Pembrolizumab (MK-3475) Plus Investigational Agents in Resectable Non-small Cell Lung Cancer (NSCLC) (MK-3475-01E/KEYMAKER-U01)

Phase 2

Recruiting

• Conditions: Lung Neoplasm Malignant
• Interventions: Biological: Pembrolizumab (neoadjuvant); Drug: Cisplatin; Drug: Gemcitabine; Drug: Pemetrexed; Drug: Carboplatin; Drug: Sacituzumab tirumotecan; Biological: Pembrolizumab (adjuvant); Drug: H1 receptor antagonist; Drug: Paclitaxel; Drug: H2 receptor antagonist; Drug: Acetaminophen (or equivalent); Drug: Dexamethasone (or equivalent); Drug: Steroid mouthwash (dexamethasone or equivalent)

• Registration Number: NCT06788912
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

The main goals are after treatment given before surgery, to measure the number of people who have no signs of cancer cells in tumors and lymph nodes removed during surgery; and to learn about whether the cancer gets smaller or goes away by measuring the number of people with a certain number of living cancer cells in the tumor removed during surgery.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-01-17
• Study First Submitted QC: 2025-01-17
• Study First Posted: 2025-01-23
• Study Start: 2025-03-20
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-14
• Last Update Posted: 2025-07-17
• Primary Completion: 2031-11-05
• Study Completion: 2032-02-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Has previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) non-small cell lung cancer (NSCLC)
• Able to undergo protocol therapy, including necessary surgery
• Confirmation that epidermal growth factor receptor (EGFR) -directed therapy is not indicated as primary therapy
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1 as assessed within 10 days before initiation of study intervention.
• Is able to provide archival or newly obtained core/excisional biopsy of the primary lung tumor or lymph node metastasis.

Exclusion Criteria

• Has one of the following tumor locations/types: NSCLC involving the superior sulcus, large-cell neuro-endocrine cancer, mixed tumors containing small cell and non-small cell elements, or sarcomatoid tumor.
• Has Grade ≥2 peripheral neuropathy.
• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea).
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Received prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
• Known additional malignancy that is progressing or has required active treatment within the past 5 years.
• Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid) is allowed.
• History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Active infection requiring systemic therapy.
• Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C virus (defined as detectable hepatitis C virus (HCV) ribonucleic acid (RNA) [qualitative]) infection.
• Known history of human immunodeficiency virus (HIV) infection.
• History of allogeneic tissue/solid organ transplant.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pembrolizumab + Platinum	Pembrolizumab (neoadjuvant)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Platinum	Cisplatin	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Platinum	Gemcitabine	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Platinum	Pemetrexed	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Platinum	Carboplatin	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Platinum	Pembrolizumab (adjuvant)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Platinum	Paclitaxel	Neoadjuvant: Prior to surgery pembrolizumab 200 mg every three weeks (Q3W) for 4 cycles (each cycle is 21 days); Cisplatin 75 mg/m\^2 Q3W with gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or paclitaxel 175 mg/m\^2 or 200 mg/m\^2 q3w (any histology) OR Carboplatin AUC 5 mg/mL• min or AUC 6 mg/mL• min with paclitaxel 175 mg/m\^2 or 200 mg/m\^2 Q3W (any histology), pemetrexed 500 mg/m\^2 Q3W (nonsquamous tumors), or gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 Q3W (squamous tumors); followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days).
Pembrolizumab + Sacituzumab tirumotecan	Pembrolizumab (neoadjuvant)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Cisplatin	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Gemcitabine	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Pemetrexed	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Sacituzumab tirumotecan	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	H1 receptor antagonist	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	H2 receptor antagonist	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Acetaminophen (or equivalent)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Dexamethasone (or equivalent)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Carboplatin	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Paclitaxel	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Pembrolizumab (adjuvant)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.
Pembrolizumab + Sacituzumab tirumotecan	Steroid mouthwash (dexamethasone or equivalent)	Neoadjuvant: Prior to surgery pembrolizumab 200 mg Q3W for 4 cycles (each cycle is 21 days); sacituzumab tirumotecan 4 mg/kg Q2W for 6 cycles (each cycle is 14 days), followed by surgery. Adjuvant: After surgery pembrolizumab 200 mg Q3W for 13 cycles (each cycle is 21 days). Optional adjuvant platinum-based doublet chemotherapy up to 4 cycles may be given at the investigator's discretion.

Primary Outcome Measures

Name	Time	Method
Pathological Complete Response (pCR)	Up to approximately 20 weeks	pCR is defined as absence of residual viable invasive cancer on hematoxylin- and eosin-stained slides of the resected lung specimen and lymph nodes.
Percent Residual Viable Tumor (%RVT)	Up to approximately 20 weeks	%RVT is defined as the percentage of residual tumor estimated by comparing the estimated cross-sectional area of viable tumor with estimated cross-sectional areas of remainder of tumor bed. The tumor bed is defined as the area of tissue occupied by viable tumor or tumoral regression (includes areas of necrosis, foamy macrophages, giant cell reaction, cholesterol cleft granuloma, and inflammation.)

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Report at Least 1 Adverse Event (AE)	Up to approximately 5 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.
Percentage of Participants Who Discontinue 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.
Percentage of Participants Who Experience a Perioperative Complication	Up to approximately 20 weeks	Perioperative Complications include both intraoperative and postoperative complications.
Mean Length of Hospital Stay	Up to approximately 20 weeks	Hospital Stay is the length of inpatient time spent in hospital.
Percentage of Participants Who Require Hospital Readmission after Discharge	Up to approximately 20 weeks	In participants previously discharged from hospital, the percentage requiring readmission to hospital.
Mean Length of Surgery	Up to approximately 20 weeks	Length of surgery is the time spent in surgery.
Percentage of Participants Who Require a Blood Transfusion	Up to approximately 20 weeks	Blood transfusion is the transfer of donated blood into the vein of a recipient.
Event-free Survival (EFS)	Up to approximately 5 years	EFS is defined as the time from randomization to any of the following events: radiographic disease progression per Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) (for participants who have not had or will not have surgery, or participants who have gross residual disease after an incomplete resection \[R2 resection\]); local progression (primary tumor or regional lymph nodes) or distant metastasis precluding planned surgery; tumor determined to be unresectable in the operating room; local or distant recurrence (for participants who are disease free after surgery or participants with microscopic positive margins \[R1 resection\]); occurrence of new primary NCSLC; death due to any cause.
Overall Survival (OS)	Up to approximately 5 years	OS is defined as the time from randomization to death due to any cause.
Distant Metastasis-Free Survival (DMFS)	Up to approximately 5 years	DMFS is defined as the time from randomization to the date of diagnosis of distant metastasis or death, whichever occurs first.
Objective Response Rate (ORR)	Up to approximately 12 weeks	OR is defined as a complete response or partial response with or without confirmation per RECIST 1.1 as assessed by the investigator during the Neoadjuvant Phase.

Trial Locations

Locations (11)

Hacettepe Universite Hastaneleri-oncology hospital ( Site 0700); 🇹🇷 Ankara, Turkey

MNPE LTMU Multidisc. Clin. Hosp. of Emerg. and Intens. Care ( Site 0132); 🇺🇦 Lviv, Lvivska Oblast, Ukraine

MedStar Franklin Square Medical Center ( Site 0033); 🇺🇸 Baltimore, Maryland, United States

Centro de Estudios Clínicos SAGA ( Site 0162); 🇨🇱 Santiago., Region M. De Santiago, Chile

FALP ( Site 0161); 🇨🇱 Santiago, Region M. De Santiago, Chile

Bradfordhill ( Site 0160); 🇨🇱 Santiago, Region M. De Santiago, Chile

Azienda Ospedaliera Universitaria Careggi ( Site 0173); 🇮🇹 Firenze, Toscana, Italy

Ospedale San Raffaele. ( Site 0171); 🇮🇹 Milano, Italy

Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 0150); 🇵🇱 Gdansk, Pomorskie, Poland

Wielkopolskie Centrum Pulmonologii i Torakochirurgii-Oddzial Onkologii Klinicznej z Pododdzialem Dz ( Site 0153); 🇵🇱 Poznan, Wielkopolskie, Poland

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