A Trial of Pembrolizumab in Combination With Chemotherapy and Radiotherapy in Stage III NSCLC (KEYNOTE-799, MK-3475-799)
- Conditions
- Non-small Cell Lung Cancer
- Interventions
- Registration Number
- NCT03631784
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in combination with platinum doublet chemotherapy and standard thoracic radiotherapy followed by pembrolizumab monotherapy. The primary hypothesis of the trial is that within each platinum doublet chemotherapy cohort, the percentage of participants who develop Grade 3 or higher pneumonitis is ≤10% and objective response rate (ORR) by blinded independent central review (BICR).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 217
- Male/female participants, who are at least 18 years of age on the day of signing informed consent with previously untreated, unresectable, pathologically confirmed NSCLC and Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8.
- No evidence of metastatic disease by whole body positron emission tomography/computed tomography (PET/ CT) scan, diagnostic quality CT scan, and brain imaging.
- Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
- Have provided tumor tissue sample (core, incisional, or excisional biopsy).
- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Have adequate pulmonary function test (PFT)
- Have adequate organ function
- A male participant must agree to use contraception through the end of treatment and refrain from donating sperm during this period.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation
- Has small cell lung cancer.
- Has had documented weight loss >10% in the preceding 3 months.
- Participants whose radiation treatment plans are likely to encompass a volume of whole lung receiving >20 Gy in total (V20) of more than 31% of lung volume.
- Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or for breast cancer.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (programmed cell death protein 1 [PD-1] and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 [PD-L2]) or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
- Has received a live vaccine within 30 days prior to the first dose of study drug.
- Has had an allogenic tissue/solid organ transplant.
- Is 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.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
- Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
- Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its excipients.
- Has a known severe hypersensitivity (Grade 3 or higher) to any of the study chemotherapy agents and/or to any of their excipients.
- Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by local health authority.
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
- Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study through the end of treatment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort A Carboplatin AUC6 Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort A Paclitaxel 200 mg/m^2 Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort A Carboplatin AUC2 Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort A Pembrolizumab 200 mg Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort A Paclitaxel 45 mg/m^2 Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort B Pembrolizumab 200 mg Participants received 3 cycles of cisplatin 75 mg/m\^2 with pemetrexed 500 mg/m\^2 and pembrolizumab 200 mg on Day 1 of each cycle. Treatment was given in conjunction with standard TRT (60 Gy in 2 Gy fractions administered 5 days per week for 6 weeks) in cycles 2 and 3. Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort B Cisplatin 75 mg/m^2 Participants received 3 cycles of cisplatin 75 mg/m\^2 with pemetrexed 500 mg/m\^2 and pembrolizumab 200 mg on Day 1 of each cycle. Treatment was given in conjunction with standard TRT (60 Gy in 2 Gy fractions administered 5 days per week for 6 weeks) in cycles 2 and 3. Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort B Thoracic Radiation Therapy (TRT) Participants received 3 cycles of cisplatin 75 mg/m\^2 with pemetrexed 500 mg/m\^2 and pembrolizumab 200 mg on Day 1 of each cycle. Treatment was given in conjunction with standard TRT (60 Gy in 2 Gy fractions administered 5 days per week for 6 weeks) in cycles 2 and 3. Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort A Thoracic Radiation Therapy (TRT) Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days. Cohort B Pemetrexed 500 mg/m^2 Participants received 3 cycles of cisplatin 75 mg/m\^2 with pemetrexed 500 mg/m\^2 and pembrolizumab 200 mg on Day 1 of each cycle. Treatment was given in conjunction with standard TRT (60 Gy in 2 Gy fractions administered 5 days per week for 6 weeks) in cycles 2 and 3. Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days.
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Up to approximately 3 years ORR was defined as the percentage of participants who experienced 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) and was assessed using modified RECIST 1.1 by blinded independent central review (BICR).
Percentage of Participants Who Developed Grade 3 or Higher Pneumonitis Up to approximately 3 years Pneumonitis included the MedDRA preferred terms for radiation pneumonitis are acute interstitial pneumonitis, autoimmune lung disease, interstitial lung disease, pneumonitis, idiopathic pneumonia syndrome, organizing pneumonia, and immune-mediated pneumonitis. As per common terminology criteria for Adverse Events, version 4.0, pneumonitis was graded as follows: Grade (Gr) 1- asymptomatic, clinical or diagnostic observations only; intervention not indicated; Gr 2- symptomatic, medical intervention indicated, limiting instrumental activities of daily living (ADL); Gr 3- severe symptoms; limiting self-care activities of daily living (ADL), oxygen indicated; Gr 4- life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation); Gr 5- death.
- Secondary Outcome Measures
Name Time Method Number of Participants Who Experienced an Adverse Event (AE) Up to approximately 1 1/4 years An AE is 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE was assessed.
Overall Survival (OS) Up to approximately 5 years OS is defined as the time from enrollment to death due to any cause. OS was estimated and analyzed using the product-limit (Kaplan-Meier) method for censored data.
Number of Participants Who Discontinued From Study Treatment Due to an AE Up to approximately 1 year An AE is 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed.
Progression Free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Up to approximately 5 years PFS was defined as the time from the first dose of study treatment to the date of the first documentation of disease progression, as determined by BICR per RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeters \[mm\]) in the sum of diameter of target lesions, taking as reference the smallest sum, and/or unequivocal progression of existing non-target lesions, and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using the product-limit (Kaplan-Meier) method for censored data.
Trial Locations
- Locations (56)
Fox Chase Cancer Center ( Site 1433)
🇺🇸Philadelphia, Pennsylvania, United States
Parkview Cancer Institute ( Site 1415)
🇺🇸Fort Wayne, Indiana, United States
UMass Memorial Medical Center ( Site 1417)
🇺🇸Worcester, Massachusetts, United States
North Shore University Health System ( Site 1413)
🇺🇸Evanston, Illinois, United States
Blacktown Hospital Western Sydney Local Health District ( Site 0204)
🇦🇺Blacktown, New South Wales, Australia
Universitatsklinikum Mannheim GmbH ( Site 0413)
🇩🇪Mannheim, Baden-Wurttemberg, Germany
Klinikum Chemnitz gGmbH ( Site 0410)
🇩🇪Chemnitz, Sachsen, Germany
Charite Universitaetsmedizin Berlin - Campus-Virchow-Klinikum ( Site 0414)
🇩🇪Berlin, Germany
Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 0910)
🇷🇺Kazan, Tatarstan, Respublika, Russian Federation
ICO Centre Paul Papin ( Site 0309)
🇫🇷Angers, Maine-et-Loire, France
Institut de Cancerologie Gustave Roussy ( Site 0305)
🇫🇷Villejuif, Val-de-Marne, France
Republican Clinical Oncology Dispensary of Republic of Bashkortostan ( Site 0903)
🇷🇺Ufa, Baskortostan, Respublika, Russian Federation
C.H. de Saint Quentin ( Site 0306)
🇫🇷Saint Quentin, Aisne, France
Osrodek Badan Klinicznych przy Szpitalu Specjalistycznym ( Site 0802)
🇵🇱Krakow, Malopolskie, Poland
Szpital Morski im. PCK. Szpitale Pomorskie Sp. Z o.o ( Site 0812)
🇵🇱Gdynia, Pomorskie, Poland
St. Francis Cancer Treatment Center ( Site 1421)
🇺🇸Grand Island, Nebraska, United States
Sanford Cancer Center Oncology Clinic ( Site 1434)
🇺🇸Sioux Falls, South Dakota, United States
Rutgers Cancer Institute of New Jersey ( Site 1422)
🇺🇸New Brunswick, New Jersey, United States
CHU Jean Minjoz ( Site 0301)
🇫🇷Besancon, Doubs, France
C.H.R.U. de Rennes. Hopital de Pontchaillou ( Site 0302)
🇫🇷Rennes., Ille-et-Vilaine, France
Southampton General Hospital ( Site 1204)
🇬🇧Southampton, Hampshire, United Kingdom
Beacon Centre ( Site 1203)
🇬🇧Taunton, Somerset, United Kingdom
Ballarat Health Services ( Site 0206)
🇦🇺Ballarat, Victoria, Australia
Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 0811)
🇵🇱Bydgoszcz, Kujawsko-pomorskie, Poland
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie ( Site 0800)
🇵🇱Warszawa, Mazowieckie, Poland
Szpital Wojewodzki w Koszalinie im. Mikolaja Kopernika ( Site 0813)
🇵🇱Koszalin, Zachodniopomorskie, Poland
Blokhin National Medical Oncology ( Site 0902)
🇷🇺Moscow, Moskva, Russian Federation
National Medical Research Center of Oncology N.A. N.N. Petrov ( Site 0904)
🇷🇺St. Petersburg, Sankt-Peterburg, Russian Federation
Samsung Medical Center ( Site 1001)
🇰🇷Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of
St Joseph Heritage Healthcare ( Site 1403)
🇺🇸Santa Rosa, California, United States
CTCA Southwestern ( Site 1428)
🇺🇸Tulsa, Oklahoma, United States
Southern Medical Day Care Centre ( Site 0201)
🇦🇺Wollongong, New South Wales, Australia
MNCCI Port Macquarie Base Hospital ( Site 0200)
🇦🇺Port Macquarie, New South Wales, Australia
Clinique Clairval ( Site 0311)
🇫🇷Marseille, Bouches-du-Rhone, France
Institut du Cancer de Montpellier ( Site 0300)
🇫🇷Montpellier, Herault, France
Centre Jean Perrin ( Site 0304)
🇫🇷Clermont Ferrand, Puy-de-Dome, France
Clinique de L'Europe ( Site 0308)
🇫🇷Amiens, Somme, France
Augusta-Kranken-Anstalt Bochum ( Site 0401)
🇩🇪Bochum, Nordrhein-Westfalen, Germany
Bethanien Krankenhaus Moers ( Site 0406)
🇩🇪Moers, Nordrhein-Westfalen, Germany
Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0404)
🇩🇪Heidelberg, Baden-Wurttemberg, Germany
LungenClinic Grosshansdorf GmbH ( Site 0408)
🇩🇪Grosshansdorf, Schleswig-Holstein, Germany
Auckland City Hospital ( Site 0700)
🇳🇿Auckland, New Zealand
Katholisches Marienkrankenhaus gGmbH ( Site 0411)
🇩🇪Hamburg, Germany
Chungbuk National University Hospital ( Site 1003)
🇰🇷Cheongju si, Chungcheongbuk-do [Chungbuk], Korea, Republic of
National Cancer Center ( Site 1002)
🇰🇷Goyang-si, Kyonggi-do, Korea, Republic of
Ulsan University Hospital ( Site 1000)
🇰🇷Ulsan, Ulsan-Kwangyokshi, Korea, Republic of
Hospital Universitari Vall d Hebron ( Site 1101)
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Hospital Clinic de Barcelona ( Site 1100)
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Hospital Son Llatzer ( Site 1105)
🇪🇸Palma de Mallorca, Illes Balears [Islas Baleares], Spain
Clinica Universitaria de Navarra ( Site 1102)
🇪🇸Madrid, Spain
Charing Cross Hospital ( Site 1208)
🇬🇧London, London, City Of, United Kingdom
Royal Free NHS Foundation Trust ( Site 1200)
🇬🇧London, London, City Of, United Kingdom
Queen's Hospital ( Site 1201)
🇬🇧Rom Valley, United Kingdom
Hospital Universitario Virgen Macarena ( Site 1103)
🇪🇸Sevilla, Spain
Leeds Teaching Hospitals NHS Trust ( Site 1209)
🇬🇧Leeds, United Kingdom
Henry Ford Hospital ( Site 1418)
🇺🇸Detroit, Michigan, United States