LIBTAYO SIDE EFFECTS
- Generic Name: cemiplimab-rwlc injection
- Brand Name: Libtayo
- Drug Class: PD-1PD-L1 Inhibitors
SIDE EFFECTS
The following serious adverse reactions are described elsewhere in the labeling.
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in Warnings and Precautions reflect exposure to LIBTAYO as a single agent in 810 patients in three open-label, single-arm, multicohort studies (Study 1423, Study 1540 and Study 1620), and one open-label randomized multi-center study (Study 1624). These studies included 219 patients with advanced CSCC (Studies 1540 and 1423), 132 patients with advanced BCC (Study 1620), 355 patients with NSCLC (Study 1624), and 104 patients with other advanced solid tumors (Study 1423). LIBTAYO was administered intravenously at doses of 3 mg/kg every 2 weeks (n=235), 350 mg every 3 weeks (n=543), or other doses (n=32; 1 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, 200 mg every 2 weeks). Among the 810 patients, 57% were exposed for ≥ 6 months and 25% were exposed for ≥ 12 months. In this pooled safety population, the most common adverse reactions (≥15%) were musculoskeletal pain, fatigue, rash, and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥2%) were lymphopenia, hyponatremia, hypophosphatemia, increased aspartate aminotransferase, anemia, and hyperkalemia.
Cutaneous Squamous Cell Carcinoma (CSCC)
The safety of LIBTAYO was evaluated in 219 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1423 and Study 1540. Of these 219 patients, 131 had mCSCC (nodal or distant) and 88 had laCSCC. Patients received LIBTAYO 1 mg/kg every 2 weeks (n=1), 3 mg/kg every 2 weeks (n=162) or 350 mg every 3 weeks (n=56) as an intravenous infusion until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 38 weeks (2 weeks to 110 weeks).
The safety population characteristics were: median age of 72 years (38 to 96 years), 83% male, 96% White, and European Cooperative Oncology Group (ECOG) performance score (PS) of 0 (44%) and 1 (56%).
Serious adverse reactions occurred in 35% of patients. Serious adverse reactions that occurred in at least 2% of patients were pneumonitis, cellulitis, sepsis, and pneumonia.
Permanent discontinuation due to an adverse reaction occurred in 8% of patients. Adverse reactions resulting in permanent discontinuation were pneumonitis, cough, pneumonia, encephalitis, aseptic meningitis, hepatitis, arthralgia, muscular weakness, neck pain, soft tissue necrosis, complex regional pain syndrome, lethargy, psoriasis, rash maculopapular, proctitis, and confusional state.
The most common (≥20%) adverse reactions were fatigue, rash, diarrhea, musculoskeletal pain, and nausea. The most common Grade 3 or 4 adverse reactions (≥ 2%) were cellulitis, anemia, hypertension, pneumonia, musculoskeletal pain, fatigue, pneumonitis, sepsis, skin infection, and hypercalcemia. The most common (≥4%) Grade 3 or 4 laboratory abnormalities worsening from baseline were lymphopenia, anemia, hyponatremia, and hypophosphatemia.
Table 1 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 2 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving LIBTAYO.
Table 1: Adverse Reactions in ≥ 10% of Patients with Advanced CSCC Receiving LIBTAYO in Study 1423 and Study 1540
| Adverse Reactions | LIBTAYO N = 219 |
|
| All Grades % | Grades 3-4 % | |
| General and Administration Site | ||
| Fatiguea | 34 | 3 |
| Skin and Subcutaneous Tissue | ||
| Rashb | 31 | 1 |
| Pruritusc | 18 | 0 |
| Gastrointestinal | ||
| Diarrhead | 25 | 0.5 |
| Nausea | 21 | 0 |
| Constipation | 13 | 0.5 |
| Vomiting | 10 | 0.5 |
| Musculoskeletal and Connective Tissue | ||
| Musculoskeletal paine | 24 | 3 |
| Arthralgia | 11 | 1 |
| Respiratory | ||
| Coughf | 14 | 0 |
| Hematology | ||
| Anemia | 11 | 4 |
| Endocrine | ||
| Hypothyroidism | 10 | 0 |
| Metabolism and Nutrition | ||
| Decreased appetite | 10 | 0 |
| Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 a Composite term includes fatigue and asthenia b Composite term includes rash, rash maculopapular, erythema, dermatitis, dermatitis bullous, rash generalized, pemphigoid, rash erythematous, rash macular, rash pruritic, drug eruption, psoriasis, and skin reaction c Composite term includes pruritus and pruritus allergic d Composite term includes diarrhea and colitis e Composite term includes back pain, pain in extremity, myalgia, musculoskeletal pain, and neck pain f Composite term includes cough and upper airway cough syndrome |
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Table 2: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥ 1% of Patients with Advanced CSCC Receiving LIBTAYO in Study 1423 and Study 1540
| Laboratory Abnormality | Grade 3-4 (%)a |
| Chemistry | |
| Increased aspartate aminotransferase | 2 |
| Increased INR | 2 |
| Hematology | |
| Lymphopenia | 9 |
| Anemia | 5 |
| Electrolytes | |
| Hyponatremia | 5 |
| Hypophosphatemia | 4 |
| Hypercalcemia | 2 |
| Toxicity graded per NCI CTCAE v. 4.03 a Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter |
|
Basal Cell Carcinoma (BCC)
The safety of LIBTAYO was evaluated in 132 patients with advanced BCC (mBCC N=48, laBCC N=84) in an open-label, single-arm trial (Study 1620). Patients received LIBTAYO 350 mg every 3 weeks as an intravenous infusion for up to 93 weeks or until disease progression or unacceptable toxicity. The median duration of exposure was 42 weeks (range: 2.1 weeks to 94 weeks).
The safety population characteristics were: median age of 68 years (38 to 90 years), 67% male, 74% White, and ECOG performance score (PS) of 0 (62%) and 1 (38%).
Serious adverse reactions occurred in 32% of patients. Serious adverse reactions that occurred in > 1.5% (at least 2 patients) were urinary tract infection, colitis, acute kidney injury, adrenal insufficiency, anemia, infected neoplasm, and somnolence. Fatal adverse reactions occurred in 1.5% of patients who received LIBTAYO, including acute kidney injury and cachexia.
Permanent discontinuation of LIBTAYO due to an adverse reaction occurred in 13% of patients. Adverse reactions resulting in permanent discontinuation of LIBTAYO in > 1.5% (at least 2 patients) were colitis and general physical health deterioration.
Dosage delays of LIBTAYO due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage delay in > 2% of patients (at least 3 patients) included blood creatinine increased, diarrhea, colitis, fatigue, headache, pneumonitis, and urinary tract infection.
The most common adverse reactions reported in at least 15% of patients were fatigue, musculoskeletal pain, diarrhea, rash, pruritus, and upper respiratory tract infection.
The most common Grade 3 or 4 adverse reactions (> 2%) were hypertension, colitis, fatigue, urinary tract infection, pneumonia, increased blood pressure, hypokalemia and visual impairment. The most common (> 3%) laboratory abnormality worsening from baseline to Grade 3 or 4 was hyponatremia.
Table 3 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 5 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving LIBTAYO.
Table 3: Adverse Reactions in ≥ 10% of Patients with Advanced BCC Receiving LIBTAYO in Study 1620
| Adverse Reactions | LIBTAYO N = 132 |
|
| All Grades % | Grades 3-4 % | |
| General disorders and administration site conditions | ||
| Fatiguea | 49 | 3.8 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal painb | 33 | 1.5 |
| Gastrointestinal disorders | ||
| Diarrhea | 25 | 0 |
| Nausea | 12 | 0.8 |
| Constipation | 11 | 0.8 |
| Skin and subcutaneous tissue disorders | ||
| Rashc | 22 | 0.8 |
| Pruritus | 20 | 0 |
| Infections and infestations | ||
| Upper respiratory tract infectiond | 15 | 0 |
| Urinary tract infection | 12 | 2.3 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 14 | 1.5 |
| Blood and lymphatic system disorders | ||
| Anemia | 13 | 0.8 |
| Nervous system disorders | ||
| Headache | 12 | 1.5 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspneae | 11 | 0 |
| Vascular disorders | ||
| Hypertensionf | 11 | 4.5 |
| Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 a Composite term includes fatigue, asthenia, and malaise b Composite term includes arthralgia, back pain, myalgia, pain in extremity, musculoskeletal pain, neck pain, musculoskeletal stiffness, musculoskeletal chest pain, musculoskeletal discomfort, and spinal pain c Composite term includes rash maculo-papular, rash, dermatitis, dermatitis acneiform, erythema, rash pruritic, dermatitis bullous, dyshidrotic eczema, pemphigoid, rash erythematous, and urticaria d Composite term includes upper respiratory tract infection, nasopharyngitis, rhinitis, sinusitis, pharyngitis, respiratory tract infection, and viral upper respiratory tract infection e Composite term includes dyspnea and dyspnea exertional f Composite term includes hypertension and hypertensive crisis |
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Table 4: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥ 1% of Patients with Advanced BCC Receiving LIBTAYO in Study 1620
| Laboratory Abnormality | Grade 3-4 (%)a |
| Electrolytes | |
| Hyponatremia | 3.1 |
| Hypokalemia | 1.5 |
| Coagulation | |
| Activated partial thromboplastin time prolonged | 2.3 |
| Hematology | |
| Lymphocyte count decreased | 2.3 |
| Toxicity graded per NCI CTCAE v. 4.03 a Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter |
|
Non-Small Cell Lung Cancer (NSCLC)
The safety of LIBTAYO was evaluated in 355 patients with locally advanced or metastatic NSCLC in Study 1624 .Patients received LIBTAYO 350 mg every 3 weeks (n=355) or investigator’s choice of chemotherapy (n=342), consisting of paclitaxel plus cisplatin or carboplatin; gemcitabine plus cisplatin or carboplatin; or pemetrexed plus cisplatin or carboplatin followed by optional pemetrexed maintenance. The median duration of exposure was 27.3 weeks (9 days to 115 weeks) in the LIBTAYO group and 17.7 weeks (18 days to 86.7 weeks) in the chemotherapy group. In the LIBTAYO group, 54% of patients were exposed to LIBTAYO for ≥ 6 months and 22 % were exposed for ≥ 12 months.
The safety population characteristics were: median age of 63 years (31 to 79 years), 44% of patients 65 or older, 88% male, 86%White, 82% had metastatic disease and 18% had locally advanced disease and ECOG performance score (PS) of 0 (27%) and 1 (73%).
LIBTAYO was permanently discontinued due to adverse reactions in 6% of patients; adverse reactions resulting in permanent discontinuation in at least 2 patients were pneumonitis, pneumonia, ischemic stroke and increased aspartate aminotransferase. Serious adverse reactions occurred in 28% of patients. The most frequent serious adverse reactions in at least 2% of patients were pneumonia and pneumonitis.
Table 5 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 7 summarizes Grade 3 or 4 laboratory abnormalities in patients receiving LIBTAYO.
Table 5: Adverse Reactions in ≥ 10% of Patients with Locally Advanced or Metastatic NSCLC Receiving LIBTAYO in Study 1624
| Adverse Reactions | LIBTAYO N=355 |
Chemotherapy N=342 |
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| All Grades % | Grades 3-4 % | All Grades % | Grades 3-4 % | |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal paina | 26 | 0.6 | 27 | 1.5 |
| Skin and subcutaneous tissue disorders | ||||
| Rashb | 15 | 1.4 | 6 | 0 |
| Blood and lymphatic system disorders | ||||
| Anemia | 15 | 3.4 | 50 | 16 |
| General disorders and administration site conditions | ||||
| Fatiguec | 14 | 1.1 | 26 | 2 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 12 | 0.6 | 18 | 0.3 |
| Infections and infestations | ||||
| Pneumoniad | 11 | 5 | 12 | 5 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Coughe | 11 | 0 | 8 | 0.3 |
| Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 a Musculoskeletal pain is a composite term that includes back pain, arthralgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia, neck pain, spinal pain, and musculoskeletal stiffness b Rash is a composite term that includes rash, dermatitis, urticaria, rash maculo-papular, erythema, rash erythematous, rash pruritic, psoriasis, autoimmune dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, drug eruption, dyshidrotic eczema, lichen planus, and skin reaction c Fatigue is a composite term that includes fatigue, asthenia, and malaise d Pneumonia is a composite term that includes atypical pneumonia, embolic pneumonia, lower respiratory tract infection, lung abscess, paracancerous pneumonia, pneumonia, pneumonia bacterial, and pneumonia klebsiella e Cough is a composite term that includes cough and productive cough |
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Table 6: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥1% of Patients with Locally Advanced or Metastatic NSCLC Receiving LIBTAYO in Study 1624
| Laboratory Abnormality | LIBTAYO N=355 |
Chemotherapy N=342 |
| Grades 3-4a % | ||
| Chemistry | ||
| Increased aspartate aminotransferase | 3.9 | 1.2 |
| Increased alanine aminotransferase | 2.7 | 0.3 |
| Increased alkaline phosphatase | 2.4 | 0.3 |
| Increased blood bilirubin | 2.1 | 0.3 |
| Hypoalbuminemia | 1.8 | 1.3 |
| Increased creatinine | 1.2 | 1.6 |
| Hematology | ||
| Lymphopenia | 7 | 9 |
| Anemia | 2.7 | 16 |
| Electrolytes | ||
| Hyponatremia | 6 | 7 |
| Hyperkalemia | 4.2 | 1.9 |
| Hypocalcemia | 3.9 | 3.4 |
| Hypophosphatemia | 2.4 | 4.1 |
| Hypermagnesemia | 2.1 | 1.6 |
| Hypokalemia | 1.5 | 2.2 |
| Hypercalcemia | 1.2 | 2.2 |
| Toxicity graded per NCI CTCAE v. 4.03 a Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter. |
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Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cemiplimab-rwlc in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
Anti-drug antibodies (ADA) were tested in 823 patients who received LIBTAYO. The incidence of cemiplimab-rwlc treatment-emergent ADAs was 2.2% using an electrochemiluminescent (ECL) bridging immunoassay; 0.4% were persistent ADA responses. In the patients who developed anti-cemiplimab-rwlc antibodies.
SRC: NLM .