Endometrial Neoplasms
Conditions
Keywords
programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), programmed cell death ligand 2 (PD-L2, PDL2), vascular endothelial growth factor (VEGF) receptors, lenvatinib, pembrolizumab, doxorubicin, paclitaxel, phase 3 endometrial cancer
Brief 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.
Interventions
DRUGPembrolizumab
200 mg administered by IV infusion on Day 1 of each 21-day cycle.
DRUGLenvatinib
20 mg administered orally (PO) QD during each 21-day cycle.
DRUGPaclitaxel
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.
DRUGDoxorubicin
60 mg/m\^2 administered by IV on Day 1 of each 21-day cycle.
Sponsors
Eisai Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR) in Mismatch Repair Proficient (pMMR) Participants | Up to approximately 27 months | 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. |
| PFS Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on BICR in All-comer Participants | Up to approximately 27 months | 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. |
| Overall Survival (OS) in pMMR Participants | Up to approximately 43 months | 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. |
| OS in All-comer Participants | Up to approximately 43 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in pMMR Participants | Up to approximately 80 months | 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. |
| ORR in All-comer Participants | Up to approximately 80 months | 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. |
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) in pMMR Participants | Baseline, Week 12 | 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. |
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) in All-comer Participants | Baseline, Week 12 | 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. |
| Number of Partricipants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Immune-Related Adverse Events (irAEs) | Up to approximately 77 months | TEAEs were AEs that occurred (or worsened, if present at baseline) after the first dose of study drug through 28 days after the last dose. An AE was any untoward medical occurrence in a participant temporally associated with use of study treatment, whether or not related to the treatment. An SAE was any untoward medical occurrence at any dose that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital anomaly/birth defect. An irAE was any unfavorable and unintended immune-related sign, symptom, or disease (new or worsening) temporally associated with study therapy, regardless of whether a causal relationship with the therapy could be determined. |
| Number of Participants Who Discontinued Study Treatment Due to a TEAE in pMMR Participants | Up to approximately 77 months | 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. |
| Number of Participants Who Discontinued Study Treatment Due to a TEAE in All-comer Participants | Up to approximately 77 months | 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. |
| Time to Treatment Failure Due to Toxicity in pMMR Participants | Up to approximately 77 months | 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. |
| Time to Treatment Failure Due to Toxicity in All-comer Participants | Up to approximately 77 months | 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. |
| Plasma Concentration of Lenvatinib Versus Time in All-comer Participants | Cycle 1 day 1 0.5-4 hours (h), 6-10 postdose; Cycle 1 day 15 predose; Cycle 1 day 15 2-12h postdose, Cycle 2 day 1 predose, 0.5-4h, 6-10 h (Each cycle is 21 days) | Pharmacokinetic (PK) samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted plasma concentration of lenvatinib was then derived from the PK model. |
| Plasma Concentration of Lenvatinib Versus Time in pMMR Participants | Cycle 1 day 1 0.5-4 hour (h), 6-10 postdose; Cycle 1 day 15 predose; Cycle 1 day 15 2-12h postdose, Cycle 2 day 1 predose, 0.5-4h, 6-10 h (Each cycle is 21 days) | PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted plasma concentration of lenvatinib was then derived from the PK model. |
| Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib | 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) | 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. |
| Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib | 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) | 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. |
Countries
Argentina, Australia, Brazil, Canada, Colombia, France, Germany, Ireland, Israel, Italy, Japan, Mexico, New Zealand, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Eisai Inc.
Participant flow
Recruitment details
Participants took part in the study at 167 investigative sites in Argentina, Australia, Brazil, Canada, Colombia, France, Germany, Ireland, Israel, Italy, Japan, Korea, Mexico, New Zealand, Poland, Russia, Spain, Taiwan, Turkey, United Kingdom and the United States
Pre-assignment details
A total of 1178 participants were screened, of which 351 were screen failures and 827 (697 mismatch repair proficient \[pMMR\] participants and 130 MMR deficient \[dMMR\] participants) were enrolled and randomized, out of which 794 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg Participants with EC received lenvatinib 20 mg orally, once daily, plus pembrolizumab 200 mg intravenously, every 3 weeks in each 21-day cycle. Participants continued to receive treatment until disease progression, development of unacceptable toxicity, withdrawal of consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, or sponsor termination of the study. | 411 |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel Participants with EC received either doxorubicin 60 mg/m\^2 intravenously, every 3 weeks, in each 21-day treatment cycle, or paclitaxel 80 mg/m\^2 intravenously, weekly (3 weeks on/1 week off), in each 28-day treatment cycle. Participants continued to receive treatment until a lifetime cumulative dose of 500 mg/m\^2 doxorubicin, a maximum dose of paclitaxel per standard of care, or until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study. | 416 |
| Total | 827 |
Baseline characteristics
| Characteristic | Lenvatinib 20 mg + Pembrolizumab 200 mg | Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 9.1 | 63.8 years STANDARD_DEVIATION 9.2 | 63.5 years STANDARD_DEVIATION 9.1 |
| Age, Customized 85 years and over | 0 Participants | 2 Participants | 2 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 206 Participants | 204 Participants | 410 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 205 Participants | 210 Participants | 415 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 = Fully active; no performance restrictions | 246 Participants | 241 Participants | 487 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 = Limited activity, ambulant, can-do light work | 165 Participants | 175 Participants | 340 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 59 Participants | 73 Participants | 132 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 309 Participants | 288 Participants | 597 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 43 Participants | 55 Participants | 98 Participants |
| Geographic region Region 1 | 234 Participants | 240 Participants | 474 Participants |
| Geographic region Region 2 | 177 Participants | 176 Participants | 353 Participants |
| Mismatch repair (MMR) status Deficient (dMMR) | 65 Participants | 65 Participants | 130 Participants |
| Mismatch repair (MMR) status Proficient MMR (pMMR) | 346 Participants | 351 Participants | 697 Participants |
| Prior history of pelvic radiation Participants without pelvic radiation | 235 Participants | 229 Participants | 464 Participants |
| Prior history of pelvic radiation Participants with pelvic radiation | 176 Participants | 187 Participants | 363 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 7 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 85 Participants | 92 Participants | 177 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 14 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 13 Participants | 20 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 36 Participants | 43 Participants | 79 Participants |
| Race (NIH/OMB) White | 261 Participants | 247 Participants | 508 Participants |
| Sex: Female, Male Female | 411 Participants | 416 Participants | 827 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 317 / 406 | 362 / 388 | 8 / 21 | 1 / 6 |
| other Total, other adverse events | 404 / 406 | 379 / 388 | 20 / 21 | 6 / 6 |
| serious Total, serious adverse events | 237 / 406 | 121 / 388 | 4 / 21 | 1 / 6 |
Outcome results
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.
Time frame: 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)
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Overall Survival (OS) | 18.3 Months |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Overall Survival (OS) | 11.4 Months |
p-value: <0.000195% CI: [0.51, 0.75]Log Rank
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.
Time frame: 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)
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Progression-free Survival (PFS) | 7.2 Months |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Progression-free Survival (PFS) | 3.8 Months |
p-value: <0.000195% CI: [0.47, 0.66]Log Rank
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.
Time frame: 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
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.
Time frame: 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)
Population: The population pharmacokinetic analysis set includes all the participants who have received at least 1 dose of study treatment with documented dosing history in the lenvatinib plus pembrolizumab arm, and have measurable plasma levels of lenvatinib. Here overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib | 4.69 liter per hour (L/h) | Standard Deviation 1.39 |
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.
Time frame: 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)
Population: The population pharmacokinetic analysis set includes all the participants who have received at least 1 dose of study treatment with documented dosing history in the lenvatinib plus pembrolizumab arm, and have measurable plasma levels of lenvatinib. Here overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib | 4134 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 1350 |
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.
Time frame: From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Population: Safety analysis population included all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | Participants With TEAEs | 405 Participants |
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | Participants With SAEs | 214 Participants |
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | Participants With irAEs | 273 Participants |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | Participants With TEAEs | 386 Participants |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | Participants With SAEs | 118 Participants |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | Participants With irAEs | 17 Participants |
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.
Time frame: 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)
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Objective Response Rate (ORR) | 31.9 Percentage of participants |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Objective Response Rate (ORR) | 14.7 Percentage of participants |
p-value: <0.000195% CI: [11.5, 22.9]Miettinen & Nurminen method
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.
Time frame: From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months)
Population: Safety analysis population included all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 20 mg + Pembrolizumab 200 mg | Percentage of Participants Discontinued Study Treatment Due to TEAEs | 33.0 Percentage of participants |
| Treatment of Physician's Choice (TPC): Doxorubicin or Paclitaxel | Percentage of Participants Discontinued Study Treatment Due to TEAEs | 8.0 Percentage of participants |
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.
Time frame: From the date of randomization to the date of discontinuation of study treatment due to TEAEs (up to 5 years 5 months)