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Advanced Merkel cell carcinoma (MCC) is characterized by aggressive tumor growth and high rate of disease recurrence1-3

HIGH PROPORTION OF 
REGIONAL OR DISTANT DISEASE4

~1/3

of patients at 
presentation*
of patients 
at presentation*
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HIGH RATE OF 
DISEASE RECURRENCE3

≥30%

within 5 years of an advanced MCC diagnosis—
and most within 3 years†
within 5 years of an advanced MCC diagnosis—and most within 3 years†

*Per SEER database analysis of 9,557 patients diagnosed with MCC and followed up between 2000 and 2018.4

†Based on a prospective cohort study of patients with pathologically confirmed MCC (N=618). Recurrence was defined as reappearance of disease or considerable progression of existing disease after initial treatment. Only the first recurrence was considered, which may have been local, in-transit, nodal, or distantly metastatic.3

SEER, Surveillance, Epidemiology, and End Results program.

From 2000 to 2013, the annual incidence of MCC in the US increased at a markedly higher rate than that of other skin cancers and solid tumors5

3.5-FOLD INCREASE

In the overall age-adjusted incidence rate of MCC from 1987-1991 to 2012-2016.6

MCC-increase-icon

The increasing incidence of MCC is expected to continue in association with the aging population.5

Risk factors for MCC include:

Advanced age7
Advanced7

83% of people diagnosed with MCC are ≥65 years old.2

White7

MCC is almost exclusively a disease of White patients.6

Ultraviolet radiation exposure6

MCC tends to affect sun-exposed regions of the body (eg, head, neck, and extremities).

MCPyV infection8,9

Approximately 80% of MCC cases are associated with MCPyV infection.

MCPyV, Merkel cell polyomavirus.

Highly immunogenic MCC tumor

MCC is a highly immunogenic tumor that has demonstrated response to immunotherapy regardless of viral or PD-(L)1 status.10,11

PD-(L)1, programmed death receptor-1/programmed death-ligand 1.

Significant need in advanced MCC warrants first-line treatment with a PD-(L)1–blocking antibody to help improve patient outcomes.1,12 

References: 1. Bhatia S, Afanasiev O, Nghiem P. Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer. Curr Oncol Rep. 2011;13(6):488-497. doi:10.1007/s11912-011-0197-5. 2. Paulson KG, Bhatia S. Advances in immunotherapy for metastatic Merkel cell carcinoma: a clinician’s guide. J Natl Compr Canc Netw. 2018;16(6):782-790. doi:10.6004/jnccn.2018.7049. 3. McEvoy AM, Lachance K, Hippe DS, et al. Recurrence and mortality risk of Merkel cell carcinoma by cancer stage and time from diagnosis. JAMA Dermatol. 2022;158(4):382-389. doi:10.1001/jamadermatol.2021.6096. 4. Mohsin N, Martin MR, Reed DJ, et al. Differences in Merkel cell carcinoma presentation and outcomes among racial and ethnic groups. JAMA Dermatol. 2023;159(5):536-540. doi:10.1001/jamadermatol.2023.0061. 5. Paulson KG, Park SY, Vandeven NA, et al. Merkel cell carcinoma: current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018;78(3):457-463. doi:10.1016/j.jaad.2017.10.028. 6. Jacobs D, Huang H, Olino K, et al. Assessment of age, period, and birth cohort effects and trends in Merkel cell carcinoma incidence in the United States. JAMA Dermatol. 2021;157(1):59-65. doi:10.1001/ jamadermatol.2020.4102. 7. Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008;58(3):375-381. doi:10.1016/j.jaad.2007.11.020. 8. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096-1100. doi:10.1126/science.1152586. 9. Lipson EJ, Vincent JG, Loyo M, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus, and overall survival. Cancer Immunol Res. 2013;1(1):54-63. doi:10.1158/2326-6066.CIR-13-0034. 10. Stachyra K, Dudzisz-Śledź M, Bylina E, et al. Merkel cell carcinoma from molecular pathology to novel therapies. Int J Mol Sci. 2021;22(12):6305. doi:10.3390/ijms22126305. 11. Garza-Davila VF, Valdespino-Valdes J, Barrera FJ, Ocampo-Candiani J, Garza-Rodríguez V. Clinical impact of immunotherapy in Merkel cell carcinoma patients: a systematic review and meta-analysis. J Am Acad Dermatol. 2022;87(1):121-130. doi:10.1016/ j.jaad.2021.04.024. 12. Zaggana E, Konstantinou MP, Krasagakis GH, et al. Merkel cell carcinoma—update on diagnosis, management and future perspectives. Cancers. 2023;15(1):103. doi:10.3390/cancers15010103.

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

Systemic corticosteroids were required in 77% (10/13) of patients. Pneumonitis resolved in 10 of the 13 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.

Immune-mediated colitis occurred in 1.6% (7/440) of patients, 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 in 0.9%.

Systemic corticosteroids were required in 71% (5/7) of patients. Colitis resolved in 4/7 patients.

Immune-Mediated Hepatitis

ZYNYZ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 3% (13/440) of patients, 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 in 0.9%.

Systemic corticosteroids were required in 85% (11/13) of patients. Hepatitis resolved in 6/13 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.

Adrenal insufficiency occurred in 0.7% (3/440) of patients, including Grade 3 (0.5%) and Grade 2 (0.2%). 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 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, and can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

Hypophysitis occurred in 0.5% (2/440, both Grade 2) of patients. 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.

Thyroiditis occurred in 0.7% (3/440, 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% (42/440) of patients receiving ZYNYZ, including Grade 2 (4.8%). No patients discontinued due to hypothyroidism. ZYNYZ was withheld 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%).

ZYNYZ was not discontinued in any patient and was withheld 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.

Type 1 diabetes mellitus occurred in 0.2% (1/440) of patients, including Grade 3 (0.2%) adverse reactions.

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 in 1 patient.

Systemic corticosteroids were required in 57% (4/7) of patients. Nephritis resolved in 3/7 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 8% (36/440) of patients, 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 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.

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 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.

Infusion-Related Reactions

A severe infusion-related reaction (Grade 3) occurred in 1 (0.2%) of 440 patients. 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

The safety of ZYNYZ was evaluated in 105 patients with metastatic or recurrent locally advanced MCC.

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. Adverse reactions or laboratory abnormalities that required dosage interruption in ≥ 2% of patients were increased transaminases, increased lipase, increased amylase, pneumonitis, and pyrexia.

The most common (≥ 10%) adverse reactions were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea.

 

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Incyte Corporation at 1-855-463-3463.

Please see the full Prescribing Information for ZYNYZ for additional Important Safety Information.