Overview
The objective of this prospective multicenter study is to evaluate whether the analysis of immunological biomarkers present in circulating extracellular vesicles is associated with the response to anti-PD-1/PD-L1 treatments in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) or unresectable melanoma.
Patients will receive standard-of-care treatment and will be followed according to routine clinical practice. The study involves the collection of four study-specific blood samples at different time points during follow-up, as well as the collection of standard immunohistochemistry results, thoraco-abdomino-pelvic CT scans, and tumor DNA genotyping analyses performed as part of routine care.
The study aims to determine:
- whether baseline biomarkers in extracellular vesicles are associated with response to anti-PD-1/PD-L1 treatment,
- how these biomarkers change over the course of treatment, and
- to provide exploratory data for the development of predictive immunological response signatures.
Description
Immune checkpoint inhibitors (anti-PD-1/PD-L1) have become standard treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) or melanoma. However, not all patients respond to these therapies, and current biomarkers are imperfect.
Circulating extracellular vesicles (EVs) are nanovesicles derived from tumor and immune cells, carrying proteins, nucleic acids, and lipids. They represent an accessible and stable source of immunological biomarkers, allowing monitoring of the tumor microenvironment without additional invasive procedures.
This prospective multicenter study aims to determine, in a prospective cohort of patients with locally advanced or metastatic lung cancer or melanoma, the impact of baseline immune biomarkers present in extracellular vesicles on response to anti-PD-(L)1 therapy
Secondary objectives have also been defined :
- To evaluate the association between longitudinal changes in EV-associated immune biomarkers during follow-up and response to anti-PD-(L)1 therapy.
- To develop a predictive score (immune signature) of response to anti-PD-(L)1 therapy by combining baseline EV-associated immune biomarkers.
- To stratify analyses by tumor type (NSCLC versus melanoma) to determine whether tumor-specific characteristics influence the predictive performance of the identified immune signature.
- To obtain preliminary evidence on the contribution of EV-associated biomarkers to the prediction of primary or secondary resistance to anti-PD-(L)1 therapy.
- In the NSCLC cohort, to compare the predictive performance of the EV-based score with that of a score based solely on the tumor expression (assessed on biopsy specimens) of immunosuppressive proteins, without incorporating EV-associated biomarkers, for predicting best overall response (BOR) at 6 months.
- To explore EV-derived miRNA profiles in responders and non-responders.
- In each cohort, to compare the predictive performance of the EV-based score with that of a score integrating tumor mutational biomarkers derived from ctDNA and/or tumor tissue DNA for predicting BOR at 6 months.
- To evaluate PFS, including PFS at 6 and 12 months, as well as median PFS.
- To establish a prospective plasma biobank from patients treated with anti-PD-(L)1 therapies for future retrospective analyses following completion of the EVpredict study in the field of cancer immunology
Study procedures for participants include:
- Blood sample collection: Four study-specific blood draws performed during standard treatment or tumor assessment visits (baseline, 2nd administration, first evaluation, second evaluation).
- Collection of additional information: Standard immunohistochemistry results thoraco-abdomino-pelvic CT scans; circulating or tumor DNA genotyping analyses.
- Clinical follow-up: Conducted according to routine care standards, with no changes to treatment or additional study-specific visits.
Eligibility
Inclusion Criteria:
- Age ≥18 years.
- Histologically confirmed diagnosis of non-small cell lung cancer (NSCLC) or locally advanced/metastatic unresectable melanoma.
- Patient scheduled to initiate anti-PD-(L)1 therapy, either as monotherapy or in combination (other immune checkpoint inhibitors, chemotherapy, etc.).
- Baseline tumor assessment performed within 28 days prior to enrollment (CT scan of thorax, abdomen, and pelvis) with at least one measurable lesion according to RECIST 1.1 criteria.
- Life expectancy \>6 months.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at enrollment.
- Patient able to provide informed consent and comply with study procedures.
- Patient covered by a social security system or equivalent.
Exclusion Criteria:
- Prior treatment with immunotherapy.
- Presence of EGFR or ALK mutation (applicable only to the lung cohort).
- Presence of another synchronous malignancy.
- Diagnosis of uveal melanoma.
- Treatment with systemic immunosuppressants, including within 28 days prior to enrollment, or corticosteroids \>10 mg/day, including within 14 days prior to enrollment.
- Disease not measurable according to RECIST 1.1 criteria.
- Positive serology for HIV, HBV, or HCV.
- Pregnant or breastfeeding women.
- Inability to comply with study follow-up and visits for geographic, social, or psychological reasons.
- Individuals deprived of liberty or under legal guardianship (including curatorship).
