ZYNYZ Solution for injection Ref.[107364] Active ingredients: Retifanlimab

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

ZYNYZ is a monoclonal antibody that belongs to a class of drugs that binds to either the programmed death receptor-1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions. Important immune‑mediated adverse reactions listed under Warnings and Precautions may not be inclusive of 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 with a 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. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

Early identification and management of immune‐mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1–blocking antibodies. Monitor patients 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 ZYNYZ depending on severity [see Dosage and Administration (2.2)]. In general, if ZYNYZ 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 corticosteroids.

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

ZYNYZ 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 3% (13/440) of patients receiving ZYNYZ, including 1 (0.2%) patient with fatal pneumonitis, Grade 3 (0.9%), and Grade 2 (1.4%). Pneumonitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 0.9% of patients.

Systemic corticosteroids were required in 77% (10/13) of patients with pneumonitis. Pneumonitis resolved in 10 of the 13 patients. Of the 4 patients in whom ZYNYZ was withheld for pneumonitis, 3 reinitiated ZYNYZ after symptom improvement; of these, 1 had recurrence of pneumonitis.

Immune-Mediated Colitis

ZYNYZ can cause immune-mediated colitis. Cytomegalovirus infection/reactivation have occurred in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1–blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 1.6% (7/440) of patients receiving ZYNYZ, including Grade 4 (0.2%), Grade 3 (0.2%), and Grade 2 (0.7%). Colitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 0.9% of patients.

Systemic corticosteroids were required in 71% (5/7) of patients. Colitis resolved in 4 of the 7 patients. Of the 4 patients in whom ZYNYZ was withheld for colitis, 1 reinitiated ZYNYZ after symptom improvement; this patient did not have recurrence of colitis.

Immune-Mediated Hepatitis

ZYNYZ can cause immune-mediated hepatitis.

Immune-mediated hepatitis occurred in 3% (13/440) of patients receiving ZYNYZ, including Grade 4 (0.2%), Grade 3 (2.3%), and Grade 2 (0.5%). Hepatitis led to permanent discontinuation of ZYNYZ in 1.4% of patients and withholding of ZYNYZ in 0.9% of patients.

Systemic corticosteroids were required in 85% (11/13) of patients. Hepatitis resolved in 6 of the 13 patients. Of the 4 patients in whom ZYNYZ was withheld for hepatitis, 2 reinitiated ZYNYZ after symptom improvement; of these, 1 had recurrence of hepatitis.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency:

ZYNYZ can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity [see Dosage and Administration (2.2)].

Adrenal insufficiency occurred in 0.7% (3/440) of patients receiving ZYNYZ, including Grade 3 (0.5%) and Grade 2 (0.2%). Adrenal insufficiency did not lead to permanent discontinuation of ZYNYZ. ZYNYZ was withheld for 1 patient with adrenal insufficiency. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 1 of the 3 patients.

Hypophysitis:

ZYNYZ 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 hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity [see Dosage and Administration (2.2)].

Hypophysitis occurred in 0.5% (2/440, both Grade 2) of patients receiving ZYNYZ. No patients discontinued or withheld ZYNYZ due to hypophysitis. All patients required systemic steroids. Hypophysitis resolved in 1 of the 2 patients.

Thyroid Disorders:

ZYNYZ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity [see Dosage and Administration (2.2)].

Thyroiditis occurred in 0.7% (3/440, all Grade 1) of patients receiving ZYNYZ. No patients discontinued or withheld ZYNYZ due to thyroiditis. Thyroiditis resolved in 1 of the 3 patients.

Hypothyroidism:

Hypothyroidism occurred in 10% (42/440) of patients receiving ZYNYZ, including Grade 2 (4.8%). No patients discontinued ZYNYZ due to hypothyroidism. Hypothyroidism led to withholding of ZYNYZ in 0.5% of patients. Systemic corticosteroids were required for 1 patient and 79% (33/42) of patients received endocrine therapy.

Hyperthyroidism:

Hyperthyroidism occurred in 6% (24/440) of patients receiving ZYNYZ, including Grade 2 (2.5%). No patients discontinued ZYNYZ due to hyperthyroidism. Hyperthyroidism led to withholding of ZYNYZ in 1 patient. Systemic corticosteroids were required for 13% (3/24) of patients and 46% (11/24) of patients received endocrine 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 ZYNYZ depending on severity [see Dosage and Administration (2.2)].

Type 1 diabetes mellitus occurred in 0.2% (1/440) of patients receiving ZYNYZ, including Grade 3 (0.2%) adverse reactions. Type 1 diabetes mellitus led to withholding of ZYNYZ in 1 patient. This event led to ZYNYZ being withheld and did not lead to permanent discontinuation of ZYNYZ. The patient received insulin.

Immune-Mediated Nephritis with Renal Dysfunction

ZYNYZ can cause immune-mediated nephritis.

Immune-mediated nephritis occurred in 1.6% (7/440) of patients receiving ZYNYZ, including Grade 4 (0.5%), Grade 3 (0.7%), and Grade 2 (0.5%). Nephritis led to permanent discontinuation of ZYNYZ in 0.9% of patients and withholding of ZYNYZ in 1 patient.

Systemic corticosteroids were required in 57% (4/7) of patients. Nephritis resolved in 3 of the 7 patients. The 1 patient in whom ZYNYZ was withheld for immune-mediated nephritis had ZYNYZ reinitiated after symptom improvement and did not have recurrence of immune-mediated nephritis.

Immune-Mediated Dermatologic Adverse Reactions

ZYNYZ can cause immune-mediated rash or dermatitis. Bullous and 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 ZYNYZ depending on severity [see Dosage and Administration (2.2)].

Immune-mediated skin reactions occurred in 8% (36/440) of patients receiving ZYNYZ, including Grade 3 (1.1%) and Grade 2 (7%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 2.3% of patients.

Systemic corticosteroids were required in 25% (9/36) of patients. Immune-mediated dermatologic adverse reactions resolved in 75% (27/36) of patients. Of the 10 patients in whom ZYNYZ was withheld for immune-mediated dermatologic adverse reactions, 7 reinitiated ZYNYZ after symptom improvement; of these, 1 had recurrence of immune-mediated dermatologic adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in 440 patients who received ZYNYZ [see Adverse Reactions (6.1)] or were reported with the use of other PD-1/PD-L1–blocking antibodies, including severe or fatal cases.

Cardiac/vascular: myocarditis, pericarditis, vasculitis

Gastrointestinal: pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal: myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica

Neurological: 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. 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.

Endocrine: hypoparathyroidism

Other (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.

5.2 Infusion-Related Reactions

A severe infusion-related reaction (Grade 3) occurred in 1 (0.2%) of 440 patients receiving ZYNYZ [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of infusion‑related reactions. Interrupt or slow the rate of infusion or permanently discontinue ZYNYZ based on severity of reaction [see Dosage and Administration (2.2)]. Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins.

5.3 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 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.

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action, ZYNYZ 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 ZYNYZ and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following adverse reactions are described elsewhere in the labeling.

• Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
• Infusion-Related Reactions [see Warnings and Precautions (5.2)]
• Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]

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 pooled safety population described in Warnings and Precautions reflect exposure to ZYNYZ 500 mg as an intravenous infusion every 4 weeks as a single agent in 105 patients with MCC enrolled in the POD1UM-201 trial and in 335 patients with other solid tumors. All patients received ZYNYZ until disease progression or unacceptable toxicity; those in the POD1UM-201 trial received ZYNYZ for up to 24 months. The median duration of exposure of the pooled population was 4.6 months (range: 1 day to 27 months).

The safety of ZYNYZ was evaluated in 105 patients enrolled in the POD1UM-201 trial with metastatic or recurrent locally advanced MCC [see Clinical Studies (14)]. Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The median duration of exposure was 5.6 months (range: 1 day to 23 months). The median age of patients who received ZYNYZ was 71 years (range: 38-90); 74% ≥65 years; 68% male; 79% White, 20% were race unknown or not reported, and 1% were Asian.

Serious adverse reactions occurred in 22% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥2% of patients) were fatigue, arrhythmia, and pneumonitis.

Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 11% of patients. These included asthenia, atrial fibrillation, concomitant disease progression of chronic lymphocytic leukemia, demyelinating polyneuropathy, eosinophilic fasciitis, increased transaminases, infusion-related reaction, lung disorder, pancreatitis, polyarthritis, and radiculopathy (1 patient each).

Dosage interruptions due to an adverse reaction occurred in 25% of patients who received ZYNYZ. Adverse reactions or laboratory abnormalities that required dosage interruption in ≥2% of patients who received ZYNYZ were increased transaminases, increased lipase, increased amylase, pneumonitis, and pyrexia.

The most common (≥10%) adverse reactions that occurred in patients receiving ZYNYZ were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea.

Table 2 and Table 3 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-201.

Table 2. Adverse Reactions in ≥10% of Patients with Metastatic or Recurrent Locally Advanced MCC Receiving ZYNYZ in POD1UM-201:

Graded according to NCI CTCAE v5.0.
^* Includes fatigue and asthenia.
^† Includes arthralgia, back pain, bone pain, pain in extremity, neck pain, and myalgia.
^‡ Includes rash, dermatitis, dermatitis bullous, rash erythematous, rash maculo-papular, rash papular, and rash pruritic.

Table 3. Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥1% of Patients with Metastatic or Recurrent Locally Advanced MCC Receiving ZYNYZ in POD1UM-201:

Graded according to NCI CTCAE v5.0.
^* The denominator used to calculate the rate varied from 86 to 92 based on the number of patients with a baseline value and at least one post-treatment value.

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of ZYNYZ or of other retifanlimab products.

ADAs were tested in 104 patients with MCC who received ZYNYZ. The incidence of retifanlimab treatment-emergent ADAs was 2.9% (3/104) using a bridging enzyme-linked immunosorbent assay following a median exposure time of 169 days. Neutralizing antibodies were detected in 2 of 3 patients with treatment-emergent ADAs. The effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of retifanlimab products is unknown.

Risk Summary

Based on its mechanism of action, ZYNYZ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of ZYNYZ 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 resulting in fetal death (see Data). Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, retifanlimab-dlwr has the potential to 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.

Data

Animal Data

Animal reproduction studies have not been conducted with ZYNYZ 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 ZYNYZ during pregnancy 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 retifanlimab-dlwr may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Risk Summary

There is no information regarding the presence of retifanlimab-dlwr 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 ZYNYZ are unknown. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose of ZYNYZ.

ZYNYZ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ZYNYZ [see Use in Specific Populations (8.1)].

Contraception

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

The safety and effectiveness of ZYNYZ have not been established in pediatric patients.

Of the 65 patients with metastatic or recurrent locally advanced MCC treated with ZYNYZ, 79% were 65 years or older, and 37% were 75 years or older. Clinical studies of ZYNYZ did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.