Clinical Trials List
Protocol NumberMK3475-598
NCT Number(ClinicalTrials.gov Identfier)NCT03302234
2017-10-01 - 2023-05-31
Phase III
Terminated7
ICD-10C34
Malignant neoplasm of bronchus and lung
ICD-9162.9
Malignant neoplasm of bronchus and lung, unspecified
A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo in Previously Untreated, Stage IV, Metastatic Non-small Cell Lung Cancer Subjects Whose Tumors Are PD-L1 Positive (TPS ≥ 50%) (KEYNOTE-598)
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Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
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Sponsor
Merck Sharp & Dohme Corp.
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Wu-Chou Su Division of Hematology & Oncology
- Wei-Pang Chung Division of Hematology & Oncology
- Jui-Hung Tsai Division of Hematology & Oncology
- Wen-Pin Su Division of Hematology & Oncology
- Chien-Chung Lin Division of Thoracic Medicine
- Yu-Min Yeh Division of Hematology & Oncology
- Seu-Chun Yang Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Co-Principal Investigator
- Chia-Hsiang Li Division of Thoracic Medicine
- Yu-Chao Lin Division of Thoracic Medicine
- Chih-Yen Tu Division of Thoracic Medicine
- 陳韋成 Division of Thoracic Medicine
- 陳鴻仁 Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 林孟志 Division of Thoracic Medicine
- 李易濰 Division of Radiology
- CHIN-CHOU WANG Division of Thoracic Medicine
- 林理涵 Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
楊政達
Co-Principal Investigator
- Chih-Hsi Kuo Division of Hematology & Oncology
- Shih-Hong Li Division of Hematology & Oncology
- 柯皓文 Division of Hematology & Oncology
- 枋岳甫 Division of Hematology & Oncology
- Chih-Hung Chen Division of Hematology & Oncology
- Chien-Ying Liu Division of Hematology & Oncology
- Chih-Hung Chen Division of Hematology & Oncology
- Wen-Cheng Chang Division of Hematology & Oncology
- Chih-Liang Wang Division of Hematology & Oncology
- Ping-Chih Hsu Division of Hematology & Oncology
- 謝任富 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
2 Terminated
Audit
None
Co-Principal Investigator
- 徐偉勛 Division of Hematology & Oncology
- 廖斌志 Division of Hematology & Oncology
- 楊景堯 Division of Thoracic Medicine
- Chia-Chi Lin Division of Hematology & Oncology
- CHAO-CHI HO CHAO-CHI HO Division of Thoracic Medicine
- Jih-Hsiang Lee Division of Hematology & Oncology
- 蔡子修 Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Condition/Disease
Stage IV, Metastatic Non-small Cell Lung Cancer
Objectives
Primary Objective(s) & Hypothesis(es)
1. Objective: To compare the overall survival (OS) in subjects treated with
pembrolizumab plus ipilimumab versus pembrolizumab plus placebo
Hypothesis: Pembrolizumab plus ipilimumab demonstrates superior OS
compared to pembrolizumab plus placebo
2. Objective: To compare the PFS per RECIST 1.1 based on BICR in subjects
treated with pembrolizumab plus ipilimumab versus pembrolizumab plus
placebo
Hypothesis: Pembrolizumab plus ipilimumab demonstrates superior PFS per
RECIST 1.1 (based on BICR) compared to pembrolizumab plus placebo
Secondary Objective(s) & Hypothesis(es)
1. Objective: To compare the confirmed ORR per RECIST 1.1 based on BICR
in subjects treated with pembrolizumab plus ipilimumab versus
pembrolizumab plus placebo
Hypothesis: Pembrolizumab plus ipilimumab demonstrates superior confirmed ORR per RECIST 1.1 (based on BICR) compared to
pembrolizumab plus placebo
2. Objective: To evaluate the DOR per RECIST 1.1 (based on BICR) in
subjects treated with pembrolizumab plus ipilimumab and pembrolizumab
plus placebo.
3. Objective: To compare time to true deterioration (TTD) in the composite
endpoint of cough (European Organization for Research and Treatment of
Cancer Quality of Life Questionnaire and Lung Cancer Module 13 [EORTC
QLQ-LC13] Q1), pain in chest (EORTC QLQ LC13 Q10), and shortness of
breath (EORTC QLQ-C30 Q8) in subjects treated with pembrolizumab plus
ipilimumab and pembrolizumab plus placebo.
4. Objective: To evaluate the safety and tolerability profile of pembrolizumab
plus ipilimumab in subjects treated with pembrolizumab plus ipilimumab.
Test Drug
Keytruda
Active Ingredient
Pembrolizumab
Dosage Form
Injection
Dosage
100 mg/ 4mL
Endpoints
Primary:
Overall survival (OS) has been recognized as the gold standard for the demonstration
of superiority of a new antineoplastic therapy in randomized clinical studies and is a standard
assessment of clinical benefit in subjects with metastatic NSCLC.
Overall survival (OS) has been recognized as the gold standard for the demonstration
of superiority of a new antineoplastic therapy in randomized clinical studies and is a standard
assessment of clinical benefit in subjects with metastatic NSCLC.
Inclution Criteria
Diagnosis/Condition for Entry into the Trial
Male/female subjects with Stage IV metastatic NSCLC whose tumors are PD-L1
positive (TPS ≥50%), do not harbor EGFR-sensitizing mutations and ALK
translocations that are amenable to treatment with respective tyrosine kinase
inhibitor therapy, and who have received no systemic anticancer therapy for their
Stage IV metastatic NSCLC will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The
subject may also provide consent/assent for future biomedical research
(FBR); however, the subject may participate in the main trial without
participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have a histologically or cytologically confirmed diagnosis of Stage IV
metastatic NSCLC (AJCC version 8).
4. Have measurable disease per RECIST 1.1 as assessed by the local site
investigator/radiology. Lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesion.
5. Have a life expectancy of at least 3 months.
6. Have an ECOG Performance Status of 0 or 1.
7. Have adequate organ function as indicated by the following laboratory
values in Table 1.
8. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated.
Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to
slides. Newly obtained biopsies are preferred to archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be
submitted to the testing laboratory within 14 days from the date slides are
cut (details pertaining to tumor tissue submission can be found in the
Procedures Manual). Tumor demonstrates PD-L1 expression in ≥50% of
tumor cells (TPS ≥ 50%) as assessed by IHC at a central laboratory.
9. Female subjects of childbearing potential must have a negative urine or
serum pregnancy test within 72 hours prior to receiving the first dose of
study medication. If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in Section 5.7.2 – Contraception, for the
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
11. Male subjects of childbearing potential must agree to use an adequate
method of contraception as outlined in Section 5.7.2 – Contraception,
starting with the first dose of study therapy through 120 days after the last
dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
Male/female subjects with Stage IV metastatic NSCLC whose tumors are PD-L1
positive (TPS ≥50%), do not harbor EGFR-sensitizing mutations and ALK
translocations that are amenable to treatment with respective tyrosine kinase
inhibitor therapy, and who have received no systemic anticancer therapy for their
Stage IV metastatic NSCLC will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The
subject may also provide consent/assent for future biomedical research
(FBR); however, the subject may participate in the main trial without
participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have a histologically or cytologically confirmed diagnosis of Stage IV
metastatic NSCLC (AJCC version 8).
4. Have measurable disease per RECIST 1.1 as assessed by the local site
investigator/radiology. Lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesion.
5. Have a life expectancy of at least 3 months.
6. Have an ECOG Performance Status of 0 or 1.
7. Have adequate organ function as indicated by the following laboratory
values in Table 1.
8. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated.
Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to
slides. Newly obtained biopsies are preferred to archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be
submitted to the testing laboratory within 14 days from the date slides are
cut (details pertaining to tumor tissue submission can be found in the
Procedures Manual). Tumor demonstrates PD-L1 expression in ≥50% of
tumor cells (TPS ≥ 50%) as assessed by IHC at a central laboratory.
9. Female subjects of childbearing potential must have a negative urine or
serum pregnancy test within 72 hours prior to receiving the first dose of
study medication. If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in Section 5.7.2 – Contraception, for the
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
11. Male subjects of childbearing potential must agree to use an adequate
method of contraception as outlined in Section 5.7.2 – Contraception,
starting with the first dose of study therapy through 120 days after the last
dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
Exclusion Criteria
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has received prior systemic chemotherapy/other targeted or biological
antineoplastic therapy treatment for their Stage IV metastatic NSCLC.
Note: 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 disease.
2. Tumor harbors an EGFR-sensitizing (activating) mutation or an ALK
translocation.
Note: EGFR-sensitizing mutations are those mutations that are amenable
to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or
afatinib. Subjects with non-squamous histologies will not be randomized
until EGFR mutation status and/or ALK translocation status is available in
source documentation at the site.
For subjects enrolled who are known to have a tumor of predominantly
squamous histology, molecular testing for EGFR mutation and ALK translocation will not be required as this is not SOC and is not part of
current diagnostic guidelines.
3. Is currently participating in or has participated in a trial of an investigational
agent or has used an investigational device within 4 weeks prior to the first
dose of trial treatment.
Note: Subjects who have entered the follow-up phase of an investigational
trial may participate as long as it has been 4 weeks after the last dose of the
previous investigational agent.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2
agent or with an agent directed to another stimulatory or co-inhibitory T-cell
receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior radiotherapy within 2 weeks of start of trial treatment or
received lung radiation therapy of >30 Gy within 6 months of the first dose
of trial treatment. Subjects 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-CNS disease.
6. The subject’s NSCLC can be treated with curative intent with surgical
resection, localized radiotherapy, or chemoradiation.
Note: If subject received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention
prior to starting trial treatment.
7. Tumor specimen is not evaluable for PD-L1 expression.
8. Is receiving systemic steroid therapy ≤7 days prior to the first dose of trial
treatment or receiving any other form of immunosuppressive medication.
a. Corticosteroid use on study after Cycle 1 for management of AEs,
SAEs, and events of clinical interest (ECIs), as a pre-medication for IV
contrast allergies/reactions or if considered necessary for a subject’s
welfare, is allowed.
b. Subjects who receive daily steroid replacement therapy serve as an
exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or
hydrocortisone equivalent doses) is an example of replacement therapy.
c. Subjects who use inhaled steroids for the control of asthma serve as an
exception to this rule.
9. Has a known additional malignancy that is progressing or has required
active treatment within the past 3 years.
Note: Subjects with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical
cancer in situ) that have undergone potentially curative therapy are not
excluded.
10. Has known untreated-CNS metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided
they are radiologically stable (i.e., without evidence of progression for at
least 4 weeks by repeat imaging [note that the repeat imaging should be
performed during study screening]), clinically stable, and without
requirement of steroid treatment for at least 14 days prior to first dose of
trial treatment.
11. Has an active autoimmune disease that has required systemic treatment in
past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin,
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment.
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic
steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent)
or any other form of immunosuppressive therapy within 7 days prior the
first dose of trial drug.
13. Has a history of (non-infectious) pneumonitis that required systemic steroids
or current pneumonitis/interstitial lung disease.
14. Has had an allogeneic tissue/solid organ transplant.
15. Has received a live vaccine within 30 days prior to the first dose of trial
treatment. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccines (e.g., FluMist®
) are
live attenuated vaccines and are not allowed.
16. Has an active infection requiring systemic therapy.
17. Has a known history of human immunodeficiency virus (HIV) infection.
No HIV testing is required unless mandated by local health authority.
18. Has a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis c
virus (HCV) RNA [qualitative] is detected) infection.
Note: no testing for hepatitis B and hepatitis C is required unless mandated
by local health authority.
19. Has a known history of active tuberculosis (TB; Bacillus Tuberculosis).
20. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating
investigator.
21. Has known psychiatric or substance abuse disorders that would interfere
with cooperating with the requirements of the trial.
22. Is, at the time of signing informed consent, a regular user (including
“recreational use”) of any illicit drugs or had a recent history (within the last
year) of substance abuse (including alcohol).
23. Is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the trial, starting with the screening visit
(Visit 1) through 120 days after the last dose of pembrolizumab or 90 days
after the last dose of ipilimumab.
24. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its
excipients.
The subject must be excluded from participating in the trial if the subject:
1. Has received prior systemic chemotherapy/other targeted or biological
antineoplastic therapy treatment for their Stage IV metastatic NSCLC.
Note: 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 disease.
2. Tumor harbors an EGFR-sensitizing (activating) mutation or an ALK
translocation.
Note: EGFR-sensitizing mutations are those mutations that are amenable
to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or
afatinib. Subjects with non-squamous histologies will not be randomized
until EGFR mutation status and/or ALK translocation status is available in
source documentation at the site.
For subjects enrolled who are known to have a tumor of predominantly
squamous histology, molecular testing for EGFR mutation and ALK translocation will not be required as this is not SOC and is not part of
current diagnostic guidelines.
3. Is currently participating in or has participated in a trial of an investigational
agent or has used an investigational device within 4 weeks prior to the first
dose of trial treatment.
Note: Subjects who have entered the follow-up phase of an investigational
trial may participate as long as it has been 4 weeks after the last dose of the
previous investigational agent.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2
agent or with an agent directed to another stimulatory or co-inhibitory T-cell
receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior radiotherapy within 2 weeks of start of trial treatment or
received lung radiation therapy of >30 Gy within 6 months of the first dose
of trial treatment. Subjects 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-CNS disease.
6. The subject’s NSCLC can be treated with curative intent with surgical
resection, localized radiotherapy, or chemoradiation.
Note: If subject received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention
prior to starting trial treatment.
7. Tumor specimen is not evaluable for PD-L1 expression.
8. Is receiving systemic steroid therapy ≤7 days prior to the first dose of trial
treatment or receiving any other form of immunosuppressive medication.
a. Corticosteroid use on study after Cycle 1 for management of AEs,
SAEs, and events of clinical interest (ECIs), as a pre-medication for IV
contrast allergies/reactions or if considered necessary for a subject’s
welfare, is allowed.
b. Subjects who receive daily steroid replacement therapy serve as an
exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or
hydrocortisone equivalent doses) is an example of replacement therapy.
c. Subjects who use inhaled steroids for the control of asthma serve as an
exception to this rule.
9. Has a known additional malignancy that is progressing or has required
active treatment within the past 3 years.
Note: Subjects with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical
cancer in situ) that have undergone potentially curative therapy are not
excluded.
10. Has known untreated-CNS metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided
they are radiologically stable (i.e., without evidence of progression for at
least 4 weeks by repeat imaging [note that the repeat imaging should be
performed during study screening]), clinically stable, and without
requirement of steroid treatment for at least 14 days prior to first dose of
trial treatment.
11. Has an active autoimmune disease that has required systemic treatment in
past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin,
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment.
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic
steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent)
or any other form of immunosuppressive therapy within 7 days prior the
first dose of trial drug.
13. Has a history of (non-infectious) pneumonitis that required systemic steroids
or current pneumonitis/interstitial lung disease.
14. Has had an allogeneic tissue/solid organ transplant.
15. Has received a live vaccine within 30 days prior to the first dose of trial
treatment. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccines (e.g., FluMist®
) are
live attenuated vaccines and are not allowed.
16. Has an active infection requiring systemic therapy.
17. Has a known history of human immunodeficiency virus (HIV) infection.
No HIV testing is required unless mandated by local health authority.
18. Has a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis c
virus (HCV) RNA [qualitative] is detected) infection.
Note: no testing for hepatitis B and hepatitis C is required unless mandated
by local health authority.
19. Has a known history of active tuberculosis (TB; Bacillus Tuberculosis).
20. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating
investigator.
21. Has known psychiatric or substance abuse disorders that would interfere
with cooperating with the requirements of the trial.
22. Is, at the time of signing informed consent, a regular user (including
“recreational use”) of any illicit drugs or had a recent history (within the last
year) of substance abuse (including alcohol).
23. Is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the trial, starting with the screening visit
(Visit 1) through 120 days after the last dose of pembrolizumab or 90 days
after the last dose of ipilimumab.
24. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its
excipients.
The Estimated Number of Participants
-
Taiwan
22 participants
-
Global
548 participants
