Lenvatinib in Combination With Pembrolizumab Versus Treatment of Physician's Choice in Participants With Advanced Endometrial Cancer (MK-3475-775/E7080-G000-309 Per Merck Standard Convention [KEYNOTE-775])

Endometrial Neoplasms Clinical Trial

Official title:

A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Pembrolizumab Versus Treatment of Physician's Choice in Participants With Advanced Endometrial Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03517449
• Other study ID #: E7080-G000-309
• Secondary ID: 2017-004387-35MK
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 11, 2018
• Est. completion date: October 7, 2024

Study information

• Verified date: October 2023
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a study of pembrolizumab (MK-3475, KEYTRUDA®) in combination with lenvatinib (E7080) versus treatment of physician's choice (doxorubicin or paclitaxel) for the treatment of advanced endometrial cancer. Participants will be randomly assigned to receive either pembrolizumab and lenvatinib or treatment of physician's choice. The primary study hypothesis is that pembrolizumab in combination with lenvatinib prolongs progression free survival (PFS) and overall survival (OS) when compared to treatment of physician's choice.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 827
• Est. completion date: October 7, 2024
• Est. primary completion date: October 26, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Has a histologically confirmed diagnosis of endometrial carcinoma (EC)

2. Documented evidence of advanced, recurrent or metastatic EC.

3. Has radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for EC. Participants may have received up to 1 additional line of platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment setting.

Note: There is no restriction regarding prior hormonal therapy.

4. Has historical or fresh tumor biopsy specimen for determination of mismatch repair (MMR) status.

5. Has at least 1 measurable target lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and confirmed by Blinded Independent Central Review BICR.

6. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study treatment.

7. Is not pregnant, breastfeeding, and agrees to use a highly effective method of contraception during the treatment period and for at least 120 days (for participants treated with lenvatinib plus pembrolizumab) or at least 180 days (for participants treated with treatment of physician's choice [TPC]) after the last dose of study treatment.

Exclusion Criteria:

1. Has carcinosarcoma (malignant mixed mullerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas.

2. Has unstable central nervous system (CNS) metastases.

3. Has active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas [e.g. breast, cervix, bladder], or basal or squamous cell carcinoma of the skin) within 24 months of study start.

4. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.

5. Has a pre-existing greater than or equal (>=) Grade 3 gastrointestinal or non-gastrointestinal fistula.

6. Has radiographic evidence of major blood vessel invasion/infiltration.

7. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment.

8. Has a history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability within 12 months of the first dose of study treatment.

9. Has an active infection requiring systemic treatment.

10. Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.

11. Is positive for Human Immunodeficiency Virus (HIV).

12. Has active Hepatitis B or C.

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

14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to study start -Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years.

16. Is pregnant or breastfeeding.

17. Has had an allogenic tissue/solid organ transplant.

18. Has received >1 prior systemic chemotherapy regimen (other than adjuvant or neoadjuvant) for Endometrial Cancer. Participants may receive up to 2 regimens of platinum-based chemotherapy in total, as long as one is given in the neoadjuvant or adjuvant treatment setting.

19. Has received prior anticancer treatment within 28 days of study start. All acute toxicities related to prior treatments must be resolved to Grade =1, except for alopecia and Grade =2 peripheral neuropathy.

20. Has received prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

21. Has received prior treatment with an agent directed to a stimulatory or co-inhibitory T-cell receptor other than an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, and who has discontinued from that treatment due to a Grade 3 or higher immune-related adverse event.

22. Has received prior radiation therapy within 21 days of study start with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks of study start. Participants must have recovered from all radiation-related toxicities and/or complications prior to randomization.

23. Has received a live vaccine within 30 days of study start.

24. Has a known intolerance to study treatment (or any of the excipients).

25. Prior enrollment on a clinical study evaluating pembrolizumab and lenvatinib for endometrial carcinoma, regardless of treatment received.

26. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of study start.

27. Participants with urine protein =1 gram (g)/24 hour.

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

29. Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).

Related Conditions & MeSH terms

• Endometrial Neoplasms

Intervention

Drug:
• Pembrolizumab
200 mg administered by IV infusion on Day 1 of each 21-day cycle.
• Lenvatinib
20 mg administered orally (PO) QD during each 21-day cycle.
• Paclitaxel
80 mg/m^2 administered by IV on a 28-day cycle: 3 weeks receiving paclitaxel once a week and 1 week not receiving paclitaxel.
• Doxorubicin
60 mg/m^2 administered by IV on Day 1 of each 21-day cycle.

Locations

Country	Name	City	State
Argentina	Centro de Oncologia e Investigacion Buenos Aires COIBA	Berazategui	Buenos Aires
Argentina	Hospital Aleman	Buenos Aires
Argentina	Instituto de Investigaciones Metabolicas	Buenos Aires
Argentina	Instituto de Oncologia Angel H. Roffo	Buenos Aires
Argentina	Instituto Medico Especializado Alexander Fleming	Buenos Aires
Argentina	Centro Oncologico Riojano Integral	La Rioja
Argentina	Hospital Privado de la Comunidad	Mar del Plata	Buenos Aires
Australia	Royal Brisbane and Women s Hospital	Herston	Queensland
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	St John of God	Subiaco	Western Australia
Australia	Royal North Shore Hospital	Sydney	New South Wales
Brazil	Faculdade de Medicina da Universidade Federal de Minas Gerais	Belo Horizonte
Brazil	Hospital Araujo Jorge	Goiania	GO
Brazil	Fundacao Dr Amaral Carvalho	Jau	SP
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RS
Brazil	Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs	Porto Alegre	RS
Brazil	Instituto Nacional do Cancer II	Rio de Janeiro	RJ
Brazil	Clinica de Pesquisas e Ctro de Estudos Onc. Ginecol. e Mamaria Ltda	Sao Paulo	SP
Brazil	Instituto do Cancer de Sao Paulo - ICESP	Sao Paulo	SP
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	London Health Sciences Centre	London	Ontario
Canada	Centre Hospitalier de l Universite de Montreal - CHUM	Montreal	Quebec
Canada	CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Ottawa General Hospital	Ottawa	Ontario
Canada	CHU de Quebec-Universite Laval-Hotel Dieu de Quebec	Quebec
Canada	CIUSSS de l'Estrie-CHUS	Sherbrooke	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Sunnybrook Health Science Centre	Toronto	Ontario
Canada	Cancer Care Manitoba	Winnipeg	Manitoba
Colombia	Biomelab S A S	Barranquilla
Colombia	Clinica Colsanitas S.A. - Sede Clinica Universitaria Colombia	Bogota
Colombia	Clinica del Country	Bogota	Cundinamarca
Colombia	Fundacion Valle del Lili	Cali	Valle Del Cauca
Colombia	Fundacion Colombiana de Cancerologia Clinica Vida	Medellin
Colombia	Rodrigo Botero SAS	Medellin
Colombia	Oncomedica S.A.	Monteria
France	Institut Bergonie	Bordeaux
France	Centre de Lutte Contre le Cancer Francois Baclesse	Caen
France	Centre Oscar Lambret	Lille
France	Centre Leon Berard	Lyon
France	Institut Regional du Cancer de Montpellier - ICM	Montpellier
France	Hopital prive du Confluent	Nantes
France	Groupe Hospitalier Broca Cochin Hotel Dieu	Paris
France	Hopital Diaconesses Croix Saint Simon	Paris
France	Centre Hospitalier Lyon Sud	Pierre Benite
France	Centre Armoricain de Radiotherapie Imagerie medicale et Oncologie	Plerin
France	Centre Eugene Marquis	Rennes
France	Institut Gustave Roussy	Villejuif
Germany	EISAI Trial Site 4	Berlin
Germany	EISAI Trial Site 2	Dresden
Germany	EISAI Trial Site 1	Erlangen
Germany	EISAI Trial Site 6	Hamburg
Germany	EISAI Trial Site 3	Rostock
Germany	EISAI Trial Site 5	Tuebingen
Ireland	Mater Misericordiae University Hospital	Dublin
Israel	Soroka Medical Center	Beer Sheva
Israel	Rambam Medical Center	Haifa
Israel	Edith Wolfson Medical Center	Holon
Israel	Hadassah Medical Center. Ein Kerem	Jerusalem
Israel	Rabin Medical Center	Petah Tikva
Israel	Chaim Sheba Medical Center	Ramat Gan
Italy	Azienda Ospedaliera per l Emergenza Cannizzaro	Catania
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan
Italy	Istituto Europeo di Oncologia	Milano
Italy	Ospedale San Raffaele	Milano
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli
Italy	Policlinico Universitario Agostino Gemelli	Roma
Japan	EISAI Trial Site 8	Akashi	Hyogo
Japan	EISAI Trial Site 1	Hidaka	Saitama
Japan	EISAI Trial Site 19	Isehara	Kanagawa
Japan	EISAI Trial Site 16	Kagoshima
Japan	EISAI Trial Site 18	Kashiwa	Chiba
Japan	EISAI Trial Site 5	Kurume	Fukoka
Japan	EISAI Trial Site 7	Matsuyama	Ehime
Japan	EISAI Trial Site 4	Morioka	Iwate
Japan	EISAI Trial Site 9	Nagoya	Aichi
Japan	EISAI Trial Site 3	Niigata
Japan	EISAI Trial Site 11	Sapporo	Hokkaido
Japan	EISAI Trial Site 14	Sendai	Miyagi
Japan	EISAI Trial Site 2	Sunto-gun	Shizuoka
Japan	EISAI Trial Site 10	Tokyo
Japan	EISAI Trial Site 12	Tokyo
Japan	EISAI Trial Site 13	Tokyo
Japan	EISAI Trial Site 6	Tokyo
Japan	EISAI Trial Site 15	Toon	Ehime
Japan	EISAI Trial Site 17	Tsukuba	Ibaraki
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Mexico	Investigacion Onco Farmaceutica S de RL de CV	La Paz	Baja California
Mexico	Grupo Medico Camino SC	Mexico City
Mexico	Alivia Clinica de Alta Especialidad S.A. de C.V.	Monterrey	Nuevo Leon
Mexico	Centro Hemato Oncologico Privado	Toluca
Mexico	Faicic S de RL de CV	Veracruz
New Zealand	Auckland City Hospital	Auckland
Poland	Beskidzkie Centrum Onkologii im. Jana Pawla II	Bielsko-Biala
Poland	Szpital Morski im. PCK Szpitale Wojewodzkie w Gdyni Sp. z o.o.	Gdynia
Poland	Centrum Onkologii Instytut im. Marii Sklodowskiej Curie	Gliwice
Poland	Centrum Onkologii Instytut im. Marii Sklodowskiej Curie	Krakow	Malopolskie
Poland	Instytut Centrum Zdrowia Matki Polki	Lodz
Poland	Pomorski Uniwersytet Medyczny w Szczecinie	Szczecin
Poland	Centrum Onkologii. Instytut im. Marii Sklodowskiej-Curie	Warszawa	Mazowieckie
Poland	Szpital Kliniczny im Ks Anny Mazowieckiej	Warszawa
Russian Federation	Altay Regional Oncology Dispensary	Barnaul
Russian Federation	Republican Clinical Oncology Dispensary of Tatarstan MoH	Kazan
Russian Federation	FSBI National Medical Oncology Research Center n.a. N.N. Blokhina	Moscow
Russian Federation	FSBI-FRCC of Special Types Med. Care & Technologies FMBA of Russia	Moscow
Russian Federation	SPb SBHI City Clinical Oncological Dispensary	Saint Petersburg
Russian Federation	Leningrad Regional Oncology Center	Saint-Petersburg
Russian Federation	Mordovia Republican Oncological Dispensary	Saransk
Russian Federation	Tomsk National Research Medical Center of Russian Academy of Sciences	Tomsk
Russian Federation	Republican Clinical Oncology Dispensary of Republic of Bashkortostan	Ufa
Spain	Hospital General Universitari Vall d Hebron	Barcelona
Spain	Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals	Hospitalet de Llobregat	Barcelona
Spain	Clinica Universitaria Navarra - Madrid	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario y Politecnico La Fe de Valencia	Valencia
Taiwan	Kaohsiung Chang Gung Memorial Hospital of the C.G.M.F.	Kaohsiung
Taiwan	Kaohsiung Veterans General Hospital	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei	Beitou
Taiwan	Chang Gung Medical Foundation. Linkou Branch	Taoyuan
Turkey	Basken Adana Dr.Turgut Noyan Uygulama ve Arastirma Merkezi	Adana
Turkey	Baskent Universitesi Ankara Hastanesi	Ankara
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Acibadem Bursa Hastanesi	Bursa
Turkey	Acibadem Universitesi Atakent Hastanesi	Istanbul
Turkey	Florence Nightingale Gayrettepe Hastanesi	Istanbul
Turkey	Ege Universitesi Tip Fakultesi	Izmir
United Kingdom	Royal Sussex County Hospital	Brighton
United Kingdom	Addenbrookes Hospital	Cambridge
United Kingdom	Barts Health NHS Trust - St Bartholomew s Hospital	London
United Kingdom	Guy s & St Thomas NHS Foundation Trust	London
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	The Royal Marsden Foundation Trust	London
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	University College Hospital	London
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United States	Georgia Cancer Center at Augusta University	Augusta	Georgia
United States	Texas Oncology-South Austin	Austin	Texas
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Willamette Valley Cancer Institute and Research Center	Eugene	Oregon
United States	North Shore University Health System	Evanston	Illinois
United States	UT West Cancer Center	Germantown	Tennessee
United States	John Theurer Cancer Center at Hackensack University Med Ctr	Hackensack	New Jersey
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Miami Health System	Miami	Florida
United States	Smilow Cancer Hospital at Yale New Haven	New Haven	Connecticut
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	Arizona Oncology Associates, PC- HAL	Phoenix	Arizona
United States	University of Rochester	Rochester	New York
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Texas Oncology-San Antonio Medical Center	San Antonio	Texas
United States	University of California San Francisco	San Francisco	California
United States	University of California Los Angeles	Santa Monica	California
United States	Sanford Gynecology Oncology	Sioux Falls	South Dakota
United States	Holy Name Medical Center	Teaneck	New Jersey
United States	Maryland Oncology Hematology, P.A.	Wheaton	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Colombia,  France,  Germany,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  New Zealand,  Poland,  Russian Federation,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of the first documentation of disease progression, as determined by Blinded Independent Central Review (BICR) per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.	From the date of randomization to the date of the first documentation of disease progression or death, whichever occurred first or up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Primary	Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who were lost to follow-up and those who were alive at the date of data cut-off were censored at the date the participant was last known alive, or date of data cut-off, whichever occurred first.	From the date of randomization until the date of death from any cause or up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Secondary	Objective Response Rate (ORR)	ORR was defined as the percentage of participants who had best overall response of either complete response (CR) or partial response (PR) as determined by BICR per RECIST 1.1. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.	From date of randomization up to first documentation of PD or date of death, whichever occurred first up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Secondary	Health-Related Quality of Life (HRQoL) Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQC30) Score	EORTC QLQ-C30 was a questionnaire which included 30 questions that rates 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. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. Data for this outcome measure will be reported after study completion (anticipated study completion date is November 2023).	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length of either 21 or 28 days), and at the post-treatment visit (up to 5 years and 5 months)
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs)	TEAEs was defined as AEs that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. AE was defined as any untoward medical occurrence in a participants or clinical study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. A SAE was defined as any untoward medical occurrence at any dose 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. irAE was defined as any unfavorable and unintended immune-related sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.	From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Secondary	Percentage of Participants Discontinued Study Treatment Due to TEAEs	TEAEs was defined as those 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 study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment.	From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Secondary	Time to Treatment Failure Due to Toxicity	Time to treatment failure due to toxicity was defined as the time from the date of randomization to the date a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is November 2023).	From the date of randomization to the date of discontinuation of study treatment due to TEAEs (up to 5 years 5 months)
Secondary	Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib	Sparse pharmacokinetic (PK) samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted CL/F for lenvatinib was then derived from the PK model. The data was collected and analyzed for lenvatinib plus pembrolizumab arm only.	Cycle 1 Day 1: 0.5-10 hours post-dose; Cycle 1 Day 15: 0-12 hours post-dose; Cycle 2 Day 1: 0.5-10 hours post-dose (each cycle length=21 days)
Secondary	Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib	Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted AUC for lenvatinib was then derived from the PK model. The data was collected and analyzed for lenvatinib plus pembrolizumab arm only.	Cycle 1 Day 1: 0.5-10 hours post-dose; Cycle 1 Day 15: 0-12 hours post-dose; Cycle 2 Day 1: 0.5-10 hours post-dose (each cycle length=21 days)