multicenter, multicohort trial conducted in a single country. The trial included a total of 172 patients with unresectable or metastatic NPC who had received prior platinum-based chemotherapy for treatment of recurrent or metastatic NPC or had disease progression within 6 months of completion of platinum-based chemotherapy administered as neoadjuvant, adjuvant, or definitive chemoradiation treatment for locally advanced disease. Key exclusion criteria included previous treatment with an anti-PD-(L)1 antibody; active autoimmune disease or other medical conditions requiring immunosuppressive therapy.

Patients received LOQTORZI 3 mg/kg intravenously every 2 weeks until disease progression per RECIST v1.1 or unacceptable toxicity. Tumor response assessments were performed every 8 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were confirmed ORR and duration of response (DOR) as assessed by a Blinded Independent Review Committee (BIRC) using RECIST v1.1.

Patients had received a median of 2 prior systemic therapies for recurrent/metastatic disease (range: 1-13). Ninety-five percent of patients had metastatic disease, 95% had non-keratinizing NPC, 2.9% had keratinizing squamous cell carcinoma and 1.7% did not have the subtype identified. Efficacy results for POLARIS-02 are summarized in Table 8 below.

Table 8: Efficacy Results for POLARIS-02

Table 7: Efficacy Results in JUPITER-02
Endpoints	LOQTORZI Cisplatin/Gemcitabine N =146	Placebo Cisplatin/Gemcitabine N =143
BIRC=blinded independent review committee; CI= confidence interval; NR=Not Reached; NE=Not estimable.
BIRC-Assessed Progression-free Survival PFS and ORR results are based on the pre-specified interim analysis with data cutoff of May 30, 2020.
Number of Events, n (%)	49 (34)	79 (55)
Median, months (95% CI)	11.7 (11.0, NE)	8.0 (7.0, 9.5)
Hazard Ratio (95% CI) Based on the stratified Cox proportional-hazards model using the stratification factors at randomization, ECOG performance status and disease stage.	0.52 (0.36, 0.74)
p-value Two-sided p-value, based on the stratified log-rank test, as compared with an alpha boundary of 0.010.	0.0003
BIRC-Assessed Overall Response Rate
ORR, % (95% CI)	77 (70, 84)	66 (58, 74)
Complete Response Rate (%)	19	11
Partial Response Rate (%)	58	55
p-value Two-sided p-value, based upon Cochran-Mantel-Haenszel test.	0.0353
BIRC-Assessed Duration of Response
Median, months (95% CI)	10.0 (8.8, NE)	5.7 (5.4, 6.8)
Overall Survival OS results are based on the final analysis with a data cutoff of November 18, 2022.
Number of Deaths, n (%)	57 (39)	76 (53)
Median, months (95% CI)	NR (38.7, NE)	33.7 (27.0, 44.2)
Hazard Ratio (95% CI)	0.63 (0.45, 0.89)
p-value Two-sided p-value, based on the stratified log-rank test, as compared with an alpha boundary of 0.049995.	0.0083

Table 8: Efficacy Results for POLARIS-02
Endpoint	LOQTORZI (N=172)
CI=confidence interval. n=number. NE = not estimable. BIRC=blinded independent review committee
BIRC-Assessed Overall Response Rate Confirmed overall response rate assessed by BIRC
Overall Response Rate, % (95% CI)	21 (15, 28)
Complete Response Rate, %	2.3
Partial Response Rate, %	19
BIRC-Assessed Duration of Response (DOR)	(N = 36)
Median, months (95% CI)	14.9 (10.3, NE)
Patients with DOR≥ 6 months Based on observed duration of response, n (%)	30 (83%)
Patients with DOR ≥ 12 months, n (%)	14 (39%)

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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