Inclusion Criteria:
* Must have newly diagnosed CD20+ large cell lymphoma.
* Is ineligible for anthracycline-based therapy/cytotoxic chemotherapy due to:
* Being age ≥80 years; AND/OR
* Being age ≥75 years and having important comorbid condition(s), which are likely to have a negative impact on tolerability of anthracycline-based therapy/cytotoxic chemotherapy.
* Have Immune Effector Cell-Associated Encephalopathy (ICE) score of at least 8 out of 10.
* Have Ann Arbor Stage II-IV disease.
* Have ECOG PS of 0, 1, or 2; (ECOG PS of 3 may be considered if impairment is attributed to current lymphoma/DLBCL and if pre-phase treatment during the screening phase results in an improvement of ECOG PS to ≤2 prior to enrollment).
* Have measurable disease as per Lugano criteria.
* Have acceptable organ function based on baseline bloodwork.
* Must have fresh (preferred) or archival biopsy material at screening.
Exclusion Criteria:
* Has known active, clinically significant bacterial, viral, fungal, mycobacterial, parasitic, or other infection at trial enrollment, including COVID-19 infection.
* Has severe cardiovascular disease (other than those eligibility criteria that preclude the subject from receiving anthracycline-based therapy/cytotoxic chemotherapy),
* Has been exposed to/received any of the following prior therapies, treatments, or procedures within the specified timeframes:
* Major surgery within 4 weeks prior to the first dose of epcoritamab;
* Non-investigational antineoplastic agents (except anti-CD20 monoclonal antibodies) or any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of epcoritamab;
* Autologous hematopoietic stem cell transplantation (HSCT), CAR-T, allogeneic stem cell transplantation, or solid organ transplantation;
* Live, attenuated vaccines within 30 days prior to initiation of epcoritamab;
* Investigational vaccines within 28 days before the planned first dose of epcoritamab (ie, experimental and/or non-authorized SARS-CoV-2 vaccinations and therapies are not allowed);
* Invasive investigational medical device use within 28 days before the planned first dose of epcoritamab.
* Has primary central nervous system (CNS) tumor or known CNS involvement or intracranial involvement as confirmed by mandatory brain magnetic resonance imaging/computed tomography (MRI/CT) scan at screening and, if clinically indicated, by lumbar puncture.
* Has a seizure disorder requiring anti-epileptic therapy or experienced a seizure within 6 months of signing an informed consent form.
* Has known past or current malignancy other than inclusion diagnosis, with exceptions as stated in protocol.
* Has known or suspected allergies, hypersensitivity, or intolerance to either of the trial treatments or has known or suspected contraindication to the use of all locally available anti-cytokine therapies per local guidelines for management of cytokine release syndrome (CRS).
* Has active hepatitis B virus (HBV) (DNA polymerase chain reaction \[PCR\]-positive) or hepatitis C virus (HCV) (RNA PCR-positive) infection, current alcohol abuse, or cirrhosis.
* Has active cytomegalovirus (CMV) infection (DNA PCR-positive) requiring treatment.
* Has suspected active or inadequately treated latent tuberculosis.
* Has a known history of seropositivity for HIV. Note: HIV testing is required at screening only if required per local health authorities or institutional standards.
Note: Other protocol defined inclusion/exclusion criteria may apply.
