Eligible participants with limited stage-small cell lung cancer (LS-SCLC) will be enrolled after completion of chemotherapy and radiation. Participants will be randomized to either tarlatamab in combination with durvalumab or durvalumab alone as consolidation therapy. Treatment will continue until disease progression, unacceptable side effects or withdrawal of consent.

Tarlatamab is a targeted cancer treatment. It works by acting as a matchmaker between the immune system's T-cells and the cancer cells, forcing them to come together so the T-cells can attack the cancer.

Image testing will be done standardly during treatment. These tests show whether the cancer has progressed and if further treatment may be needed.

The purpose of this trial is to evaluate how well the treatment works (how long before your cancer comes back and how long you live).

The purpose of this trial is to evaluate the clinical efficacy of tarlatamab in combination with durvalumab as consolidation therapy for LS-SCLC after completion of chemotherapy and radiation compared to durvalumab alone. Tarlatamab has demonstrated significant clinical activity against SCLC in the extensive stage setting and demonstrated improved overall survival compared to second line chemotherapy. The durability of response and progression-free survival (PFS) rates are encouraging that this therapy has the ability to achieve more long-term disease control than traditional treatments like chemotherapy and programmed cell death-ligand 1 (PD-L1) immunotherapy alone. Given the high risk of recurrence and death for LS-SCLC, tarlatamab may be an effective strategy to improve the risk of recurrence and death in this earlier disease setting.

Tarlatamab is a bi-specific T-cell engager that targets delta-like ligand 3 (DLL3) and CD3 and was developed with the intent to treat small cell lung cancer due to the high level of expression of DLL3 on the cell surface. The anti-tumor activity of tarlatamab requires simultaneous binding to both target cells and T cells.

RECIST 1.1 criteria will be used for disease response. This is will be measured by the investigators as well as a Blinded Independent Central Review (BICR).

Archived tumor tissue will be requested at baseline for future research. Research peripheral blood samples will be obtained to measure the level of tarlatamab and for future research.

Patient-reported outcomes will also be performed.

• Patient must have histologically or cytologically confirmed Small Cell Lung Cancer (SCLC).

• SCLC must be diagnosed as Limited-Stage-SCLC (LS-SCLC) (Stage I-III, disease can be encompassed within a radical radiation portal per investigator assessment) and treated with 3 to 4 cycles of chemotherapy and radiation therapy. Three cycles of chemotherapy will be acceptable if the planned radiation therapy course is completed concurrently with chemotherapy.

  • Patient must not be eligible for surgical resection or have had prior surgical resection for the current diagnosis of LS-SCLC.

  • Small cell carcinoma may not be transformed from previous diagnosis of non-small cell lung cancer (e.g., Epidermal Growth Factor Receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with SCLC transformation). Mixed histology (aka combined small cell) histology tumors are permitted if the majority component is small cell histology.

  • Chemotherapy must consist of a platinum agent (carboplatin or cisplatin) and etoposide.

  • Definitive radiation may include daily treatment ≥ 60 gray (Gy) or twice-daily treatments 45 Gy or other biologically equivalent regimens given concurrently with chemotherapy.

  • For early LS-SCLC (e.g., T1-2, N0, M0) without lymph node involvement, treatment with stereotactic ablative radiotherapy (SABR/SBRT) and chemotherapy is allowed.

  • Prophylactic cranial radiation (PCI) is permitted but not required. If PCI is administered, 7 day wash-out period is required before start of study treatment.

    • PCI consists of whole brain radiation therapy delivered in the absence of brain metastases. Hippocampal-sparing whole brain plans are considered PCI.

  • Patient must be able to be randomized and have planned cycle 1 day 1 treatment within 42 days of the last dose of thoracic radiation therapy or end of last cycle of chemotherapy, whichever was given most recently.

• Completed chemotherapy and radiation with no evidence of progression of disease per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1 (i.e., achieved complete response, partial response, or stable disease), including no evidence of metastatic disease on brain MRI, after treatment but prior to randomization.

• Patient must be ≥ 18 years of age.

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• Patient must have the ability to understand and willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.

• Patient must be willing to provide archived tumor tissue (if available) for research.

• Patient must have adequate organ function and marrow function as defined below, obtained ≤ 14 days prior to randomization (Echocardiogram (ECHO)/Multi-Gated Acquisition (MUGA) ≤ 28 days).

  • Absolute Neutrophil Count (ANC) ≥ 1500/microliter (mcL)
  • Hemoglobin ≥ 8.0 g/dL
  • Platelets ˃100,000/mcL
  • Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5x upper limit normal (ULN) except for patients on stable dose anticoagulation for 6 weeks prior to randomization.
  • Activated partial thromboplastin Time (aPTT) ≤ 1.5x ULN except for patients on stable dose anticoagulation for 6 weeks prior to randomization.
  • Serum Creatinine ≤ 2x ULN
  • Creatinine clearance(CrCl) ≥ 30 mL/min
  • ALT (Alanine Aminotransferase) and AST (Aspartate Aminotransferase) ≤ 2.5x ULN
  • Total Bilirubin ≤ 1.5x ULN or ≤ 2x ULN for patients with documented Gilbert's disease
  • No evidence of human immunodeficiency virus (HIV) within 6 months of randomization.
  • Hepatitis B virus (HBV) and Hepatitis C virus (HCV) negative within 6 months of randomization.
  • Pulmonary Function: No oxygen supplementation
  • Electrocardiogram (ECG) with no findings of acute/subacute ischemia and/or clinically significant arrythmia
  • Cardiac Function: Cardiac ejection fraction ≥ 50% and no large or symptomatic pericardial effusion requiring intervention

• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

• Patient must not expect to conceive, or father children by using an accepted and highly effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study, and for 90 days after the last dose of study drug(s). Also, patient must not expect to breastfeed, donate eggs, or donate sperm during study or for 90 days after the last dose of study drug(s).

• Patient with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Patient must not have had major surgery within 28 days, or minor surgery within 10 days, before randomization.

• Patient must not have a history of clinically significant interstitial lung disease or active pneumonitis requiring steroid treatment. Patients with grade 1 radiation pneumonitis or fibrosis are permitted to enroll.

• Patient with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification (NYHA Classification). To be eligible for this trial, patient must be class IIB or better.

• Patients with history of autoimmune disorders are eligible to enroll only if no disease flares and not requiring any systemic immunosuppressive agents in the past 5 years. Topical or inhaled steroids are permitted. The following are not exclusionary: vitiligo, asthma, endocrine disorders that required only hormone replacement, psoriasis or other skin disorders that do not require systemic treatment, celiac disease controlled by diet alone.

• Patients with active primary immunodeficiency are not permitted to enroll.

• Prior history of severe or life-threatening events (Common Terminology Criteria for Adverse Events (CTCAE) V6.0 grade ≥ 3) from any immune-related therapy.

• Patients with any condition requiring chronic oral corticosteroids is eligible if steroid dose is ≤ 10 mg/day prednisone equivalent. Physiologic replacement doses for adrenal insufficiency are permitted even if dose exceeds 10 mg/day. Inhaled corticosteroids and local steroid injections are permitted. All other uses of steroids must be tapered to ≤ 10 mg/day before randomization.

• Patients must not have a history of allogeneic solid organ, allogeneic bone marrow or stem cell transplantation.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within for 6 months of before randomization are eligible for this trial.

• Patient must not have received any live vaccine within 28 days prior to randomization.

• Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible.

• Any prior therapy with a selective inhibitor of the DLL3 pathway is not permitted.

• Any prior therapy with immune-mediated therapy including anti-CTLA-4, anti-PD-1, or anti PD-L1 is not permitted.

• Receiving another anti-cancer therapy is not permitted except for hormonal therapy for breast or prostate cancer, topical therapies for cutaneous malignancies, or superficial treatments for non-muscle invasive bladder cancers.

• Patients with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the treatment according to the protocol are not eligible.

• Patients may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial during treatment on this study without prior approval from PrECOG.

Data is proprietary