Understanding resistance to chemo-immunotherapy in aggressive lung cancers

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.