Advanced Melanoma
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)
Brief summary
This study will evaluate the safety and efficacy of combination therapy of lenvatinib (E7080/MK-7902) and pembrolizumab following approximately 2 years of pembrolizumab therapy and approximately 2 years or more lenvatinib therapy in adult participants with unresectable or advanced melanoma who have been exposed to anti-programmed cell death ligand 1 (PD-1/L1) agents approved for unresectable or metastatic melanoma. No statistical hypothesis will be tested in this study.
Interventions
DRUGlenvatinib
Administered orally once a day during each 21-day cycle.
BIOLOGICALpembrolizumab
Administered as an IV infusion on Day 1 Q3W.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically or cytologically confirmed melanoma * Has unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8 that is not amenable to local therapy * Has the presence of ≥1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 as confirmed by BICR. * Has progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies * Has submitted pre-trial imaging * Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 * Has provided a baseline tumor biopsy * Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of \>30 Gray (Gy), they must have recovered from the toxicity and/or complications from the Intervention * Male participants must agree to use approved contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period * Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study intervention * Has adequate organ function
Exclusion criteria
* 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 before the first dose of study treatment * Has a known additional malignancy that is progressing or requires active treatment * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has ocular melanoma * Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody * Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) * Has an active infection requiring systemic therapy * Has known history of Human Immunodeficiency Virus (HIV) or HIV 1/2 antibodies * Has known history of or is positive for hepatitis B (hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (HCV RNA qualitative\] is detected) * Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease * Has a history of active tuberculosis (Bacillus tuberculosis) * Has presence of a gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib * Has had major surgery within 4 weeks prior to first dose of study interventions (adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility) * Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula * Has radiographic evidence of major blood vessel invasion/infiltration * Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug * Has clinically significant cardiovascular disease within 12 months from first dose of study drug, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability * Has received prior radiotherapy within 2 weeks of Cycle 1 Day 1 with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to Cycle 1 Day 1 * Has received a live vaccine within 30 days before the first dose of study treatment * 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 treatment * Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator * Has had an allogeneic tissue/solid organ transplant * Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 55 months | ORR was defined as the percentage of participants in the analysis population who have a confirmed Complete Response (CR: disappearance of all lesions) or a Partial Response (PR: ≥30% decrease in the sum of target lesion diameters without progression in other lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR). Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 55 months | OS was defined as the time from the first day of study intervention to 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. OS was calculated using the nonparametric Kaplan-Meier method. |
| Duration of Response (DOR) | Up to approximately 55 months | For participants who demonstrated a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: ≥30% decrease in the sum of target lesion diameters without progression in other lesions) per RECIST 1.1, DOR was defined as the time from first documented CR or PR until progressive disease (PD) or death from any cause, whichever occurs first. Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). DOR was calculated using the nonparametric Kaplan-Meier method for censored data. |
| Progression-free Survival (PFS) | Up to approximately 55 months | PFS was defined as the time from first day of study intervention to the first documented progressive disease (PD) per RECIST 1.1 by BICR, or death from any cause, whichever occurred first. Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). PFS was calculated using the nonparametric Kaplan-Meier method; participants who did not experience a PFS event were censored at the last disease assessment, or the last assessment before new anticancer treatment if new treatment was initiated. |
| Number of Participants Who Experience At Least One Adverse Event (AE) | Up to approximately 55 months | An AE was 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 could therefore have been 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 who experienced an AE is presented. |
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 48 months | An AE was 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 could therefore have been 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 who discontinued study treatment due to an AE is presented. |
| Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf) | Cycle 1 Day 1: 0.5 to 4 hours and 6 to 10 hours postdose; Cycle 1 Day 15: Predose and 2 to 12 hours postdose; Cycle 2 Day 1: Predose, 0.5 to 4 hours, and 6 to 10 hours post-dose (each cycle =21 days) | AUC0-inf was defined as the area under the concentration-time curve from time zero extrapolated to infinity. Plasma blood samples collected at specified timepoints, were used to estimate AUC0-inf following Lenvatinib and Pembrolizumab administration. Based on the lenvatinib plasma concentration data obtained on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, a protocol specified population PK analysis was performed to characterize the steady state AUC0-inf of lenvatinib when co-administered with pembrolizumab. |
Countries
Australia, Canada, Spain, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib + Pembrolizumab Participants received lenvatinib 20 mg orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity. | 103 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 85 |
| Overall Study | Sponsor Decision | 15 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Lenvatinib + Pembrolizumab |
|---|---|
| Age, Continuous | 60.7 Years STANDARD_DEVIATION 13.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 98 Participants |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 86 / 103 |
| other Total, other adverse events | 101 / 103 |
| serious Total, serious adverse events | 48 / 103 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants in the analysis population who have a confirmed Complete Response (CR: disappearance of all lesions) or a Partial Response (PR: ≥30% decrease in the sum of target lesion diameters without progression in other lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR). Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ).
Time frame: Up to approximately 55 months
Population: All participants who received at least one dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | 21.4 Percentage of Participants |
Secondary
Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf)
AUC0-inf was defined as the area under the concentration-time curve from time zero extrapolated to infinity. Plasma blood samples collected at specified timepoints, were used to estimate AUC0-inf following Lenvatinib and Pembrolizumab administration. Based on the lenvatinib plasma concentration data obtained on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, a protocol specified population PK analysis was performed to characterize the steady state AUC0-inf of lenvatinib when co-administered with pembrolizumab.
Time frame: Cycle 1 Day 1: 0.5 to 4 hours and 6 to 10 hours postdose; Cycle 1 Day 15: Predose and 2 to 12 hours postdose; Cycle 2 Day 1: Predose, 0.5 to 4 hours, and 6 to 10 hours post-dose (each cycle =21 days)
Population: All participants who received at least one dose of study intervention, and had data available for AUC0-inf.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lenvatinib + Pembrolizumab | Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf) | 3005 ng*hr/mL | Geometric Coefficient of Variation 39.5 |
Secondary
Duration of Response (DOR)
For participants who demonstrated a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: ≥30% decrease in the sum of target lesion diameters without progression in other lesions) per RECIST 1.1, DOR was defined as the time from first documented CR or PR until progressive disease (PD) or death from any cause, whichever occurs first. Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). DOR was calculated using the nonparametric Kaplan-Meier method for censored data.
Time frame: Up to approximately 55 months
Population: All participants who received at least one dose of study intervention, and who experience a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Duration of Response (DOR) | 8.5 Months |
Secondary
Number of Participants Who Discontinue Study Treatment Due to an AE
An AE was 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 could therefore have been 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 who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 48 months
Population: All participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Discontinue Study Treatment Due to an AE | 15 Participants |
Secondary
Number of Participants Who Experience At Least One Adverse Event (AE)
An AE was 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 could therefore have been 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 who experienced an AE is presented.
Time frame: Up to approximately 55 months
Population: All participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Number of Participants Who Experience At Least One Adverse Event (AE) | 102 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the first day of study intervention to 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. OS was calculated using the nonparametric Kaplan-Meier method.
Time frame: Up to approximately 55 months
Population: All participants who received at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Overall Survival (OS) | 14.0 Months |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from first day of study intervention to the first documented progressive disease (PD) per RECIST 1.1 by BICR, or death from any cause, whichever occurred first. Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). PFS was calculated using the nonparametric Kaplan-Meier method; participants who did not experience a PFS event were censored at the last disease assessment, or the last assessment before new anticancer treatment if new treatment was initiated.
Time frame: Up to approximately 55 months
Population: All participants who received at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Progression-free Survival (PFS) | 4.2 Months |