114 Chapter 6 PATIENTS AND METHODS At the start of the study, only patients with stage IV NSCLC were enrolled. However, due to slow inclusion rate, the registration of 1st line immunotherapy in stage IV NSCLC patients, as well as the interest in neo-adjuvant immunotherapy treatment, the study protocol was amended in July 2019. This amendment allowed inclusion of patients with resectable early-stage NSCLC receiving neo-adjuvant avelumab treatment. Patients with stage IV NSCLC (n=4) enrolled before this protocol amendment, were only evaluated for imaging purposes. Patients Eligible patients were aged ≥18 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one lesion with a diameter of ≥1 cm. PD-L1 expression on baseline tumor sample was not an inclusion criterion. All patients with early-stage NSCLC were scheduled for curative intent surgical resection by multi-disciplinary tumor board. The PINNACLE study (NCT03514719) was performed at the Radboudumc in Nijmegen, the Netherlands. Procedures [89Zr]Zr-DFO-avelumab PET/CT All patients received an intravenous injection of 2 mg protein dose avelumab radiolabeled with 37 MBq activity dose Zirconium-89. Based on prior dose finding studies with [89Zr]-labeled antibodies, we planned to enroll 3-6 patients per dose cohort (2, 10 or 50 mg avelumab)14. For the 10mg and 50mg cohort, [89Zr]Zr-DFO-avelumab was complemented with 8 and 48 mg unlabeled avelumab, respectively, prior to injection. The first 13 patients were enrolled for antibody dose and timepoint optimization. PET-imaging was performed at day 2 and 4 post injection and for pharmacokinetic purposes, blood plasma samples were drawn within 10 minutes after injection and at day 2 and 4. Plasma radioactivity was measured in a gamma counter and reported as the percentage injected dose (%ID/g). The optimal dose and timing for [89Zr]Zr-DFO-avelumab PET/ CT imaging was determined based on visual and quantitative PET analyses and pharmacokinetic analyses. After optimizing the dose and timing, the dose finding study was ended and subsequent patients entering the study were injected with 10 mg [89Zr]Zr-DFO-avelumab and scanned at day 4 post injection. Details on acquisition and reconstruction protocols, conjugation, radiolabeling, and quality control of [89Zr]Zr-DFO-avelumab are described in the supplements. Avelumab treatment and follow-up All patients with early-stage NSCLC were planned for 2 cycles of avelumab treatment (10mg/ kg q2w), starting within one week after [89Zr]Zr-DFO-avelumab PET/CT scan. Avelumab was administered according to European product characteristics with paracetamol and antihistamine as pre-treatment to limit infusion-related adverse events15. Surgical resection of the tumor was scheduled within 6 weeks of the finalization of diagnostic work-up. Data on adverse events were collected during treatment up to 90 days after the last treatment dose and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Evaluation contrast enhanced (ce)CT was performed every 3 months post-surgery for 1 year.
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