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CLEAR: Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma

Sponsor
Eisai Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02811861
Collaborator
Merck Sharp & Dohme LLC (Industry)
1,069
Enrollment
183
Locations
3
Arms
96.6
Anticipated Duration (Months)
5.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary purpose of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review [IIR] using Response Evaluation Criteria in Solid Tumors [RECIST 1.1]) as first-line treatment in participants with advanced renal cell carcinoma (RCC).

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
1069 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line Treatment of Subjects With Advanced Renal Cell Carcinoma (CLEAR)
Actual Study Start Date :
Oct 13, 2016
Actual Primary Completion Date :
Aug 28, 2020
Anticipated Study Completion Date :
Oct 31, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Lenvatinib 18 mg plus Everolimus 5 mg

Lenvatinib 18 milligrams (mg) administered orally, once daily, plus everolimus 5 mg administered orally, once daily in each 21-day cycle.

Drug: Lenvatinib

Drug: Everolimus
Experimental: Lenvatinib 20 mg plus Pembrolizumab 200 mg

Lenvatinib 20 mg administered orally, once daily, in each 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV), every 3 weeks on Day 1 of each 21-day cycle.

Drug: Lenvatinib

Drug: Pembrolizumab
Active Comparator: Sunitinib 50 mg

Sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment in each 21-day cycle.

Drug: Sunitinib

Outcome Measures

Primary Outcome Measures

  1. Progression-free Survival (PFS) by Independent Imaging Review (IIR) [From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to data cutoff date 28 Aug 2020 (up to approximately 46 months)]

    PFS assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or death (whichever occurred first) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method.

Secondary Outcome Measures

  1. Objective Response Rate (ORR) [Up to approximately 69 months]

    ORR is defined as the proportion of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1. CR is defined as disappearance of all (targeted and non-target [NT]) lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  2. Overall Survival (OS) [Up to approximately 69 months]

    OS is defined as the time from the date of randomization to the date of death from any cause. Participants who were lost to follow-up and those who were alive at the data cutoff date were censored, either at the last date the participant was last known alive or at the data cutoff date, whichever occurred first. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  3. Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Up to approximately 69 months]

    TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug.An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  4. Number of Participants Who Discontinued Treatment Due to Toxicity [Up to approximately 69 months]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  5. Time to Treatment Failure Due to Toxicity [Up to approximately 69 months]

    Time to treatment failure due to toxicity is defined as time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  6. Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores [Up to approximately 69 months]

    The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  7. HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score [Up to approximately 69 months]

    EORTC QLQ-C30 is a questionnaire including 30 questions that rate the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. For the overall HRQoL and functioning scales, a higher score is correlated with better HRQoL, whereas a higher score represents worse HRQoL for symptom scales. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  8. HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score [Up to approximately 69 months]

    EQ-5D-3L is a health profile questionnaire consisting of the EQ-5D descriptive system and the EuroQol visual analog scale (EQ-VAS). For the EQ-5D, participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) at 1 of 3 levels (1=no problems; 2=some problems; 3=extreme problems). The EQ-5D Health Utilities Index (HUI) is derived from the five dimensions of the EQ-5D, using country-specific preference weights (tariffs) to summarize how good or bad each health state is on a scale from 1 (full health) to <0 (worse health/dead). The EQ-VAS measures self-rated global health status using a vertically oriented VAS, where 100 represents the "best imaginable health state" and 0 represents the "worst imaginable health state." Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  9. PFS on Next-line of Therapy (PFS2) [Up to approximately 69 months]

    PFS2 is defined as the time from randomization to disease progression as assessed by investigator on next-line treatment or death from any cause (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  10. PFS by Investigator Assessment [Up to approximately 69 months]

    PFS by investigator assessment is defined as the time from the date of randomization to the date of first documentation of disease progression based on the investigator assessment per RECIST 1.1 or death (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  11. Model-predicted Clearance for Lenvatinib and Everolimus [Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length=21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

  12. Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus [Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length = 21 days]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  1. Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable).

  2. Documented evidence of advanced RCC.

  3. At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria:

  • Lymph node (LN) lesion that measures at least 1 dimension as greater than or equal to (>=) 1.5 cm in the short axis

  • Lymph node (LN) lesion that measures at least 1 dimension as greater than or equal to (>=) 1.5 centimeter (cm) in the short axis

  • Non-nodal lesion that measures greater than or equal to (>=) 1.0 cm in the longest diameter

  • The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.

3.Karnofsky Performance Status (KPS) of >=70 4.Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal (<=) 150/90 millimeter of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week prior to Cycle 1/Day 1 (C1/D1) 5.Adequate renal function defined as creatinine <=1.5upper limit of normal (ULN); or for participants with creatinine greater than (>) 1.5ULN, the calculated creatinine clearance >=30 milliliters per minute (mL/min) (per the Cockcroft-Gault formula) is acceptable.

6.Adequate bone marrow function defined by:

  • Absolute neutrophil count (ANC) >=1500/cubic millimeter (mm^3)

  • Platelets >=100,000/mm^3

  • Hemoglobin >=9 grams per deciliter (g/dL) NOTE: Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within the previous 2 weeks.

7.Adequate blood coagulation function defined by International Normalized ratio (INR) <=1.5 unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range of intended use of anticoagulants.

8.Adequate liver function defined by:

  • Total bilirubin <=1.5*ULN except for unconjugated hyperbilirubinemia of Gilbert's syndrome.

  • Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3ULN (in the case of liver metastases <=5ULN), unless there are bone metastases. Participants with ALP values >3*ULN and known to have bone metastases can be included.

9.Provide written informed consent. 10.Willing and able to comply with all aspects of the protocol.

Exclusion Criteria:

  1. Participants who have received any systemic anticancer therapy for RCC, including anti-vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agent. Prior adjuvant treatment with an investigational anticancer agent is not allowed unless the investigator can provide evidence of participant's randomization to placebo arm.

  2. Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (example, whole brain radiation therapy (WBRT), surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (example, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment

  3. Active malignancy (except for RCC, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix or bladder) within the past 24 months. Participants with history of localized & low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no prostate specific antigen (PSA) recurrence within the past 5 years

  4. Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start

  5. Participants who are using other investigational agents or who had received investigational drugs <=4 weeks prior to study treatment start.

  6. Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). Examples of live vaccines include, but are not limited to, measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (example, FluMist®) are live attenuated vaccines and are not allowed.

  7. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein

=1 g/24 h will be ineligible

  1. Fasting total cholesterol >300 milligram per deciliter (mg/dL) (or ˃7.75 millimole per liter (mmol/L)) and/or fasting triglycerides level ˃2.5 x upper limit of normal (ULN). Note: these participants can be included after initiation or adjustment of lipid-lowering medication

  2. Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. Note: these participants can be included after initiation or adjustment of glucose-lowering medication

  3. Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms)

  4. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.

  5. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib, everolimus, and/or sunitinib.

  6. Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy

  7. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug

  8. Significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction, cerebrovascular accident, or cardiac arrhythmia associated with hemodynamic instability. The following is also excluded: left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multiple-gated acquisition MUGA scan or echocardiogram

  9. Active infection (any infection requiring systemic treatment)

  10. Participants known to be positive for Human Immunodeficiency Virus (HIV).

  11. Known active Hepatitis B (example, Hepatitis B surface antigen (HBsAg) reactive) or Hepatitis C (example, hepatitis C virus ribonucleic acid (HCV RNA) [qualitative] is detected)

  12. Known history of, or any evidence of, interstitial lung disease

  13. Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis

  14. Participants with a diagnosis of immunodeficiency or who are receiving chronic systemic steroid therapy (doses exceeding 10 mg/day of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Physiologic doses of corticosteroids (up to 10 mg/day of prednisone or equivalent) may be used during the study

  15. Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years (that is, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

  16. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.

  17. Females of childbearing potential who:

  • Do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation, that is:

  • total abstinence (if it is their preferred and usual lifestyle)

  • an intrauterine device (IUD) or hormone-releasing system (IUS)

  • a contraceptive implant

  • an oral contraceptive (with additional barrier method) OR

  • Do not have a vasectomized partner with confirmed azoospermia. For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.

  1. Males who have not had a successful vasectomy (confirmed azoospermia) and do not agree to use condom + spermicide OR have a female partner who does not meet the criteria above (that is, is of childbearing potential and not practicing highly effective contraception throughout the study period), starting with the first dose of study therapy through 120 days after the last dose of study therapy, unless sexually abstinent. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.

  2. Known intolerance to any of the study drugs (or any of the excipients)

  3. Participant has had an allogenic tissue/solid organ transplant.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Stanford School of Medicine Stanford California United States 94305-5826
2 Boca Raton Community Hospital Boca Raton Florida United States 33486
3 Florida Cancer Specialists Fort Myers Florida United States 33901
4 Mount Sinai Medical Center Miami Beach Florida United States 33136
5 University of Miami Miami Florida United States 33136
6 Florida Hospital Cancer Institute Orlando Florida United States 32804
7 Florida Cancer Specialists ( North Region) Saint Petersburg Florida United States 33705
8 Florida Cancer Specialists West Palm Beach Florida United States 33401
9 Joliet Oncology - Hematology Associates Joliet Illinois United States 60435
10 Healthcare Research Network III, LLC Tinley Park Illinois United States 60487
11 Health Midwest Ventures Group, Inc d/b/a HCA MidAmerica Division, LLC Overland Park Kansas United States 66209
12 Cotton-Oneil Clinical Research Center Topeka Kansas United States 66604
13 Ochsner Clinic Foundation New Orleans Louisiana United States 70121
14 Associates in Oncology & Hematology, PC Bethesda Maryland United States 20817
15 Massachusetts General Hospital- MGH Boston Massachusetts United States 02214
16 Dana Farber Cancer Institute Boston Massachusetts United States 02215
17 Karmanos Cancer Center Detroit Michigan United States 48201
18 GU Research Network Omaha Nebraska United States 68130
19 Nebraska Cancer Specialists Omaha Nebraska United States 68130
20 Hackensack Medical Center Hackensack New Jersey United States 07601
21 Montefiore Medical Center Bronx New York United States 10461
22 Rosewell Park Cancer Institute Buffalo New York United States 14263
23 Broome Oncology Johnson City New York United States 13790
24 Weill Cornell Medical College New York Presbyterian Hospital New York New York United States 10021
25 Memorial Sloan Kettering Cancer Center New York New York United States 10065
26 Mission Hospital_ Cancer Care of Western North Carolina Asheville North Carolina United States 28801
27 Oncology Hematology Care Cincinnati Ohio United States 45242
28 Medical University of South Carolina Charleston South Carolina United States 29412
29 SCRI - Tennessee Oncology Nashville Tennessee United States 37203
30 Texas Oncology, P.A. Dallas Texas United States 75231
31 Texas Oncology PA Fort Worth Texas United States 76104
32 Texas Oncology PA - McAllen McAllen Texas United States 78503
33 Texas Oncology PA - Paris Paris Texas United States 75460
34 USOR Texas Oncology The Woodlands Texas United States 77380
35 Texas Oncology PA - Tyler Tyler Texas United States 75702
36 Eastern Clinical Research Unit Box Hill Victoria Australia 3128
37 Austin Hospital Heidelberg Victoria Australia 3084
38 Royal Hobart Hospital Hobart Australia
39 Macquarie University Hospital Macquarie park Australia
40 ICON Cancer Foundation South Brisbane Australia
41 Sunshine Hospital St Albans Australia
42 Medizinische Universitat Innsbruck Innsbruck Austria
43 Krankenhaus der barmherzigen Schwestern Linz Linz Austria
44 AKH - Medizinische Universität Wien Vienna Austria 1090
45 O.L.V Ziekenhuis Aalst Belgium
46 ZNA Middelheim Antwerpen Belgium 2260
47 Imeldaziekenhuis Bonheiden Belgium
48 Institut Jules Bordet Bruxelles Belgium 1000
49 Jessa Ziekenhuis - Campus Virga Jesse Hasselt Belgium 3500
50 Domaine Universitaire Liege Belgium 4000
51 GZA Ziekenhuizen - Campus Sint-Augustinus Wilrijk Belgium 2610
52 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
53 BC Cancer Agency Vancouver Centre Vancouver British Columbia Canada V5Z 1H7
54 St. Joseph's Healthcare Hamilton Hamilton Ontario Canada L8N 4A6
55 London Institute of Health Sciences London Ontario Canada N6A4L6
56 Ottawa Hospital Cancer Centre Ottawa Ontario Canada K1H 8
57 Sunnybrook Research Institute - University of Toronto Toronto Ontario Canada M4N 3M5
58 Centre de santé et de services sociaux Champlain-Charles-Le Moyne Greenfield Park Quebec Canada J4V 2H1
59 Fakultni nemocnice u sv. Anny v Brne Brno Czechia
60 Masarykuv onkologicky ustav Brno Czechia
61 Fakultni nemocnice Olomouc, Neurologicka klinika Olomouc Czechia
62 Thomayerova nemocnice Praha 4 Czechia
63 Fakultni nemocnice v Motole Praha 5 Czechia
64 Nemocnice Na Bulovce Praha 8 Czechia
65 ICO - Site Paul Papin Angers Maine Et Loire France 49055
66 Centre Georges François Leclerc Dijon cedex France 21079
67 Clinique Victor Hugo - Centre Jean Bernard Le Mans Cedex France
68 Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes Lyon France
69 Institut Regional du Cancer de Montpellier Montpellier France
70 Hopital la Petie Salpetriere Paris France cedex 13 75651
71 Hopital Europeen Georges Pompidou Paris France
72 Boulevard du Professeur Jacques Monod Saint Herblain France 4805
73 CHU Strasbourg - Nouvel Hopital Civil Strasbourg France
74 EISAI Trial site 4 Stuttgart Baden Wuerttemberg Germany 70174
75 EISAI Trial site 1 Tuebingen Baden Wuerttemberg Germany 72076
76 EISAI Trial site 7 München Bayern Germany 81377
77 EISAI Trial site 6 Frankfurt Hessen Germany 60590
78 EISAI Trial site 14 Greifswald Mecklenburg-Vorpommern Germany
79 EISAI Trial site 8 Hannover Niedersachsen Germany 30625
80 EISAI Trial site 13 Münster Nordrhein Westfalen Germany 48149
81 EISAI Trial site 2 Homburg/Saar Saarland Germany 66421
82 EISAI Trial site 5 Berlin Germany 12200
83 General Hospital of Athens "Alexandra" Athens Greece 11528
84 University of Patras Medical School Patras Greece 26504
85 General Hospital Papageorgiou Thessaloníki Greece 56429
86 Interbalkan Hospital of Thessaloniki Thessaloníki Greece 57001
87 Cork University Hospital,Wilton Cork Ireland
88 Adelaide and Meath Hospital Incorp The National Children's Hospital Dublin Ireland
89 Beaumont Hospital Dublin Ireland
90 University Hospital Galway Galway Ireland
91 Assaf Harofeh Medical Center Be'er Ya'aqov Israel
92 Rambam MC Haifa Israel
93 Sapir Medical Center, Meir Hospital Kfar-Saba Israel
94 Rabin Medical Center-Beilinson Campus Petah Tikva Israel 49100
95 Chaim Sheba Medical Center Ramat-Gan Israel
96 Tel Aviv Sourasky Medical Center Tel Aviv Israel
97 Azienda Unità Sanitaria Locale- Ravenna Faenza Ravenna Italy 48018
98 Ospedale San Donato Arezzo Italy
99 Azienda Ospedaliera Universitaria Policlinico SantOrsola Malpighi Bologna Italy
100 Istituto Nazionale per la Ricerca sul Cancro di Genova Genova Italy 16132
101 Presidio Ospedaliero Vito Fazzi Lecce Italy 73100
102 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST Meldola Italy
103 Fondazione IRCCS Istituto Nazionale dei Tumori Milano Italy 20133
104 A.O.U. Policlinico di Modena Modena Italy 41124
105 Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli Napoli Italy 80131
106 Istituto Nazionale Tumori Fondazione G. Pascale Napoli Italy
107 Fondazione IRCCS Policlinico San Matteo Pavia Italy
108 I.R.C.S.S Fondazione Maugeri Pavia Italy
109 Azienda Ospedaliera Santa Maria Degli Angeli Pordenone Italy 33170
110 Azienda Ospedaliera San Camillo Forlanini Roma Italy
111 Universita Campus Bio-Medico di Roma Rome Italy
112 Facility #1 Aichi Japan
113 Facility #1 Akita Japan
114 Facility #1 Aomori Japan
115 Facility #2 Chiba Japan
116 Facility #1 Fukuoka Japan
117 Facility #1 Hiroshima Japan
118 Facility #1 Hokkaido Japan
119 Facility #2 Hokkaido Japan
120 Facility #1 Hyogo Japan
121 Facility #1 Kagawa Japan
122 Facility #2 Kanagawa Japan
123 Facility #3 Kanagawa Japan
124 Facility #1 Nagasaki Japan
125 Facility #1 Nara Japan
126 Facility #1 Niigata Japan
127 Facility #1 Okayama Japan
128 Facility #1 Osaka Japan
129 Facility #2 Osaka Japan
130 Facility #1 Saitama Japan
131 Facility #1 Tokushima Japan
132 Facility #1 Tokyo Japan
133 Facility #2 Tokyo Japan
134 Facility #3 Tokyo Japan
135 Facility #4 Tokyo Japan
136 Facility #5 Tokyo Japan
137 Facility #6 Tokyo Japan
138 Kyungpook National University Chilgok Hospital Daegu Korea, Republic of 41404
139 National Cancer Center Goyang-si Korea, Republic of
140 Asan Medical Center: Medical Oncology Department Seoul Korea, Republic of
141 Asan Medical Center: Urology Department Seoul Korea, Republic of
142 Department of Internal Medicine Division of Hematology/Oncology Cancer center 11F Seoul Korea, Republic of
143 Samsung Medical Center Seoul Korea, Republic of
144 Seoul National University Hospital Seoul Korea, Republic of
145 Severance Hospital, Yonsei University Health System Seoul Korea, Republic of
146 The Catholic University of Korea, Seoul St. Mary's Hospital Seoul Korea, Republic of
147 Antoni van Leeuwenhoek Amsterdam Netherlands 1066 CX
148 VU Medisch Centrum Amsterdam Netherlands 1081 HV
149 UMC Utrecht Utrecht Netherlands 3584 CX
150 Uniwersyteckie Centrum Kliniczne Gdansk Poland
151 Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie Lublin Poland
152 SPWSZ w Szczecinie im. Marii Sklodowskiej-Curie Szczecin Poland
153 FSBSI Russian Oncological Scientific Center n.a. N.N. Blokhin - Department of Oncology Moscow Russian Federation 115478
154 FSBI "Moscow scientific research oncology institute n.a. P.A. Gertsen" of MoH of RF Moscow Russian Federation 125284
155 FSBSI Russian Oncological Scientific Center n.a. N.N. Blokhin - Department of Urology Moscow Russian Federation
156 FBHI Privolzhskiy District Medical Centre FMBA of Russia Nizhniy Novgorod Russian Federation
157 SBHI of Novosibirsk region "Novosibirsk Regional Oncological Dispensary" Novosibirsk Russian Federation 630108
158 FSBI "National Medical Research Radiological Center" of the MoH of the RF Obninsk Russian Federation 249036
159 BHI of Omsk region "Clinical Oncology Dispensary" Omsk Russian Federation 644013
160 Hospital Universitario Marques de Valdecilla Santander Cantabria Spain 39008
161 Hospital Clinic i Provincial de Barcelona Barcelona Spain 08036
162 ICO l'Hospitalet - Hospital Duran I Reynals Barcelona Spain 08908
163 Hospital de la Santa Creu i Sant Pau Barcelona Spain
164 Hospital Universitari Vall d'Hebron Barcelona Spain
165 Hospital San Pedro de Alcantara Caceres Spain 10003
166 Hospital Universitario Reina Sofia Cordoba Spain
167 Hospital Universitario Ramon y Cajal Madrid Spain 28034
168 Hospital General Universitario Gregorio Maranon Madrid Spain
169 Hospital Universitario Clinico San Carlos Madrid Spain
170 Hospital Universitario HM Madrid Sanchinarro Madrid Spain
171 MD Anderson Cancer Centre Madrid Spain
172 Hospital Universitario Central de Asturias Oviedo Spain 33011
173 Hospital Universitario Virgen del Rocio Seville Spain
174 Oncologia Valencia Spain 46009
175 Inselspital - Universitaetsspital Bern Bern Switzerland
176 Royal Bournemouth General Hospital Bournemouth United Kingdom
177 Velindre Cancer Centre Cardiff United Kingdom
178 Western General Hospital Edinburgh United Kingdom
179 Beatson West Of Scotland Cancer Centre Glasgow United Kingdom G12 0YN
180 St. James's University Hospital Leeds United Kingdom LS9 7TF
181 Guy's Hospital London United Kingdom
182 Royal Free Hospital London United Kingdom
183 Christie Hospital NHS Foundation Trust Manchester United Kingdom M20 4BX

Sponsors and Collaborators

  • Eisai Inc.
  • Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT02811861
Other Study ID Numbers:
  • E7080-G000-307
  • KEYNOTE-581
  • 2016-000916-14
First Posted:
Jun 23, 2016
Last Update Posted:
Jul 6, 2022
Last Verified:
Jun 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Eisai Inc.
Renal Cell Carcinoma (RCC)
Lenvatinib
First-line RCC
Treatment-naive RCC
Everolimus
Pembrolizumab
Sunitinib
Phase 3 RCC
Phase 3 first-line RCC
Phase 3 treatment-naive RCC
Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Pembrolizumab
Everolimus
Sunitinib
Lenvatinib

Study Results

Participant Flow

Recruitment Details Participants took part in the study at 181 investigative sites in Austria, Belgium, Canada, France, Germany, Greece, Ireland, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom of Great Britain and Northern Ireland, the United States of America, Australia, Czechia, Israel, Japan, Korea, Russian Federation, from 13 October 2016 to 28 August 2020 (date of data cutoff for the primary analysis of PFS and second interim analysis of Overall Survival).
Pre-assignment Detail A total of 1417 participants were screened, of which, 1069 were randomized. Of the 1069 randomized, 1047 participants were treated in the study.
Arm/Group Title Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg
Arm/Group Description Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent. Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study. Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.
Period Title: Overall Study
STARTED 357 355 357
Treated 355 352 340
COMPLETED 0 0 0
NOT COMPLETED 357 355 357

Baseline Characteristics

Arm/Group Title Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg Total
Arm/Group Description Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent. Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study. Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent. Total of all reporting groups
Overall Participants 357 355 357 1069
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
61.9
(10.86)
62.3
(10.23)
60.8
(9.96)
61.7
(10.36)
Sex: Female, Male (Count of Participants)
Female
91
25.5%
100
28.2%
82
23%
273
25.5%
Male
266
74.5%
255
71.8%
275
77%
796
74.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
23
6.4%
12
3.4%
20
5.6%
55
5.1%
Not Hispanic or Latino
328
91.9%
339
95.5%
334
93.6%
1001
93.6%
Unknown or Not Reported
6
1.7%
4
1.1%
3
0.8%
13
1.2%
Race/Ethnicity, Customized (Count of Participants)
White
254
71.1%
263
74.1%
270
75.6%
787
73.6%
Black or African American
1
0.3%
2
0.6%
3
0.8%
6
0.6%
Asian
77
21.6%
81
22.8%
67
18.8%
225
21%
American Indian or Alaskan Native
1
0.3%
0
0%
0
0%
1
0.1%
Native Hawaiian or Other Pacific Islander
1
0.3%
0
0%
0
0%
1
0.1%
Other
7
2%
4
1.1%
7
2%
18
1.7%
Missing
16
4.5%
5
1.4%
10
2.8%
31
2.9%

Outcome Measures

1. Primary Outcome
Title Progression-free Survival (PFS) by Independent Imaging Review (IIR)
Description PFS assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or death (whichever occurred first) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method.
Time Frame From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to data cutoff date 28 Aug 2020 (up to approximately 46 months)

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of the treatment actually received.
Arm/Group Title Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg
Arm/Group Description Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent. Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study. Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.
Measure Participants 357 355 357
Median (95% Confidence Interval) [months]
14.7
23.9
9.2
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lenvatinib 18 mg Plus Everolimus 5 mg, Sunitinib 50 mg
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Stratified Log-rank Test
Comments Hazard ratio is based on a Cox Proportional Hazards Model including treatment group as a factor.
Method of Estimation Estimation Parameter Stratified Hazard Ratio
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.53 to 0.80
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lenvatinib 20 mg Plus Pembrolizumab 200 mg, Sunitinib 50 mg
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Stratified Log-rank Test
Comments Hazard ratio is based on a Cox Proportional Hazards Model including treatment group as a factor.
Method of Estimation Estimation Parameter Stratified Hazard Ratio
Estimated Value 0.39
Confidence Interval (2-Sided) 95%
0.32 to 0.49
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Objective Response Rate (ORR)
Description ORR is defined as the proportion of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1. CR is defined as disappearance of all (targeted and non-target [NT]) lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
3. Secondary Outcome
Title Overall Survival (OS)
Description OS is defined as the time from the date of randomization to the date of death from any cause. Participants who were lost to follow-up and those who were alive at the data cutoff date were censored, either at the last date the participant was last known alive or at the data cutoff date, whichever occurred first. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
4. Secondary Outcome
Title Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug.An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
5. Secondary Outcome
Title Number of Participants Who Discontinued Treatment Due to Toxicity
Description Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
6. Secondary Outcome
Title Time to Treatment Failure Due to Toxicity
Description Time to treatment failure due to toxicity is defined as time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
7. Secondary Outcome
Title Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores
Description The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
8. Secondary Outcome
Title HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score
Description EORTC QLQ-C30 is a questionnaire including 30 questions that rate the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. For the overall HRQoL and functioning scales, a higher score is correlated with better HRQoL, whereas a higher score represents worse HRQoL for symptom scales. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
9. Secondary Outcome
Title HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score
Description EQ-5D-3L is a health profile questionnaire consisting of the EQ-5D descriptive system and the EuroQol visual analog scale (EQ-VAS). For the EQ-5D, participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) at 1 of 3 levels (1=no problems; 2=some problems; 3=extreme problems). The EQ-5D Health Utilities Index (HUI) is derived from the five dimensions of the EQ-5D, using country-specific preference weights (tariffs) to summarize how good or bad each health state is on a scale from 1 (full health) to <0 (worse health/dead). The EQ-VAS measures self-rated global health status using a vertically oriented VAS, where 100 represents the "best imaginable health state" and 0 represents the "worst imaginable health state." Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
10. Secondary Outcome
Title PFS on Next-line of Therapy (PFS2)
Description PFS2 is defined as the time from randomization to disease progression as assessed by investigator on next-line treatment or death from any cause (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
11. Secondary Outcome
Title PFS by Investigator Assessment
Description PFS by investigator assessment is defined as the time from the date of randomization to the date of first documentation of disease progression based on the investigator assessment per RECIST 1.1 or death (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Up to approximately 69 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
12. Secondary Outcome
Title Model-predicted Clearance for Lenvatinib and Everolimus
Description Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length=21 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
13. Secondary Outcome
Title Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus
Description Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022).
Time Frame Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length = 21 days

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description

Adverse Events

Time Frame From first dose of study drug (Baseline) up to 30 days after last dose of study drug or up to data cutoff date 28 Aug 2020 (up to approximately 46 months)
Adverse Event Reporting Description Safety analysis set included all participants who received at least 1 dose of any study drug.
Arm/Group Title Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg
Arm/Group Description Participants received lenvatinib 18 milligrams (mg) administered orally, once daily in each 21-day cycle, plus everolimus 5 mg administered orally, once daily in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent. Participants received lenvatinib 20 mg administered orally, once daily in each 21-day cycle, plus pembrolizumab 200 mg administered intravenously, every 3 weeks in each 21-day cycle until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study. Participants received sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment until participant had disease progression, development of unacceptable toxicity, participant request, withdrawal of consent.
All Cause Mortality
Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 119/355 (33.5%) 78/352 (22.2%) 99/340 (29.1%)
Serious Adverse Events
Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 164/355 (46.2%) 178/352 (50.6%) 113/340 (33.2%)
Blood and lymphatic system disorders
Anaemia 3/355 (0.8%) 0/352 (0%) 4/340 (1.2%)
Blood loss anaemia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Eosinophilia myalgia syndrome 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Febrile neutropenia 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Leukopenia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Neutropenia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Thrombocytopenia 2/355 (0.6%) 1/352 (0.3%) 5/340 (1.5%)
Thrombotic thrombocytopenic purpura 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Cardiac disorders
Acute coronary syndrome 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Acute myocardial infarction 0/355 (0%) 5/352 (1.4%) 0/340 (0%)
Angina unstable 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Arrhythmia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Atrial fibrillation 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Atrial flutter 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Bradycardia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Cardiac arrest 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Cardiac failure 3/355 (0.8%) 0/352 (0%) 1/340 (0.3%)
Cardiac failure acute 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Cardiac failure congestive 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Cardio-respiratory arrest 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Cardiogenic shock 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Cardiomyopathy 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Congestive cardiomyopathy 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Myocardial infarction 3/355 (0.8%) 6/352 (1.7%) 1/340 (0.3%)
Myocarditis 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Pericardial effusion 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Postinfarction angina 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Stress cardiomyopathy 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Tachycardia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Ventricular arrhythmia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Endocrine disorders
Adrenal insufficiency 0/355 (0%) 7/352 (2%) 0/340 (0%)
Hypophysitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hypopituitarism 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hypothyroidism 2/355 (0.6%) 3/352 (0.9%) 0/340 (0%)
Secondary hypothyroidism 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Steroid withdrawal syndrome 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Eye disorders
Cataract 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Eyelid ptosis 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Retinal vascular occlusion 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Retinal vein occlusion 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Vogt-Koyanagi-Harada disease 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Gastrointestinal disorders
Abdominal hernia 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Abdominal pain 6/355 (1.7%) 5/352 (1.4%) 1/340 (0.3%)
Abdominal pain upper 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Anal fissure 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Anal fistula 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Ascites 1/355 (0.3%) 0/352 (0%) 2/340 (0.6%)
Colitis 1/355 (0.3%) 2/352 (0.6%) 0/340 (0%)
Colonic fistula 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Constipation 0/355 (0%) 3/352 (0.9%) 0/340 (0%)
Diarrhoea 14/355 (3.9%) 12/352 (3.4%) 4/340 (1.2%)
Diverticular perforation 1/355 (0.3%) 0/352 (0%) 1/340 (0.3%)
Duodenal ulcer perforation 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Dyspepsia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Dysphagia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Enteritis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Enterocolitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Eosinophilic gastritis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Food poisoning 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Gastric haemorrhage 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Gastric ulcer 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Gastritis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Gastroduodenal haemorrhage 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Gastrointestinal haemorrhage 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Haematemesis 0/355 (0%) 2/352 (0.6%) 1/340 (0.3%)
Ileus 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Immune-mediated enterocolitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Immune-mediated pancreatitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Inguinal hernia 2/355 (0.6%) 1/352 (0.3%) 0/340 (0%)
Intestinal obstruction 2/355 (0.6%) 1/352 (0.3%) 0/340 (0%)
Intestinal perforation 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Intra-abdominal haemorrhage 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Large intestinal haemorrhage 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Large intestine perforation 3/355 (0.8%) 0/352 (0%) 0/340 (0%)
Lower gastrointestinal haemorrhage 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Mallory-Weiss syndrome 1/355 (0.3%) 0/352 (0%) 1/340 (0.3%)
Mechanical ileus 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Melaena 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Nausea 5/355 (1.4%) 5/352 (1.4%) 1/340 (0.3%)
Obstructive pancreatitis 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Odynophagia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Pancreatitis 1/355 (0.3%) 6/352 (1.7%) 0/340 (0%)
Pancreatitis acute 2/355 (0.6%) 1/352 (0.3%) 1/340 (0.3%)
Proctitis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Retroperitoneal haemorrhage 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Small intestinal haemorrhage 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Subileus 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Upper gastrointestinal haemorrhage 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Vomiting 10/355 (2.8%) 10/352 (2.8%) 3/340 (0.9%)
General disorders
Asthenia 4/355 (1.1%) 2/352 (0.6%) 4/340 (1.2%)
Death 2/355 (0.6%) 1/352 (0.3%) 2/340 (0.6%)
Face oedema 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Fatigue 2/355 (0.6%) 0/352 (0%) 2/340 (0.6%)
General physical health deterioration 3/355 (0.8%) 1/352 (0.3%) 3/340 (0.9%)
Generalised oedema 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Inadequate analgesia 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Malaise 2/355 (0.6%) 0/352 (0%) 1/340 (0.3%)
Multiple organ dysfunction syndrome 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Non-cardiac chest pain 1/355 (0.3%) 2/352 (0.6%) 0/340 (0%)
Oedema 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Oedema peripheral 2/355 (0.6%) 0/352 (0%) 1/340 (0.3%)
Pain 2/355 (0.6%) 2/352 (0.6%) 1/340 (0.3%)
Pyrexia 4/355 (1.1%) 6/352 (1.7%) 7/340 (2.1%)
Hepatobiliary disorders
Autoimmune hepatitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Bile duct obstruction 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Bile duct stone 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Biliary colic 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Cholangitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Cholecystitis 5/355 (1.4%) 2/352 (0.6%) 1/340 (0.3%)
Cholecystitis acute 8/355 (2.3%) 2/352 (0.6%) 1/340 (0.3%)
Cholecystitis chronic 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Cholelithiasis 2/355 (0.6%) 1/352 (0.3%) 0/340 (0%)
Drug-induced liver injury 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hepatic function abnormal 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Immune-mediated hepatitis 0/355 (0%) 4/352 (1.1%) 0/340 (0%)
Portal vein thrombosis 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Cholestasis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Infections and infestations
Abdominal infection 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Acute sinusitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Anal abscess 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Appendicitis 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Bacteraemia 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Bronchitis 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
COVID-19 pneumonia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Cellulitis 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Cholecystitis infective 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Clostridium difficile infection 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Colonic abscess 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Diverticulitis 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Ear infection 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Empyema 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Encephalitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Encephalitis viral 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Enteritis infectious 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Enterocolitis infectious 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Gastroenteritis 3/355 (0.8%) 2/352 (0.6%) 2/340 (0.6%)
Gastroenteritis viral 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Infection 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Infectious pleural effusion 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Influenza 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Klebsiella sepsis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Localised infection 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Necrotising fasciitis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Oropharyngeal candidiasis 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Osteomyelitis 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Otitis externa 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Peritonitis 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Peritonitis bacterial 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Peritonsillar abscess 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Pharyngitis 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Pneumocystis jirovecii pneumonia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Pneumonia 15/355 (4.2%) 7/352 (2%) 6/340 (1.8%)
Pneumonia influenzal 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Pneumonia necrotising 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Postoperative wound infection 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Prostatic abscess 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Pyelonephritis 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Respiratory tract infection 0/355 (0%) 2/352 (0.6%) 1/340 (0.3%)
Retroperitoneal abscess 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Sepsis 2/355 (0.6%) 3/352 (0.9%) 3/340 (0.9%)
Septic arthritis staphylococcal 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Sinusitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Skin infection 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Staphylococcal bacteraemia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Subdiaphragmatic abscess 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Urinary tract infection 3/355 (0.8%) 4/352 (1.1%) 4/340 (1.2%)
Urosepsis 2/355 (0.6%) 2/352 (0.6%) 0/340 (0%)
Wound infection 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Injury, poisoning and procedural complications
Accidental overdose 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Arterial injury 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Fall 3/355 (0.8%) 0/352 (0%) 0/340 (0%)
Femoral neck fracture 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Femur fracture 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Head injury 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Incisional hernia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Infusion related reaction 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Lower limb fracture 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Radiation injury 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Radiation proctitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Rib fracture 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Spinal cord injury cervical 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Spinal fracture 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Stress fracture 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Subdural haematoma 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Tibia fracture 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Toxicity to various agents 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Upper limb fracture 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Wound dehiscence 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Investigations
Alanine aminotransferase increased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Amylase increased 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Aspartate aminotransferase increased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Blood bilirubin increased 0/355 (0%) 1/352 (0.3%) 2/340 (0.6%)
Blood calcium increased 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Blood creatinine increased 2/355 (0.6%) 1/352 (0.3%) 0/340 (0%)
Ejection fraction decreased 0/355 (0%) 0/352 (0%) 2/340 (0.6%)
Electrocardiogram T wave inversion 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Electrocardiogram change 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Glomerular filtration rate decreased 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Haemoglobin increased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hepatic enzyme increased 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Lipase increased 0/355 (0%) 4/352 (1.1%) 0/340 (0%)
Neutrophil count decreased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Platelet count decreased 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Transaminases increased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Troponin increased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Weight decreased 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
White blood cell count decreased 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Metabolism and nutrition disorders
Cachexia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Decreased appetite 4/355 (1.1%) 3/352 (0.9%) 0/340 (0%)
Dehydration 4/355 (1.1%) 1/352 (0.3%) 4/340 (1.2%)
Diabetes mellitus 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Diabetic ketoacidosis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Electrolyte imbalance 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Hypercalcaemia 5/355 (1.4%) 0/352 (0%) 1/340 (0.3%)
Hypercholesterolaemia 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Hyperglycaemia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hyperglycaemic hyperosmolar nonketotic syndrome 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hyperkalaemia 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Hypocalcaemia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hypoglycaemia 1/355 (0.3%) 1/352 (0.3%) 2/340 (0.6%)
Hyponatraemia 4/355 (1.1%) 2/352 (0.6%) 2/340 (0.6%)
Hypophosphataemia 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 3/355 (0.8%) 2/352 (0.6%) 1/340 (0.3%)
Back pain 3/355 (0.8%) 2/352 (0.6%) 4/340 (1.2%)
Bone lesion 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Bone pain 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Flank pain 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Musculoskeletal chest pain 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Musculoskeletal pain 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Myalgia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Myositis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Neck pain 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Osteoarthritis 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Osteonecrosis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Osteoporotic fracture 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Pain in extremity 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Pathological fracture 3/355 (0.8%) 6/352 (1.7%) 2/340 (0.6%)
Spinal stenosis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Rhabdomyolysis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain 3/355 (0.8%) 2/352 (0.6%) 1/340 (0.3%)
Chronic myeloid leukaemia 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
External ear neoplasm malignant 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Malignant ascites 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Malignant neoplasm progression 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Malignant pleural effusion 2/355 (0.6%) 0/352 (0%) 1/340 (0.3%)
Metastases to bone 0/355 (0%) 0/352 (0%) 2/340 (0.6%)
Metastases to central nervous system 0/355 (0%) 1/352 (0.3%) 2/340 (0.6%)
Metastases to chest wall 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Metastases to lung 1/355 (0.3%) 1/352 (0.3%) 1/340 (0.3%)
Metastases to skin 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Metastases to spine 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Pericardial effusion malignant 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Prostate cancer 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Tumour associated fever 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Tumour haemorrhage 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Tumour pain 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Nervous system disorders
Ataxia 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Carotid artery stenosis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Cerebral ischaemia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Cerebrovascular accident 1/355 (0.3%) 2/352 (0.6%) 0/340 (0%)
Cytotoxic oedema 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Dementia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Depressed level of consciousness 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Dizziness 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Dysgeusia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Encephalopathy 0/355 (0%) 2/352 (0.6%) 0/340 (0%)
Generalised tonic-clonic seizure 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Haemorrhage intracranial 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Headache 2/355 (0.6%) 2/352 (0.6%) 2/340 (0.6%)
Hypertensive encephalopathy 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Ischaemic stroke 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Loss of consciousness 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Myasthenic syndrome 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Noninfective encephalitis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Paralysis 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Paralysis recurrent laryngeal nerve 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Paraparesis 1/355 (0.3%) 0/352 (0%) 1/340 (0.3%)
Peripheral sensory neuropathy 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Posterior reversible encephalopathy syndrome 0/355 (0%) 2/352 (0.6%) 1/340 (0.3%)
Seizure 0/355 (0%) 0/352 (0%) 2/340 (0.6%)
Somnolence 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Spinal cord compression 2/355 (0.6%) 1/352 (0.3%) 2/340 (0.6%)
Subarachnoid haemorrhage 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Syncope 1/355 (0.3%) 2/352 (0.6%) 1/340 (0.3%)
Transient ischaemic attack 2/355 (0.6%) 2/352 (0.6%) 0/340 (0%)
Product Issues
Device deposit issue 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Psychiatric disorders
Confusional state 2/355 (0.6%) 0/352 (0%) 0/340 (0%)
Delirium 1/355 (0.3%) 2/352 (0.6%) 0/340 (0%)
Mania 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Mental status changes 0/355 (0%) 5/352 (1.4%) 0/340 (0%)
Renal and urinary disorders
Acute kidney injury 10/355 (2.8%) 8/352 (2.3%) 5/340 (1.5%)
Haematuria 0/355 (0%) 0/352 (0%) 4/340 (1.2%)
Haemorrhage urinary tract 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Nephritis 0/355 (0%) 3/352 (0.9%) 0/340 (0%)
Oliguria 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Proteinuria 2/355 (0.6%) 1/352 (0.3%) 0/340 (0%)
Renal failure 2/355 (0.6%) 4/352 (1.1%) 2/340 (0.6%)
Renal haemorrhage 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Ureterolithiasis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Urinary retention 1/355 (0.3%) 2/352 (0.6%) 1/340 (0.3%)
Urinary tract obstruction 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Reproductive system and breast disorders
Scrotal pain 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Bronchial obstruction 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Chronic obstructive pulmonary disease 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Cough 3/355 (0.8%) 0/352 (0%) 0/340 (0%)
Dyspnoea 6/355 (1.7%) 7/352 (2%) 2/340 (0.6%)
Epistaxis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Haemoptysis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Haemothorax 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Hypoxia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Interstitial lung disease 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Lung disorder 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Pleural effusion 3/355 (0.8%) 4/352 (1.1%) 5/340 (1.5%)
Pneumonia aspiration 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Pneumonitis 0/355 (0%) 9/352 (2.6%) 0/340 (0%)
Pneumothorax 3/355 (0.8%) 1/352 (0.3%) 1/340 (0.3%)
Pneumothorax spontaneous 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Pulmonary embolism 2/355 (0.6%) 5/352 (1.4%) 3/340 (0.9%)
Pulmonary haemorrhage 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Pulmonary mass 1/355 (0.3%) 1/352 (0.3%) 0/340 (0%)
Respiratory failure 2/355 (0.6%) 1/352 (0.3%) 2/340 (0.6%)
Skin and subcutaneous tissue disorders
Erythema multiforme 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hyperhidrosis 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Pyoderma gangrenosum 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Rash 1/355 (0.3%) 2/352 (0.6%) 0/340 (0%)
Rash maculo-papular 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Skin ulcer 0/355 (0%) 1/352 (0.3%) 1/340 (0.3%)
Stevens-Johnson syndrome 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Toxic epidermal necrolysis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Urticaria 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Surgical and medical procedures
Spinal laminectomy 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Vascular disorders
Aneurysm ruptured 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Aortic dissection 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Aortic stenosis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Deep vein thrombosis 0/355 (0%) 2/352 (0.6%) 1/340 (0.3%)
Embolism venous 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Haematoma 1/355 (0.3%) 0/352 (0%) 0/340 (0%)
Hypertension 2/355 (0.6%) 8/352 (2.3%) 2/340 (0.6%)
Hypertensive crisis 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Hypotension 0/355 (0%) 0/352 (0%) 2/340 (0.6%)
Peripheral ischaemia 0/355 (0%) 1/352 (0.3%) 0/340 (0%)
Phlebitis 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Thrombophlebitis migrans 0/355 (0%) 0/352 (0%) 1/340 (0.3%)
Other (Not Including Serious) Adverse Events
Lenvatinib 18 mg Plus Everolimus 5 mg Lenvatinib 20 mg Plus Pembrolizumab 200 mg Sunitinib 50 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 353/355 (99.4%) 351/352 (99.7%) 332/340 (97.6%)
Blood and lymphatic system disorders
Anaemia 57/355 (16.1%) 43/352 (12.2%) 66/340 (19.4%)
Thrombocytopenia 39/355 (11%) 14/352 (4%) 53/340 (15.6%)
Neutropenia 11/355 (3.1%) 9/352 (2.6%) 46/340 (13.5%)
Leukopenia 4/355 (1.1%) 5/352 (1.4%) 23/340 (6.8%)
Endocrine disorders
Hypothyroidism 95/355 (26.8%) 164/352 (46.6%) 90/340 (26.5%)
Hyperthyroidism 9/355 (2.5%) 28/352 (8%) 12/340 (3.5%)
Gastrointestinal disorders
Diarrhoea 233/355 (65.6%) 214/352 (60.8%) 166/340 (48.8%)
Stomatitis 169/355 (47.6%) 122/352 (34.7%) 131/340 (38.5%)
Nausea 139/355 (39.2%) 125/352 (35.5%) 113/340 (33.2%)
Vomiting 107/355 (30.1%) 91/352 (25.9%) 67/340 (19.7%)
Constipation 73/355 (20.6%) 87/352 (24.7%) 64/340 (18.8%)
Abdominal pain 72/355 (20.3%) 72/352 (20.5%) 28/340 (8.2%)
Dyspepsia 34/355 (9.6%) 39/352 (11.1%) 55/340 (16.2%)
Abdominal pain upper 45/355 (12.7%) 34/352 (9.7%) 26/340 (7.6%)
Dry mouth 23/355 (6.5%) 36/352 (10.2%) 11/340 (3.2%)
Gastrooesophageal reflux disease 16/355 (4.5%) 16/352 (4.5%) 30/340 (8.8%)
Toothache 24/355 (6.8%) 19/352 (5.4%) 9/340 (2.6%)
Haemorrhoids 19/355 (5.4%) 20/352 (5.7%) 11/340 (3.2%)
Abdominal discomfort 19/355 (5.4%) 8/352 (2.3%) 8/340 (2.4%)
General disorders
Fatigue 149/355 (42%) 141/352 (40.1%) 124/340 (36.5%)
Asthenia 63/355 (17.7%) 77/352 (21.9%) 61/340 (17.9%)
Oedema peripheral 72/355 (20.3%) 42/352 (11.9%) 35/340 (10.3%)
Pyrexia 44/355 (12.4%) 48/352 (13.6%) 41/340 (12.1%)
Infections and infestations
Nasopharyngitis 34/355 (9.6%) 40/352 (11.4%) 25/340 (7.4%)
Urinary tract infection 32/355 (9%) 24/352 (6.8%) 23/340 (6.8%)
Sinusitis 14/355 (3.9%) 19/352 (5.4%) 6/340 (1.8%)
Upper respiratory tract infection 24/355 (6.8%) 31/352 (8.8%) 21/340 (6.2%)
Investigations
Weight decreased 116/355 (32.7%) 105/352 (29.8%) 31/340 (9.1%)
Platelet count decreased 59/355 (16.6%) 21/352 (6%) 61/340 (17.9%)
Lipase increased 22/355 (6.2%) 64/352 (18.2%) 44/340 (12.9%)
Aspartate aminotransferase increased 52/355 (14.6%) 39/352 (11.1%) 37/340 (10.9%)
Alanine aminotransferase increased 49/355 (13.8%) 42/352 (11.9%) 35/340 (10.3%)
Blood creatinine increased 36/355 (10.1%) 48/352 (13.6%) 34/340 (10%)
Amylase increased 16/355 (4.5%) 62/352 (17.6%) 28/340 (8.2%)
Blood thyroid stimulating hormone increased 22/355 (6.2%) 39/352 (11.1%) 21/340 (6.2%)
Blood cholesterol increased 41/355 (11.5%) 24/352 (6.8%) 14/340 (4.1%)
Neutrophil count decreased 14/355 (3.9%) 7/352 (2%) 40/340 (11.8%)
Blood triglycerides increased 21/355 (5.9%) 22/352 (6.3%) 15/340 (4.4%)
White blood cell count decreased 11/355 (3.1%) 9/352 (2.6%) 33/340 (9.7%)
Blood creatine phosphokinase increased 19/355 (5.4%) 14/352 (4%) 17/340 (5%)
Electrocardiogram QT prolonged 15/355 (4.2%) 22/352 (6.3%) 13/340 (3.8%)
Blood alkaline phosphatase increased 20/355 (5.6%) 17/352 (4.8%) 9/340 (2.6%)
Metabolism and nutrition disorders
Decreased appetite 143/355 (40.3%) 142/352 (40.3%) 105/340 (30.9%)
Hypertriglyceridaemia 80/355 (22.5%) 42/352 (11.9%) 41/340 (12.1%)
Hypercholesterolaemia 37/355 (10.4%) 31/352 (8.8%) 7/340 (2.1%)
Hyperglycaemia 31/355 (8.7%) 24/352 (6.8%) 18/340 (5.3%)
Hypophosphataemia 32/355 (9%) 22/352 (6.3%) 15/340 (4.4%)
Hyponatraemia 17/355 (4.8%) 27/352 (7.7%) 20/340 (5.9%)
Hypokalaemia 30/355 (8.5%) 22/352 (6.3%) 11/340 (3.2%)
Hyperkalaemia 14/355 (3.9%) 27/352 (7.7%) 18/340 (5.3%)
Hypomagnesaemia 17/355 (4.8%) 27/352 (7.7%) 13/340 (3.8%)
Musculoskeletal and connective tissue disorders
Arthralgia 75/355 (21.1%) 99/352 (28.1%) 52/340 (15.3%)
Back pain 60/355 (16.9%) 57/352 (16.2%) 52/340 (15.3%)
Musculoskeletal pain 39/355 (11%) 48/352 (13.6%) 21/340 (6.2%)
Pain in extremity 33/355 (9.3%) 41/352 (11.6%) 33/340 (9.7%)
Myalgia 34/355 (9.6%) 56/352 (15.9%) 12/340 (3.5%)
Muscle spasms 14/355 (3.9%) 24/352 (6.8%) 12/340 (3.5%)
Musculoskeletal chest pain 20/355 (5.6%) 16/352 (4.5%) 11/340 (3.2%)
Nervous system disorders
Headache 81/355 (22.8%) 80/352 (22.7%) 54/340 (15.9%)
Dysgeusia 59/355 (16.6%) 42/352 (11.9%) 95/340 (27.9%)
Dizziness 17/355 (4.8%) 34/352 (9.7%) 29/340 (8.5%)
Psychiatric disorders
Insomnia 40/355 (11.3%) 38/352 (10.8%) 21/340 (6.2%)
Renal and urinary disorders
Haematuria 15/355 (4.2%) 17/352 (4.8%) 19/340 (5.6%)
Proteinuria 121/355 (34.1%) 104/352 (29.5%) 43/340 (12.6%)
Respiratory, thoracic and mediastinal disorders
Cough 84/355 (23.7%) 70/352 (19.9%) 53/340 (15.6%)
Dysphonia 84/355 (23.7%) 105/352 (29.8%) 14/340 (4.1%)
Dyspnoea 50/355 (14.1%) 51/352 (14.5%) 32/340 (9.4%)
Epistaxis 70/355 (19.7%) 25/352 (7.1%) 37/340 (10.9%)
Oropharyngeal pain 33/355 (9.3%) 23/352 (6.5%) 12/340 (3.5%)
Pneumonitis 19/355 (5.4%) 12/352 (3.4%) 0/340 (0%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome 81/355 (22.8%) 101/352 (28.7%) 127/340 (37.4%)
Rash 87/355 (24.5%) 95/352 (27%) 47/340 (13.8%)
Pruritus 47/355 (13.2%) 58/352 (16.5%) 26/340 (7.6%)
Dry skin 31/355 (8.7%) 22/352 (6.3%) 27/340 (7.9%)
Rash maculo-papular 23/355 (6.5%) 28/352 (8%) 7/340 (2.1%)
Yellow skin 1/355 (0.3%) 0/352 (0%) 32/340 (9.4%)
Dermatitis acneiform 23/355 (6.5%) 5/352 (1.4%) 3/340 (0.9%)
Vascular disorders
Hypertension 162/355 (45.6%) 194/352 (55.1%) 141/340 (41.5%)
Hypotension 17/355 (4.8%) 24/352 (6.8%) 6/340 (1.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Eisai Medical Information
Organization Eisai, Inc.
Phone +1-888-274-2378
Email esi_oncmedinfo@eisai.com
Responsible Party:
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT02811861
Other Study ID Numbers:
  • E7080-G000-307
  • KEYNOTE-581
  • 2016-000916-14
First Posted:
Jun 23, 2016
Last Update Posted:
Jul 6, 2022
Last Verified:
Jun 1, 2022