INLYTA in Combination with Avelumab
The safety of INLYTA in combination with avelumab was evaluated in JAVELIN Renal 101. Patients with autoimmune disease other than type I diabetes mellitus, vitiligo, psoriasis, or thyroid disorders not requiring immunosuppressive treatment were excluded. Patients received INLYTA 5 mg twice daily (N=434) in combination with avelumab 10 mg/kg every 2 weeks administered or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks off (N=439).
In the INLYTA plus avelumab arm, 70% were exposed to avelumab for ≥6 months and 29% were exposed for ≥1 year in JAVELIN Renal 101 [see Clinical Studies (14.1)].
The median age of patients treated with INLYTA in combination with avelumab was 62 years (range: 29 to 83), 38% of patients were 65 years or older, 71% were male, 75% were White, and the Eastern Cooperative Oncology Group (ECOG) performance score was 0 (64%) or 1 (36%).
Fatal adverse reactions occurred in 1.8% of patients receiving INLYTA in combination with avelumab. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).
Serious adverse reactions occurred in 35% of patients receiving INLYTA in combination with avelumab. Serious adverse reactions in ≥1% of patients included diarrhea (2.5%), dyspnea (1.8%), hepatotoxicity (1.8%), venous thromboembolic disease (1.6%), acute kidney injury (1.4%), and pneumonia (1.2%).
Permanent discontinuation due to an adverse reaction of either INLYTA or avelumab occurred in 22% of patients: 19% avelumab only, 13% INLYTA only, and 8% both drugs. The most common adverse reactions (>1%) resulting in permanent discontinuation of avelumab or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%).
Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of avelumab infusions due to infusion-related reactions, occurred in 76% of patients receiving INLYTA in combination with avelumab. This includes interruption of avelumab in 50% of patients. INLYTA was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reaction (>10%) resulting in interruption of avelumab was diarrhea (10%). The most common adverse reactions resulting in either interruption or dose reduction of INLYTA were diarrhea (19%), hypertension (18%), palmar-plantar erythrodysesthesia (18%), and hepatotoxicity (10%).
The most common adverse reactions (≥20%) in patients receiving INLYTA in combination with avelumab were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.
Forty-eight (11%) of patients treated with INLYTA in combination with avelumab received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5.12)].
Table 4 summarizes adverse reactions that occurred in ≥20% of INLYTA in combination with avelumab-treated patients.
Table 4: Adverse Reactions (≥20%) of Patients Receiving INLYTA in Combination with Avelumab (JAVELIN Renal 101 Trial)*Adverse Reactions | INLYTA plus Avelumab (N=434) | Sunitinib (N=439) |
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| All Grades % | Grade 3–4 % | All Grades % | Grade 3–4 % |
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Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03 (NCI CTCAE v4). |
|
Gastrointestinal Disorders |
Diarrhea† | 62 | 8 | 48 | 2.7 |
Nausea | 34 | 1.4 | 39 | 1.6 |
Mucositis‡ | 34 | 2.8 | 35 | 2.1 |
Hepatotoxicity§ | 24 | 9 | 18 | 3.6 |
Abdominal pain¶ | 22 | 1.4 | 19 | 2.1 |
General Disorders and Administration Site Conditions |
Fatigue# | 53 | 6 | 54 | 6 |
Vascular Disorders |
HypertensionÞ | 50 | 26 | 36 | 17 |
Musculoskeletal and Connective Tissue Disorders |
Musculoskeletal painß | 40 | 3.2 | 33 | 2.7 |
Skin and Subcutaneous Tissue Disorders |
Palmar-plantar erythrodysesthesia | 33 | 6 | 34 | 4 |
Rashà | 25 | 0.9 | 16 | 0.5 |
Respiratory, Thoracic and Mediastinal Disorders |
Dysphonia | 31 | 0.5 | 3.2 | 0 |
Dyspneaè | 23 | 3.0 | 16 | 1.8 |
Cough | 23 | 0.2 | 19 | 0 |
Metabolism and Nutrition Disorders |
Decreased appetite | 26 | 2.1 | 29 | 0.9 |
Endocrine Disorders |
Hypothyroidism | 25 | 0.2 | 14 | 0.2 |
Nervous System Disorders |
Headache | 21 | 0.2 | 16 | 0.2 |
Other clinically important adverse reactions that occurred in less than 20% of patients in JAVELIN Renal 101 included arthralgia, weight decreased, and chills.
Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with INLYTA in combination with avelumab.
Table 5 summarizes selected laboratory abnormalities that occurred in ≥20% of INLYTA in combination with avelumab-treated patients.
Table 5: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving INLYTA in Combination with Avelumab (JAVELIN Renal 101 Trial)*Laboratory Abnormality | INLYTA plus Avelumab | Sunitinib† |
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| Any Grade % | Grade 3–4 % | Any Grade % | Grade 3–4 % |
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|
Chemistry |
Blood triglycerides increased | 71 | 13 | 48 | 5 |
Blood creatinine increased | 62 | 2.3 | 68 | 1.4 |
Blood cholesterol increased | 57 | 1.9 | 22 | 0.7 |
Alanine aminotransferase increased (ALT) | 50 | 9 | 46 | 3.2 |
Aspartate aminotransferase increased (AST) | 47 | 7 | 57 | 3.2 |
Blood sodium decreased | 38 | 9 | 37 | 10 |
Lipase increased | 37 | 14 | 25 | 7 |
Blood potassium increased | 35 | 3.0 | 28 | 3.9 |
Blood bilirubin increased | 21 | 1.4 | 23 | 1.4 |
Hematology |
Platelet count decreased | 27 | 0.7 | 80 | 1.5 |
Hemoglobin decreased | 21 | 2.1 | 65 | 8 |
INLYTA in Combination with Pembrolizumab
The safety of INLYTA in combination with pembrolizumab was investigated in KEYNOTE-426 [see Clinical Studies (14.1)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received INLYTA 5 mg orally twice daily and pembrolizumab 200 mg intravenously every 3 weeks, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of INLYTA and pembrolizumab was 10.4 months (range: 1 day to 21.2 months).
The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90–100 and 20% KPS of 70–80.
Fatal adverse reactions occurred in 3.3% of patients receiving INLYTA in combination with pembrolizumab. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.
Serious adverse reactions occurred in 40% of patients receiving INLYTA in combination with pembrolizumab. Serious adverse reactions in ≥1% of patients receiving INLYTA in combination with pembrolizumab included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction of either INLYTA or pembrolizumab occurred in 31% of patients; 13% pembrolizumab only, 13% INLYTA only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of INLYTA, pembrolizumab, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%).
Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving pembrolizumab in combination with INLYTA. This includes interruption of pembrolizumab in 50% of patients. INLYTA was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in either interruption or reduction of INLYTA were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%) and the most common adverse reactions (>10%) resulting in interruption of pembrolizumab were hepatotoxicity (14%) and diarrhea (11%).
The most common adverse reactions (≥20%) in patients receiving INLYTA and pembrolizumab were diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
Twenty-seven percent (27%) of patients treated with INLYTA in combination with pembrolizumab received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction.
Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with INLYTA and pembrolizumab in KEYNOTE-426.
Table 6: Adverse Reactions Occurring in ≥20% of Patients Treated with INLYTA and Pembrolizumab (KEYNOTE-426 Trial)Adverse Reactions | INLYTA plus Pembrolizumab N=429 | Sunitinib N=425 |
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| All Grades* % | Grades 3–4 % | All Grades % | Grades 3–4 % |
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|
Gastrointestinal Disorders |
Diarrhea† | 56 | 11 | 45 | 5 |
Nausea | 28 | 0.9 | 32 | 0.9 |
Constipation | 21 | 0 | 15 | 0.2 |
General |
Fatigue/Asthenia | 52 | 5 | 51 | 10 |
Vascular |
Hypertension‡ | 48 | 24 | 48 | 20 |
Hepatobiliary |
Hepatotoxicity§ | 39 | 20 | 25 | 4.9 |
Endocrine |
Hypothyroidism | 35 | 0.2 | 32 | 0.2 |
Metabolism and Nutrition |
Decreased appetite | 30 | 2.8 | 29 | 0.7 |
Skin and Subcutaneous Tissue |
Palmar-plantar erythrodysesthesia syndrome | 28 | 5 | 40 | 3.8 |
Stomatitis/Mucosal inflammation | 27 | 1.6 | 41 | 4 |
Rash¶ | 25 | 1.4 | 21 | 0.7 |
Respiratory, Thoracic, and Mediastinal |
Dysphonia | 25 | 0.2 | 3.3 | 0 |
Cough | 21 | 0.2 | 14 | 0.5 |
Table 7: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving INLYTA With Pembrolizumab in KEYNOTE-426Laboratory Test* | INLYTA plus Pembrolizumab | Sunitinib |
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| All Grades† % | Grade 3–4 % | All Grades % | Grade 3–4 % |
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|
Chemistry |
Hyperglycemia | 62 | 9 | 54 | 3.2 |
Increased ALT | 60 | 20 | 44 | 5 |
Increased AST | 57 | 13 | 56 | 5 |
Increased creatinine | 43 | 4.3 | 40 | 2.4 |
Hyponatremia | 35 | 8 | 29 | 8 |
Hyperkalemia | 34 | 6 | 22 | 1.7 |
Hypoalbuminemia | 32 | 0.5 | 34 | 1.7 |
Hypercalcemia | 27 | 0.7 | 15 | 1.9 |
Hypophosphatemia | 26 | 6 | 49 | 17 |
Increased alkaline phosphatase | 26 | 1.7 | 30 | 2.7 |
Hypocalcemia‡ | 22 | 0.2 | 29 | 0.7 |
Blood bilirubin increased | 22 | 2.1 | 21 | 1.9 |
Activated partial thromboplastin time prolonged§ | 22 | 1.2 | 14 | 0 |
Hematology |
Lymphopenia | 33 | 11 | 46 | 8 |
Anemia | 29 | 2.1 | 65 | 8 |
Thrombocytopenia | 27 | 1.4 | 78 | 14 |