Pembrolizumab-PET Imaging

Rationale: Immunotherapy targeting specific immune-regulatory checkpoints, mainly cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed Death (PD1) or PD ligand 1 (PD-L1) have shown spectacular effects in a broad range of solid malignancies, including melanoma and non-small cell lung cancer (NSCLC). Pembrolizumab, is a monoclonal antibody that blocks the interaction between PD-1 on T-cells with its ligands PD-L1 and PD-L2. Anti-tumor activity with an acceptable side effect profile have been shown in melanoma and NSCLC. Radio-labeling of pembrolizumab with the positron emission tomography (PET) radionuclide 89Zirkonium (89Zr) enables serial non-invasive imaging and quantification of distribution of PD-1 in melanoma patients. By performing a 89Zr-pembrolizumab-PET scan prior to treatment with pembrolizumab, the uptake of the tracer in the tumor lesions and normal organ distribution can be evaluated, this could lead to new insights about heterogeneity of PD-1 expression, as well as the use of a 89Zr-pembrolizumab-PET as a complementary tool for patient selection in the future. Objective: Primary objective: To evaluate whole body distribution of 89Zr-pembrolizumab in patients with locally advanced or metastatic melanoma or NSCLC. Secondary objectives: i) To evaluate pharmacokinetics of 89Zr-pembrolizumab; ii) To assess the heterogeneity of 89Zr-pembrolizumab tumor uptake; iii) To describe safety of 89Zr-pembrolizumab; iv) To correlate the tumor response of pembrolizumab, as measured by objective response rate (ORR) according to standard RECIST v1.1 as assessed by the investigator, with specific tumor tracer uptake. Study design: This is a two center, single arm, investigator sponsored trail (IST) with the PET tracer 89Zr-pembrolizumab to evaluate in vivo whole body distribution of 89Zr-pembrolizumab in a registered indication for locally advanced metastatic melanoma or NSCLC before Pembrolizumab treatment. Study population: Eligible are patients with locally advanced or metastatic melanoma or NSCLC, who are eligible to receive Pembrolizumab treatment and who have at least one tumor site that is accessible for a tumor biopsy. Intervention : In part A of the imaging trial, a dose finding imaging study will be performed to assess the optimal tracer protein dose of 89Zr-pembrolizumab and the optimal interval between tracer injection and scanning. Approximately 3 cohorts of about 2-3 patients each will undergo 89Zr-pembrolizumab-PET imaging before start of treatment with pembrolizumab. In part B, 12 eligible patients will undergo 89Zr-pembrolizumab-PET imaging at baseline, with the optimal tracer protein dose and scanning schedule as determined in part A. In total, a maximum of 21 patients will be included.The purpose of part B of the study is to analyze the whole body distribution and pharmacokinetics (PK) of 89Zr-Pembrolizumab. Tumor and normal organ radioactive tracer uptake will be quantified as standardized uptake values (SUV). Tumor biopsies will be collected at baseline and studied for various characteristics including Programmed cell death-ligand 1 (PDL-1), PD-1 expression and tumor infiltrating lymphocytes. Pembrolizumab treatment will be administered as standard of care Main study parameters/endpoints: To evaluate whole body distribution of 89Zr-pembrolizumab in patients with locally advanced or metastatic melanoma. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: For this imaging study patients have to make maximal 6 extra visits to the clinic for screening, to receive tracer injection and for maximal 3 PET/CT scans and the biopsy before start of standard treatment with pembrolizumab. The study ends after the last imaging or biopsy (whichever comes first) and will approximately take 7 days. Whenever possible, all procedures that are part of the study protocol will be planned during regular visits to the hospital as part of care as usual. 89Zr-pembrolizumab-PET/CT implements a radiation burden of about 20 millisievert (mSv), and 1.5 mSv per low-dose CT scan. Besides PET imaging, patients will be asked to give in total 12 blood samples (85 mL), which will give minor discomfort. A metastases biopsy will be performed, preferably from an easily accessible lesion to minimize the burden and risk for the patient. Based on a literature review, the risk of tumor biopsies is considered low with a small risk on significant/major complications or death. The risk associated with the 89Zr-pembrolizumab seems minor and although patients do not directly benefit from this study, results of this study will be valuable for our understanding of the tumor immune response and will guide further prospective research.