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ZYNYZ® safety profile1

Combination therapy safety profile (POD1UM-303)1

Safety was evaluated in 306 patients with inoperable locally recurrent or metastatic recurrent squamous cell carcinoma of the anal canal (SCAC).

ADVERSE REACTIONS (≥10%) WITH A BETWEEN-ARM DIFFERENCE OF ≥5% FOR ALL GRADES OR ≥2% FOR GRADES 3 OR 4 IN PATIENTS RECEIVING ZYNYZ + CARBOPLATIN/PACLITAXEL

 

 

A chart depicting the adverse reactions (≥10%) with a between-arm difference of ≥5% for all grades or ≥2% for grades 3 or 4 in patients receiving ZYNYZ® + carboplatin/paclitaxel and placebo + carboplatin/paclitaxel documented during the POD1UM-303 study.
A chart depicting the adverse reactions (≥10%) with a between-arm difference of ≥5% for all grades or ≥2% for grades 3 or 4 in patients receiving ZYNYZ® + carboplatin/paclitaxel and placebo + carboplatin/paclitaxel documented during the POD1UM-303 study.

Graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.


a Includes diarrhea, colitis, and frequent bowel movements.

b Includes stomatitis, aphthous ulcer, cheilitis, mouth ulceration, and mucosal inflammation.

c Includes peripheral neuropathy, paresthesia, peripheral sensory neuropathy, neuralgia, hypoesthesia, peripheral sensorimotor neuropathy, dysesthesia, peripheral motor neuropathy, and hyperesthesia.

d Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.

e Includes hemorrhage, anal hemorrhage, anal ulcer hemorrhage, conjunctival hemorrhage, epistaxis, gastrointestinal hemorrhage, genital hemorrhage, hematuria, hemoptysis, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, lymph node hemorrhage, rectal hemorrhage, stoma site hemorrhage, tumor hemorrhage, urinary bladder hemorrhage, uterine hemorrhage, vaginal hemorrhage, and wound hemorrhage.

f Includes rash, eczema, dermatitis acneiform, dermatitis, rash erythematous, rash maculo-papular, rash papular, rash pustular, and rash pruritic.

  • Serious adverse reactions occurred in 47% of patients receiving ZYNYZ in combination with carboplatin and paclitaxel (vs 39% of patients on placebo2). The most frequent serious adverse reactions (≥2% of patients) were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%)
  • Treatment with ZYNYZ in combination with carboplatin and paclitaxel led to permanent discontinuation due to adverse reactions in 11% of patients (vs 3% of patients on placebo2). Adverse reactions resulting in permanent discontinuation of ZYNYZ included immune-mediated enterocolitis (2 patients), warm autoimmune hemolytic anemia, hepatitis, adrenal insufficiency, blood bilirubin increased, AST increased, blood alkaline phosphatase increased, arthritis, encephalopathy, peripheral sensorimotor neuropathy, hypothyroidism, immune-mediated cholangitis, pruritus, malaise, and rash (1 patient each)
  • Dosage interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 55% of patients who received ZYNYZ plus carboplatin and paclitaxel. Adverse reactions leading to interruptions in ≥2% of patients were neutropenia, anemia, thrombocytopenia, leukopenia, fatigue, COVID-19, and urinary tract infection
  • The most common (≥20%) adverse reactions were fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain

LABORATORY ABNORMALITIES THAT WORSENED FROM BASELINE TO GRADE 3 OR 4 OCCURRING IN ≥1% OF PATIENTS RECEIVING ZYNYZ + CARBOPLATIN/PACLITAXEL

 

 

A chart depicting any laboratory abnormalities that worsened from baseline to grade 3 or 4 occurring in ≥1% of patients receiving ZYNYZ® + carboplatin/paclitaxel and placebo + carboplatin/paclitaxel during the POD1UM-303 study.

Graded according to NCI CTCAE v5.0.

aThe denominator used to calculate the rate varied from 142 to 153 based on the number of patients with a baseline value and at least one post-treatment value.

Monotherapy safety profile (POD1UM-202)1

POD1UM-202 evaluated the safety of ZYNYZ in 94 patients with platinum-refractory or intolerant locally recurrent or metastatic SCAC.

ADVERSE REACTIONS IN ≥10% OF PATIENTS
RECEIVING ZYNYZ1

 

 

A chart depicting the adverse reactions in ≥10% of patients receiving ZYNYZ® during the POD1UM-202 study.

Graded according to NCI CTCAE v5.0.

aIncludes fatigue and asthenia.

bIncludes arthralgia, back pain, bone pain, musculoskeletal chest pain, myalgia, non-cardiac chest pain, osteoarthritis, pain in extremity, and spinal pain.

cIncludes diarrhea, gastroenteritis, and immune-mediated enterocolitis.

dIncludes abdominal pain, abdominal discomfort, and abdominal pain upper.

eIncludes anal abscess, cellulitis, cholangitis, cholecystitis, cholecystitis acute, device related infection, herpes zoster, Lyme disease, pelvic infection, peritonitis, Pneumocystis jirovecii pneumonia, pneumonia, postoperative wound infection, pseudomonas infection, sepsis, skin infection, stoma site infection, and wound infection bacterial.

fIncludes urinary tract infection, cystitis, escherichia urinar tract infection, and pyelonephritis.

gIncludes anorectal discomfort, pelvic pain, proctalgia, and vulvovaginal discomfort.

hIncludes epistaxis, hematochezia, hematuria, proctitis hemorrhagic, rectal hemorrhage, stoma site hemorrhage, and vaginal hemorrhage.

iIncludes rash, dermatitis, dermatitis acneiform, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash erythematous, and rash maculo-papular.

jIncludes decreased appetite and hypophagia.

kIncludes cough and productive cough.

SAFETY RESULTS FROM THE POD1UM-202 STUDY

  • Serious adverse reactions occurred in 40% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥2%) were non-urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain, and dyspnea
  • Permanent discontinuation due to adverse reactions occurred in 4.3% of patients, including diarrhea, non-urinary tract infection, perineal pain, and rash
  • Dosage interruptions due to adverse reactions occurred in 21% of patients. Adverse reactions leading to dose delays in ≥2% of patients were non-urinary tract infection, rash, diarrhea, abdominal pain, hemorrhage, musculoskeletal pain, pyrexia, and urinary tract infection
  • The most common (≥10%) adverse reactions were fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight

Graded according to NCI CTCAE v5.0.

a Includes fatigue and asthenia.

b Includes arthralgia, back pain, bone pain, musculoskeletal chest pain, myalgia, non-cardiac chest pain, osteoarthritis, pain in extremity, and spinal pain.

c Includes diarrhea, gastroenteritis, and immune-mediated enterocolitis.

d Includes abdominal pain, abdominal discomfort, and abdominal pain upper.

e Includes anal abscess, cellulitis, cholangitis, cholecystitis, cholecystitis acute, device related infection, herpes zoster, Lyme disease, pelvic infection, peritonitis, Pneumocystis jirovecii pneumonia, pneumonia, postoperative wound infection, pseudomonas infection, sepsis, skin infection, stoma site infection, and wound infection bacterial.

f Includes urinary tract infection, cystitis, escherichia urinary tract infection, and pyelonephritis.

g Includes anorectal discomfort, pelvic pain, proctalgia, and vulvovaginal discomfort.

h Includes epistaxis, hematochezia, hematuria, proctitis hemorrhagic, rectal hemorrhage, stoma site hemorrhage, and vaginal hemorrhage.

i Includes rash, dermatitis, dermatitis acneiform, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash erythematous, and rash maculo-papular.

j Includes decreased appetite and hypophagia.

k Includes cough and productive cough.

ADVERSE REACTIONS IN ≥10% OF PATIENTS RECEIVING ZYNYZ1

 

 

A chart depicting the adverse reactions in ≥10% of patients receiving ZYNYZ® during the POD1UM-202 study.

LABORATORY ABNORMALITIES THAT WORSENED FROM BASELINE TO GRADE 3 OR 4 IN ≥1% OF PATIENTS RECEIVING ZYNYZ

A chart depicting any laboratory abnormalities that worsened from baseline to grade 3 or 4 in ≥1% of patients receiving ZYNYZ® during the POD1UM-202 study.
A chart depicting any laboratory abnormalities that worsened from baseline to grade 3 or 4 in ≥1% of patients receiving ZYNYZ® during the POD1UM-202 study.

Graded according to NCI CTCAE v5.0.

aThe denominator used to calculate the rate varied from 59 to 87 based on the number of patients with a baseline value and at least one post-treatment value.

References: 1. ZYNYZ Prescribing Information. Wilmington, DE: Incyte Corporation. 2. Rao S, Samalin-Scalzi E, Evesque L, et al. Retifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic squamous cell carcinoma of the anal canal (POD1UM-303/InterAACT-2): a global, phase 3 randomised controlled trial. Lancet. 2025;405(10495):2144-2152.

How ZYNYZ works

View Mechanism of Action

Indications and Usage

Squamous Cell Carcinoma of the Anal Canal

ZYNYZ, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC).

ZYNYZ, as a single agent, is indicated for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed 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, can occur at any time after starting or discontinuing treatment with a PD-1/PD-L1–blocking antibody, and can affect more than one body system simultaneously.

Monitor patients closely for symptoms and signs that may be clinical manifestations of such reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1–blocking antibodies. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. If suspected, 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. In general, if ZYNYZ requires interruption or discontinuation, administer systemic corticosteroid therapy (1-2 mg/kg/day prednisone or equivalent) until improvement to ≤ Grade 1. Then, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroids.

Immune-Mediated Pneumonitis

ZYNYZ can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 3.1% (14/452) of patients, including 1 (0.2%) patient with fatal pneumonitis, Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Pneumonitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding in 1.1%.

Systemic corticosteroids were required in 71% (10/14) of patients. Pneumonitis resolved in 11 of the 14 patients.

Immune-Mediated Colitis

ZYNYZ can cause immune-mediated colitis. Cytomegalovirus infections/reactivations 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.

ZYNYZ as a Single Agent: Immune-mediated colitis occurred in 2.7% (12/452) of patients, including Grade 4 (0.2%), Grade 3 (0.4%), and Grade 2 (1.1%). Colitis led to permanent discontinuation of ZYNYZ in 0.9% of patients and withholding in 1.3%. Systemic corticosteroids were required in 75% (9/12) of patients. Colitis resolved in 8/12 patients.

ZYNYZ in Combination with Carboplatin and Paclitaxel: Immune-mediated colitis occurred in 10% (16/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 4 (0.6%), Grade 3 (2.6%), and Grade 2 (3.2%). Colitis led to permanent discontinuation of ZYNYZ in 2 patients and withholding of ZYNYZ in 2 patients. Systemic corticosteroids were required in 94% (15/16) of patients. Colitis resolved in 15 of the 16 patients.

Immune-Mediated Hepatitis

ZYNYZ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 3.5% (16/452) of patients, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (0.9%). Hepatitis led to permanent discontinuation of ZYNYZ in 1.5% of patients and withholding in 1.1%.

Systemic corticosteroids were required in 81% (13/16) of patients. Hepatitis resolved in 9/16 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

ZYNYZ can cause primary or secondary adrenal insufficiency. For ≥ Grade 2 adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

ZYNYZ as a Single Agent: Adrenal insufficiency occurred in 0.9% (4/452) of patients, including Grade 3 (0.4%) and Grade 2 (0.4%). ZYNYZ was permanently discontinued in no patients and was withheld for 1 patient with adrenal insufficiency. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 1 of the 4 patients.

ZYNYZ in Combination with Carboplatin and Paclitaxel: Adrenal insufficiency occurred in 5.8% (9/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 3 and Grade 2 (1.9% each). Adrenal insufficiency led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 3 patients. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 4 of the 9 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, and can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

Hypophysitis occurred in 0.7% (3/452) of patients receiving ZYNYZ, including Grade 3 (0.2%) and Grade 2 (0.4%). Hypophysitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 1 patient.

All patients required systemic steroids. Hypophysitis resolved in 1 of the 3 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.

Thyroiditis occurred in 0.7% (3/452, all Grade 1) of patients. No patients discontinued or withheld ZYNYZ due to thyroiditis. Thyroiditis resolved in 1 of the 3 patients.

Hypothyroidism

Hypothyroidism occurred in 10% (46/452) of patients receiving ZYNYZ, including Grade 2 (4.9%). No patients discontinued due to hypothyroidism. ZYNYZ was withheld in 0.4% of patients.

Systemic corticosteroids were required for 1 patient, and 78% (36/46) of patients received endocrine therapy.

Hyperthyroidism

Hyperthyroidism occurred in 6% (26/452) of patients receiving ZYNYZ, including Grade 2 (2.7%). ZYNYZ was not discontinued in any patient and was withheld in 0.4% of patients. Systemic corticosteroids were required for 15% (4/26) of patients, and 50% (13/26) 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.

Type 1 diabetes mellitus occurred in 0.2% (1/452) of patients, including Grade 3 (0.2%).

Immune-Mediated Nephritis with Renal Dysfunction

ZYNYZ can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 2% (9/452) of patients receiving ZYNYZ, including Grade 4 (0.4%), Grade 3 (1.1%), and Grade 2 (0.4%). Nephritis led to permanent discontinuation of ZYNYZ in 1.1% of patients and withholding in 0.7% of patients.

Systemic corticosteroids were required in 67% (6/9) of patients. Nephritis resolved in 4/9 patients.

Immune-Mediated Dermatologic Adverse Reactions

ZYNYZ can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, 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.

Immune-mediated skin reactions occurred in 10% (43/452) of patients, including Grade 4 (0.2%), Grade 3 (1.1%), and Grade 2 (8%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation of ZYNYZ in 0.7% of patients and withholding in 2.7% of patients.

Systemic corticosteroids were required in 33% (14/43) of patients. Immune-mediated dermatologic adverse reactions resolved in 72% (31/43) of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 452 patients who received ZYNYZ 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

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

A severe infusion-related reaction (Grade 3) occurred in 5 (0.8%) of 606 patients receiving ZYNYZ. Monitor patients for signs and symptoms; interrupt or slow the rate of infusion or permanently discontinue ZYNYZ based on severity of reaction. Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins.

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), which 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

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 and for 4 months after the last dose.

Lactation

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.

Adverse Reactions

Inoperable Locally Recurrent or Metastatic SCAC: ZYNYZ in Combination with Carboplatin and Paclitaxel

The safety of ZYNYZ in patients with inoperable locally recurrent or metastatic SCAC was evaluated in 154 patients enrolled in the POD1UM-303 trial.

Serious adverse reactions occurred in 47% of patients receiving ZYNYZ in combination with carboplatin and paclitaxel. The most frequent serious adverse reactions (≥ 2% of patients) were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%).

In patients receiving ZYNYZ in combination with carboplatin and paclitaxel, ZYNYZ was permanently discontinued due to an adverse reaction in 11% of patients. Adverse reactions that resulted in permanent discontinuation of ZYNYZ included immune-mediated enterocolitis (2 patients) and warm autoimmune hemolytic anemia, hepatitis, adrenal insufficiency, blood bilirubin increased, AST increased, blood alkaline phosphatase increased, arthritis, encephalopathy, peripheral sensorimotor neuropathy, hypothyroidism, immune‑mediated cholangitis, pruritus, malaise, and rash (1 patient each).

Dosage interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 55% of patients who received ZYNYZ in combination with carboplatin and paclitaxel. Adverse reactions that resulted in dosage interruptions in ≥ 2% of patients were neutropenia, anemia, thrombocytopenia, leukopenia, fatigue, COVID-19, and urinary tract infection.

The most common (≥ 20%) adverse reactions were fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain.

Platinum-refractory Intolerant Locally Recurrent or Metastatic SCAC: ZYNYZ as a Single Agent

The safety of ZYNYZ in patients with platinum-refractory intolerant locally recurrent or metastatic SCAC was evaluated in 94 patients in the POD1UM-202 trial.

Serious adverse reactions occurred in 40% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥ 2% of patients) were non-urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain, and dyspnea.

Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 4.3% of patients. These adverse reactions included diarrhea, non-urinary tract infection, perineal pain, and rash.

Dosage interruptions due to an adverse reaction occurred in 21% of patients who received ZYNYZ. Adverse reactions that resulted in dose delay in ≥ 2% of patients who received ZYNYZ were non-urinary tract infection, rash, diarrhea, abdominal pain, hemorrhage, musculoskeletal pain, pyrexia, and urinary tract infection.

The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight.

Please see additional Important Safety Information throughout and the Full Prescribing Information.

 
 

Indications and Usage

Squamous Cell Carcinoma of the Anal Canal

ZYNYZ, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC).

ZYNYZ, as a single agent, is indicated for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed 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, can occur at any time after starting or discontinuing treatment with a PD-1/PD-L1–blocking antibody, and can affect more than one body system simultaneously.

Monitor patients closely for symptoms and signs that may be clinical manifestations of such reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1–blocking antibodies. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. If suspected, 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. In general, if ZYNYZ requires interruption or discontinuation, administer systemic corticosteroid therapy (1-2 mg/kg/day prednisone or equivalent) until improvement to ≤ Grade 1. Then, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroids.

Immune-Mediated Pneumonitis

ZYNYZ can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 3.1% (14/452) of patients, including 1 (0.2%) patient with fatal pneumonitis, Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Pneumonitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding in 1.1%.

Systemic corticosteroids were required in 71% (10/14) of patients. Pneumonitis resolved in 11 of the 14 patients.

Immune-Mediated Colitis

ZYNYZ can cause immune-mediated colitis. Cytomegalovirus infections/reactivations 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.

ZYNYZ as a Single Agent: Immune-mediated colitis occurred in 2.7% (12/452) of patients, including Grade 4 (0.2%), Grade 3 (0.4%), and Grade 2 (1.1%). Colitis led to permanent discontinuation of ZYNYZ in 0.9% of patients and withholding in 1.3%. Systemic corticosteroids were required in 75% (9/12) of patients. Colitis resolved in 8/12 patients.

ZYNYZ in Combination with Carboplatin and Paclitaxel: Immune-mediated colitis occurred in 10% (16/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 4 (0.6%), Grade 3 (2.6%), and Grade 2 (3.2%). Colitis led to permanent discontinuation of ZYNYZ in 2 patients and withholding of ZYNYZ in 2 patients. Systemic corticosteroids were required in 94% (15/16) of patients. Colitis resolved in 15 of the 16 patients.

Immune-Mediated Hepatitis

ZYNYZ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 3.5% (16/452) of patients, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (0.9%). Hepatitis led to permanent discontinuation of ZYNYZ in 1.5% of patients and withholding in 1.1%.

Systemic corticosteroids were required in 81% (13/16) of patients. Hepatitis resolved in 9/16 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

ZYNYZ can cause primary or secondary adrenal insufficiency. For ≥ Grade 2 adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

ZYNYZ as a Single Agent: Adrenal insufficiency occurred in 0.9% (4/452) of patients, including Grade 3 (0.4%) and Grade 2 (0.4%). ZYNYZ was permanently discontinued in no patients and was withheld for 1 patient with adrenal insufficiency. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 1 of the 4 patients.

ZYNYZ in Combination with Carboplatin and Paclitaxel: Adrenal insufficiency occurred in 5.8% (9/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 3 and Grade 2 (1.9% each). Adrenal insufficiency led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 3 patients. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 4 of the 9 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, and can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

Hypophysitis occurred in 0.7% (3/452) of patients receiving ZYNYZ, including Grade 3 (0.2%) and Grade 2 (0.4%). Hypophysitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 1 patient.

All patients required systemic steroids. Hypophysitis resolved in 1 of the 3 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.

Thyroiditis occurred in 0.7% (3/452, all Grade 1) of patients. No patients discontinued or withheld ZYNYZ due to thyroiditis. Thyroiditis resolved in 1 of the 3 patients.

Hypothyroidism

Hypothyroidism occurred in 10% (46/452) of patients receiving ZYNYZ, including Grade 2 (4.9%). No patients discontinued due to hypothyroidism. ZYNYZ was withheld in 0.4% of patients.

Systemic corticosteroids were required for 1 patient, and 78% (36/46) of patients received endocrine therapy.

Hyperthyroidism

Hyperthyroidism occurred in 6% (26/452) of patients receiving ZYNYZ, including Grade 2 (2.7%). ZYNYZ was not discontinued in any patient and was withheld in 0.4% of patients. Systemic corticosteroids were required for 15% (4/26) of patients, and 50% (13/26) 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.

Type 1 diabetes mellitus occurred in 0.2% (1/452) of patients, including Grade 3 (0.2%).

Immune-Mediated Nephritis with Renal Dysfunction

ZYNYZ can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 2% (9/452) of patients receiving ZYNYZ, including Grade 4 (0.4%), Grade 3 (1.1%), and Grade 2 (0.4%). Nephritis led to permanent discontinuation of ZYNYZ in 1.1% of patients and withholding in 0.7% of patients.

Systemic corticosteroids were required in 67% (6/9) of patients. Nephritis resolved in 4/9 patients.

Immune-Mediated Dermatologic Adverse Reactions

ZYNYZ can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, 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.

Immune-mediated skin reactions occurred in 10% (43/452) of patients, including Grade 4 (0.2%), Grade 3 (1.1%), and Grade 2 (8%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation of ZYNYZ in 0.7% of patients and withholding in 2.7% of patients.

Systemic corticosteroids were required in 33% (14/43) of patients. Immune-mediated dermatologic adverse reactions resolved in 72% (31/43) of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 452 patients who received ZYNYZ 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

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

A severe infusion-related reaction (Grade 3) occurred in 5 (0.8%) of 606 patients receiving ZYNYZ. Monitor patients for signs and symptoms; interrupt or slow the rate of infusion or permanently discontinue ZYNYZ based on severity of reaction. Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins.

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), which 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

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 and for 4 months after the last dose.

Lactation

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.

Adverse Reactions

Inoperable Locally Recurrent or Metastatic SCAC: ZYNYZ in Combination with Carboplatin and Paclitaxel

The safety of ZYNYZ in patients with inoperable locally recurrent or metastatic SCAC was evaluated in 154 patients enrolled in the POD1UM-303 trial.

Serious adverse reactions occurred in 47% of patients receiving ZYNYZ in combination with carboplatin and paclitaxel. The most frequent serious adverse reactions (≥ 2% of patients) were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%).

In patients receiving ZYNYZ in combination with carboplatin and paclitaxel, ZYNYZ was permanently discontinued due to an adverse reaction in 11% of patients. Adverse reactions that resulted in permanent discontinuation of ZYNYZ included immune-mediated enterocolitis (2 patients) and warm autoimmune hemolytic anemia, hepatitis, adrenal insufficiency, blood bilirubin increased, AST increased, blood alkaline phosphatase increased, arthritis, encephalopathy, peripheral sensorimotor neuropathy, hypothyroidism, immune‑mediated cholangitis, pruritus, malaise, and rash (1 patient each).

Dosage interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 55% of patients who received ZYNYZ in combination with carboplatin and paclitaxel. Adverse reactions that resulted in dosage interruptions in ≥ 2% of patients were neutropenia, anemia, thrombocytopenia, leukopenia, fatigue, COVID-19, and urinary tract infection.

The most common (≥ 20%) adverse reactions were fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain.

Platinum-refractory Intolerant Locally Recurrent or Metastatic SCAC: ZYNYZ as a Single Agent

The safety of ZYNYZ in patients with platinum-refractory intolerant locally recurrent or metastatic SCAC was evaluated in 94 patients in the POD1UM-202 trial.

Serious adverse reactions occurred in 40% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥ 2% of patients) were non-urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain, and dyspnea.

Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 4.3% of patients. These adverse reactions included diarrhea, non-urinary tract infection, perineal pain, and rash.

Dosage interruptions due to an adverse reaction occurred in 21% of patients who received ZYNYZ. Adverse reactions that resulted in dose delay in ≥ 2% of patients who received ZYNYZ were non-urinary tract infection, rash, diarrhea, abdominal pain, hemorrhage, musculoskeletal pain, pyrexia, and urinary tract infection.

The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight.

Please see additional Important Safety Information throughout and the Full Prescribing Information.

Incyte Corporate Site Link

ZYNYZ and the ZYNYZ logo are registered trademarks of Incyte. Incyte and the Incyte logo are registered trademarks of Incyte. All other trademarks are the property of their respective owners.

© 2025, Incyte. RET-0132  06/26

Incyte Corporate Site Link

ZYNYZ and the ZYNYZ logo are registered trademarks of Incyte. Incyte and the Incyte logo are registered trademarks of Incyte. All other trademarks are the property of their respective owners.

© 2025, Incyte. RET-0132  06/26

Incyte Corporate Site Link

ZYNYZ and the ZYNYZ logo are registered trademarks of Incyte. Incyte and the Incyte logo are registered trademarks of Incyte. All other trademarks are the property of their respective owners.

© 2025, Incyte. RET-0132  06/26

Incyte Corporate Site Link

ZYNYZ and the ZYNYZ logo are registered trademarks of Incyte. Incyte and the Incyte logo are registered trademarks of Incyte. All other trademarks are the property of their respective owners.

© 2025, Incyte. RET-0132  06/26