This study will compare the clinical activity of novel regimens (in combination or as single agents) to SoC in participants with relapsed/refractory advanced NSCLC. The study will be conducted in two parts. Part 1 is an open-label, optional, non-randomized part based on safety and pharmacokinetics/pharmacodynamics (PK/PD) evaluation intended to generate additional data to qualify novel regimens for the randomized study. Part 2 is a randomized, Phase II open-label part comparing the efficacy and safety of these novel regimens with SoC. Drug name mentioned as GSK4428859A (belrestotug) and EOS884448 are interchangeable for the same compound and will be referred to as GSK4428859A/EOS884448/belrestotug.

Inclusion Criteria:

• Participants capable of giving signed informed consent/assent.

• Male or female, aged 18 years or older at the time consent is obtained. Participants in Korea must be age 19 years or older at the time consent is obtained.

• Participants with histologically or cytologically confirmed diagnosis of NSCLC (squamous or non-squamous) and

  a) Documented disease progression based on radiographic imaging, during or after a maximum of 2 lines of systemic treatment for locally/regionally advanced recurrent, Stage IIIb/Stage IIIc/Stage IV or metastatic disease. Two components of treatment must have been received in the same line or as separate lines of therapy: i) No more than or less than 1 line of platinum-containing chemotherapy regimen, and ii) No more than or less than 1 line of Programmed cell death ligand 1 (PD[L]1) monoclonal antibody (mAb) containing regimen.

  b) Participants with known BRAF molecular alterations must have had disease progression after receiving the locally available SoC treatment for the molecular alteration.

  c) Participants who received prior anti-PD(L)1 therapy must fulfill the following requirements: i) Have achieved a CR, PR or SD and subsequently had disease progression (per RECIST 1.1 criteria) either on or after completing PD(L)1 therapy ii) Have not progressed or recurred within the first 12 weeks of PD(L)1 therapy, either clinically or per RECIST 1.1 criteria

• Measurable disease, presenting with at least 1 measurable lesion per RECIST 1.1.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.

• A tumor tissue sample obtained at any time from the initial diagnosis of NSCLC to time of study entry is mandatory. Although a fresh tumor tissue sample obtained during screening is preferred, archival tumor specimen is acceptable.

• Adequate organ function as defined in the protocol.

• A male participant must agree to use a highly effective contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions apply:

  i) Not a woman of childbearing potential (WOCBP) or ii) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.

• Life expectancy of at least 12 weeks.

Exclusion Criteria:

• Participants who received prior treatment with the following therapies (calculation is based on date of last therapy to date of first dose of study treatment):

  1. Docetaxel at any time.
  2. Any of the investigational agents being tested in the current study.
  3. Systemic approved or investigational anticancer therapy within 30 days or 5 half-lives of the drug, whichever is shorter. At least 14 days must have elapsed between the last dose of prior anticancer agent and the first dose of study drug is administered.
  4. Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is available for assessment per RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 2 weeks before start of study drug for radiation of any intended use is required.

• Received greater than (>)2 prior lines of therapy for NSCLC, including participants with BRAF molecular alternations.

• Invasive malignancy or history of invasive malignancy other than disease under study within the last 2 years, except

  • Any other invasive malignancy for which the participant was definitively treated, has been disease-free for at least 2 years and in the opinion of the principal investigator and GlaxoSmithKline Medical Monitor will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy, may be included in this clinical trial.
  • Curatively treated non-melanoma skin cancer or successfully treated in situ carcinoma.

• Carcinomatous meningitis (regardless of clinical status) and uncontrolled or symptomatic Central nervous system (CNS) metastases.

• Major surgery less than or equal to (<=) 28 days of first dose of study treatment.

• Autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years. Replacement therapies which include physiological doses of corticosteroids for treatment of endocrinopathies (for example, adrenal insufficiency) are not considered systemic treatments.

• Receiving systemic steroids (>10 milligrams [mg]) oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to first dose of study treatment.

• Prior allogeneic/autologous bone marrow or solid organ transplantation.

• Receipt of any live vaccine within 30 days prior to first dose of study treatment.

• Toxicity from previous anticancer treatment that includes:

  1. Greater than or equal to (>=) Grade 3 toxicity considered related to prior immunotherapy and that led to treatment discontinuation.
  2. History of myocarditis of any grade during a previous treatment with immunotherapy
  3. Toxicity related to prior treatment that has not resolved to <= Grade 1 (except alopecia, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be <= Grade 2).

• History (current and past) of idiopathic pulmonary fibrosis, pneumonitis (for past- pneumonitis exclusion only if steroids were required for treatment), interstitial lung disease, or organizing pneumonia.

• Recent history (within the past 6 months) of uncontrolled symptomatic ascites, pleural or pericardial effusions.

• Recent history (within the past 6 months) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess.

• History or evidence of cardiac abnormalities within the 6 months prior to enrollment which include

  1. Serious, uncontrolled cardiac arrhythmia or clinically significant electrocardiogram abnormalities including second degree (Type II) or third degree atrioventricular block.
  2. Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting or bypass grafting.
  3. Symptomatic pericarditis.

• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypo-albuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.

• Active infection requiring systemic therapy <=7 days prior to first dose of study treatment.

• Participants with known human immunodeficiency virus infection.

• Participants with history of severe hypersensitivity to mAb or hypersensitivity to any of the study treatment(s) or their excipients.

• Participants requiring ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome P 3A4 (CYP3A4) enzymes.

• Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other condition that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures in the opinion of the investigator.

• Pregnant or lactating female participants.

• Participant who is currently participating in or has participated in a study of an investigational device within 4 weeks prior to the first dose of study treatment.

• Participants with presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.

• Participants with positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.

• Participants with positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.

• Receipt of transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, and recombinant erythropoietin) within 14 days before the first dose of study intervention.

IPD for this study will be made available via the Clinical Study Data Request site.

IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted when justified, for up to another 12 months.

The study will be open-label.