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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03515837




Registration number
NCT03515837
Ethics application status
Date submitted
23/04/2018
Date registered
4/05/2018
Date last updated
7/07/2020

Titles & IDs
Public title
Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789)
Scientific title
A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)
Secondary ID [1] 0 0
MK-3475-789
Secondary ID [2] 0 0
3475-789
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-small Cell Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - pembrolizumab
Treatment: Drugs - pemetrexed
Treatment: Drugs - carboplatin
Treatment: Drugs - cisplatin
Treatment: Drugs - saline solution

Experimental: Pembro+Pemetrexed+Chemo - Participants receive pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).

Active Comparator: Placebo+Pemetrexed+Chemo - Participants receive normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).


Other interventions: pembrolizumab
IV infusion

Treatment: Drugs: pemetrexed
IV infusion

Treatment: Drugs: carboplatin
IV infusion

Treatment: Drugs: cisplatin
IV infusion

Treatment: Drugs: saline solution
IV infusion

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PFS will be assessed by blinded independent central review (BICR) using RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 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 at least 5 mm. Note: The appearance of one or more new lesions is also considered PD. The PFS for participants will be presented.
Timepoint [1] 0 0
Up to approximately 32 months
Primary outcome [2] 0 0
Overall Survival (OS) - OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis will be censored at the date of the last follow-up. The OS of participants will be presented.
Timepoint [2] 0 0
Up to approximately 59 months
Secondary outcome [1] 0 0
Objective Response Rate (ORR) Per RECIST 1.1 - ORR is defined as the percentage of participants in the analysis population who experience 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, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR for participants will be presented.
Timepoint [1] 0 0
Up to approximately 32 months
Secondary outcome [2] 0 0
Duration of Response (DOR) Per RECIST 1.1 - For participants who experience a response of CR or PR, DOR is defined as the time from the earliest date of qualifying response until earliest date of PD or death from any cause, whichever comes first. DOR will be assessed per RECIST 1.1 based on BICR. The DOR of participants who experience a CR or PR will be presented.
Timepoint [2] 0 0
Up to approximately 32 months
Secondary outcome [3] 0 0
Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Item (QLQ-C30) Global Health Status (Item 29) Scale Score - The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Global Health Status, participants are asked "How would you rate your overall health during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Global Health Status will be presented.
Timepoint [3] 0 0
Baseline and Week 12, Week 27
Secondary outcome [4] 0 0
Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea - TTD is the time from baseline to first onset of 10 points or more decrease from baseline with confirmation by the subsequent visit of 10 points or more deterioration from baseline in the composite endpoint of cough [EORTC QLQ-Lung Cancer Module 13 (LC13) Item 1; How much did you cough?], chest pain [EORTC QLQ-LC13 Item 10; Have you had pain in your chest?], or dyspnea [EORTC QLQ-C30 Item 8; Were you short of breath?]. Individual responses are given on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating a better outcome. The time to true deterioration in the composite endpoint of cough, chest pain or dyspnea will be presented.
Timepoint [4] 0 0
Up to approximately 32 months
Secondary outcome [5] 0 0
Adverse Events (AEs) - An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experience an AE will be presented.
Timepoint [5] 0 0
Up to 90 days after last dose of study treatment (Up to approximately 42 months)
Secondary outcome [6] 0 0
Study Treatment Discontinuations Due to AEs - The number of participants who discontinue study treatment due to an AE will be presented.
Timepoint [6] 0 0
Up to approximately 39 months
Secondary outcome [7] 0 0
Change from Baseline in EORTC-QLQ-C30 Quality of Life (Item 30) Scale Score - The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Quality of Life, participants are asked "How would you rate your overall quality of life during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Quality of Life will be presented.
Timepoint [7] 0 0
Baseline and Week 12, Week 27

Eligibility
Key inclusion criteria
- Histologically or cytologically confirmed diagnosis of Stage IV non-squamous NSCLC.

- Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R.

- Investigator-determined radiographic disease progression per RECIST 1.1 after
treatment with an EGFR TKI therapy: a) Participants previously treated with 1st or 2nd
generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have confirmed
documented absence of EGFR T790M mutation; b) Participants with confirmed acquired
T790M mutation after 1st or 2nd generation EGFR TKI (e.g.
erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure
prior to enrollment; c) Participants previously failed osimertinib TKI treatment as
1st line therapy are eligible regardless of their EGFR T790M mutation status. Note:
TKI washout period for all participants is 1 week or 2 half-lives after last treatment
dose, whichever is longer. TKI washout should be completed prior to first dose of
study treatment.

- Measurable disease per RECIST 1.1 as assessed by the local site
investigator/radiology.

- Provided archival tumor tissue sample or newly obtained (no anti-neoplastic therapy
since biopsy) 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 treatment but before randomization.

- Male participants must agree to use contraception during the treatment period and for
at least 120 days after the last dose of pembrolizumab and up to 180 days after last
dose of chemotherapeutic agents.

- Female participants must not be pregnant, not breastfeeding, and must agree to use
contraception during the treatment period and for at least 120 days after the last
dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic
agents.

- Adequate organ function.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the
predominant cell type; if small cell elements are present, the participant is
ineligible.

- Symptomatic ascites or pleural effusion. A participant who is clinically stable
following treatment for these conditions (including therapeutic thoraco- or
paracentesis) is eligible.

- Received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1),
anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent
directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic
T-lymphocyte-associated protein-4 [CTLA-4], OX-40, CD137).

- Received prior systemic cytotoxic chemotherapy or investigational agent(s), excluding
EGFR TKIs, for metastatic NSCLC. [Notes: 1) 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. 2) If
participant received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting study treatment.
3) Prior exposure to traditional medicine(s) is allowed as long as therapy was
discontinued at least 4 weeks prior to the first dose of study treatment.]

- Received prior radiotherapy within 2 weeks of start of study treatment or has received
lung radiation therapy of >30 Gray (Gy) within 6 months before the first dose of study
treatment. Participants must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (=2 weeks of radiotherapy) to non-central nervous
system (CNS) disease.

- Received a live vaccine within 30 days prior to the first dose of study treatment.

- 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.

- 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 prior the first dose of study treatment.

- Known additional malignancy that is progressing or has required active treatment
within the past 5 years. (Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ
(e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially
curative therapy are not excluded.)

- Known active untreated CNS metastases and/or carcinomatous meningitis.

- Severe hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients.

- Known sensitivity to any component of cisplatin, carboplatin, or pemetrexed.

- Active autoimmune disease that has required systemic treatment in past 2 years.

- History of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

- Active infection requiring systemic therapy.

- Known history of human immunodeficiency virus (HIV) infection.

- Known history of Hepatitis B or known active Hepatitis C virus.

- Known history of active tuberculosis (TB; Bacillus tuberculosis)

- Pregnant, 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 up to 180 days after the last dose of
chemotherapeutic agents.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Chris OBrien Lifehouse ( Site 0200) - Camperdown
Recruitment hospital [2] 0 0
Westmead Hospital ( Site 0201) - Westmead
Recruitment hospital [3] 0 0
Eastern Health ( Site 0202) - Box Hill
Recruitment hospital [4] 0 0
Austin Health ( Site 0203) - Heidelberg
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
3128 - Box Hill
Recruitment postcode(s) [4] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
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Illinois
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Minnesota
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Missouri
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Oregon
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Utah
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Zhejiang
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Bayern
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Kowloon
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Tuen Mun
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Bari
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Firenze
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Italy
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Napoli
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Italy
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Roma
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Japan
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Aichi
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Chiba
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Ehime
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Hyogo
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Ishikawa
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Kanagawa
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Osaka
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Fukuoka
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Niigata
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Okayama
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Tokyo
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Wakayama
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Chungcheongbuk-do [Chungbuk]
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Korea, Republic of
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Incheon-gwangyeoksi [Incheon]
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Korea, Republic of
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Kyonggi-do
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Korea, Republic of
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Seoul-teukbyeolsi [Seoul]
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Korea, Republic of
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Mexico
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Jalisco
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Mexico City
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Mexico
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Oaxaca
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Mexico
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Tlalpan
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Spain
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Spain
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Malaga
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Spain
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Sevilla
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Sweden
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Skane Lan [se-12]
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Sweden
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Stockholms Lan [se-01]
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Sweden
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Vastra Gotalands Lan [se-14]
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Taiwan
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New Taipei
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Taiwan
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Changhua
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Hsinchu
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Hualien
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Taiwan
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Kaohsiung
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Taichung
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Taiwan
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Tainan
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Taiwan
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Taipei
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Taiwan
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Taoyuan
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United Kingdom
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Brighton And Hove
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United Kingdom
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Edinburgh, City Of
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United Kingdom
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Leicestershire
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United Kingdom
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London, City Of
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United Kingdom
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Birmingham
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United Kingdom
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Leeds
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United Kingdom
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Romford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum
chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in
the treatment of adults with the following types of tyrosine kinase inhibitor
(TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous
non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®]
failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior
exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation
status.

The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has
superior efficacy compared to saline placebo plus chemotherapy in terms of: 1)
Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1
(RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This
study will be considered to have met its success criteria if the combination of pembrolizumab
plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.
Trial website
https://clinicaltrials.gov/show/NCT03515837
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications