KEYMAKER-U01 Umbrella Master Study: Studies of Investigational Agents With Either Pembrolizumab (MK-3475) Alone or With Pembrolizumab PLUS Chemotherapy in Participants With Non-small Cell Lung Cancer (NSCLC) (MK-3475-U01/KEYMAKER-U01)

This study is referred to as the "umbrella master protocol" for pembrolizumab (MK-3475) in the treatment of non-small cell lung cancer (NSCLC). This pembrolizumab NSCLC umbrella master protocol uses a platform design and consists of this master screening study and seven substudies. Each substudy will enroll a different population of NSCLC participants.

The goal of this umbrella master protocol is to screen potential participants with NSCLC for enrollment into 1 of 7 substudies. Participants must first enroll in this pembrolizumab master protocol study and undergo screening for NSCLC that will be used to assign them to participation in 1 of 7 pembrolizumab substudies.

The following 7 pembrolizumab substudies will evaluate the efficacy of different investigational agents in combination with pembrolizumab given in sequence or in combination with pembrolizumab PLUS chemotherapy:

* KEYMAKER-U01 Substudy 01A: A Phase 1/2, Umbrella Study With Rolling Arms of Investigational Agents, With Pembrolizumab With or Without Chemotherapy in Treatment-Naive Participants With Stage IV Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A) - NCT04165070
* KEYMAKER-U01 Substudy 2: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents in Combination with Pembrolizumab in Treatment Naïve Patients with PD-L1 Positive Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-01B) - NCT04165083
* KEYMAKER-U01 Substudy 3: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents in Combination with Pembrolizumab in Patients with Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated with anti-PD-(L)1 Therapy (MK-3475-01C) - NCT04165096
* KEYMAKER-U01 Substudy 01E: A Phase 2 Umbrella Study With Rolling Arms of Investigational Agents With or Without Chemotherapy in Combination With Pembrolizumab in Treatment of Participants With Newly Diagnosed Resectable Stages II-IIIB (N2) Non-small Cell Lung Cancer (NSCLC) (MK-3475-01E) - NCT06788912
* KEYMAKER-U01 Substudy 01G: A Phase 2, Umbrella Study With Rolling Arms of Investigational Agents in Combination With Pembrolizumab With or Without Platinum-based Chemotherapy in Treatment-Naïve Participants With Stage IV Non-small Cell Lung Cancer (NSCLC) (MK-3475-01G) - NCT06731907
* KEYMAKER-U01 Substudy 01H: A Phase 2, Randomized, Umbrella Study With Rolling Arms of Investigational Agents in Participants with Previously Treated Stage IV Nonsquamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01H) - NCT06780085
* KEYMAKER-U01 Substudy 01I: A Phase 2, Randomized, Umbrella Study With Rolling Arms of Investigational Agents in Participants With Previously Treated Stage IV Squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-01I) - NCT06780098

Eligibility Criteria:
Inclusion Criteria:

* Has histologically- or cytologically-confirmed diagnosis of Stage IV squamous or nonsquamous NSCLC
* Participants with nonsquamous NSCLC who are not eligible for an approved targeted therapy
* Is able to to provide archival tumor tissue sample collected either within 5 years or within the interval from completion of last treatment but before entering the screening period or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated obtained within 90 days of treatment initiation
* Has not received prior systemic treatment for their metastatic NSCLC
* Has adequate organ function within 10 days of initiation of study treatment
* Male participants must agree to use contraception and should refrain from donating sperm during the treatment period and:
* Substudy 01A: for at least 120 days after the last dose of pembrolizumab and for at least 180 days after the last dose of chemotherapy
* Substudies 01B and 01C: for at least 120 days after study treatments
* Substudy 01E: for at least 100 days after the last dose of MK-2870 or MK-7684A, and for at least 90 days after the last dose of radiation therapy
* Substudy 01G: for at least 90 days after the last dose of chemotherapy or 120 days after the last dose of HER3-DXd
* Substudies 01H and 01I: for at least 120 days after the last dose of I-DXd or R-DXd and 95 days after the last dose of docetaxel
* Female participants must not be pregnant or breastfeeding, and at least 1 of the following conditions apply:

  1. Not a woman of childbearing potential (WOCBP), OR
  2. A WOCBP who agrees to use contraception during the treatment period and:
* Substudy 01A: for at least 120 days after the last dose of pembrolizumab and for at least 180 days after the last dose of chemotherapy.
* Substudies 01B and 01C: for at least 120 days after study treatment
* Substudy 01E: for at least 120 days after the last dose of pembrolizumab, 190 days after the last dose of MK-2870, 120 days after the last dose of MK-7684A, 120 days after the last dose of vibostolimab, 190 days after the last dose of chemotherapy, and 180 days after the last dose of radiation therapy
* Substudy 01G: for at least 120 days after the last dose of pembrolizumab, 180 days after the last dose of chemotherapy, and 210 days after the last dose of HER3-DXd
* Substudies 01H and 01I: for at least 210 days after the last dose of I-DXd or R-DXd and 35 days after the last dose of docetaxel

  * Substudies 01A, 01B, and 01C only:
* Is able to complete all screening procedures within the 35-day screening window

  * Substudies 01A and 01B only:
* Has not received prior systemic treatment for their metastatic NSCLC

  * Substudy 01B only:
* Has a programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥1%

  * Substudy 01C only:
* Has progressed on treatment with an anti-PD-(L)1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies
* Has progressive disease during/after platinum doublet chemotherapy

  * Substudy 01E only:
* Participant has previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC per American Joint Committee on Cancer 8th Edition
* Tumors must be resectable in the judgment of a thoracic surgeon

Exclusion Criteria:

* Has preexisting neuropathy that is moderate in intensity
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study treatment. Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment
* Has a 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 before the first dose of study treatment
* Has an active autoimmune disease that has required systemic treatment in the past 2 years
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* Has an active infection requiring systemic therapy
* Has a known history of HIV infection
* Has a known history of Hepatitis B or known active Hepatitis C virus infection
* Has had an allogenic tissue/solid organ transplant

  * Substudies 01A, 01B, and 01C only:
* Has a diagnosis of small cell lung cancer
* Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment administration, or New York Heart Association Class III or IV congestive heart failure
* Has had major surgery \<3 weeks before the first dose of study treatment
* Is expected to require any other form of antineoplastic therapy while on study
* Has received prior radiation therapy to the lung that is \>30 Gray (Gy) within 6 months of the first dose of study treatment
* Has received any prior immunotherapy and was discontinued from that treatment due to a severe or worse immune-related adverse event (irAE)
* Has had chemotherapy or biological cancer therapy within 4 weeks before the first dose of study treatment or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks before the first dose of study treatment (including participants who had previous immunomodulatory therapy with residual irAEs)
* Previously had a severe hypersensitivity reaction to treatment with monoclonal antibodies (including pembrolizumab) and/or any of their excipients
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment

  \* Substudy 01A only:
* Has symptomatic ascites or pleural effusion (if receiving pemetrexed)
* Has a history or current evidence of a gastrointestinal (GI) condition (e.g. inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral medications
* Is getting chemotherapy and has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, or peritoneal carcinomatosis
* Is unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than aspirin dose less than or equal to 1.3 gm/day for a 5-day period (8-day period for long acting agents such as peroxicam), for participants who will receive pemetrexed
* Is unable or unwilling to take folic acid or vitamin B12 supplementation, for participants who will receive pemetrexed
* Has a known sensitivity to any component of carboplatin, paclitaxel, pemetrexed or any of their excipients

  * Substudies 01A and 01B only:
* Has received prior systemic cytotoxic chemotherapy or other targeted or biological antineoplastic therapy for metastatic disease
* Has received prior therapy with an anti-programmed cell death-1 (PD-1), anti-programmed cell death-ligand 1 (PD-L1), or anti-PD-L2 agent or prior therapy targeting other immunoregulatory receptors or mechanisms

  * Substudy 01C only:
* Has received prior therapy targeting other immuno-regulatory receptors or mechanisms, not including anti-PD-(L)1 agents
* Has participated in Substudies 01A or 01B

  * Substudy 01E only:
* 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
  * Sarcomatoid tumor
  * Documentation by local test report indicating presence of ALK gene rearrangements (ALK status not required and unknown or undetermined ALK status are acceptable)
* Has a known severe hypersensitivity (≥ Grade 3) to any of the investigational agents and/or any of their excipients, the study chemotherapy agents and/or to any of their excipients, pembrolizumab and/or any of its excipients, and/or to another biologic therapy
* History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor
* Received prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids
* Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
* Has not adequately recovered from major surgery or has ongoing surgical complications

  * Substudy 01G only:
* Has a known severe hypersensitivity (≥ Grade 3) to any of the investigational agents and/or any of their excipients
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
* Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years