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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,069
Progression-free Survival (PFS) by Independent Imaging Review (IIR)
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)
Objective Response Rate (ORR)
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 March 2026).
Time frame: Up to approximately 69 months
Overall Survival (OS)
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 March 2026).
Time frame: Up to approximately 69 months
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Stanford School of Medicine
Stanford, California, United States
Boca Raton Community Hospital
Boca Raton, Florida, United States
Florida Cancer Specialists
Fort Myers, Florida, United States
University of Miami
Miami, Florida, United States
Mount Sinai Medical Center
Miami Beach, Florida, United States
Florida Hospital Cancer Institute
Orlando, Florida, United States
Florida Cancer Specialists ( North Region)
St. Petersburg, Florida, United States
Florida Cancer Specialists
West Palm Beach, Florida, United States
Joliet Oncology - Hematology Associates
Joliet, Illinois, United States
Healthcare Research Network III, LLC
Tinley Park, Illinois, United States
...and 173 more locations
Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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 March 2026).
Time frame: Up to approximately 69 months
Number of Participants Who Discontinued Treatment Due to Toxicity
Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2026.
Time frame: Up to approximately 69 months
Time to Treatment Failure Due to Toxicity
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 March 2026).
Time frame: Up to approximately 69 months
Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores
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 March 2026).
Time frame: Up to approximately 69 months
HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score
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 March 2026)
Time frame: Up to approximately 69 months
HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score
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 March 2026)
Time frame: Up to approximately 69 months
PFS on Next-line of Therapy (PFS2)
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 March 2026)
Time frame: Up to approximately 69 months
PFS by Investigator Assessment
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 March 2026).
Time frame: Up to approximately 69 months
Model-predicted Clearance for Lenvatinib and Everolimus
Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2026)
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)
Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus
Data for this outcome measure will be reported after study completion (anticipated study completion date is March 2026)
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