Renal Cell Carcinoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Pembrolizumab, Lenvatinib
Brief summary
This study is being performed as a single-arm open-label study in order to rapidly provide information on the potential benefits of the combination of pembrolizumab and lenvatinib in participants with previously untreated advanced/metastatic non-clear cell renal cell carcinoma.
Interventions
BIOLOGICALPembrolizumab
Pembrolizumab 400 mg, every 6 weeks (Q6W) intravenous (IV) up to 18 infusions or up to progressive disease or discontinuation.
DRUGLenvatinib
Lenvatinib 20 mg, daily (QD), oral, until progressive disease or discontinuation.
Sponsors
Eisai Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
1. Must have a histologically confirmed diagnosis of nccRCC. 2. Has locally advanced/metastatic disease (ie, Stage IV per the American Joint Committee on Cancer). 3. Has received no prior systemic therapy for advanced nccRCC. Note: Prior neoadjuvant/adjuvant therapy for nccRCC is acceptable if completed \>12 months prior to allocation. 4. Male participants agree to use approved contraception during the treatment period for at least 7 days after the last dose of study medication, or refrain from heterosexual intercourse during this period. 5. Female participants are not pregnant or breastfeeding, and are not a woman of childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during the treatment period and for at least 120 days post pembrolizumab, or 30 days post lenvatinib, whichever occurs last. 6. Has measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 7. Has submitted an archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 8. Has Karnofsky Performance Status (KPS) ≥70% as assessed within 10 days prior to the start of study intervention. 9. Has adequately controlled blood pressure with or without antihypertensive medications 10. Have adequate organ function.
Exclusion criteria
1. Has collecting duct histology. 2. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention. 3. Has a left ventricular ejection fraction below the institutional (or local laboratory) normal range. 4. Has radiographic encasement or invasion of a major blood vessel, or of intratumoral cavitation. 5. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention. 6. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib. 7. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug. 8. Has had major surgery within 3 weeks prior to first dose of study intervention. 9. Has received prior therapy with an anti-programmed cell-death 1 (PD-1), anti-programmed cell-death ligand 1 (PD-L1), or anti-programmed cell-death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137). 10. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to allocation. 11. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease. 12. Has received a live or attenuated vaccine within 30 days before the first dose of study intervention. 13. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. 14. 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 the first dose of study intervention. 15. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 16. Has known active CNS metastases and/or carcinomatous meningitis. 17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients. 18. Has an active autoimmune disease that has required systemic treatment in past 2 years 19. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 20. Has an active infection requiring systemic therapy. 21. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. 22. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus. 23. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). 24. Has had an allogenic tissue/solid organ transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 47 months | ORR was defined as the percentage of participants who had a best overall response of either Complete Response (CR): Disappearance of all target lesions or Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions as assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experienced a CR or PR as assessed per RECIST 1.1 by blinded independent central review (BICR) is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Up to approximately 47 months | PFS was defined as the time from date of study treatment to the first documented progressive disease (PD) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The percentage of participants who experienced PFS per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented. |
| Overall Survival (OS) | Up to approximately 47 months | OS was defined as the time from the date of study treatment to the date of death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants is presented. |
| Clinical Benefit Rate (CBR) | Up to approximately 47 months | CBR is defined as the percentage of participants who have achieved Complete Response (CR): Disappearance of all target lesions or Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm\]) of ≥6 months per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR). |
| Duration of Response (DOR) | Up to approximately 47 months | For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. Duration of response per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented. |
| Number of Participants With One or More Adverse Events (AEs) | Up to approximately 56 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one or more AE is presented. |
| Number of Participants Who Discontinued From Study Treatment Due to an AE | Up to approximately 56 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one or more AE is presented. |
| Disease Control Rate (DCR) | Up to approximately 47 months | DCR was defined per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm\]). The appearance of one or more new lesions is also considered PD\]). Disease Control rate per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented. |
Countries
Australia, Canada, France, Hungary, Ireland, Italy, Poland, Russia, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 56 centers in 14 countries.
Pre-assignment details
Per protocol, six participants who experienced progression of Renal Cell Carcinoma (RCC) by radiographic evaluation continued second course treatment.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Lenvatinib Participants with non-clear cell Renal Cell Carcinoma (nccRCC) received 400 mg Pembrolizumab (Pembro) intravenously (IV) on Day 1 of a 42-day cycle (every 6 weeks (Q6W)) for approximately 2 years PLUS 20 mg Lenvatinib (Lenva) orally once daily (QD) on Days 1 and 22 of a 42-day cycle (Q6W). Participants continued study intervention until progressive disease or discontinuation. | 160 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 78 |
| Overall Study | Participants Ongoing | 80 |
| Overall Study | Screen Failure | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab + Lenvatinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 60 Participants |
| Age, Categorical Between 18 and 65 years | 100 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 144 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 137 Participants |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 79 / 160 | 0 / 6 |
| other Total, other adverse events | 155 / 158 | 4 / 6 |
| serious Total, serious adverse events | 76 / 158 | 2 / 6 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants who had a best overall response of either Complete Response (CR): Disappearance of all target lesions or Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions as assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experienced a CR or PR as assessed per RECIST 1.1 by blinded independent central review (BICR) is presented.
Time frame: Up to approximately 47 months
Population: All allocated participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Objective Response Rate (ORR) | 50.6 Percentage of participants |
Secondary
Clinical Benefit Rate (CBR)
CBR is defined as the percentage of participants who have achieved Complete Response (CR): Disappearance of all target lesions or Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm\]) of ≥6 months per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR).
Time frame: Up to approximately 47 months
Population: All allocated participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Clinical Benefit Rate (CBR) | 71.5 Percentage of participants |
Secondary
Disease Control Rate (DCR)
DCR was defined per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm\]). The appearance of one or more new lesions is also considered PD\]). Disease Control rate per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented.
Time frame: Up to approximately 47 months
Population: All allocated participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Disease Control Rate (DCR) | 82.3 Percentage of Participants |
Secondary
Duration of Response (DOR)
For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. Duration of response per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented.
Time frame: Up to approximately 47 months
Population: All allocated participants who received at least 1 dose of study intervention and had confirmed complete response or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Duration of Response (DOR) | 23.5 Months |
Secondary
Number of Participants Who Discontinued From Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one or more AE is presented.
Time frame: Up to approximately 56 months
Secondary
Number of Participants With One or More Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one or more AE is presented.
Time frame: Up to approximately 56 months
Secondary
Overall Survival (OS)
OS was defined as the time from the date of study treatment to the date of death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants is presented.
Time frame: Up to approximately 47 months
Population: All allocated participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Overall Survival (OS) | 41.5 Months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from date of study treatment to the first documented progressive disease (PD) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The percentage of participants who experienced PFS per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented.
Time frame: Up to approximately 47 months
Population: All allocated participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Progression Free Survival (PFS) | 17.9 Months |