Efficacy Comparison of Dostarlimab Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy in Participants With Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC)

Inclusion Criteria:

Participant must be greater than equal to (>=) 18 years old, must be able to understand the study procedures, and agrees to participate in the study by providing written informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Participant has histologically- or cytologically-confirmed metastatic non-squamous NSCLC with documented absence of a sensitizing EGFR, ALK, ROS-1, or BRAFV600E mutation or other genomic aberration for which an approved targeted therapy is available. Mixed tumors will be categorized by the predominant cell type; if the tumor has predominantly squamous cell histology or if small cell elements are present, the participant is ineligible.
Participants must have measurable disease, that is (i.e.) presenting with at least 1 measurable lesion per RECIST v1.1 as determined by the local site Investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions and if there are other target lesions. If there is only 1 target lesion that was previously irradiated, the participant is not eligible.
Participant has documented PD L1 status by the 22C3 pharmDx assay (Agilent/Dako). If no prior PD L1 result is available at the time of Screening, the participant can be tested locally using the stated method, or central PD L1 testing can be completed. Results are needed for stratification and must be available prior to randomization.
Participant has an ECOG performance status score of 0 or 1.
Participant has a life expectancy of at least 3 months.
Participant has adequate organ function.
Participant has recovered to Grade less than equal to (<=)1 from any prior treatment related toxicities at the time of randomization. A participant with Grade 2 alopecia is an exception to this criterion and may qualify for this study.
Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during the Treatment Period and for at least 150 days after the last dose of study treatment:
Refrain from donating sperm plus, either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
Must agree to use contraception/barrier as follows:
Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception, as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.
Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
Is a woman of non childbearing potential (WONCBP),
Is a WOCBP, using a contraceptive method that is highly effective (with a failure rate of <1% per year and, preferably, with low user dependency) during the Treatment Period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova or oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the potential for contraceptive method failure ( for example [e.g.], noncompliance and recently initiated) in relationship to the first dose of study treatment.
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local guidelines) within 72 hours before the first dose of study treatment. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

Exclusion Criteria:

Participant has received prior systemic therapy for the treatment of metastatic NSCLC. Participants who have received neoadjuvant or adjuvant chemotherapy are eligible if the neoadjuvant/adjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
Participant has received prior therapy with a PD (L)1 or PD L2 inhibitor, a cytotoxic T lymphocyte associated protein 4 (CTLA 4) inhibitor, a T cell immunoglobulin and mucin domain containing 3 (TIM 3) inhibitor, or any other immunotherapy agent (eg, OX40) for the treatment of cancer.
Participant has received radiation to the lung that is >30 Gray (Gy) within 6 months of the first dose of study treatment.
Participant has completed palliative radiotherapy within 7 days of the first dose of study treatment.
Participant is ineligible if any of the following hepatic characteristics are present:
Alanine aminotransferase (ALT) >2.5 times upper limit of normal (ULN) without liver metastases/tumor infiltration.
ALT >5 times ULN with liver metastases/tumor infiltration.
Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)
Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per Investigator assessment)
Participant has a corrected QT interval (QTc) >450 milliseconds (msec) (or QTc >480 msec for participants with bundle branch block).
Participant has had major surgery within 3 weeks of the first dose of study treatment or has not adequately recovered from any AEs (Grade <=1) and/or complications from any major surgery. Surgical implantation of a port catheter is not exclusionary.
Participant has an additional malignancy or a history of prior malignancy, with the exception of adequately treated basal or squamous skin cancer, cervical carcinoma in situ, or bladder carcinoma in situ without evidence of disease, or had a malignancy treated with curative intent and with no evidence of disease recurrence for 5 years since the initiation of that therapy.
Participant has known active brain metastases and/or leptomeningeal metastases. Participants who have received prior therapy for their brain metastases and have radiographically stable central nervous system disease may participate, provided they are neurologically stable for at least 2 weeks before study entry and must be off corticosteroids within 3 days prior to the first dose of study treatment. Stable brain metastases by this definition should be established prior to the first dose of study treatment. Participants with known untreated, asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesions >1.5 centimeters [cm]) may participate, but will require regular imaging of the brain as a site of disease.
Participant has tested positive for the presence of hepatitis B surface antigen or has a positive hepatitis C antibody test result at Screening, or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, participants who test positive for the presence of hepatitis B core antibody should also be excluded.
Participant has an active infection requiring systemic therapy within 1 week prior to the anticipated first dose of study treatment.
Participant has known human immunodeficiency virus (HIV) (positive for HIV 1 or HIV 2 antibodies).
Participant has active autoimmune disease that required systemic treatment in the past 2 years, is immunocompromised in the opinion of the Investigator, or is receiving systemic immunosuppressive treatment. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
Participant has received systemic steroid therapy within 3 days prior to the first dose of the study treatment or is receiving any other form of immunosuppressive medication. Replacement therapy is not considered a form of systemic therapy. Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.
Participant has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoraco or paracentesis) is eligible.
Participant has current interstitial lung disease, current pneumonitis, or a history of pneumonitis that required the use of oral or IV glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
Participant has a history or current evidence of any medical condition, therapy, or laboratory abnormality that might confound the study results, interfere with their participation for the full duration of the study treatment, or indicate it is not in the best interest of the participant to participate, in the opinion of the Investigator.
Participant has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.
Participant has preexisting peripheral neuropathy that is Grade >=2 by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 criteria.
Participant has received a live vaccine within 30 days of the first dose of study treatment. Seasonal flu vaccines that do not contain live virus are permitted.
Participant does not meet requirements per local prescribing guidelines for receiving treatment with either pemetrexed and cisplatin or carboplatin.
Participant has sensitivity to any of the study treatments, or components thereof, or a history of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation.
Participant is unable to interrupt aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs), other than an aspirin dose <=1.3 gram (g) per day, for a 5 day period (8 day period for long acting agents, such as piroxicam).