Genomic and Methylation Markers in SCLC and LCNEC for Chemo-Immunotherapy Resistance Prediction (STRATUS)

Inclusion Criteria: * Age: Adults aged 18-85 years. * Histologically confirmed locally advanced extensive-stage small cell lung cancer (ES-SCLC). * Histologically confirmed locally advanced or metastatic large cell neuroendocrine carcinoma (LCNEC). * Treatment Plan: Eligible patients must be initiating standard-of-care chemo-immunotherapy, including platinum-based chemotherapy (cisplatin or carboplatin) combined with immune checkpoint inhibitors (atezolizumab or durvalumab). * Measurable Disease: At least one measurable or evaluable lesion as defined by RECIST 1.1 criteria. * Baseline Biospecimen Availability: Patients must agree to provide baseline blood and tumor biopsy samples for molecular and genomic analyses. * Treatment Naïve for Study Indication: Patients should not have received prior systemic therapy for ES-SCLC or LCNEC. * Life Expectancy: Estimated life expectancy of at least 3 months, as determined by the treating physician. * Follow-Up Commitment: Willingness to attend scheduled follow-up visits and provide additional biospecimens (blood and/or tissue) during treatment and at progression. * Performance Status: ECOG performance status of 0-2. * Organ Function: Adequate hematologic, renal, and hepatic function as per the treating physician's discretion. * Consent: Ability and willingness to provide written informed consent for participation in the study and collection of biospecimens (e.g., blood and tumor tissue). * Compliance with Study Protocol: Demonstrated ability and willingness to comply with all study-related procedures, including biospecimen collection and follow-up visits. * Non-Pregnant and Non-Lactating: Women of childbearing potential must have a negative pregnancy test at baseline and agree to use effective contraception during the study period. * Immunotherapy Eligibility: Patients must not have contraindications to immune checkpoint inhibitors (e.g., autoimmune diseases requiring systemic immunosuppressive therapy). * Platinum-Based Therapy Tolerance: Patients must be deemed medically fit to receive platinum-based chemotherapy (cisplatin or carboplatin) as determined by the treating physician. * No Active Infections: Patients must not have active, uncontrolled infections, including but not limited to tuberculosis, hepatitis B, hepatitis C, or HIV. * Psychosocial Stability: Patients must have adequate psychosocial support and the mental capacity to understand and provide informed consent for participation in the study. * Stable Brain Metastases: Patients with brain metastases are eligible if the metastases have been treated (e.g., surgery or radiotherapy) and are stable for at least 4 weeks prior to enrollment, as confirmed by imaging. * Steroid Use for Brain Metastases: Patients requiring corticosteroids for brain metastases are eligible only if they are on a stable or tapering dose equivalent to ≤10 mg/day of prednisone for at least 2 weeks prior to enrollment. Exclusion Criteria: * Uncontrolled Brain Metastases: Patients with untreated or progressive brain metastases causing significant neurological symptoms. * Concurrent Malignancies: Presence of any active malignancy other than ES-SCLC or LCNEC within the past 3 years, except for treated non-melanoma skin cancer or in situ cervical carcinoma. * Previous Systemic Therapy: Prior systemic chemotherapy or immunotherapy for ES-SCLC or LCNEC. * Severe Comorbidities: Significant comorbidities, such as uncontrolled cardiovascular, respiratory, or autoimmune diseases, that could interfere with study participation or treatment. * Active Infection: Patients with active infections requiring systemic therapy, including tuberculosis, hepatitis B or C, or HIV. * Pregnancy or Lactation: Pregnant or lactating women, or women of childbearing potential who are not using effective contraception. * Immunosuppressive Therapy: Patients requiring systemic immunosuppressive therapy, including high-dose corticosteroids (equivalent to \>10 mg/day prednisone), within 2 weeks prior to enrollment. * Severe Allergic Reactions: History of severe hypersensitivity reactions to any component of the planned treatment regimen, including platinum-based chemotherapy or immune checkpoint inhibitors. * Life-Threatening Conditions: Life expectancy less than 3 months, as assessed by the treating physician. * Inability to Comply: Patients unable or unwilling to adhere to study protocols, including biospecimen collection and follow-up visits.