Advanced/Metastatic Gastroesophageal Adenocarcinoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Brief summary
The purpose of this study is to assess the efficacy and safety of lenvatinib (E7080/MK-7902) plus pembrolizumab (MK-3475) plus chemotherapy compared with chemotherapy alone in participants with advanced/metastatic gastroesophageal cancer. The primary study hypotheses are that lenvatinib plus pembrolizumab plus chemotherapy is superior to chemotherapy alone for both overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), in participants with programmed cell death-ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 and in all participants.
Detailed description
There will be 2 parts to the study: a Safety Run-in (Part 1) and the Main Study (Part 2). In Part 1 (Safety Run-in), approximately 12 participants will be treated with lenvatinib in combination with pembrolizumab and chemotherapy with either capecitabine and oxaliplatin (CAPOX), or 5-fluorouracil (5-FU), Leucovorin, and oxaliplatin (mFOLFOX6). Participants will be closely followed for dose-limiting toxicities for 21 days after the first dose of study intervention. In Part 2, up to 878 eligible participants (not including those participating in Part 1) will be randomly assigned in a 1:1 ratio to either lenvatinib plus pembrolizumab plus chemotherapy (CAPOX or mFOLFOX6) or Chemotherapy alone (CAPOX or mFOLFOX6). Participants can receive up to 18 infusions (up to 2 years) of pembrolizumab in the first course. Participants may be eligible to receive a second course of pembrolizumab (approximately 1 year) at the investigator's discretion. As of Amendment 8 (Effective 06/10/2025), Second Course will no longer be offered. Any participant currently receiving Second Course retreatment will be able to continue treatment as planned. Imaging will be performed per local standard of care.
Interventions
BIOLOGICALPembrolizumab
400 mg Q6W by IV infusion
BIOLOGICALLenvatinib
Administered PO QD, 8 mg induction/20 mg consolidation.
DRUGOxaliplatin
130 mg/m\^2 administered by IV infusion on Day 1 of Weeks 1 and 4 of each Q6W cycle as part of CAPOX chemotherapy, or 85 mg/m\^2 administered by IV infusion on Day 1 and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.
DRUGCapecitabine
1000 mg/m\^2 administered PO twice daily (BID) on Days 1-14, 22-35 of each Q6W cycle as part of CAPOX chemotherapy.
DRUGLeucovorin (or Levoleucovorin)
Administered by IV infusion at 400 mg/m\^2 (leucovorin) or 200 mg/m\^2 (levoleucovorin) on Day 1, and Week 1, 3 and 5 of each Q6W cycle as part of mFOLFOX6 chemotherapy.
DRUG5-FU
400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous IV infusion administered on Day 1, and Week 1, 3, 5, of each Q2W cycle as part of mFOLFOX6 chemotherapy.
Sponsors
Merck Sharp & Dohme LLC
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically and/or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma * Is not expected to require tumor resection during the treatment course * Has gastroesophageal adenocarcinoma that is not human epidermal growth factor receptor 2 (HER-2)/neu positive * Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by scan with IV contrast as determined by the local site investigator * Male participants agree to refrain from donating sperm and agree to either remain abstinent from heterosexual intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for ≥7 days after last dose of lenvatinib or 90 days after last dose of chemotherapy-whichever comes last * Female participants not pregnant or breastfeeding are eligible to participate if not a women of childbearing potential (WOCBP), or if a WOCBP they either use a contraceptive method that is highly effective OR remain abstinent from heterosexual intercourse as their preferred and usual lifestyle, and do not donate eggs (ova, oocytes) to others or freeze/store for their own use, and abstain from breastfeeding during the intervention period through 120 days after last dose of pembrolizumab, 30 days after last dose of lenvatinib, or 180 days after last dose of chemotherapy-whichever occurs last * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to the first dose of study treatment * Has adequately controlled blood pressure with or without antihypertensive medications * Has adequate organ function
Exclusion criteria
* Has had previous therapy for locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) esophageal adenocarcinoma * Has had major surgery within 28 days prior to first dose of study interventions * Has had radiotherapy within 14 days of randomization * Has a known additional malignancy that is progressing or has required active treatment within the past 5 years * Has known central nervous system (CNS) metastases and/or carcinomatous meningitis * Has severe hypersensitivity (≥Grade 3) to treatment with an monoclonal antibody (mAb) or known sensitivity or intolerance to any component of lenvatinib, pembrolizumab, study chemotherapy agents and/or to any excipients, murine proteins, or platinum containing products * Has had an allogeneic tissue/solid organ transplant * Has perforation risks or significant gastrointestinal (GI) bleeding * Has GI obstruction, poor oral intake (CAPOX participants), or difficulty in taking oral medication (CAPOX participants) * Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor * Has received prior therapy with anti- vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor or anti-VEGF mAb * Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug * Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) * Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation * Has inadequate cardiac function * Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * Has poorly controlled diarrhea * Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment * Has peripheral neuropathy ≥Grade 2 * Has a known history of human immunodeficiency virus (HIV) or HIV 1/2 antibodies * Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) \[qualitative\] is detected) infection * Has weight loss of \>20% within the last 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | Up to ~21 days | A DLT was defined as a specific adverse event graded for toxicity using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Hematologic DLTs included Grade 4 neutropenia lasting for ≥7 days, Grade 3 or Grade 4 febrile neutropenia, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 anemia. Nonhematologic DLTs included any other Grade 4 or Grade 5 toxicity, Grade 3 toxicities lasting \>3 days (excluding nausea, vomiting, and diarrhea controlled by medical intervention within 72 hours, and Grade 3 rash in the absence of desquamation with no mucosal involvement), Grade 3 hypertension not able to be controlled by medication, ≥ Grade 3 gastrointestinal perforation, ≥Grade 3 wound dehiscence requiring medical or surgical intervention, any grade thromboembolic event, or any Grade 3 nonhematologic laboratory value if medical intervention was required or the abnormality led to hospitalization. The number of participants in Part 1 with DLTs is reported. |
| Part 1: Number of Participants With Adverse Events (AEs) | Up to ~44 months | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 1 with AEs is reported |
| Part 1: Number of Participants Who Discontinued Study Treatment Due to an AE | Up to ~29 months | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 1 that discontinued study treatment due to an AE is reported. |
| Part 2: Overall Survival (OS) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | Up to ~41 months | OS is defined as the time from randomization to death due to any cause. OS is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2. |
| Part 2: OS in All Participants | Up to ~41 months | OS is defined as the time from randomization to death due to any cause. OS is reported by treatment arm for all participants in Part 2. |
| Part 2: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 | Up to ~29 months | PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. PFS is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2. |
| Part 2: PFS Per RECIST 1.1 as Assessed by BICR in All Participants | Up to ~29 months | PFS is defined as the time from randomization to the first documented PD per RECIST 1.1 by BICR or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. PFS is reported by treatment arm for all participants in Part 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1 | Up to ~29 months | ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and assessed by BICR. ORR is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2. |
| Part 2: ORR Per RECIST 1.1 as Assessed by BICR in All Participants | Up to ~29 months | ORR is defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and assessed by BICR. ORR is reported by treatment arm for all participants in Part 2. |
| Part 2: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1 | Up to ~41 months | For participants who demonstrated confirmed CR or PR, DOR is defined as the time from the first CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) to subsequent PD or death due to any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. DOR is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2. |
| Part 2: DOR Per RECIST 1.1 as Assessed by BICR in All Participants | Up to ~41 months | For participants who demonstrated confirmed CR or PR, DOR is defined as the time from the first CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) to subsequent PD or death due to any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. DOR is reported by treatment arm for all participants in Part 2. |
| Part 2: Number of Participants With AEs | Up to ~41 months | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 2 with AEs is reported by treatment arm. |
| Part 2: Number of Participants Who Discontinued Study Treatment Due to an AE | Up to ~41 months | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 2 that discontinued study treatment due to an AE is reported by treatment arm. |
Countries
Argentina, Australia, Belgium, Canada, Chile, China, Colombia, Costa Rica, France, Germany, Guatemala, Hong Kong, Ireland, Israel, Italy, Japan, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
This study included 2 parts: Part 1 was an open-label, safety run-in to evaluate the safety and tolerability of treatment with pembrolizumab + lenvatinib + chemotherapy. Participants in Part 1 continued to receive study intervention and were followed in the posttreatment period as applicable. Part 2 (main study) evaluated safety and efficacy. Participants were randomized to receive either treatment with pembrolizumab + lenvatinib + chemotherapy, or chemotherapy only.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Lenvatinib +Pembrolizumab + Chemotherapy Participants received lenvatinib administered orally QD in combination with IV pembrolizumab Q6W plus chemotherapy with either CAPOX or chemotherapy with mFOLFOX6. Induction with lenvatinib 8 mg QD plus pembrolizumab (plus chemotherapy (CAPOX or mFOLFOX6) was administered for 2 cycles, followed by consolidation with lenvatinib 20 mg QD plus pembrolizumab for up to 16 cycles. A cycle is 6 weeks (42 days). | 15 |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy Participants received lenvatinib administered orally QD in combination with IV pembrolizumab Q6W plus chemotherapy with either CAPOX or chemotherapy with mFOLFOX6. Induction with lenvatinib 8 mg QD plus pembrolizumab (plus chemotherapy (CAPOX or mFOLFOX6) was administered for 2 cycles, followed by consolidation with lenvatinib 20 mg QD plus pembrolizumab for up to 16 cycles. A cycle is 6 weeks (42 days). | 443 |
| Part 2: Chemotherapy Participants received chemotherapy with either CAPOX Q3W or mFOLFOX6 Q2W. | 437 |
| Total | 895 |
Baseline characteristics
| Characteristic | Part 1: Lenvatinib +Pembrolizumab + Chemotherapy | Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Chemotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 55.9 Years STANDARD_DEVIATION 59.7 | 59.7 Years STANDARD_DEVIATION 12.5 | 59.1 Years STANDARD_DEVIATION 12 | 59.3 Years STANDARD_DEVIATION 12.3 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 0 | 11 Participants | 204 Participants | 204 Participants | 419 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 1 | 4 Participants | 239 Participants | 233 Participants | 476 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 116 Participants | 115 Participants | 238 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 319 Participants | 313 Participants | 640 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 8 Participants | 9 Participants | 17 Participants |
| Geographic Region of Enrolling Site East Asia | 4 Participants | 161 Participants | 160 Participants | 325 Participants |
| Geographic Region of Enrolling Site North America + Western Europe | 5 Participants | 125 Participants | 122 Participants | 252 Participants |
| Geographic Region of Enrolling Site Rest of the World | 6 Participants | 157 Participants | 155 Participants | 318 Participants |
| Intended Chemotherapy CAPOX | 7 Participants | 232 Participants | 225 Participants | 464 Participants |
| Intended Chemotherapy mFOLFOX6 | 8 Participants | 209 Participants | 204 Participants | 421 Participants |
| Intended Chemotherapy Missing | 0 Participants | 2 Participants | 8 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 11 Participants | 15 Participants | 26 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 164 Participants | 161 Participants | 329 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 30 Participants | 36 Participants | 66 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 235 Participants | 223 Participants | 469 Participants |
| Sex: Female, Male Female | 8 Participants | 151 Participants | 131 Participants | 290 Participants |
| Sex: Female, Male Male | 7 Participants | 292 Participants | 306 Participants | 605 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 15 | 333 / 443 | 374 / 437 | 1 / 1 | 0 / 3 |
| other Total, other adverse events | 14 / 15 | 435 / 441 | 406 / 429 | 0 / 1 | 1 / 3 |
| serious Total, serious adverse events | 6 / 15 | 226 / 441 | 137 / 429 | 0 / 1 | 1 / 3 |
Outcome results
Primary
Part 1: Number of Participants Who Discontinued Study Treatment Due to an AE
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 1 that discontinued study treatment due to an AE is reported.
Time frame: Up to ~29 months
Population: All randomized participants who received at least 1 dose of study intervention. Per protocol, only participants in part 1 were included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 1: Number of Participants Who Discontinued Study Treatment Due to an AE | 5 Participants |
Primary
Part 1: Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 1 with AEs is reported
Time frame: Up to ~44 months
Population: All randomized participants who received at least 1 dose of study intervention. Per protocol, only participants in part 1 were included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 1: Number of Participants With Adverse Events (AEs) | 15 Participants |
Primary
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
A DLT was defined as a specific adverse event graded for toxicity using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Hematologic DLTs included Grade 4 neutropenia lasting for ≥7 days, Grade 3 or Grade 4 febrile neutropenia, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 anemia. Nonhematologic DLTs included any other Grade 4 or Grade 5 toxicity, Grade 3 toxicities lasting \>3 days (excluding nausea, vomiting, and diarrhea controlled by medical intervention within 72 hours, and Grade 3 rash in the absence of desquamation with no mucosal involvement), Grade 3 hypertension not able to be controlled by medication, ≥ Grade 3 gastrointestinal perforation, ≥Grade 3 wound dehiscence requiring medical or surgical intervention, any grade thromboembolic event, or any Grade 3 nonhematologic laboratory value if medical intervention was required or the abnormality led to hospitalization. The number of participants in Part 1 with DLTs is reported.
Time frame: Up to ~21 days
Population: All randomized participants who received at least 1 dose of study intervention. Per protocol, only participants in part 1 were included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
Primary
Part 2: OS in All Participants
OS is defined as the time from randomization to death due to any cause. OS is reported by treatment arm for all participants in Part 2.
Time frame: Up to ~41 months
Population: All randomized participants, whether or not study intervention was administered and who had available data for the outcome measure at the time of final analysis. Per protocol, participants in part 1 of the study were not included in the OS analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: OS in All Participants | 13.1 Months |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: OS in All Participants | 13.0 Months |
p-value: 0.03395% CI: [0.75, 1.01]Log Rank
Primary
Part 2: Overall Survival (OS) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
OS is defined as the time from randomization to death due to any cause. OS is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.
Time frame: Up to ~41 months
Population: All randomized participants, whether or not study intervention was administered, with PD-L1 CPS≥1 and who had available data for the outcome measure at the time of final analysis. Per protocol, participants in part 1 of the study were not included in the OS analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Overall Survival (OS) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 12.6 Months |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Overall Survival (OS) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 12.9 Months |
p-value: 0.024495% CI: [0.71, 1]Log Rank
Primary
Part 2: PFS Per RECIST 1.1 as Assessed by BICR in All Participants
PFS is defined as the time from randomization to the first documented PD per RECIST 1.1 by BICR or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. PFS is reported by treatment arm for all participants in Part 2.
Time frame: Up to ~29 months
Population: All randomized participants, whether or not study intervention was administered and who had available data for the outcome measure at the time of final analysis. Per protocol, participants in part 1 of the study were not included in the PFS analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: PFS Per RECIST 1.1 as Assessed by BICR in All Participants | 7.2 Months |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: PFS Per RECIST 1.1 as Assessed by BICR in All Participants | 7.0 Months |
p-value: 0.001995% CI: [0.66, 0.92]Log Rank
Primary
Part 2: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1
PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. PFS is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.
Time frame: Up to ~29 months
Population: All randomized participants, whether or not study intervention was administered, with PD-L1 CPS ≥1 and who had available data for the outcome measure at the time of final analysis. Per protocol, participants in part 1 of the study were not included in the PFS analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 | 7.3 Months |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 | 6.9 Months |
p-value: 0.001295% CI: [0.62, 0.9]Log Rank
Secondary
Part 2: DOR Per RECIST 1.1 as Assessed by BICR in All Participants
For participants who demonstrated confirmed CR or PR, DOR is defined as the time from the first CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) to subsequent PD or death due to any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. DOR is reported by treatment arm for all participants in Part 2.
Time frame: Up to ~41 months
Population: All randomized participants who achieved CR or PR and who had available data for the outcome measure at the time of final analysis. Participants were analyzed in the treatment group to which they were randomized. Per protocol, participants in part 1 of the study were not included in the DOR analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: DOR Per RECIST 1.1 as Assessed by BICR in All Participants | 8.6 Months |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: DOR Per RECIST 1.1 as Assessed by BICR in All Participants | 6.7 Months |
Secondary
Part 2: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1
For participants who demonstrated confirmed CR or PR, DOR is defined as the time from the first CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) to subsequent PD or death due to any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, 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. DOR is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.
Time frame: Up to ~41 months
Population: All randomized participants who achieved CR or PR with PD-L1 CPS \> or =1 and who had available data for the outcome measure at the time of final analysis. Participants were analyzed in the treatment group to which they were randomized. Per protocol, participants in part 1 of the study were not included in the DOR analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1 | 8.5 Months |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1 | 6.5 Months |
Secondary
Part 2: Number of Participants Who Discontinued Study Treatment Due to an AE
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 2 that discontinued study treatment due to an AE is reported by treatment arm.
Time frame: Up to ~41 months
Secondary
Part 2: Number of Participants With AEs
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants in Part 2 with AEs is reported by treatment arm.
Time frame: Up to ~41 months
Secondary
Part 2: Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1
ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and assessed by BICR. ORR is reported by treatment arm for PD-L1 CPS ≥1 participants in Part 2.
Time frame: Up to ~29 months
Population: All randomized participants, whether or not study intervention was administered, with PD-L1 CPS ≥1 and who had available data for the outcome measure at the time of final analysis. Per protocol, participants in part 1 of the study were not included in the ORR analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1 | 59.5 Percentage of Participants |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥1 | 45.4 Percentage of Participants |
Comparison: ORR comparison between groups is based on Miettinen \& Nurminen method stratified by region, ECOG performance status, and type of chemotherapyp-value: <0.000195% CI: [6.9, 21.5]t-test, 1 sided
Secondary
Part 2: ORR Per RECIST 1.1 as Assessed by BICR in All Participants
ORR is defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and assessed by BICR. ORR is reported by treatment arm for all participants in Part 2.
Time frame: Up to ~29 months
Population: All randomized participants, whether or not study intervention was administered and who had available data for the outcome measure at the time of final analysis. Per protocol, participants in part 1 of the study were not included in the ORR analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 : Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: ORR Per RECIST 1.1 as Assessed by BICR in All Participants | 58.0 Percentage of Participants |
| Part 2: Lenvatinib + Pembrolizumab + Chemotherapy | Part 2: ORR Per RECIST 1.1 as Assessed by BICR in All Participants | 43.9 Percentage of Participants |
Comparison: ORR comparison between groups is based on Miettinen \& Nurminen method stratified by region, ECOG performance status, and type of chemotherapyp-value: <0.000195% CI: [7.7, 20.6]t-test, 1 sided