A Phase 3, multicenter, randomized, open-label trial to compare the efficacy and safety of pembrolizumab (MK-3475) in combination with lenvatinib (E7080/MK-7902) versus docetaxel in previously treated participants with metastatic non-small cell lung cancer (NSCLC) and progressive disease (PD) after platinum doublet chemotherapy and immunotherapy (LEAP-008)
- Trial ID
- 2022-501439-18-00
- Protocol
- MK-7902-008
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of **pembrolizumab** (MK-3475) in combination with **lenvatinib** (MK-7902) compared to **docetaxel** in terms of overall survival (OS) in patients with metastatic non-small cell lung cancer (NSCLC) who have experienced disease progression following platinum doublet chemotherapy and immunotherapy. Additionally, the study aims to compare the progression-free survival (PFS) between the two treatment regimens, assessed per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR). These objectives are clinically relevant as they address the potential for improved survival outcomes in a patient population with limited treatment options.
Secondary objectives include:
- Comparing pembrolizumab + lenvatinib to docetaxel regarding objective response rate (ORR) per RECIST 1.1 by BICR.
- Comparing pembrolizumab + lenvatinib to lenvatinib monotherapy with respect to ORR per RECIST 1.1 by BICR.
- Assessing the duration of response (DOR) with pembrolizumab + lenvatinib and docetaxel per RECIST 1.1 by BICR.
- Evaluating the safety and tolerability of pembrolizumab + lenvatinib versus docetaxel, and lenvatinib monotherapy.
- Comparing pembrolizumab + lenvatinib to docetaxel concerning the mean change from baseline in global health status/quality of life (QoL), cough, chest pain, dyspnea, and physical functioning.
- Comparing pembrolizumab + lenvatinib to docetaxel with respect to time to true deterioration (TTD) in global health status/QoL, cough, chest pain, dyspnea, and physical functioning scales.
Participants
The clinical trial involves a total of **286 participants** diagnosed with **non-small cell lung cancer (NSCLC)**, specifically with squamous or nonsquamous histology. The study population includes both male and female subjects, with age categories ranging from adults to the elderly. Participants were selected based on specific inclusion criteria, such as having a histologically or cytologically confirmed diagnosis of metastatic NSCLC at Stage IV, a life expectancy of at least three months, and adequate organ function. The trial also considers lifestyle factors, requiring participants to have adequately controlled blood pressure and to adhere to specific contraceptive guidelines during the study period. The population includes individuals who have experienced disease progression on prior anti-PD-1/PD-L1 monoclonal antibody therapy and platinum doublet chemotherapy. The trial does not exclude vulnerable populations, indicating a comprehensive approach to participant selection. Participants must have at least one measurable lesion and provide tumor tissue for PD-L1 biomarker analysis. The study aims to compare the efficacy of pembrolizumab combined with lenvatinib against docetaxel in terms of overall survival and progression-free survival.
Plans and Procedures
The clinical trial is a **Phase 3**, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with **lenvatinib** versus **docetaxel** in participants with metastatic non-small cell lung cancer (NSCLC) who have experienced progressive disease following platinum doublet chemotherapy and immunotherapy. The trial aims to compare overall survival (OS) and progression-free survival (PFS) as primary endpoints, with secondary endpoints including objective response rate (ORR), duration of response (DOR), and quality of life measures. The study is expected to conclude by August 2026, with recruitment having commenced in April 2019.
Participants will be randomly assigned to receive either pembrolizumab plus lenvatinib or docetaxel. The trial will involve several study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as a confirmed diagnosis of metastatic NSCLC, adequate organ function, and a life expectancy of at least three months. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.
The expected duration of participant involvement in the trial is up to 60 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring that all procedures are in compliance with regulatory standards and that participant safety is prioritized throughout the study.
Treatment
The clinical trial involves the administration of **Lenvatinib**, a chemical-origin medication provided in **capsule** form. The active substance, lenvatinib, is manufactured by Merck & Co. Inc. and is identified by the sponsor product code MK-7902. The maximum daily dose of lenvatinib is 24 mg, with a total maximum dose of 43,200 mg over a treatment period of 60 days. The route of administration is **oral**, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the trial.
Another experimental treatment in the trial is **Pembrolizumab**, marketed under the name KEYTRUDA, which is a biological product provided as a **concentrate for solution for infusion**. The active substance, pembrolizumab, is produced by Merck Sharp & Dohme BV and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 104,000 mg over a 36-day treatment period. Pembrolizumab is not a pediatric formulation, and its administration is carefully monitored to ensure adherence to the dosing regimen.
The comparator treatment in the study is **Docetaxel**, a chemical-origin medication administered as a **solution for infusion**. The maximum daily dose is 75 mg/m², with a total maximum dose of 6,500 mg/m² over a 60-day treatment period. Docetaxel is administered via **intravenous infusion**. This treatment serves as the standard-of-care therapy against which the experimental treatments are compared. Participant compliance with the dosing schedule is closely monitored to ensure the integrity of the trial results.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Overall Survival (OS)** and **Progression-free Survival (PFS)**, evaluated according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by a blinded independent central review (BICR). Secondary endpoints encompass the Objective Response Rate (ORR) per RECIST 1.1, comparing pembrolizumab plus lenvatinib versus docetaxel, and pembrolizumab plus lenvatinib versus lenvatinib monotherapy. Additionally, the Duration of Response (DOR) per RECIST 1.1 will be measured.
Patient-reported outcomes will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the Lung Cancer Module 13 (QLQ-LC13). Changes from baseline in various scales, such as Global Health Status/Quality of Life, Cough, Chest Pain, Dyspnea, and Physical Functioning, will be evaluated. Time to True Deterioration (TTD) in these scales will also be analyzed. The number of participants experiencing adverse events and those discontinuing treatment due to adverse events will be recorded.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has a histologically or cytologically confirmed diagnosis of metastatic squamous or nonsquamous NSCLC (Stage IV: M1a, M1b, M1c).
- Has PD on treatment with one prior anti-PD-1/PD-L1 monoclonal antibody (mAb) administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. Retreatment with the same anti-PD-L1/PD-L1 mAb is acceptable in the overall course of treatment.
- Has PD during/after platinum doublet chemotherapy for metastatic disease.
- Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of absence of tumor-activating EGFR mutations [eg, DEL19 or L858R], and absence of ALK and ROS1 gene rearrangements OR presence of a K-ras mutation).
- Has submitted pre-study imaging that confirmed evidence of PD following initiation of an anti-PD-1/PD-L1 inhibitor.
- Has at least 1 measurable lesion by computerized tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1, as determined by the local site assessment.
- Has provided tumor tissue for PD-L1 biomarker analysis from an archival sample (defined as: from initial diagnosis of NSCLC and prior to receiving immunotherapy [antiPD-1/PD-L1], from the primary lesion or a metastatic lesion).
- Has provided prior to allocation tissue from a newly obtained formalin-fixed sample from a new biopsy (defined as: after completion of immunotherapy [anti-PD-1/PD-L1] and before receiving a randomization number), of a tumor lesion not previously irradiated.
- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before the first dose of study intervention but before randomization.
- Has a life expectancy of at least 3 months
- Male participants receiving pembrolizumab ± lenvatinib or lenvatinib must agree to refrain from donating sperm, and either 1) be abstinent from heterosexual intercourse; or 2) follow contraceptive guidance during the treatment period or 7 days after the last dose of lenvatinib. Male participants receiving docetaxel agree to adhere to the same conditions during the treatment period and for ≥90 days after the last dose of study treatment. Contraceptive use should either follow the study requirements or the local regulations for the study interventions, whichever is more stringent.
- Female participants must not be pregnant, not be breastfeeding, and not be a woman of child-bearing potential (WOCBP). If a WOCBP, agrees to not donate eggs and either use contraception, or be abstinent from heterosexual intercourse during the treatment period and for ≥120 days after the last dose of pembrolizumab or 30 days after the last dose of lenvatinib, whichever occurs last. If a WOCBP receiving docetaxel, agrees to adhere to the same conditions during the treatment period and for ≥30 days after the last dose of study treatment. Contraception use should either follow the study requirements or the local regulations for the study interventions, whichever is more stringent.
- Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg and no change in antihypertensive medications within 1 week before randomization
- If participant received major surgery or radiation therapy of >30 Gy, they have recovered from the toxicity and/or complications from the intervention.
- Has adequate organ function.
Exclusion Criteria
- Has received docetaxel as monotherapy or in combination with other therapies.
- Has received lenvatinib as monotherapy or in combination with an anti-PD-1/PD-L1 mAb.
- Has received: 1) radiotherapy within 2 weeks before the first dose of study treatment; or 2) lung radiation therapy >30 Gy within 6 months before the first dose of study treatment.
- Has received a live vaccine within 30 days before the first dose of study treatment.
- Has clinically significant hemoptysis or tumor bleeding within 2 weeks before the first dose of study treatment.
- Has radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel.
- Has clinically significant cardiovascular impairment within 12 months of the first dose of study treatment.
- Has a history of a gastrointestinal condition or procedure that may affect oral absorption of study treatment.
- Has a pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
- Is currently participating in a clinical trial and receiving study therapy or participated in a study of an investigational agent within 4 weeks of the first dose of study treatment.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment.
- Has a known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of disease recurrence for 3 years since initiation of that therapy.
- Has known active central nervous system metastases and/or carcinomatous meningitis.
- Has severe hypersensitivity to pembrolizumab and/or any of its excipients.
- Has a sensitivity to any of the excipients contained in lenvatinib and/or docetaxel.
- Has an active autoimmune disease that has required systemic treatment in the past 2 years.
- Has a history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has a known history of hepatitis B reactive or known active hepatitis C virus infection.
- Has active tuberculosis.
- Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through at least 120 days after the last dose of pembrolizumab or lenvatinib, or 90 days (male participants) or 30 days (for female participants) after the last dose of docetaxel.
- Has had an allogeneic tissue/solid organ transplant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 12 Apr 2019 | 36 |
 Germany | Not Recruiting | 12 Apr 2019 | 12 |
 Greece | Not Recruiting | 12 Apr 2019 | 21 |
 Hungary | Not Recruiting | 12 Apr 2019 | 35 |
 Italy | Not Recruiting | 12 Apr 2019 | 45 |
 Portugal | Not Recruiting | 12 Apr 2019 | 11 |
 Spain | Not Recruiting | 12 Apr 2019 | 46 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lenvatinib | Test | CAPSULE | ORAL | 24 | 60 | PRD9414230 |
Lenvatinib | Test | CAPSULE | ORAL | 24 | 60 | PRD9414231 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 36 | PRD4323105 |
DOCETAXEL | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 75 | 60 | SCP725130 |