| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Nonsquamous Non-small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Nonsquamous Non-small Cell Lung Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: To evaluate the safety and tolerability of treatment with lenvatinib + platinum doublet chemotherapy + pembrolizumab.
Part 2: To compare PFS as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1 as defined in Section 4.2.1.1.3) for lenvatinib + platinum doublet chemotherapy + pembrolizumab versus matching placebo + platinum doublet chemotherapy + pembrolizumab. - Hypothesis (H1): The combination of lenvatinib +platinum doublet chemotherapy + pembrolizumab prolongs PFS per RECIST 1.1 by BICR compared to matching placebo + platinum doublet chemotherapy +pembrolizumab.
Part 2: To compare OS for the combinations of lenvatinib + platinum doublet chemotherapy + pembrolizumab versus matching placebo + platinum doublet chemotherapy +pembrolizumab. |
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| E.2.2 | Secondary objectives of the trial |
Part 2: To compare objective response rate (ORR) as assessed by BICR according to RECIST 1.1 for the combinations of lenvatinib + platinum doublet chemotherapy+pembrolizumab versus matching placebo + platinum doublet chemotherapy + pembrolizumab.
Part 2: To compare duration of response (DOR) per RECIST 1.1 by BICR for the combinations of lenvatinib + platinum doublet chemotherapy + pembrolizumab versus matching placebo + platinum doublet chemotherapy + pembrolizumab.
Part 2: To compare the safety and tolerability for the combinations of lenvatinib + platinum doublet chemotherapy + pembrolizumab versus matching placebo + platinum doublet chemotherapy + pembrolizumab.
Part 2: To compare the mean change from baseline in global health status/quality of life (QoL), cough, chest pain, dyspnea, and physical functioning for the combinations of lenvatinib + platinum doublet chemotherapy + pembrolizumab versus matching placebo + platinum doublet chemotherapy + pembrolizumab. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participant must:
1. Have a histologically or cytologically confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC], version 8 or current version) nonsquamous NSCLC.
2. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as
primary treatment (documentation of absence of tumor-activating EGFR mutations AND absence of ALK and ROS1 gene rearrangements OR presence of a KRAS mutation).
3. Have measurable disease based on RECIST 1.1.
4. Have provided an evaluable archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (that was not previously irradiated) for central PD L1 testing. Formalin fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
Newly obtained biopsies are preferred to archived tissue. Formalin fixed specimens after the participant has been diagnosed with metastatic disease are preferred. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy are permitted if recent biopsy is not feasible.
5. Be male or female ≥18 years of age inclusive, at the time of signing the informed consent form (ICF).
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study intervention but before randomization.
8. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 120 days after the last dose of pembrolizumab and/or lenvatinib/matching placebo and up to 180 days after the last dose of chemotherapeutic agents.
A male participant must also agree to the following:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
Is not a woman of childbearing potential (WOCBP)
OR
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days after the last dose of study intervention The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 72 hours before the first dose of study intervention.
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the study.
11. Have adequate organ function as indicated by the laboratory values.
Specimens must be collected and reviewed within 10 days prior to the first dose of study intervention.
12. Have 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 prior to randomization.
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| E.4 | Principal exclusion criteria |
If Participant:
1. Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression for at least 4 weeks by repeat imaging [the repeat imaging must be performed during the screening period]), clinically stable, and have not required steroids for at least 14 days prior to the first dose of study intervention.
2. Has a history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
3. Radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after treatment with lenvatinib.
4. Has a known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
5. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by the local health authority.
9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive or HBV-DNA detected) or known active Hepatitis C virus (defined as HCV
RNA [qualitative] detected or HCV antibody reactive, if HCV-RNA is not the local SOC) infection. No testing for Hepatitis B or Hepatitis C is required unless mandated by the
local health authority.
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the investigator may affect oral drug absorption.
11. Has active hemoptysis (at least 0.5 tsp of bright red blood) within 2 weeks prior to the first dose of study intervention.
12. Has significant cardiovascular impairment within 12 months prior to the first dose of study intervention, including history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, cerebrovascular accident (CVA)/stroke, or cardiac arrhythmia associated with hemodynamic instability.
13. Has a known history of active tuberculosis.
14. Has an active infection requiring systemic therapy.
15. Has not recovered adequately from any toxicity and/or complication from major surgery prior to the first dose of study intervention.
16. Has known psychiatric or substance abuse disorders that would interfere with the participant’s cooperation to meet with the requirements of the study.
17. Previously had a severe hypersensitivity reaction to treatment with a monoclonal antibody or has a known sensitivity to any component of lenvatinib or pembrolizumab, or as applicable, carboplatin, cisplatin, or pemetrexed.
18. WOCBP who has a positive urine pregnancy test within 72 hours prior to the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
19. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab and/or lenvatinib/matching placebo and up to 180 days after last dose of chemotherapeutic agents.
20. Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy for their metastatic NSCLC.
21. Has received prior treatment with pembrolizumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2 agent, with lenvatinib or any other RTKi, or with an agent directed to another stimulatory or co-inhibitory T cell receptor (eg, CTLA-4, OX-40, CD137, GITR).
22. Has received radiotherapy within 14 days prior to the first dose of study intervention or received lung radiation therapy of >30 Gy within 6 months prior to the first dose of study intervention.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Part 1: Number of Participants with a Dose-limiting Toxicity
2.Part 1: Number of Participants with One or More Adverse Events
3.Part 2: Progression-free Survival (PFS) as Assessed by BICR according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
4. Part 2: Overall Survival (OS)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1; each cycle is 21 days (up to 21 days)
2. Through 90 days post last dose of study treatment (Up to approximately 27 months)
3. Up to approximately 24 months
4. Up to approximately 60 months
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| E.5.2 | Secondary end point(s) |
1. Part 2: Objective Response Rate (ORR) as Assessed by BICR according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
2. Part 2; Duration of Response (DOR) as Assessed by BICR according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
3. Part 2: Number of Participants with One or More Adverse Events
4. Part 2: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event
5. Part 2: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 [EORTC QLQ-C30] Global Health Status/Quality of Life (QoL)(EORTC QLQ-C30 Items 29 and 30); Cough (EORTC QLQ-Lung Cancer Module [LC13] Item 31); Chest Pain (EORTC QLQ-LC13 Item 40); Dyspnea (EORTC QLQ-C30 Item 8); and Physical Functioning (EORTC QLQ-C30 Items 1-5) Combined Score
6. Part 2: Time to True Deterioration as Assessed by Change from Baseline in Global Health Status/QoL (EORTC QLQ-C30 Items 29 and 30), Cough (EORTC QLQ-LC13 Item 31), Chest Pain (EORTC QLQ-LC13 Item 40), Dyspnea (EORTC QLQ-C30 Item 8), and Physical Functioning (EORTC QLQ-C30 Items 1-5) Combined Score
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Up to approximately 24 months
3. Up to approximately 24 months
4. Up to approximately 24 months
5. Baseline (Cycle 1 Day 1) and at designated timepoints up to 30 days post last dose. Each cycle is 21 days. (Up to approximately 25 months)
6. Baseline (Cycle 1 Day 1) and at designated timepoints up to 30 days post last dose. Each cycle is 21 days. (Up to approximately 25 months)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Chile |
| China |
| France |
| Germany |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| Turkey |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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