Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) for Advanced Melanoma in Anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/L1)-Exposed Participants (MK-7902-004/E7080-G000-225/LEAP-004)

A Multicenter, Open-label, Phase 2 Trial to Assess the Efficacy and Safety of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Melanoma Previously Exposed to an Anti-PD-1/L1 Agent (LEAP-004)

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.

Study Overview

• Status: Completed
• Conditions: Advanced Melanoma
• Intervention / Treatment: Drug: lenvatinib; Biological: pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Lismore, Australia, 2480
    • Lismore Base Hospital ( Site 0153)
  • New South Wales
    • Wollstonecraft, New South Wales, Australia, 2065
      • Melanoma Institute Australia ( Site 0152)
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital ( Site 0154)
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital ( Site 0157)
  • Western Australia
    • Perth, Western Australia, Australia, 6150
      • Fiona Stanley Hospital ( Site 0156)
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute ( Site 0654)
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre ( Site 0655)
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre ( Site 0651)
    • Montreal, Quebec, Canada, H2X 3E4
      • Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0652)
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial Barcelona ( Site 0001)
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon ( Site 0003)
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen de la Macarena ( Site 0004)
  • Valencia, Spain, 46014
    • Hospital General Universitario de Valencia ( Site 0002)
• Sweden
  • Goteborg, Sweden, 413 45
    • Sahlgrenska Universitetssjukhuset ( Site 0052)
  • Lund, Sweden, 221 85
    • Skanes Universitetssjukhus ( Site 0053)
  • Solna, Sweden, 171 64
    • Karolinska Universitetssjukhuset ( Site 0051)
  • Umea, Sweden, 901 85
    • Norrlands Universitetssjukhus ( Site 0056)
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Cancer & Research Centers ( Site 0312)
  • California
    • Santa Monica, California, United States, 90404
      • John Wayne Cancer Institute ( Site 0301)
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Advocate Medical Group-Park Ridge ( Site 0313)
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Southeast Nebraska Cancer Center ( Site 0316)
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 0317)
  • Virginia
    • Fairfax, Virginia, United States, 22031-4867
      • Inova Schar Cancer Institute ( Site 0314)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: lenvatinib plus pembrolizumab; Participants receive 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 will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.	Drug: lenvatinib; Administered orally once a day during each 21-day cycle.; Other Names: E7080; MK-7902; LENVIMA™; Biological: pembrolizumab; Administered as an IV infusion on Day 1 Q3W.; Other Names: MK-3475; Keytruda®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to approximately 55 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to approximately 55 months
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.	Up to approximately 55 months
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.	Up to approximately 55 months
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.	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)
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.	Up to approximately 55 months
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.	Up to approximately 48 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Eisai Inc.
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Arance A, de la Cruz-Merino L, Petrella TM, Jamal R, Ny L, Carneiro A, Berrocal A, Marquez-Rodas I, Spreafico A, Atkinson V, Costa Svedman F, Mant A, Khattak MA, Mihalcioiu C, Jang S, Cowey CL, Smith AD, Hawk N, Chen K, Diede SJ, Krepler C, Long GV. Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. J Clin Oncol. 2023 Jan 1;41(1):75-85. doi: 10.1200/JCO.22.00221. Epub 2022 Jul 22. Erratum In: J Clin Oncol. 2023 May 1;41(13):2454. doi: 10.1200/JCO.23.00439.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2019
• Primary Completion (Actual): October 11, 2023
• Study Completion (Actual): October 11, 2023

Study Registration Dates

• First Submitted: December 13, 2018
• First Submitted That Met QC Criteria: December 13, 2018
• First Posted (Actual): December 14, 2018

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1); programmed cell death ligand 2 (PD-L2, PDL2)
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: 7902-004; MK-7902-004 (Other Identifier: MSD Protocol Number); E7080-G000-225 (Other Identifier: Eisai Protocol Number); LEAP-004 (Other Grant/Funding Number: MSD); 2018-002518-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No