Non-small Cell Lung Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
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 estimation of objective response rate (ORR) by blinded independent central review (BICR).
Interventions
Pembrolizumab 200 mg intravenous (IV) infusion on Days 1 of each 3-week cycle for up to 17 cycles
DRUGPaclitaxel 45 mg/m^2
Paclitaxel 45 mg/m\^2 IV infusion on Days 1, 8, 15 of each 3-week cycle for Cycles 2, and 3 during radiation therapy.
DRUGCarboplatin AUC6
Carboplatin AUC6 IV infusion on Day 1 of the 21-day cycle for Cycle 1.
Cisplatin 75 mg/m\^2 IV infusion on Day 1 of each 21-day cycle for Cycles 1, 2, 3.
Pemetrexed 500 mg/m\^2 IV infusion on Day 1 of each 21-day cycle for Cycles 1, 2, and 3.
RADIATIONThoracic Radiation Therapy (TRT)
The target total dose of TRT will be 60 Gy in 30 daily fractions of 2 Gy, prescribed to the planning target volume.
Paclitaxel 200 mg/m\^2 IV infusion on Day 1 of the 21-day cycle of Cycle 1.
DRUGCarboplatin AUC2
Carboplatin AUC2 IV infusion on Day 1, 8, 15 for Cycles 2 and 3 during radiation therapy.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 5 1/2 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. |
| Overall Survival (OS) | Up to approximately 5 1/2 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 Experienced an Adverse Event (AE) | Up to approximately 1 1/2 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. |
| 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. |
Countries
Australia, France, Germany, New Zealand, Poland, Russia, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC), who had received no prior anticancer therapy for their disease were recruited into two cohorts.
Pre-assignment details
Of 216 participants enrolled/allocated in the trial, 214 received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin 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. | 112 |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin 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. | 104 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 71 | 49 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Participants Ongoing | 1 | 0 |
| Overall Study | Sponsor's Decision | 36 | 52 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Total | Pembrolizumab + cCRT + Paclitaxel + Carboplatin |
|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 9.4 | 64.5 Years STANDARD_DEVIATION 9.3 | 65.7 Years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 84 Participants | 185 Participants | 101 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 26 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 25 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 21 Participants | 7 Participants |
| Race (NIH/OMB) White | 75 Participants | 164 Participants | 89 Participants |
| Sex: Female, Male Female | 40 Participants | 76 Participants | 36 Participants |
| Sex: Female, Male Male | 64 Participants | 140 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 72 / 112 | 49 / 104 |
| other Total, other adverse events | 106 / 112 | 100 / 102 |
| serious Total, serious adverse events | 66 / 112 | 46 / 102 |
Outcome results
Primary
Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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).
Time frame: Up to approximately 3 years
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin | Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 71.4 Percentage of Participants |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 75.5 Percentage of Participants |
Primary
Percentage of Participants Who Developed Grade 3 or Higher Pneumonitis
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.
Time frame: Up to approximately 3 years
Population: The analysis population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin | Percentage of Participants Who Developed Grade 3 or Higher Pneumonitis | 8.0 Percentage of Participants |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Percentage of Participants Who Developed Grade 3 or Higher Pneumonitis | 6.9 Percentage of Participants |
Secondary
Number of Participants Who Discontinued From Study Treatment Due to an AE
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.
Time frame: Up to approximately 1 year
Population: The analysis population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin | Number of Participants Who Discontinued From Study Treatment Due to an AE | 48 Participants |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Number of Participants Who Discontinued From Study Treatment Due to an AE | 26 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
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.
Time frame: Up to approximately 1 1/2 years
Population: The analysis population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin | Number of Participants Who Experienced an Adverse Event (AE) | 108 Participants |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Number of Participants Who Experienced an Adverse Event (AE) | 101 Participants |
Secondary
Overall Survival (OS)
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.
Time frame: Up to approximately 5 1/2 years
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin | Overall Survival (OS) | 35.6 Months |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Overall Survival (OS) | 56.7 Months |
Secondary
Progression Free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
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.
Time frame: Up to approximately 5 1/2 years
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + cCRT + Paclitaxel + Carboplatin | Progression Free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 29.0 Months |
| Pembrolizumab + cCRT + Pemetrexed + Cisplatin | Progression Free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 45.3 Months |