Non-small Cell Lung Cancer
Conditions
Brief summary
This trial will evaluate the safety and efficacy of pembrolizumab (MK-3475) in combination with platinum doublet neoadjuvant chemotherapy (NAC) before surgery \[neoadjuvant phase\], followed by pembrolizumab alone after surgery \[adjuvant phase\] in participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) non-small cell lung cancer (NSCLC). The primary hypotheses of this study are that neoadjuvant pembrolizumab (vs. placebo) in combination with NAC, followed by surgery and adjuvant pembrolizumab (vs. placebo) will improve: 1) event free survival (EFS) by biopsy assessed by local pathologist or by investigator-assessed imaging using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); and 2) overall survival (OS).
Interventions
BIOLOGICALPembrolizumab
200 mg by IV infusion every 3 weeks (Q3W), given on cycle day 1.
DRUGPlacebo
Normal saline by IV infusion Q3W, given on cycle day 1.
DRUGCisplatin
75 mg/m\^2 by IV infusion Q3W, given on cycle day 1.
DRUGGemcitabine
1000 mg/m\^2 by IV infusion Q3W, given on cycle days 1 and 8. Given only to participants with squamous NSCLC.
DRUGPemetrexed
500 mg/m\^2 by IV infusion Q3W, given on cycle day 1. Given only to participants with nonsquamous NSCLC.
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
* Have previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC. * If male, must agree to use contraception or practice abstinence as well as refrain from donating sperm during the treatment period and for the time needed to eliminate each study intervention after the last dose of study intervention. * If female, may participate if not pregnant or breastfeeding, and at least one of the following conditions apply: 1) not a woman of childbearing potential (WOCBP); or 2) a WOCBP who agrees to follow contraceptive guidance during the treatment period and for the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. * Have available formalin-fixed paraffin embedded (FFPE) tumor tissue sample blocks for submission. If blocks are not available, have unstained slides for submission for central programmed death-ligand 1 (PD-L1) testing. * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days of randomization. * Have adequate organ function.
Exclusion criteria
* Has one of the following tumor locations/types:1) NSCLC involving the superior sulcus; 2) Large cell neuro-endocrine cancer (LCNEC); or 3) Sarcomatoid tumor. * 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 had an allogenic tissue/sold organ transplant. * Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance and/or any of its excipients. * Has a known severe hypersensitivity (≥ Grade 3) 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. * Has a known history of human immunodeficiency virus (HIV) infection. * Has a known history of Hepatitis B or Hepatitis C. * Has a known history of active tuberculosis. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate. * Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial. * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor. * Has received prior systemic anti-cancer therapy including investigational agents for the current malignancy prior to randomization/allocation. * Has received prior radiotherapy within 2 weeks of start of trial treatment. * Has received a live vaccine within 30 days prior to the first dose of trial drug. * 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. * Has a diagnosis of immunodeficiency or is receiving either systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug. * Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) | Up to approximately 5 years | EFS is defined as the time from randomization until radiographic disease progression, local progression precluding surgery, inability to resect the tumor, local or distant recurrence, or death due to any cause. EFS determined either by biopsy assessed by local pathologist or by investigator-assessed imaging using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The EFS for all participants is presented (through database cut-off date of 10-Jul-2023). |
| Overall Survival (OS) | Up to approximately 5 years | OS is defined as the time from randomization until death from any cause. The OS for all participants is presented (through database cut-off date of 10-Jul-2023). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (mPR) Rate | Up to approximately 8 weeks following completion of neoadjuvant treatment (up to Study Week 20) | mPR rate is defined as the percentage of participants having ≤10% viable tumor cells in the resected primary tumor and all resected lymph nodes following completion of neoadjuvant therapy. The mPR rates as assessed by blinded independent pathologist are presented. |
| Pathological Complete Response (pCR) Rate | Up to approximately 8 weeks following completion of neoadjuvant treatment (up to Study Week 20) | pCR rate is defined as the percentage of participants having an absence of residual invasive cancer in resected lung specimens and lymph nodes following completion of neoadjuvant therapy. The pCR rates as assessed by blinded independent pathologist are presented. |
| Change From Baseline in Neoadjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score | Baseline (cycle 1 in neoadjuvant phase) and neoadjuvant week 11 | Change from baseline in GHS/QoL score using the EORTC QLQ-C30 will be determined. The EORTC QLQ-C30 is the most widely used cancer-specific, health-related QoL instrument comprised of 30 individual items arranged as both multi-item scales and individual items. Specifically, these items are divided into 5 functional scales (15 items total), 3 symptom scales (7 items total), 6 individual items, and a GHS/QoL scale composed of 2 items: GHS and QoL. The GHS/QoL score measured here refers to only the composite score calculated for the GHS/QoL scale. Both items on the GHS/QoL scale are scored from 1 (very poor GHS/QoL) to 7 (excellent GHS/QoL) and scores for both items are averaged and a linear transformation applied to standardize the overall GHS/QoL score from 0 to 100, with higher overall scores indicating higher GHS/QoL. |
| Change From Baseline in Adjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score | Baseline (cycle 1 in neoadjuvant phase) and adjuvant week 10 (up to Study Week 30) | Change from baseline in GHS/QoL score using the EORTC QLQ-C30 will be determined. The EORTC QLQ-C30 is the most widely used cancer-specific, health-related QoL instrument comprised of 30 individual items arranged as both multi-item scales and individual items. Specifically, these items are divided into 5 functional scales (15 items total), 3 symptom scales (7 items total), 6 individual items, and a GHS/QoL scale composed of 2 items: GHS and QoL. The GHS/QoL score measured here refers to only the composite score calculated for the GHS/QoL scale. Both items on the GHS/QoL scale are scored from 1 (very poor GHS/QoL) to 7 (excellent GHS/QoL) and scores for both items are averaged and a linear transformation applied to standardize the overall GHS/QoL score from 0 to 100, with higher overall scores indicating higher GHS/QoL. |
| Number of Participants Who Experience an Adverse Event (AE) | Up to approximately 71 weeks | — |
| Number of Participants Who Experience Perioperative Complications | Up to approximately 51 weeks following surgery | Perioperative complications are a discrete set of both intraoperative and postoperative complications, potentially contributing to increased length of inpatient care and/or delay of adjuvant therapy. The number of participants experiencing perioperative complications will be assessed. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | Up to approximately 57 weeks | — |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Estonia, France, Germany, Ireland, Italy, Japan, Latvia, Lithuania, Malaysia, Poland, Romania, Russia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
Adult participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) non-small cell lung cancer (NSCLC) were recruited to evaluate the efficacy and safety of pembrolizumab (MK-3475) in combination with platinum doublet neoadjuvant chemotherapy (NAC) before surgery \[neoadjuvant phase\], followed by pembrolizumab alone after surgery \[adjuvant phase\].
Pre-assignment details
Of the 797 participants that were randomized to trial, 795 received treatment. At the time of the primary analysis data cut-off, 523 participants are ongoing in the study.
Participants by arm
| Arm | Count |
|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab Neoadjuvant: Prior to surgery, participants receive up to 4 cycles (cycle length: 3 weeks) of pembrolizumab \[200 mg, intravenous (IV); given on cycle day 1\] in combination with platinum doublet neoadjuvant chemotherapy (NAC), consisting of cisplatin \[75 mg/m\^2, IV; given on cycle day 1\] and either Gemcitabine \[1000 mg/m\^2, IV; given on cycle days 1 and 8\] or Pemetrexed \[500 mg/m\^2, IV; given on cycle day 1\].
Adjuvant: 4-12 weeks following surgery, participants receive 13 cycles (cycle length: 3 weeks) of pembrolizumab \[200 mg, IV; given on cycle day 1\]. | 397 |
| NAC + Neoadjuvant/Adjuvant Placebo Neoadjuvant: Prior to surgery, participants receive up to 4 cycles (cycle length: 3 weeks) of placebo \[normal saline, IV; given on cycle day 1\] in combination with platinum doublet NAC, consisting of cisplatin \[75 mg/m\^2, IV; given on cycle day 1\] and either Gemcitabine \[1000 mg/m\^2, IV; given on cycle days 1 and 8\] or Pemetrexed \[500 mg/m\^2, IV; given on cycle day 1\].
Adjuvant: 4-12 weeks following surgery, participants receive 13 cycles (cycle length: 3 weeks) of placebo \[normal saline, IV; given on cycle day 1\]. | 400 |
| Total | 797 |
Baseline characteristics
| Characteristic | NAC + Neoadjuvant/Adjuvant Pembrolizumab | Total | NAC + Neoadjuvant/Adjuvant Placebo |
|---|---|---|---|
| Age, Continuous | 62.7 Years STANDARD_DEVIATION 8.5 | 63.1 Years STANDARD_DEVIATION 8.3 | 63.6 Years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 36 Participants | 70 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 329 Participants | 662 Participants | 333 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 32 Participants | 65 Participants | 33 Participants |
| Histology Non-Squamous | 226 Participants | 453 Participants | 227 Participants |
| Histology Squamous | 171 Participants | 344 Participants | 173 Participants |
| Overall Cancer Staging Stage II | 118 Participants | 239 Participants | 121 Participants |
| Overall Cancer Staging Stage III | 279 Participants | 558 Participants | 279 Participants |
| PD-L1 Expression Level (50% cutoff) TPS<50% | 265 Participants | 531 Participants | 266 Participants |
| PD-L1 Expression Level (50% cutoff) TPS>=50% | 132 Participants | 266 Participants | 134 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 124 Participants | 249 Participants | 125 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 16 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 13 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 29 Participants | 16 Participants |
| Race (NIH/OMB) White | 250 Participants | 489 Participants | 239 Participants |
| Region East-Asia | 123 Participants | 244 Participants | 121 Participants |
| Region Non-East Asia | 274 Participants | 553 Participants | 279 Participants |
| Sex: Female, Male Female | 118 Participants | 234 Participants | 116 Participants |
| Sex: Female, Male Male | 279 Participants | 563 Participants | 284 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 110 / 397 | 144 / 400 |
| other Total, other adverse events | 389 / 396 | 388 / 399 |
| serious Total, serious adverse events | 165 / 396 | 133 / 399 |
Outcome results
Primary
Event Free Survival (EFS)
EFS is defined as the time from randomization until radiographic disease progression, local progression precluding surgery, inability to resect the tumor, local or distant recurrence, or death due to any cause. EFS determined either by biopsy assessed by local pathologist or by investigator-assessed imaging using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The EFS for all participants is presented (through database cut-off date of 10-Jul-2023).
Time frame: Up to approximately 5 years
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Event Free Survival (EFS) | 47.2 Months |
| NAC + Neoadjuvant/Adjuvant Placebo | Event Free Survival (EFS) | 18.3 Months |
p-value: <0.0000195% CI: [0.48, 0.72]Log Rank
Primary
Overall Survival (OS)
OS is defined as the time from randomization until death from any cause. The OS for all participants is presented (through database cut-off date of 10-Jul-2023).
Time frame: Up to approximately 5 years
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Overall Survival (OS) | NA Months |
| NAC + Neoadjuvant/Adjuvant Placebo | Overall Survival (OS) | 52.4 Months |
p-value: 0.0051795% CI: [0.56, 0.93]Log Rank
Secondary
Change From Baseline in Adjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score
Change from baseline in GHS/QoL score using the EORTC QLQ-C30 will be determined. The EORTC QLQ-C30 is the most widely used cancer-specific, health-related QoL instrument comprised of 30 individual items arranged as both multi-item scales and individual items. Specifically, these items are divided into 5 functional scales (15 items total), 3 symptom scales (7 items total), 6 individual items, and a GHS/QoL scale composed of 2 items: GHS and QoL. The GHS/QoL score measured here refers to only the composite score calculated for the GHS/QoL scale. Both items on the GHS/QoL scale are scored from 1 (very poor GHS/QoL) to 7 (excellent GHS/QoL) and scores for both items are averaged and a linear transformation applied to standardize the overall GHS/QoL score from 0 to 100, with higher overall scores indicating higher GHS/QoL.
Time frame: Baseline (cycle 1 in neoadjuvant phase) and adjuvant week 10 (up to Study Week 30)
Population: All randomized participants who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Item 30 assessment data available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Change From Baseline in Adjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score | -1.52 Sore on a scale |
| NAC + Neoadjuvant/Adjuvant Placebo | Change From Baseline in Adjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score | -3.74 Sore on a scale |
p-value: 0.119795% CI: [-0.58, 5.02]t-test, 2 sided
Secondary
Change From Baseline in Neoadjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score
Change from baseline in GHS/QoL score using the EORTC QLQ-C30 will be determined. The EORTC QLQ-C30 is the most widely used cancer-specific, health-related QoL instrument comprised of 30 individual items arranged as both multi-item scales and individual items. Specifically, these items are divided into 5 functional scales (15 items total), 3 symptom scales (7 items total), 6 individual items, and a GHS/QoL scale composed of 2 items: GHS and QoL. The GHS/QoL score measured here refers to only the composite score calculated for the GHS/QoL scale. Both items on the GHS/QoL scale are scored from 1 (very poor GHS/QoL) to 7 (excellent GHS/QoL) and scores for both items are averaged and a linear transformation applied to standardize the overall GHS/QoL score from 0 to 100, with higher overall scores indicating higher GHS/QoL.
Time frame: Baseline (cycle 1 in neoadjuvant phase) and neoadjuvant week 11
Population: All randomized participants who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Item 30 assessment data available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Change From Baseline in Neoadjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score | -9.31 Sore on a scale |
| NAC + Neoadjuvant/Adjuvant Placebo | Change From Baseline in Neoadjuvant Phase in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score | -10.73 Sore on a scale |
p-value: 0.361195% CI: [-1.64, 4.49]t-test, 2 sided
Secondary
Major Pathological Response (mPR) Rate
mPR rate is defined as the percentage of participants having ≤10% viable tumor cells in the resected primary tumor and all resected lymph nodes following completion of neoadjuvant therapy. The mPR rates as assessed by blinded independent pathologist are presented.
Time frame: Up to approximately 8 weeks following completion of neoadjuvant treatment (up to Study Week 20)
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Major Pathological Response (mPR) Rate | 30.2 Percentage of Participants |
| NAC + Neoadjuvant/Adjuvant Placebo | Major Pathological Response (mPR) Rate | 11.0 Percentage of Participants |
p-value: <0.0000195% CI: [13.9, 24.7]Stratified Miettinen and Nurminen
Secondary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Time frame: Up to approximately 57 weeks
Secondary
Number of Participants Who Experience an Adverse Event (AE)
Time frame: Up to approximately 71 weeks
Secondary
Number of Participants Who Experience Perioperative Complications
Perioperative complications are a discrete set of both intraoperative and postoperative complications, potentially contributing to increased length of inpatient care and/or delay of adjuvant therapy. The number of participants experiencing perioperative complications will be assessed.
Time frame: Up to approximately 51 weeks following surgery
Population: The analysis population consisted of all randomized participants who received at least one dose of neoadjuvant study treatment and also undergo on-study surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Number of Participants Who Experience Perioperative Complications | 233 Participants |
| NAC + Neoadjuvant/Adjuvant Placebo | Number of Participants Who Experience Perioperative Complications | 229 Participants |
Secondary
Pathological Complete Response (pCR) Rate
pCR rate is defined as the percentage of participants having an absence of residual invasive cancer in resected lung specimens and lymph nodes following completion of neoadjuvant therapy. The pCR rates as assessed by blinded independent pathologist are presented.
Time frame: Up to approximately 8 weeks following completion of neoadjuvant treatment (up to Study Week 20)
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAC + Neoadjuvant/Adjuvant Pembrolizumab | Pathological Complete Response (pCR) Rate | 18.1 Percentage of Participants |
| NAC + Neoadjuvant/Adjuvant Placebo | Pathological Complete Response (pCR) Rate | 4.0 Percentage of Participants |
p-value: <0.0000195% CI: [10.1, 18.7]Stratified Miettinen and Nurminen