Toripalimab

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.

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.

There are no data on the presence of toripalimab-tpzi 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 gastrointestinal exposure and limited systemic exposure in the breastfed child to toripalimab-tpzi 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.

No studies have been performed to test the potential of toripalimab-tpzi for carcinogenicity or genotoxicity.

Fertility studies have not been conducted with toripalimab-tpzi. In 4-week and 26-week repeat-dose toxicology studies in sexually mature cynomolgus monkeys, there were no adverse or notable effects in the male and female reproductive organs.

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 toripalimab at a dose of 240 mg every 3 weeks in combination with up to 6 cycles of cisplatin and gemcitabine, followed by toripalimab 240 mg IV every 3 weeks, in 146 patients with NPC enrolled in a randomized, double-blind, placebo-controlled trial (JUPITER-02). Among the 146 patients, 73% were exposed to toripalimab for 6 months or more and 54% were exposed for 12 months or more. The most common adverse reactions (≥20%) were: nausea (71%), vomiting (68%), decreased appetite (55%), constipation (39%), hypothyroidism (38%), rash (36%), pyrexia (32%), diarrhea (31%), peripheral neuropathy (30%), cough (26%), musculoskeletal pain (25%), upper respiratory infection (23%), insomnia (23%), dizziness (21%), and malaise (21%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were: decreased neutrophils (58%), decreased lymphocytes (57%), decreased hemoglobin (50%) decreased platelets (33%), decreased potassium (10%), decreased sodium (9%), increased alanine aminotransferase (6%) increased or decreased magnesium (4.2% each), decreased calcium (3.5%), increased aspartate aminotransferase (2.7%), and bilirubin increased (2.1%).

The data described in the WARNINGS AND PRECAUTIONS section also reflects exposure to toripalimab 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=193) or other types of tumors (n=658). Among the 851 patients treated with toripalimab as a single agent, 35% were exposed for 6 months or more and 20% were exposed for 12 months or more. In this pooled safety population, the most common (≥20%) adverse reactions were: fatigue (22%), hypothyroidism (20%), and musculoskeletal pain (20%). The most common Grade 3 or 4 laboratory abnormalities (≥2%), were decreased sodium (9%), decreased lymphocytes (8%), decreased hemoglobin (7%), decreased fibrinogen (4.5%), increased lipase (4.0%), increased amylase (2.9%), decreased phosphate (2.8%), increased aspartate aminotransferase (2.6%), increased glucose (2.5%), and increased triglycerides (2.1%).

First-line Treatment of Metastatic or Recurrent, Locally Advanced Nasopharyngeal Carcinoma (NPC)

The safety of toripalimab 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. Patients received toripalimab 240 mg (n=146) or placebo intravenously (IV) every 3 weeks (n=143), in combination with cisplatin 80 mg/m² IV every 3 weeks and gemcitabine 1000 mg/m² IV days 1 and 8 for up to 6 cycles followed by toripalimab 240 mg or placebo IV every 3 weeks until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Among patients who received toripalimab, 73% were exposed for 6 months or longer and 54% were exposed for greater than one year.

The median age of patients who received toripalimab was 48 years (range: 19 to 72), 83% male, 100% Asian, 60% had recurrent disease, and 40% presented with metastatic disease. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) was 0 (57%) or 1 (43%). 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 toripalimab in combination with cisplatin and gemcitabine. Serious adverse drug reactions in ≥2% were thrombocytopenia (14%), neutrophil count decreased (10%), pneumonia (10%), anemia (9%), abnormal hepatic function (2.7%), and rash (2.1%). Of the patients who received toripalimab 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 toripalimab, 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 toripalimab in ≥1% were pneumonia (2.1%), pulmonary tuberculosis (1.4%), rash (1.4%), and vomiting (1.4%).

Dosage interruptions of toripalimab due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruption in ≥2% were anemia (17%), decreased neutrophils (12%), thrombocytopenia (12%), acute kidney injury (4.1%), pneumonia (6%), fatigue (2.7%), upper respiratory infection (2.7%), and hypothyroidism (2.1%).

Table 1 summarizes the adverse reactions in JUPITER-02.

Table 1. Adverse Reactions (≥ 10%) in Patients with Recurrent, Locally Advanced or Metastatic NPC Who Received Toripalimab in Combination with Cisplatin and Gemcitabine in JUPITER-02:

^* NCI CTCAE v5.0.
^† Includes mouth ulceration, stomatitis, and radiation stomatitis.
^‡ Includes hypothyroidism, tri-iodothyronine decreased, tri-iodothyronine free decreased, and thyroiditis.
^§ 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.
^¶ Includes asthenia and fatigue.
^# Includes hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.
^Þ Includes cough and productive cough.
^ß Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, pain in jaw.
^à Includes acute sinusitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection.
^è Includes aspiration pneumonia and pneumonia
^ð Includes blood pressure increased, blood pressure systolic increased, hypertension, and hypertensive crisis.

Table 2 summarizes the laboratory abnormalities in JUPITER-02.

Table 2. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Recurrent, Locally Advanced or Metastatic NPC Who Received Toripalimab in Combination with Cisplatin and Gemcitabine in JUPITER-02:

^* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: toripalimab/chemotherapy (range: 139 to 146 patients) and placebo/chemotherapy (range: 136 to 143 patients).
^† Graded per NCI CTCAE v5.0; AKP=alkaline phosphatase. ALT=alanine aminotransferase. AST=aspartate aminotransferase.

Previously Treated, Unresectable or Metastatic Nasopharyngeal Carcinoma (NPC)

The safety of toripalimab was evaluated in POLARIS-02. Eligible patients had previously treated unresectable or metastatic NPC. Patients received toripalimab 3 mg/kg every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Among patients who received toripalimab, 33% were exposed for 6 months or longer and 21% were exposed for greater than one year.

The median age of patients who received toripalimab was 46 years (range: 22 to 71), 83% male, 100% Asian, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 (35%) or 1 (65%) and median weight 59 kg (range: 32 to 101 kg).

Serious adverse reactions occurred in 24% of patients who received toripalimab. Serious adverse drug reactions in (≥2%) were pneumonia (4.7%), abnormal hepatic function (2.6%), and hyperbilirubinemia (2.1%). Fatal adverse reactions occurred in 3.7% of patients who received toripalimab, including death not otherwise specified (1.6%), tumor hemorrhage (0.5%), hepatic failure and thrombocytopenia (0.5%), hyponatremia (0.5%), and sudden death (0.5%).

Permanent discontinuation of toripalimab due to an adverse reaction occurred in 9% of patients. Adverse reaction resulting in permanent discontinuation of toripalimab in ≥1% included pneumonia (1.1%), abnormal hepatic function (1.1%), and hyperbilirubinemia (1.1%).

Dosage interruptions due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥1% were pneumonia (2.1%), thrombocytopenia (2.1%), fatigue (1.6%), hyperbilirubinemia (1.6%), anemia (1.1%), decreased appetite (1.1%), abnormal hepatic function (1.1%), hypothyroidism (1.1%), and pneumonitis (1.1%).

Table 3 summarizes the adverse reactions in POLARIS-02.

Table 3. Adverse Reactions (≥10%) in Patients with Previously Treated, Unresectable or Metastatic NPC Who Received Toripalimab in POLARIS-02:

^* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
^† Includes hypothyroidism, thyroiditis, tri-iodothyronine decreased, and triiodothyronine free decreased
^‡ Includes fatigue and asthenia
^§ Includes cough and productive cough.
^¶ Includes musculoskeletal pain and myalgia.
^# Includes dermatitis allergic, eczema, and rash.

Table 4 summarizes the laboratory abnormalities in POLARIS-02.

Table 4. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Previously Treated, Unresectable or Metastatic NPC Who Received Toripalimab in POLARIS-02:

^* 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.