Prospective Evaluation of Immunological, Molecular-genetic, Image-based and Microbial Analyzes to Characterize Tumor Response and Control in Patients With Inoperable Stage III NSCLC Treated With Chemoradiotherapy Followed by Consolidation Therapy With Durvalumab

Study Overview
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Brief Summary
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This non-interventional single-center explorative biomarker study aims at longitudinal comprehensive characterization (molecular genetics, immunological, morphological, image-based and microbial features) of the patient (host) and tumor as well as changes during standard treatment and in case of recurrent disease in inoperable stage III non-small cell lung cancer (NSCLC). Comprehensive analysis will include peripheral blood cellular and humoral immunophenotyping, circulating tumor DNA and gut/saliva microbiota analyses. 18F-FDG-PET/CT before, 6 weeks, 6- and 12-months after chemoradiotherapy as well as daily in course of radiation treatment cone-beam-CT and/or MRI imaging are included for morphological analysis. This study will provide valuable information of predictive biomarkers in patients with stage III NSCLC treated with durvalumab maintenance treatment after concurrent chemoradiotherapy.

Detailed Description
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The study will enrol 40 patients with stage III inoperable non-small cell lung cancer (NSCLC) who received standard chemoradiotherapy followed by maintenance therapy with PD-L1 inhibition (durvalumab) according to the current European Medicines Agency (EMA) approval. The oncological treatment is carried out according to the international standards of radiation oncology/medical oncology. These are implemented by the department of radiation oncology at the University Hospital Munich (LMU) in their SOPs. Therefore, all patients will be treated with concurrent platinum-based chemoradiotherapy followed by durvalumab maintenance treatment 12 months after the end of chemoradiotherapy at the department of radiation oncology (University Hospital Munich (LMU)). Comprehensive characterization of all patients includes immunophenotyping of peripheral blood mono-nuclear cells, ctDNA as well as gut/saliva microbiome analyses and will be performed before, after 15 fractions of radiotherapy, at the end of concurrent chemoradiotherapy as well as 3-, 6- and 12 months after start of durvalumab. 18F-FDG-PET/CT will be performed 5-10 d before start of radiotherapy, 6 weeks, 6 months,12 and 24 months after the end of chemoradiotherapy. Lung function will be assessed before start of radiotherapy, at the end and 6 weeks after chemoradiotherapy as well as 3-, 6- and 12, 18, 24 months after start of durvalumab. Follow-up will be performed by the department of radiation oncology at the University Hospital Munich (LMU) according to the clinical SOPs.

Official Title
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Prospective Evaluation of Immunological, Molecular-genetic, Image-based and Microbial Analyzes to Characterize Tumor Response and Control in Patients With Inoperable Stage III NSCLC Treated With Chemoradiotherapy Followed by Consolidation Therapy With Durvalumab (PRECISION)

Conditions
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Oncology, Biomarker, NSCLC, Stage III, Durvalumab, Chemoradiotherapy

Intervention / Treatment
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* Other: Non-interventional


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age ≥ 18 years Histologically/cytologically confirmed diagnosis of non-small-cell lung cancer (NSCLC) Patients with non-operable NSCLC in tumor stage III A/B/C after UICC 8 Eligible for platinum-based concurrent chemoradiotherapy followed by durvalumab maintenance treatment No invasive carcinoma in the last five years. ECOG Performance Status 0-2 Lung function parameters (before or after bronchodilation): FEV1 ≥ 1.0 L and/or DLCO-SB ≥ 40% A maximum of two cycles of induction chemotherapy are permissible before start of chemoradiotherapy Exclusion Criteria: Simultaneous participation in another clinical trial Mixed histology of small-cell and non-small-cell lung cancer Brain metastases confirmed by a contrast enhanced cMRI Prior receipt of an immunotherapy or investigational medicinal product Previous exposure to an anti-PD-1 or anti-PD-L1 antibody Pneumonitis ≥ Grade 2 as a result of prior radio-/chemoradiotherapy Patients with a non-active disease in the last 5 years can be included, but only after consultation with the responsible investigator of the study or his representative Primary immunodeficiencies in previous history Prior Interstitial lung disease (ILD) Prior autoimmune disease Previous organ transplantation with subsequent therapeutic immunosuppression

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Observational group<br>In this cohort, 40 NSCLC patients with indication for chemoradiotherapy followed by durvalumab maintenance treatment (standard of care) will be consecutively recruited. Comprehensive characterization of all patients includes immunophenotyping of peripheral blood mono-nuclear cells, ctDNA as well as gut/saliva microbiome analyses and will be performed before, after 15 fractions of radiotherapy, at the end of concurrent chemoradiotherapy as well as 3-, 6- and 12 months after start of durvalumab. 18F-FDG-PET/CT will be performed 5-10 d before start of radiotherapy, 6 weeks, 6 months,12 and 24 months after the end of radiochemotherapy. Lung function will be asssed before start of radiotherapy, at the end and 6 weeks after chemoradiotherapy as well as 3-, 6- and 12, 18, 24months after start of durvalumab. | Other: Non-interventional<br>* No intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive biomarker for progression-free survival at 12 and 24 months | To identify early immunological and morphological biomarkers and their dynamic changes to predict progression-free survival at 12 and 24 months. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive biomarkers for progression-free survival, overall survival, response rate, local and distant tumor control | To identify predictive biomarkers for progression-free survival at 6 and 18 months after chemoradiotherapy and overall survival and response rate, local and distant tumor control at 6 weeks, 6-, 12-, 18 and 24 months from the end of chemoradiotherapy. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Stage III, Biomarker