Safety and Efficacy Study of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) With or Without Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-7902-006/E7080-G000-315/LEAP-006)

Phase 3

Completed

Conditions: Nonsquamous Non-small Cell Lung Cancer

Interventions: Biological: Pembrolizumab
Drug: Carboplatin
Drug: Cisplatin
Drug: Pemetrexed
Drug: Lenvatinib
Drug: Placebo matching lenvatinib

Registration Number: NCT03829319

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: The purpose of this study is to assess the safety and efficacy of pemetrexed + platinum chemotherapy + pembrolizumab (MK-3475) with or without lenvatinib (MK-7902/E7080) as first-line intervention in adults with metastatic nonsquamous non-small cell lung cancer.

The primary study hypotheses state that: 1) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Progression-free Survival (PFS) as assessed by blinded independent central review (BICR) per modified Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST 1.1) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab, and 2) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Overall Survival (OS) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 761

Inclusion Criteria

Histologically or cytologically confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC], version 8 or current version), nonsquamous NSCLC.
Confirmation that Epidermal Growth Factor Receptor (EGFR), ALK Receptor Tyrosine Kinase (ALK), or ROS1 Receptor Tyrosine Kinase (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 Kirsten Rat Sarcoma (KRAS) gene mutation).
Have measurable disease based on RECIST 1.1. Note: Lesions that appear measurable, but are situated in a previously irradiated area, can be considered measurable (eligible for selection as target lesions) if they have shown documented growth since the completion of radiation.
Provided an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (not previously irradiated).
Life expectancy of at least 3 months.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of study intervention but before randomization.
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
Male participants must agree for at least 7 days after the last dose of lenvatinib/matching placebo and up to 180 days after the last dose of chemotherapeutic agents to:
1. Refrain from donating sperm PLUS either:
2. Be abstinence from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
3. Must agree to use contraception unless confirmed to be azoopsermic (vasectomized or secondary to medical cause) as detailed below:
  1. Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.

Note: 7 days after lenvatinib/matching placebo is stopped, if the participant is on pembrolizumab only and is greater than 180 days post chemotherapy, no male contraception measures are needed.

Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
1. Is not a WOCBP OR
2. 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), during the intervention period and for at least 120 days post pembrolizumab and/or 30 days post-lenvatinib/matching placebo, and up to 180 days post last dose of chemotherapeutic agents, whichever occurs last.
Adequate organ function.
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. Note: Participants must not have a history of uncontrolled or poorly-controlled hypertension, defined as >150/90 mm Hg for >4 weeks despite standard medical management.

Exclusion Criteria

Known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, clinically stable, and have not required steroids for at least 14 days prior to the first dose of study intervention.
History of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
Radiographic evidence of intratumoral caviations, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib-therapy. (In the chest, major blood vessels include the main pulmonary artery, the left and right pulmonary arteries, the 4 major pulmonary veins, the superior or inferior vena cava, and the aorta).
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. Note: The time requirement also does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
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.
Has had allogeneic tissue/solid organ transplant.
Known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by the local health authority.
Known history of Hepatitis B or active Hepatitis C. No testing for Hepatitis B or Hepatitis C is required unless mandated by the local health authority.
History of a gastrointestinal condition or procedure that in the opinion of the investigator may affect oral drug absorption.
Active hemoptysis (at least 0.5 teaspoon of bright red blood) within 2 weeks prior to the first dose of study intervention.
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.
Known history of active tuberculosis.
Active infection requiring systemic therapy.
Has not recovered adequately from any toxicity and/or complication from major surgery prior to the first dose of study intervention.
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.
A WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization or treatment allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
Received prior systemic chemotherapy or other targeted or biological antineoplastic therapy for their metastatic NSCLC. Note: Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic NSCLC.
Received prior treatment with pembrolizumab or any other anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2 agent, with lenvatinib or any other receptor tyrosine kinase inhibitor (RTKi), or with an agent directed to another stimulatory or co-inhibitory T cell receptor.
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. Note: Participants must have recovered from all radiation-related toxicities to Grade ≤1, not required corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
Received systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) within 7 days prior to the first dose of study intervention.
Received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: killed vaccines are allowed.
Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study intervention.
Has a prolongation of QTc interval (calculated using Fridericia's formula) of >480 msecl.
Left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib	Pembrolizumab	Participants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m\^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib	Carboplatin	Participants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m\^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib	Cisplatin	Participants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m\^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib	Pemetrexed	Participants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m\^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Lenvatinib	Lenvatinib	Participants receive carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m\^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo	Pembrolizumab	In Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo	Carboplatin	In Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo	Cisplatin	In Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo	Pemetrexed	In Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily.
Pemetrexed+Platinum Chemotherapy+Pembrolizumab+Placebo	Placebo matching lenvatinib	In Parts 1 and 2: Participants receive carboplatin AUC5 or cisplatin 75 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m\^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS (Part 2 only) placebo matching lenvatinib via oral capsule once daily.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With a Dose-limiting Toxicity (DLT)	Cycle 1; each cycle is 21 days (up to 21 days)	Dose-limiting toxicity using Common Terminology Criteria for Adverse Events v4.0 for grading, is defined as any of the following hematologic toxicities: 1) Grade 4 neutropenia, 2) Grade 3 or 4 febrile neutropenia, 3) thrombocytopenia \<25,000 cells/mm\^3 associated with bleeding and/or which requires platelet transfusion, or any of the following non-hematologic toxicities: 4) any other Grade 4 or 5 toxicity, 5) Grade 3 toxicities lasting \>3 days (exclusions apply), 6) Grade 3 hypertension not controlled by medication, 7) Grade 3 or above gastrointestinal perforation, 8) Grade 3 or above wound dehiscence requiring medical or surgical intervention, 9) any grade thromboembolic event, or 10) any Grade 3 nonhematologic laboratory value if medical intervention is required or the abnormality leads to hospitalization.
Part 1: Number of Participants Who Experienced an Adverse Event (AE)	Up to approximately 48 months	An adverse event is defined as 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. The number of participants who experience one of more adverse events during Part 1 of this study will be presented.
Part 1: Number of Participants Who Discontinued Study Drug Due to an Adverse Event	Up to approximately 48 months	An adverse event is defined as 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. The number of participants who discontinue study medication due to and adverse event during Part 1 of this study will be presented.
Part 2: Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Up to approximately 36 months	PFS was defined as the time from date of randomization to the date of the first documentation of progressive disease (PD) or death from any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Data are from the product-limit (Kaplan-Meier) method for censored data. PFS as assessed by blinded independent central review (BICR) per RECIST 1.1 is presented.
Part 2: Overall Survival (OS)	Up to approximately 47 months	OS is defined as the time from randomization to the time of death from any cause. OS is presented.

Secondary Outcome Measures

Name	Time	Method
Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Up to approximately 19 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. ORR as assessed per modified RECIST 1.1 will be presented.
Part 2: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Up to approximately 48 months	For participants who demonstrated CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), DOR is defined as the time from the first documented evidence of CR or PR until PD 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, or death from any cause, PD is defined as ≥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 ≥5 mm. Note: The appearance of one or more new lesions is also considered PD. DOR as assessed per modified RECIST 1.1 will be presented.
Part 2: Number of Participants Who Experienced an Adverse Event (AE)	Up to approximately 45 months	An adverse event is defined as 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. The number of participants who experienced one of more adverse events during Part 2 of this study were presented.
Part 2: Number of Participants Who Discontinued Study Drug Due to an Adverse Event	Up to approximately 45 months	An adverse event is defined as 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. The number of participants who discontinued study treatment during Part 2 of this study were presented.
Part 2: Change From Baseline in Global Health Status (GHS) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Items 29 and 30) Score	Baseline and Week 27	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and Quality of Life (QoL; "How would you rate your overall quality of life during the past week?") are each scored on a 7-point scale (1=Very poor to 7=Excellent). The two raw scores were averaged into a combined score, then normalized using linear transformation so each participant's score ranged from 0 to 100 (0=Worst overall health/quality of life and 100=Best overall health/quality of life). The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score is presented
Part 2: Change From Baseline in Cough (EORTC Quality of Life Questionnaire-Lung Cancer Module 13 [QLQ-LC13] Item 31) Score	Baseline and week 27	The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question "How much did you cough?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in cough (EORTC QLQ-LC13 Item 31) score will be presented. A lower score indicates a better outcome.
Part 2: Change From Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) Score	Baseline and Week 27	The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question "Have you had pain in your chest?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in chest pain (EORTC QLQ-LC13 Item 40) score will be presented. A lower score indicates a better outcome.
Part 2: Change From Baseline in Dyspnea (EORTC QLQ-C30 Item 8) Score	Baseline and Week 27	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question "Were you short of breath?" are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in dyspnea (EORTC QLQ-C30 Item 8) score will be presented. A lower score indicates a better outcome.
Part 2: Change From Baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) Score	Baseline and Week 27	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score will be presented. A higher score indicates a better quality of life.
Part 2: Time to True Deterioration (TTD) Based on Change From Baseline in Global Health Status (GHS)/Quality of Life (QoL) (EORTC QLQ-C30 Items 29 and 30) Score	Baseline and Week 27	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in GHS/QoL (EORTC QLQ-C30 Items 29 and 30) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in GHS/QoL score, will be presented. A longer TTD indicates a better outcome.
Part 2: TTD Based on Change From Baseline in Cough EORTC QLQ-LC13 (Item 31) Score	Baseline And Week 27	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline cough (EORTC QLQ-LC30 Items 31) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in physical functioning score, will be presented. A longer TTD indicates a better outcome.
Part 2: TTD Based on Change From Baseline in Chest Pain EORTC QLQ-LC13 (Item 40) Score	Baseline and Week 27	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline chest pain (EORTC QLQ-C30 Item 40) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in chest pains core, will be presented. A longer TTD indicates a better outcome.
Part 2: TTD Based on Change From Baseline in Dyspnea EORTC QLQ-C30 (Item 8) Score	Baseline and Week 27	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline dyspnea (EORTC QLQ-C30 Item 8) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in dyspnea score, will be presented. A longer TTD indicates a better outcome.
Part 2: TTD Based on Change From Baseline in Physical Functioning EORTC QLQ-C30 (Items 1 Through 5) Score	Baseline and Week 27	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline physical functioning (EORTC QLQ-C30 Items 1 through 5) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in physical functioning score, will be presented. A longer TTD indicates a better outcome.
Part 2: Time to True Deterioration (TTD) Based on Change From Baseline in the Composite Endpoint of Cough (EORTC QLQ-LC13 Item 31), Chest Pain (EORTC QLQ-LC13 Item 40), or Dyspnea (EORTC QLQ-C30 Item 8)	Baseline and Week 27	TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in the composite endpoint of cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 item 40), or dyspnea (QLQ-C30 Item 8). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in the composite endpoint of cough, chest pain or dyspnea, will be presented. A longer TTD indicates a better outcome.

Trial Locations

Locations (158): Thomas Jefferson University Hospital ( Site 0548)
🇺🇸
Philadelphia, Pennsylvania, United States
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie ( Site 0603)
🇵🇱
Warszawa, Mazowieckie, Poland
Sanatorio Parque ( Site 0365)
🇦🇷
Rosario, Santa Fe, Argentina
Hospital Universitario Insular de Gran Canaria ( Site 0244)
🇪🇸
Las Palmas de Gran Canaria, Las Palmas, Spain
El Camino Hospital Cancer Center ( Site 0529)
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Mountain View, California, United States
Hospital Aleman ( Site 0368)
🇦🇷
Buenos Aires, Argentina
Instituto Medico Especializado Alexander Fleming ( Site 0369)
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Buenos Aires, Argentina
West Virginia University ( Site 0526)
🇺🇸
Morgantown, West Virginia, United States
CIUSSS de la Mauricie et du Centre du Quebec ( Site 0408)
🇨🇦
Trois-Rivieres, Quebec, Canada
Chris OBrien Lifehouse ( Site 0006)
🇦🇺
Sydney, New South Wales, Australia
Fujian Provincial Cancer Hospital ( Site 0102)
🇨🇳
Fuzhou, Fujian, China
Cancer Hospital Affiliated to Xinjiang Medical University ( Site 0110)
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Urumuqi, Xinjiang, China
Holy Cross Hospital ( Site 0512)
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Fort Lauderdale, Florida, United States
UT Southwestern Medical Center ( Site 0558)
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Dallas, Texas, United States
Westmead Hospital ( Site 0009)
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Sydney, New South Wales, Australia
Kingston Health Sciences Centre ( Site 0414)
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Kingston, Ontario, Canada
Sault Area Hospital ( Site 0413)
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Sault Ste Marie, Ontario, Canada
Cancer Hospital Chinese Academy of Medical Science ( Site 0117)
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Beijing, Beijing, China
CEMAIC ( Site 0374)
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Cordoba, Argentina
Centro de Oncologia e Investigacion Buenos Aires COIBA ( Site 0367)
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Berazategui, Buenos Aires, Argentina
Hopital Cardiologique Louis Pradel ( Site 0141)
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Bron, Rhone-Alpes, France
Parkland Health & Hospital System ( Site 0576)
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Dallas, Texas, United States
Lakeridge Health ( Site 0406)
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Oshawa, Ontario, Canada
Cairns Hospital ( Site 0002)
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Cairns, Queensland, Australia
Ballarat Health Services ( Site 0003)
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Ballarat, Victoria, Australia
CIUSSS Ouest de l Ile - St-Mary s Hospital ( Site 0412)
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Montreal, Quebec, Canada
CEMIC ( Site 0370)
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Buenos Aires, Caba, Argentina
Instituto de Investigaciones Clinicas Mar del Plata ( Site 0371)
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Mar del Plata, Buenos Aires, Argentina
Moncton Hospital - Horizon Health Network ( Site 0410)
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Moncton, New Brunswick, Canada
Bradford Hill Centro de Investigaciones Clinicas ( Site 0387)
🇨🇱
Santiago, Region M. De Santiago, Chile
Jilin Cancer Hospital ( Site 0115)
🇨🇳
Changchun, Jilin, China
Wuhan Union Hospital Cancer Center-Cancer Center ( Site 0123)
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Wuhan, Hubei, China
Klinikum Esslingen GmbH ( Site 0164)
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Esslingen, Baden-Wurttemberg, Germany
Osaka Habikino Medical Center ( Site 0020)
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Habikino, Osaka, Japan
CHU de Quebec-Universite Laval-Hotel Dieu de Quebec ( Site 0403)
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Quebec, Canada
Tokyo Metropolitan Komagome Hospital ( Site 0015)
🇯🇵
Tokyo, Japan
Port Macquarie Base Hospital ( Site 0001)
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Port Macquarie, New South Wales, Australia
Hopital Cochin ( Site 0140)
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Paris, France
Peking Union Medical College Hospital ( Site 0108)
🇨🇳
Beijing, Beijing, China
Southern Medical University Nanfang Hospital ( Site 0121)
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Guangzhou, Guangdong, China
Fundacion Arturo Lopez Perez FALP ( Site 0383)
🇨🇱
Santiago, Region M. De Santiago, Chile
Pontificia Universidad Catolica de Chile ( Site 0382)
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Santiago, Region M. De Santiago, Chile
Beijing Cancer Hospital ( Site 0120)
🇨🇳
Beijing, Beijing, China
Hopital Nord du Marseille ( Site 0147)
🇫🇷
Marseille, Bouches-du-Rhone, France
Uniklinik RWTH Aachen ( Site 0160)
🇩🇪
Aachen, Nordrhein-Westfalen, Germany
The Cancer Institute Hospital of JFCR ( Site 0021)
🇯🇵
Tokyo, Japan
The Catholic University of Korea St. Vincent s Hospital ( Site 0064)
🇰🇷
Gyeonggi-do, Kyonggi-do, Korea, Republic of
First Pavlov State Medical University of Saint Petersburg-Department of Oncology ( Site 0273)
🇷🇺
Saint-Petersburg, Sankt-Peterburg, Russian Federation
Hospital Santa Creu i Sant Pau ( Site 0241)
🇪🇸
Barcelona, Spain
Tianjin Medical University Cancer Institute & Hospital ( Site 0111)
🇨🇳
Tian Jin, Tianjin, China
National Cancer Center ( Site 0061)
🇰🇷
Goyang-si, Kyonggi-do, Korea, Republic of
Tauranga Hospital ( Site 0004)
🇳🇿
Tauranga, Bay Of Plenty, New Zealand
Pius Hospital Oldenburg ( Site 0170)
🇩🇪
Oldenburg, Niedersachsen, Germany
Krankenhaus Nordwest ( Site 0169)
🇩🇪
Frankfurt, Hessen, Germany
Fujita Health University Hospital ( Site 0016)
🇯🇵
Toyoake, Aichi, Japan
Hospital Universitario La Paz ( Site 0236)
🇪🇸
Madrid, Spain
National Cancer Center Hospital East ( Site 0024)
🇯🇵
Kashiwa, Chiba, Japan
Hopital Robert Schuman ( Site 0143)
🇫🇷
Vantoux, Moselle, France
Auckland City Hospital ( Site 0011)
🇳🇿
Auckland, New Zealand
National Cancer Center Hospital ( Site 0026)
🇯🇵
Tokyo, Japan
Hospital General Universitario Gregorio Maranon ( Site 0237)
🇪🇸
Madrid, Spain
Kanazawa University Hospital ( Site 0018)
🇯🇵
Kanazawa, Ishikawa, Japan
National Hospital Organization Nagoya Medical Center ( Site 0017)
🇯🇵
Nagoya, Aichi, Japan
Chungbuk National University Hospital ( Site 0062)
🇰🇷
Cheongju si, Chungbuk, Korea, Republic of
Shamir Medical Center-Assaf Harofeh ( Site 0227)
🇮🇱
Zerifin, Israel
City Clinical Hospital 1 na. NI. Pirogov ( Site 0270)
🇷🇺
Moscow, Moskva, Russian Federation
Severance Hospital Yonsei University Health System ( Site 0063)
🇰🇷
Seoul, Korea, Republic of
Krankenhaus Martha Maria Halle-Doelau ( Site 0166)
🇩🇪
Halle, Sachsen-Anhalt, Germany
National Medical Research Radiology Centre ( Site 0260)
🇷🇺
Moscow, Moskva, Russian Federation
Hospital General Universitario de Alicante ( Site 0240)
🇪🇸
Alicante, Spain
Wakayama Medical University Hospital ( Site 0025)
🇯🇵
Wakayama, Japan
Ankara Sehir Hastanesi ( Site 0323)
🇹🇷
Ankara, Turkey
Leicester Royal Infirmary ( Site 0284)
🇬🇧
Leicester, United Kingdom
Ankara Universitesi Tip Fakultesi. ( Site 0317)
🇹🇷
Ankara, Turkey
Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 0312)
🇹🇷
Istanbul, Turkey
North Middlesex University Hospital NHS Trust ( Site 0291)
🇬🇧
London, London, City Of, United Kingdom
Universitaetsklinikum des Saarlandes ( Site 0165)
🇩🇪
Homburg, Saarland, Germany
LungenClinic Grosshansdorf GmbH ( Site 0171)
🇩🇪
Grosshansdorf, Schleswig-Holstein, Germany
Clinica Universidad Catolica del Maule ( Site 0385)
🇨🇱
Talca, Maule, Chile
Henry Ford Health System ( Site 0563)
🇺🇸
Detroit, Michigan, United States
Stephenson Cancer Center ( Site 0504)
🇺🇸
Oklahoma City, Oklahoma, United States
Utah Cancer Specialists ( Site 0523)
🇺🇸
Salt Lake City, Utah, United States
The Second Hospital Affiliated to AMU ( Site 0119)
🇨🇳
Chongqing, Chongqing, China
The Third Affiliated Hospital of Harbin Medical University ( Site 0100)
🇨🇳
Harbin, Heilongjiang, China
Henan Cancer Hospital ( Site 0112)
🇨🇳
Zhengzhou, Henan, China
Hubei Cancer Hospital ( Site 0122)
🇨🇳
Wuhan, Hubei, China
Shanghai Pulmonary Hospital ( Site 0101)
🇨🇳
Shanghai, Shanghai, China
The First Affiliated Hospital of Wenzhou Medical University ( Site 0124)
🇨🇳
Wen Zhou, Zhejiang, China
Kansai Medical University Hospital ( Site 0022)
🇯🇵
Hirakata, Osaka, Japan
Niigata Cancer Center Hospital ( Site 0019)
🇯🇵
Niigata, Japan
Rabin Medical Center ( Site 0224)
🇮🇱
Petah Tikva, Israel
Sanford Health Roger Maris Cancer Center ( Site 0533)
🇺🇸
Fargo, North Dakota, United States
Mercy Health-Paducah Medical Oncology and Hematology ( Site 0570)
🇺🇸
Paducah, Kentucky, United States
Broome Oncology, LLC ( Site 0562)
🇺🇸
Johnson City, New York, United States
Good Samaritan Hospital Corvallis ( Site 0521)
🇺🇸
Corvallis, Oregon, United States
Abington Hospital - Asplundh Cancer Center ( Site 0575)
🇺🇸
Willow Grove, Pennsylvania, United States
West Cancer Center - East Campus ( Site 0544)
🇺🇸
Germantown, Tennessee, United States
CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica ( Site 0372)
🇦🇷
San Juan, Argentina
Blacktown Hospital Western Sydney Local Health District ( Site 0008)
🇦🇺
Blacktown, New South Wales, Australia
The Prince Charles Hospital ( Site 0010)
🇦🇺
Chermside, Queensland, Australia
Juravinski Cancer Centre ( Site 0407)
🇨🇦
Hamilton, Ontario, Canada
Hopital Cite de la Sante de Laval ( Site 0400)
🇨🇦
Laval, Quebec, Canada
OrlandiOncologia ( Site 0381)
🇨🇱
Santiago, Region M. De Santiago, Chile
First Affiliated Hospital of The Third Military Medical University ( Site 0118)
🇨🇳
Chongqing, Chongqing, China
Zhongshan Hospital Fudan University ( Site 0103)
🇨🇳
Shanghai, Shanghai, China
Zhejiang Cancer Hospital ( Site 0113)
🇨🇳
Hangzhou, Zhejiang, China
Centre Paul Strauss ( Site 0144)
🇫🇷
Strasbourg, Bas-Rhin, France
Centre de Cancerologie du Grand Montpellier ( Site 0142)
🇫🇷
Montpellier, Herault, France
Hopital Foch ( Site 0145)
🇫🇷
Suresnes, Hauts-de-Seine, France
L'hopital Nord-Ouest - Centre Hospitalier de Villefranche sur Saone ( Site 0149)
🇫🇷
Villefranche sur Saone, Rhone, France
Soroka Medical Center ( Site 0222)
🇮🇱
Beer Sheva, Israel
Meir Medical Center ( Site 0221)
🇮🇱
Kfar Saba, Israel
Hamato-Onkologie Hamburg Prof. Laack und Partner ( Site 0161)
🇩🇪
Hamburg, Germany
Holy Family Hospital ( Site 0228)
🇮🇱
Nazareth, Israel
Rambam Medical Center ( Site 0223)
🇮🇱
Haifa, Israel
Shaare Zedek Medical Center-Oncology ( Site 0229)
🇮🇱
Jerusalem, Israel
Sheba Medical Center ( Site 0220)
🇮🇱
Ramat Gan, Israel
Sourasky Medical Center ( Site 0225)
🇮🇱
Tel Aviv, Israel
Pleszewskie Centrum Medyczne w Pleszewie Sp. z o.o. ( Site 0615)
🇵🇱
Pleszew, Wielkopolskie, Poland
Centrum Onkologii im.prof. F. Lukaszczyka w Bydgoszczy ( Site 0601)
🇵🇱
Bydgoszcz, Kujawsko-pomorskie, Poland
MED-POLONIA Sp. z o.o. ( Site 0609)
🇵🇱
Poznan, Wielkopolskie, Poland
Nizhniy Novgorod Region Oncology Dispensary ( Site 0272)
🇷🇺
Nizhniy Novgorod, Nizhegorodskaya Oblast, Russian Federation
Moscow Regional Oncological Dispensary ( Site 0274)
🇷🇺
Balashikha, Moskovskaya Oblast, Russian Federation
Leningrad Regional Oncology Center ( Site 0271)
🇷🇺
Saint Petersburg, Leningradskaya Oblast, Russian Federation
Central Clinical Hospital with outpatient Clinic ( Site 0262)
🇷🇺
Moscow, Moskva, Russian Federation
FSAI Treatment and Rehabilitation Centre of the MoH and SD of RF ( Site 0264)
🇷🇺
Moscow, Moskva, Russian Federation
ICO L Hospitalet ( Site 0234)
🇪🇸
Hospitalet de Llobregat, Barcelona, Spain
Complejo Hospitalario Universitario A Coruna ( Site 0239)
🇪🇸
A Coruna, La Coruna, Spain
Omsk Clinical Oncology Dispensary ( Site 0267)
🇷🇺
Omsk, Omskaya Oblast, Russian Federation
Scientific Research Oncology Institute n.a. N.N.Petrov ( Site 0269)
🇷🇺
Saint Petersburg, Sankt-Peterburg, Russian Federation
Hospital General Universitario de Valencia ( Site 0231)
🇪🇸
Valencia, Valenciana, Comunitat, Spain
SAHI Republican Clinical Oncological Dispensary of the MoH of RT ( Site 0261)
🇷🇺
Kazan, Tatarstan, Respublika, Russian Federation
Hospital Universitario La Fe ( Site 0233)
🇪🇸
Valencia, Valenciana, Comunitat, Spain
Complejo Hospitalario de Malaga ( Site 0238)
🇪🇸
Malaga, Spain
Hospital Universitario Miguel Servet ( Site 0242)
🇪🇸
Zaragoza, Spain
Hospital Clinico San Carlos ( Site 0235)
🇪🇸
Madrid, Spain
Hacettepe Universitesi Tıp Fakultesi ( Site 0316)
🇹🇷
Ankara, Turkey
Cukurova Universitesi Tıp Fakultesi Balcalı Hastanesi ( Site 0314)
🇹🇷
Adana, Turkey
Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi-oncology ( Site 0310)
🇹🇷
Istanbul, Turkey
Inonu Universitesi Medical Fakultesi ( Site 0318)
🇹🇷
Malatya, Turkey
Ege Universitesi Tip Fakultesi ( Site 0313)
🇹🇷
Izmir, Turkey
Cambridge University Hospitals NHS Trust ( Site 0293)
🇬🇧
Cambridge, Cambridgeshire, United Kingdom
Christie NHS Foundation Trust ( Site 0275)
🇬🇧
Manchester, United Kingdom
St Georges University Hospitals NHS Foundation Trust. ( Site 0292)
🇬🇧
London, London, City Of, United Kingdom
Guys and St Thomas NHS Foundation Trust ( Site 0280)
🇬🇧
London, London, City Of, United Kingdom
Leeds Teaching Hospital NHS Trust. St. James University Hospital ( Site 0276)
🇬🇧
Leeds, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust ( Site 0286)
🇬🇧
Wirral, United Kingdom
Nottingham City Hospital Campus ( Site 0287)
🇬🇧
Nottingham, United Kingdom
Centro de Investigacion y desarrollo Oncologico SpA - CIDO SpA ( Site 0380)
🇨🇱
Temuco, Araucania, Chile
Oncocentro ( Site 0384)
🇨🇱
Vina del Mar, Valparaiso, Chile
Centro Oncologico Antofagasta ( Site 0386)
🇨🇱
Antofagasta, Chile
Hopital Laennec ( Site 0146)
🇫🇷
Nantes cedex 1, Loire-Atlantique, France
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii ( Site 0613)
🇵🇱
Lodz, Lodzkie, Poland
Szpital Wojewodzki im. Mikolaja Kopernika ( Site 0602)
🇵🇱
Koszalin, Zachodniopomorskie, Poland
Yale University ( Site 0519)
🇺🇸
New Haven, Connecticut, United States
Saint Lukes Cancer Institute ( Site 0541)
🇺🇸
Kansas City, Missouri, United States
Aberdeen Royal Infirmary ( Site 0288)
🇬🇧
Aberdeen, Scotland, United Kingdom
The First Affiliated Hospital Zhejiang University ( Site 0109)
🇨🇳
Hangzhou, Zhejiang, China