Study Design and Patient Characteristics
aTreatment was permitted beyond RECIST v1.1–defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated.
bAccording to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
BICR = blinded independent central review; ECOG PS = Eastern Cooperative Oncology Group performance status; IV = intravenously; MSI-H = microsatellite instability-high; pMMR = mismatch repair proficient; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1.
Efficacy
In KEYNOTE-775/Study 309: KEYTRUDA + LENVIMA demonstrated superiority in OS, PFS, and ORR vs doxorubicin or paclitaxel alone
Superior OS: 32% reduction in the risk of death vs doxorubicin or paclitaxel alone
cBased on the stratified Cox regression model.
dBased on stratified log-rank test.
CI = confidence interval; HR = hazard ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
Superior PFS: 40% reduction in the risk of disease progression or death vs doxorubicin or paclitaxel alone
cBased on the stratified Cox regression model.
dBased on stratified log-rank test.
ePer independent radiology review.
Additional endpoints: ORR and DOR
eResponse: Best objective response as confirmed CR or PR.
fPer independent radiology review.
gBased on Miettinen and Nurminen method stratified by ECOG PS, geographic region, and history of pelvic radiation.
CR = complete response; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group performance status; PR = partial response.
Adverse Reactions
Adverse reactions in KEYNOTE-775/Study 309
The safety of KEYTRUDA in combination with LENVIMA was investigated in KEYNOTE-775/ Study 309, a multicenter, open-label, randomized (1:1) active-controlled trial of 697 patients with advanced endometrial carcinoma that was pMMR or not MSI-H, who were previously treated with at least one prior platinum-based chemotherapy regimen in any setting. The adverse reactions listed reflect the adverse reaction profile of this population treated with KEYTRUDA in combination with LENVIMA (n=342) in the study.
KEYTRUDA | LENVIMA | |
---|---|---|
Median duration of exposure (months) | 6.8 (range: 1 day to 25.8 months) | 6.7 (range: 1 day to 26.8 months) |
Fatal adverse reactions occurred in 4.7% of patients treated with KEYTRUDA + LENVIMA, including 2 cases of pneumonia, and 1 case of the following:
Acute kidney injury
Acute myocardial infarction
Colitis
Decreased appetite
Intestinal perforation
Lower gastrointestinal hemorrhage
Malignant gastrointestinal obstruction
Multiple organ dysfunction syndrome
Myelodysplastic syndrome
Pulmonary embolism
Right ventricular dysfunction
Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA + LENVIMA. Serious adverse reactions (≥3%) were:
Hypertension (4.4%)
Urinary tract infection (3.2%)
Adverse reactions that led to discontinuation in KEYNOTE-775/Study 309
Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients. Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients.
The most common (≥1%) adverse reaction leading to discontinuation of KEYTRUDA was:
Increased alanine aminotransferase (1.2%)
The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were:
Hypertension (2%)
Asthenia (1.8%)
Diarrhea (1.2%)
Decreased appetite (1.2%)
Proteinuria (1.2%)
Vomiting (1.2%)
Discontinuation and interruption rates for KEYTRUDA + LENVIMA and dose reduction rates of LENVIMA in KEYNOTE-775/Study 309 due to adverse reactions
KEYTRUDA | LENVIMA | |
---|---|---|
Discontinuation | 15% | 26% |
Dose reduction | N/Ah | 67% |
Dose interruption | 48% | 58% |
hNo dose reduction for KEYTRUDA is recommended.
The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were:
Hypertension (18%)
Diarrhea (11%)
Palmar-plantar erythrodysesthesia syndrome (9%)
Proteinuria (7%)
Fatigue (7%)
Decreased appetite (6%)
Asthenia (5%)
Weight decreased (5%)
The most common (≥3%) adverse reactions leading to interruption of KEYTRUDA were:
Diarrhea (8%) |
Increased alanine aminotransferase (4.4%) |
Increased aspartate aminotransferase (3.8%) |
Hypertension (3.5%) |
The most common (≥2%) adverse reactions leading to interruption of LENVIMA were:
Hypertension (11%)
Diarrhea (11%)
Proteinuria (6%)
Decreased appetite (5%)
Vomiting (5%)
Increased alanine aminotransferase (3.5%)
Fatigue (3.5%)
Nausea (3.5%)
Abdominal pain (2.9%)
Weight decreased (2.6%)
Urinary tract infection (2.6%)
Increased aspartate aminotransferase (2.3%)
Asthenia (2.3%)
Palmar-plantar erythrodysesthesia (2%)
Adverse reactions occurring in ≥20% of patients receiving KEYTRUDA + LENVIMA in KEYNOTE-775/Study 309
Adverse Reaction | KEYTRUDA + LENVIMA (n=342) |
|
All Gradesi (%) | Grades 3–4 (%) | |
Hypothyroidismj | 67 | 0.9 |
Hypertensionk | 67 | 39 |
Fatiguel | 58 | 11 |
Diarrheam | 55 | 8 |
Musculoskeletal disordersn | 53 | 5 |
Nausea | 49 | 2.9 |
Decreased appetiteo | 44 | 7 |
Vomiting | 37 | 2.3 |
Stomatitisp | 35 | 2.6 |
Abdominal painq | 34 | 2.6 |
Weight loss | 34 | 10 |
Urinary tract infectionsr | 31 | 5 |
Proteinurias | 29 | 6 |
Constipation | 27 | 0 |
Headache | 26 | 0.6 |
Hemorrhagic eventst | 25 | 2.6 |
Palmar-plantar erythrodysesthesiau | 23 | 2.9 |
Dysphonia | 22 | 0 |
Rashv | 20 | 2.3 |
Doxorubicin or Paclitaxel (n=325) | |
All Gradesi (%) | Grades 3–4 (%) |
0.9 | 0 |
6 | 2.5 |
54 | 6 |
20 | 2.8 |
27 | 0.6 |
47 | 1.5 |
21 | 0 |
21 | 2.2 |
26 | 1.2 |
21 | 1.2 |
6 | 0.3 |
13 | 1.2 |
3.4 | 0.3 |
25 | 0.6 |
9 | 0.3 |
15 | 0.9 |
0.9 | 0 |
0.6 | 0 |
4.9 | 0 |
iGraded per NCI-CTCAE v4.03.
jIncludes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism, and secondary hypothyroidism.
kIncludes hypertension, blood pressure increased, hypertensive crisis, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, and blood pressure fluctuation.
lIncludes fatigue, asthenia, malaise, lethargy.
mIncludes diarrhea, gastroenteritis.
nIncludes 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.
oIncludes decreased appetite, early satiety.
pIncludes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration.
qIncludes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, epigastric discomfort.
rIncludes urinary tract infection, cystitis, pyelonephritis.
sIncludes proteinuria, protein urine present, hemoglobinuria.
tIncludes 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.
uIncludes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema, and skin reaction.
vIncludes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, application site rash.
NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events.
Selected Safety Information for
KEYTRUDA® (pembrolizumab)
MSI-H = microsatellite instability-high; pMMR = mismatch repair proficient; ALT = alanine aminotransferase.
Before prescribing KEYTRUDA® (pembrolizumab), please read the accompanying Prescribing Information. The Medication Guide also is available.
Selected Safety Information for
LENVIMA® (lenvatinib)
Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.
Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.
Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.
CNS = central nervous system; MRI = magnetic resonance imaging; QTc = corrected QT interval; ALT = alanine aminotransferase.
Before prescribing LENVIMA® (lenvatinib), please read the accompanying Prescribing Information and Patient Information.