Efficacy and Safety of Pembrolizumab (MK-3475) With Platinum Doublet Chemotherapy as Neoadjuvant/Adjuvant Therapy for Participants With Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) Non-small Cell Lung Cancer (MK-3475-671/KEYNOTE-671)

Study Overview
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Brief Summary
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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).

Official Title
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A Phase III, Randomized, Double-blind Trial of Platinum Doublet Chemotherapy +/-Pembrolizumab (MK-3475) as Neoadjuvant/Adjuvant Therapy for Participants With Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) Non-small Cell Lung Cancer (NSCLC) (KEYNOTE-671)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Placebo
* Drug: Cisplatin
* Drug: Gemcitabine
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAC + Neoadjuvant/Adjuvant Pembrolizumab<br>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]. | Biological: Pembrolizumab<br>* 200 mg by IV infusion every 3 weeks (Q3W), given on cycle day 1.<br>* Other names: MK-3475;Drug: Cisplatin<br>* 75 mg/m^2 by IV infusion Q3W, given on cycle day 1.<br>* Other names: PLATINOL®;Drug: Gemcitabine<br>* 1000 mg/m^2 by IV infusion Q3W, given on cycle days 1 and 8. Given only to participants with squamous NSCLC.<br>* Other names: GEMZAR®;Drug: Pemetrexed<br>* 500 mg/m^2 by IV infusion Q3W, given on cycle day 1. Given only to participants with nonsquamous NSCLC.<br>* Other names: Alimta®;|
| Placebo Comparator: NAC + Neoadjuvant/Adjuvant Placebo<br>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]. | Drug: Placebo<br>* Normal saline by IV infusion Q3W, given on cycle day 1.<br>Drug: Cisplatin<br>* 75 mg/m^2 by IV infusion Q3W, given on cycle day 1.<br>* Other names: PLATINOL®;Drug: Gemcitabine<br>* 1000 mg/m^2 by IV infusion Q3W, given on cycle days 1 and 8. Given only to participants with squamous NSCLC.<br>* Other names: GEMZAR®;Drug: Pemetrexed<br>* 500 mg/m^2 by IV infusion Q3W, given on cycle day 1. Given only to participants with nonsquamous NSCLC.<br>* Other names: Alimta®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 RECIST 1.1. | Up to approximately 5 years | 
| Overall Survival (OS) | OS is defined as the time from randomization until death from any cause. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 7 weeks following completion of neoadjuvant treatment (up to Study Week 20) | 
| 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. | Up to approximately 7 weeks following completion of neoadjuvant treatment (up to Study Week 20) | 
| Global Health Status/Quality of Life (GHS/QoL) Score using the European Organization for Research and Treatment (EORTC) QoL Questionnaire (QLQ-C30) | 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. | Baseline (cycle 1 in neoadjuvant phase) and end of follow-up (up to approximately 5 years) | 
| Adverse Events (AEs) | The number of participants experiencing an AE will be assessed. An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined. | Up to approximately 71 weeks | 
| Perioperative Complications | The number of participants experiencing perioperative complications will be assessed. 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. | Up to approximately 51 weeks following surgery | 
| Treatment Discontinuations Due to AEs | The number of participants discontinuing study therapy due to an AE will be assessed. | Up to approximately 57 weeks |