This study aims to evaluate the safety and mechanisms of action of the trimodality treatment (radiotherapy, immunotherapy and surgery) in early-stage non-small cell lung cancer. Half of the patients will receive stereotactic ablative radiotherapy followed by 2 cycles of immunotherapy (pembrolizumab); the other half will not receive the immunotherapy treatment. After treatment, both groups will continue treatment according to guidelines and will undergo surgery (lobectomy).
An open label randomized exploratory study of the safety and mechanisms of action of combined treatment with SBRT and immunotherapy (pembrolizumab, anti-PD1) for early stage NSCLC. Intervention: Patients will be randomized between SBRT with or without 2 cycles of pembrolizumab treatment (starting on the first day of radiotherapy). The patients will undergo a lobectomy with hilar and mediastinal lymph node dissection after SBRT +/- pembrolizumab treatment. Translational research to explore the immune mechanism of action will include biological imaging with immuno-PET (positron emission tomography). Expression rates and activation states of immune effector subsets will be assessed in tumor core biopsy specimens, peripheral blood and tumor draining lymph nodes (TDLNs) by means of fine needle aspirates of TDLNs. Main study parameters/endpoints: To assess the safety of combined SBRT and pembrolizumab treatment in early stage NSCLC and to identify the immunological mechanism of action.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Prior to surgery (lobectomy), patients receive stereotactic ablative radiotherapy.
Prior to surgery (lobectomy), patients receive stereotactic ablative radiotherapy + 2 rounds of pembrolizumab
Incidence and severity of adverse events in patients treated by combining SBRT and pembrolizumab
Safety of the combination of SBRT and pembrolizumab will be assessed by the percentage of ≥3 pneumonitis. When combined SBRT and pembrolizumab treatment results in NCIC-CTC grade ≥3 pneumonitis in ≤10% of patients, the combination is regarded as safe. Serious adverse events will be recorded to assess both incidence and severity.
Time frame: Up to 90 days post-treatment
PD-1 expression
PD-1 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Time frame: Up to 90 days post-treatment
PD-L1 expression
PD-L1 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Time frame: Up to 90 days post-treatment
CD4 expression
CD4 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Time frame: Up to 90 days post-treatment
CD8 expression
CD8 expression in tumor tissue, TDLN's and peripheral blood.
Time frame: Up to 90 days post-treatment
FoxP3 expression
FoxP3 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Time frame: Up to 90 days post-treatment
Ki67 expression
Ki67 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Time frame: Up to 90 days post-treatment
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Immune cell count
Cell count of the individual immune cells in tumordraining lymphnodes and non-tumordraining lymphnodes
Time frame: Up to 90 days post-treatment
Analysis of PET data - SUVmax (standardized uptake value)
SUVmax will be measured in all tumor lesions, enlarged lymph nodes and liver, kidneys, lungs, spleen and left ventricle of the heart.
Time frame: Up to 90 days post-treatment
Analysis of PET data - SUVpeak (standardized uptake value)
SUVpeak will be measured in all tumor lesions, enlarged lymph nodes and liver, kidneys, lungs, spleen and left ventricle of the heart.
Time frame: Up to 90 days post-treatment
Analysis of PET data -SUVmean (standardized uptake value)
SUVmean will be measured in all tumor lesions, enlarged lymph nodes and liver, kidneys, lungs, spleen and left ventricle of the heart.
Time frame: Up to 90 days post-treatment
Analysis of CT data - Hounsfield Unit density
The pre- and post SBRT +/- pembrolizumab CT scans will be assessed for HU density and f-air values
Time frame: Up to 90 days post-treatment
Analysis of CT data - f-air values
The pre- and post SBRT +/- pembrolizumab CT scans will be assessed for and f-air values
Time frame: Up to 90 days post-treatment
Correlation between PET data and Blood + Tissue markers
The data of the PET-scan will be analyzed and compared to the blood and tissue samples to find a correlation between findings.
Time frame: Up to 90 days post-treatment
Correlation between tumor uptake of Zr89-pembrolizumab and irAEs
SUV are values used to describe PET-data. irAE's are specific adverse events. This outcome aims to correlate the (possible) irAE's with the PET-data.
Time frame: Up to 90 days post-treatment