Unloxcyt Drug Information
Generic name: COSIBELIMAB
Programmed Death Ligand-1 Blocker [EPC]
Uses of Unloxcyt
1. INDICATIONS AND USAGE UNLOXCYT is indicated for the treatment of adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation.
Dosage & Administration of Unloxcyt
2. Dose Modifications for Adverse Reactions No dose reductions of UNLOXCYT are recommended. In general, withhold UNLOXCYT for severe (Grade 3) immune-mediated adverse reactions.
Permanently discontinue UNLOXCYT 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 corticosteroid dose to a prednisone equivalent of 10 mg or less per day within 12 weeks of initiating steroids. Dosage modifications for UNLOXCYT for adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Dose Modifications for 2.3.
Preparation and Administration Visually inspect the vial for particulate matter and discoloration. UNLOXCYT is clear to opalescent, colorless to yellow or slightly brown. Discard the vial if visible particles are observed.
Do not shake the vial. UNLOXCYT is compatible with an infusion bag made of polyolefin or polyvinyl chloride. Mix diluted solution by gentle inversion.
Do not shake. Discard any unused portion left in the vial. Storage of Infusion Solution: The prepared infusion solution may be stored either: At room temperature up to 25°C (77°F) for no more than 24 hours from the time of preparation until the end of infusion.
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of preparation until end of infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Discard after 24 hours.
Do not freeze. Administration: Visually inspect the infusion bag for particulate matter and discoloration prior to administration. Discard if the solution is discolored or contains particulate matter.
Administer by intravenous infusion over 60 minutes through an intravenous line containing a sterile, in-line or add-on of 0.2-micron to 0.22-micron filter. Do not administer UNLOXCYT as an intravenous push or bolus injection. Do not co-administer other drugs through the same infusion line.
| Adverse Reaction | Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5. | UNLOXCYT Dosage Modifications |
|---|---|---|
| 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-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] | ||
| Pneumonitis | Grade 2 | Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce corticosteroid to a prednisone equivalent of 10 mg/day or less within 12 weeks of initiating steroids. |
| Grade 3 or 4 | Permanently discontinue | |
| Colitis | Grade 2 or 3 | Withhold |
| Grade 4 | Permanently discontinue | |
| Hepatitis with no tumor involvement of the liver | AST or 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 |
| 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 UNLOXCYT based on recommendations for hepatitis with no tumor involvement of the liver. | 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 |
| AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN | Permanently discontinue | |
| Endocrinopathies Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. | Grade 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 |
| Grade 4 increased blood creatinine | Permanently discontinue | |
| Exfoliative dermatologic conditions | Suspected SJS, TEN, or DRESS | Withhold |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
| Myocarditis | Grade 2, 3 or 4 | Permanently discontinue |
| Neurological toxicities | Grade 2 | Withhold |
| Grade 3 or 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 | Permanently discontinue | |
Side Effects of Unloxcyt
6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Severe and fatal immune-mediated adverse reactions Infusion-related reactions Complications of Allogeneic HSCT The most common adverse reactions (≥10%) were fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection. To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800- 818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1.
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 with 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 reflects exposure to UNLOXCYT as a single agent in 223 patients in two open-label, single-arm, multicohort studies, including 141 patients with advanced CSCC and 82 patients with other solid tumors and hematologic malignancies. The safety of UNLOXCYT was evaluated in Study CK-301-101 in 141 patients with metastatic or locally advanced disease CSCC.
The median duration of exposure was 36 weeks (2 weeks to 3.7 years). Serious adverse reactions occurred in 31% of advanced patients with CSCC who received UNLOXCYT. Permanent discontinuation of UNLOXCYT due to an adverse reaction occurred in 8% of patients.
Adverse reactions resulting in permanent discontinuation of UNLOXCYT were COVID-19, COVID-19 pneumonia, sepsis, ulcerative keratitis, tumor thrombosis, axillary pain, paresthesia, cholestasis, hepatic cytolysis, wound hemorrhage, neck pain, pemphigoid, and eye pain (1 patient each). Dosage interruptions due to an adverse reaction occurred in 36% of patients who received UNLOXCYT. The adverse reaction that required dosage interruption in ≥ 2% of patients who received UNLOXCYT was COVID-19 (2%).
Table 2 and Table 3 summarize adverse reactions and laboratory abnormalities, respectively in CK-301-101.
| UNLOXCYT N = 141 % | ||
|---|---|---|
| System Organ Class Preferred Term | All Grades % | Grade 3 or 4 % |
| Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 (or later version) | ||
| General disorders and administrative site conditions | ||
| Fatigue Represents a composite of multiple related terms | 33 | 3 |
| Edema | 11 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain | 25 | 3 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 23 | 1 |
| Pruritus | 12 | 0 |
| Endocrine disorder | ||
| Hypothyroidism | 14 | 0 |
| Gastrointestinal disorders | ||
| Diarrhea | 14 | 0 |
| Nausea | 13 | 0 |
| Constipation | 13 | 0 |
| Nervous system disorders | ||
| Headache | 12 | 0 |
| Infections and infestations | ||
| Localized infection | 10 | 0.7 |
| Urinary tract infection | 10 | 0 |
| Laboratory Abnormality | UNLOXCYT (N = 141) | |
|---|---|---|
| All Grades % The denominator used to calculate the rate varied from 122-140 based on the number of patients with a baseline value and at least one post-treatment value. | Grade 3 or 4 % | |
| Toxicity graded per NCI CTCAE v5 | ||
| Hematology | ||
| Hemoglobin decreased | 45 | 4 |
| Lymphocytes decreased | 41 | 6 |
| Platelets decreased | 14 | 1 |
| Leukocytes decreased | 10 | 1 |
| Chemistry | ||
| Sodium decreased | 38 | 5 |
| Alkaline phosphatase increased | 26 | 1 |
| Alanine transferase increased | 25 | 4 |
| Lipase increased | 25 | 3 |
| Aspartate transaminase increased | 24 | 3 |
| Potassium increased | 23 | 3 |
| Calcium increased | 14 | 2 |
Warnings & Cautions for Unloxcyt
5. WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions Immune-mediated adverse reactions can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. Monitor for early identification and management.
Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue UNLOXCYT based on the severity of reaction. Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue based on severity of reaction.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 5.1.
Severe and Fatal Immune-Mediated Adverse Reactions UNLOXCYT 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 in WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which can be severe or fatal, can occur in any organ system or tissue.
Immune-mediated adverse reactions can occur at any time after starting a PD-1/PD-L1–blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1–blocking antibodies, they 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 closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. 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 UNLOXCYT depending on severity. In general, if UNLOXCYT requires interruption or discontinuation, administer systemic corticosteroids (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 reaction is not controlled with corticosteroids. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies, dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis UNLOXCYT 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 1% (3/223, Grade 2) of patients receiving UNLOXCYT.
Pneumonitis led to withholding of UNLOXCYT in 0.4% (1/223) of patients. All 3 patients required systemic corticosteroids and pneumonitis did not resolve. One patient in whom UNLOXCYT was withheld for pneumonitis, had UNLOXCYT reinitiated after symptom improvement and had recurrence of pneumonitis.
Immune-Mediated Colitis UNLOXCYT can cause immune-mediated colitis, which may present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding. Cytomegalovirus infection/reactivation has 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 0.4% (1/223, Grade 1) of patients receiving UNLOXCYT. Systemic corticosteroids were required in the patient experiencing colitis. The event of colitis did not resolve, and UNLOXCYT was not reinitiated.
Immune-Mediated Hepatitis UNLOXCYT can cause immune-mediated hepatitis, defined as requiring the use of systemic corticosteroids and the absence of a clear alternate etiology. Immune-Mediated Endocrinopathies Adrenal Insufficiency UNLOXCYT 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.
UNLOXCYT was withheld for adrenal insufficiency in one of these patients and was reinitiated after symptom improvement. Systemic corticosteroids were required in both patients with adrenal insufficiency. Hypophysitis UNLOXCYT 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.
Thyroid Disorders UNLOXCYT 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. Hypothyroidism resolved in 7 of the 22 patients. Hyperthyroidism resolved in 10 of the 12 patients.
Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis UNLOXCYT can cause 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.
Immune-Mediated Dermatologic Adverse Reactions UNLOXCYT can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), have occurred with PD-1/PD-L1–blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.
Systemic corticosteroids were required in 33% (5/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 7 of the 15 patients. Of the 2 patients in whom UNLOXCYT was withheld for dermatologic adverse reactions, 1 patient reinitiated UNLOXCYT after symptom improvement and had recurrence of the dermatologic adverse reaction, which resolved after UNLOXCYT was withheld a second time.
Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred in <1% of the 223 patients who received UNLOXCYT or were reported with the use of other PD-1/PD-L1–blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, 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. Gastrointestinal: Pancreatitis, including 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. Endocrine: Hypoparathyroidism. Other (Hematologic/Immune): Autoimmune hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. 5.2.
Infusion-Related Reactions UNLOXCYT can cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions. Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins. 5.3.
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, UNLOXCYT 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with UNLOXCYT and for 4 months after the last dose.
Pregnancy Safety for Unloxcyt
8.1. Pregnancy Risk Summary Based on its mechanism of action, UNLOXCYT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of UNLOXCYT 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 IgG1 immunoglobulins (IgG1) are known to cross the placental barrier; therefore, cosibelimab-ipdl 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 respectively. Data Animal Data: Animal reproduction studies have not been conducted with cosibelimab-ipdl 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 UNLOXCYT 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 UNLOXCYT may increase the risk of developing immune-mediated disorders or altering the normal immune response.
Pediatric Use of Unloxcyt
8.4. Pediatric Use The safety and effectiveness of UNLOXCYT have not been established in pediatric patients.
Contraindications for Unloxcyt
4. CONTRAINDICATIONS None. None.
Clinical Studies of Unloxcyt
14. CLINICAL STUDIES 14.1. Cutaneous Squamous Cell Carcinoma (CSCC) The efficacy of UNLOXCYT was evaluated in Study CK-301-101 ( NCT03212404 ), a multicenter, multicohort, open-label study in patients with metastatic CSCC (mCSCC) or locally advanced CSCC (laCSCC) who were not candidates for curative surgery or curative radiation.
Patients were excluded if they had the following: active or suspected autoimmune disease, allogeneic transplant within 6 months prior to treatment, prior treatment with anti–PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitor therapy, uncontrolled or significant cardiovascular disease, ECOG PS ≥ 2, or infection with HIV, hepatitis B or hepatitis C. Patients received UNLOXCYT 800 mg every 2 weeks until disease progression or unacceptable toxicity. Tumor response assessments were performed every 8 weeks for the first 8 months and every 12 weeks thereafter.
The major efficacy outcomes were objective response rate (ORR) and duration of response (DOR) as assessed by an independent central review committee (ICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For patients with laCSCC with externally visible target lesions not assessable by radiologic imaging, ORR was determined by ICR assessments of digital photography (WHO criteria). The efficacy population consisted of 109 patients.
Seven percent of patients received at least one prior anti-cancer systemic therapy, 66% of patients had prior surgery, and 69% of patients had prior radiotherapy. Efficacy results are summarized in Table 4. Table 4: Efficacy Results for Study CK-301-101 26 15 CI: confidence interval; NR: not reached; +: Denotes ongoing at last assessment. a Median follow up time: mCSCC: 29.3 months; laCSCC: 24.1 months. b Based on Kaplan-Meier estimate. c The numerator includes the number of patients whose observed DOR reached at least the specified times of 6 or 12 months.
Patients who did not have the opportunity to reach the specified timepoint were included in the denominator only.
| Efficacy Endpoints | mCSCC N = 78 | laCSCC N = 31 |
|---|---|---|
| Objective Response Rate (ORR) | ||
| ORR, n (%) (95% CI) | 39 (50) (38, 62) | 17 (55) (36, 73) |
| Complete response, n (%) | 10 (13) | 8 (26) |
| Partial response, n (%) | 29 (37) | 9 (29) |
| Duration of Response (DOR) a | ||
| Number of responders | N=39 | N=17 |
| Median DOR in months b (Range) | NR (1.4+, 45.3+) | NR (8.3, 31.3+) |
| Responders with observed DOR ≥ 6 months, n (%) c | 33 (85) | 17 (100) |
| Responders with observed DOR ≥ 12 months, n (%) c | 26 (67) | 15 (88) |
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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