Adverse Drug Reactions (EC + Pembrolizumab)

The incidence rates of treatment-emergent adverse events observed in clinical studies for EC in combination with pembrolizumab are presented in table 8 & 9 below.

Events are included as Adverse Drug Reactions (ADRs) based on the incidence rates of treatment emergent adverse events (TEAEs) in the placebo-controlled DTC study together with events from other indications assessed in the context of TEAE incidence rates across study treatment arms, the known pharmacology of lenvatinib and the underlying indication.


EC 2L Combination With Pembrolizumab

The safety of lenvatinib in combination with pembrolizumab was investigated in Study 309, a multicenter, open-label, randomized (1:1), active-controlled trial in 827 patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received lenvatinib 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks (n=406) or treatment of investigator’s choice (n=388), consisting of 60 mg/m2 doxorubicin every 3 weeks or 80 mg/m2 paclitaxel given weekly, 3 weeks on/1 week off.

The median duration of study treatment was 7.6 months (range 1 day to 26.8 months). The median duration of exposure to lenvatinib was 6.9 months (range 1 day to 26.8 months).

Tables 8 and 9 summarize treatment emergent adverse events and laboratory abnormalities, respectively, in patients receiving lenvatinib in combination with pembrolizumab in Study 309.

Table 8: Treatment Emergent Adverse Events in ≥10% of Patients Receiving Lenvatinib plus Pembrolizumab in Study 309 (EC)
Adverse Reaction Lenvatinib 20 mg in combination with
Pembrolizumab 200 mg
N=406
Doxorubicin or
Paclitaxel
N=388
All Grades (%)       Grades 3-4                      (%)                                           All Gradesa                (%)        Grades 3-4                           (%)                             
Endocrine
Hypothyroidism b 69 1 1 0
Hypethyroidism 12 <1 1 0
Vascular
Hypertension c 65 38 6 2
Hemorrhagic events d 24 2 13 <1
General
Fatigue e 59 11 54 7
Pyrexia 14 1 7 0
Edema peripheral 12 <1 9 <1
Gastrointestinal
Diarrhea f 54 8 21 2
Nausea 50 3 46 1
Vomiting 37 3 21 2
Stomatitis g 35 3 25 1
Abdominal pain h 33 3 21 2
Constipation 26 <1 25 <1
Pancreatitis 12 7 2 1
Musculoskeletal and Connective Tissue
Musculoskeletal disorders i 52 5 26 <1
Metabolism
Decreased appetite j 45 8 21 <1
Investigations
Decreased weight 34 10 6 <1
Renal and Urinary Disorders
Proteinuria k 30 5 3 <1
Renal impairement l 17 4 5 2
Infections
Urinary tract infection m 29 5 12 1
Nervous System
Headache 29 <1 9 <1
Dizziness 10 0 6 0
Respiratory, Thoracic and Mediastinal Disorders
Dysphonia 23 0 <1 0
Cough 13 0 13 <1
Dyspnea n 12 <1 12 1
Skin and Subcutaneous Tissue Disorders
Palmar-plantar erythrodysesthesia O 22 3 1 0
Rash P 20 2 4 0
Pruritus 10 0 3 0
a Graded per NCI CTCAE v4.03
b Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism,
and secondary hypothyroidism
c Includes hypertension, blood pressure increased, hypertensive crisis, secondary hypertension, blood pressure
abnormal, hypertensive encephalopathy, and blood pressure fluctuation
d Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion,
hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis,
hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine
hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic
stroke, injection site hemorrhage, melena, purpura, stoma site hemorrhage, upper gastrointestinal
hemorrhage, wound hemorrhage, blood urine present, coital bleeding, ecchymosis, hematemesis, hemorrhage
subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage,
pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, and vessel puncture site bruise
e Includes fatigue, asthenia, malaise, and lethargy
f Includes diarrhea and gastroenteritis
g Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis,
oral mucosal erythema, and tongue ulceration
h Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal
pain, abdominal tenderness, and epigastric discomfort
i Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis,
musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw
j Includes decreased appetite and early satiety
k Includes proteinuria, protein urine present, hemoglobinuria
l Includes blood creatinine increased, acute kidney injury, renal failure, azotemia, autoimmune nephritis, nephritis,
oliguria, urine output decreased
m Includes urinary tract infection, cystitis, and pyelonephritis
n Includes dyspnea and dyspnea exertional
o Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema, and skin reaction
p Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular,
rash vesicular, and application site rash

 

 

Table 9: Laboratory Abnormalities Worsened from Table 9: Laboratory Abnormalities Worsened from Baselinea Occurring in ≥10% (All Grades) or ≥3% (Grades 3-4) of Patients Receiving Lenvatinib plus Pembrolizumab in Study 309 (EC)
Laboratory Test b Lenvatinib 20 mg in combination with
Pembrolizumab
N=406
Doxorubicin or
Paclitaxel
N=388
All Grades c   %         Grades 3-4                              %                              All Grades  %                                               Grades 3-4 %                             
Chemistry
Hypertriglyceridemia 69 7 43 2
Hypoalbuminemia 61 3 42 2
Aspartate aminotransferase increased 58 9 22 1
Hyperglycemia 57 8 45 4
Hypomagnesemia 54 7 33 4
Alanine aminotransferase increased 53 8 21 1
Hypercholesteremia 53 3 22 <1
Hyponatremia 47 14 27 7
Alkaline phosphatase increased 43 4 19 1
Hypocalcemia 40 4 20 2
Lipase increased 35 14 12 4
Creatinine increased 35 4 17 2
Hypokalemia 34 11 23 5
Hypophosphatemia 25 8 18 4
Amylase increased 25 7 7 1
Hyperkalemia 24 2 13 2
Creatine kinase
increased
20 3 6 0
Bilirubin increased 19 3 6 2
Prothrombin international
normalized ratio
increased
18 0 13 1
Hypercalcemia 17 1 9 1
Hypoglycemia 13 2 6 1
Hematology
Lymphopenia 51 17 65 22
Thrombocytopenia 51 7 30 5
Anemia 50 8 84 16
Leukopenia 44 3 83 42
Neutropenia 33 6 75 57
a With at least 1 grade increase from baseline
b Laboratory abnormality percentage is based on the number of patients who had both baseline and at least
one post-baseline laboratory measurement for each parameter: Lenvatinib/pembrolizumab (range: 312 to 404 patients) and doxorubicin or paclitaxel (280 to 380).
c Graded per NCI CTCAE v4.03