This randomized, multi-site, three-part study will test a new treatment called BNT314, which is designed to help the body's own defense to fight cancer in combination with another new treatment (pumitamig, which is a cancer immunotherapy drug also known as BNT327 and PM8002) and chemotherapy in participants with metastatic colorectal cancer (mCRC).

Participants with microsatellite stable or mismatch repair proficient (MSS/pMMR) mCRC with progressive disease to the metastatic first line (1L) setting (Parts B and C) and beyond (Part A) as well as treatment-naïve (for Part B) are eligible to participate in the study.

The main study goals are as follows:

• Part A (Phase 1, safety run-in, dose escalation): To see if BNT314 in combination with pumitamig can be given safely, without causing severe side effects in participants.
• Part B (Phase 1, dose optimization): To see if BNT314 in combination with pumitamig and standard of care (SoC) chemotherapy is safe for participants and to find out the right dose of BNT314 that can be used in Part C.
• Part C (Phase 2, randomization against SoC): To see how well treatment works when BNT314 and pumitamig are given in combination with the usual SoC chemotherapy treatment.

In all three parts, the study will also look whether BNT314 can shrink tumors or slow down their growth when used with pumitamig and chemotherapy.

The study consists of a period to assess eligibility, a treatment period, a safety follow-up period, and a long-term survival follow-up period.

The sponsor plans to proactively assess participant safety on a regular basis for the duration of the study according to a predefined internal review committee. In addition, an independent data monitoring committee will be developed to provide medical oversight over Part C of the study.

Participants in the study will continue to receive treatment until their disease worsens, they can no longer tolerate the treatment, the participant chooses to leave the study, or the study ends. They are expected to be on treatment for about of 6-10 months on average. Participants may stop treatment early if their disease worsens or side effects occur but can continue longer if the disease stays controlled and the therapy is well-tolerated. After that, they will be monitored for their survival and any potential long-term side effects even after they stop participating in the study. Participants will be randomized to the treatment groups in Part B and Part C, which means participants will be assigned by equal chance to a treatment group.

Key Inclusion Criteria:

• Have unresectable histologically confirmed adenocarcinoma of the colon or rectum.
• Have confirmed non-microsatellite instability-high (non-MSI-H)/pMMR mCRC per Food and Drug Administration (FDA)/European Commission (EC) approved test or based on local testing.
• Have measurable disease defined by RECIST v1.1.
• Must provide a tumor tissue sample (formalin-fixed, paraffin-embedded or tissue slides) collected before C1D1 for enrollment. A newly obtained tumor sample is preferred. If it is not feasible to obtain a recent tumor sample, participants can provide archival tumor tissue (less than 2 years prior treatment).
• Have Eastern Cooperative Oncology Group Performance Status of 0 or 1.
• Have a life expectancy of ≥12 weeks.
• Have an adequate organ and bone marrow function within ≤7 days of Day 1 as defined in the protocol.
• Have had an adequate previous treatment washout period before randomization/enrollment as defined in the protocol.

Inclusion criteria applicable to only protocol-specific cohorts:

• Have histologically confirmed metastatic colorectal cancer and radiographically documented disease progression after ≥2 prior lines of systemic therapy for metastatic disease as defined in the protocol.
• Have progressed following first-line chemotherapy as specified in the protocol.
• Have not received prior systemic therapy for MSS/pMMR mCRC. Participants who received chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease in the neoadjuvant or adjuvant setting are eligible for the study if therapy was completed at least 6 months prior to initiation of study treatment.

Other cohort-specific inclusion criteria apply.

Key Exclusion Criteria:

• Confirmed MSI-H/deficient mismatch repair mCRC (per FDA/CE approved test or based on local testing).

• Prior treatment with epithelial cell-adhesion molecule or 4-1BB targeted or immunotherapy.

• Prior treatment with immune checkpoint inhibitors or programmed death-ligand 1 (PD[L]-1)/vascular endothelial growth factor bispecific antibody.

• Is a candidate to locoregional treatment (including surgical resection, stereotactic radiation therapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as "radical" intent), per investigator's assessment.

• Have uncontrolled or significant cardiovascular disease as specified in the protocol.

• Have left ventricular ejection fraction <50% by echocardiogram or multigated acquisition within 28 days before randomization/enrollment.

• Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.

• Have clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. Participants with untreated, asymptomatic brain metastases for whom local therapy is not indicated per SoC may be eligible if neurologically stable and (if deemed necessary by the investigator). Except for brain metastases history, any participants at imminent risk for spinal cord compression or leptomeningeal disease are not eligible.

• Have unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline toxicities that have resolved with sequelae (e.g., tracheostomy, chronic use of feeding tube, replacement hormones) are allowed, if not associated with increased risk of complications per investigator's assessment.

• Participants in Part B or C who fulfill one of the conditions:

  • Prior treatment with anticancer therapies (as defined in the protocol) with unusual toxicity, or
  • Known dihydropyrimidine dehydrogenase (DPD) deficiency, testing performed according to the local guidelines. If not tested, lack of DPD activity must be tested for the participants who have not received anticancer therapies (as defined in the protocol) in the prior lines of treatment; testing should be performed according to the local guidelines.

• Have a history of another primary malignancy within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated (adjuvant hormone therapy for malignancies at low risk of relapse is allowed) or have a known additional malignancy that is progressing or requires treatment.

• Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.

• Have 24-h urine protein excretion ≥1 g. If qualitative urine protein is ≤1+, a 24-h urine protein quantitative test is not required.

• Have active autoimmune disease or a history of autoimmune disease (myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, vasculitis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis) with a risk of exacerbation following PD-L1 inhibition or have an immune deficiency (allogeneic hematopoietic stem cell transplantation or organ transplantation). Participants with protocol-specified conditions may be eligible.

• Have serious non-healing wounds, ulcers, or bone fractures. This includes history of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess or esophageal and gastric varices, acute gastrointestinal bleeding for which an interval of 6 months must pass before enrollment into this study. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.

• Have evidence of major coagulation disorders or other significant risks of hemorrhage as specified in the protocol.

NOTE: Other protocol defined Inclusion/Exclusion criteria apply.

Part A and Part B of this study are open label. Only in Part C, the majority of sponsor personnel will be blinded to study treatment allocation.