95 [89Zr]Zr-DFO-durvalumab PET/CT before durvalumab treatment in R/M SCCHN patients DISCUSSION The PINCH study reported [89Zr]Zr-DFO-durvalumab PET/CT in R/M SCCHN patients treated with durvalumab to address current caveats in the predictive role of PD-L1 expression on tumor biopsies. [89Zr]Zr-DFO-durvalumab PET/CT was considered safe and feasible in a multi-center setting. Heterogenous [89Zr]Zr-DFO-durvalumab tumor accumulation was detected within and between patients. [89Zr]Zr-DFO-durvalumab uptake could not predict durvalumab treatment response. To achieve optimal tumor-to-background contrast, selection of proper antibody dose and imaging timing is essential. The PINCH study showed superior TTB ratios when performing PET/CT 5 days after [89Zr]Zr-DFO-durvalumab administration using 10 mg of durvalumab, compared with 2 and 50 mg. In agreement with previous studies, increasing the dose of unlabeled antibody saturates the spleen uptake and results in higher concentrations of circulating 89Zr-labeled antibodies and increased tumor uptake24,25. At 50 mg, TTB ratio decreased, most likely explained by a decrease in available binding sites for [89Zr]Zr-DFO-durvalumab. In line with this, low or absent tumor accumulation was also reported for [89Zr]Zr-DFO-durvalumab PET-imaging with 750 mg unlabeled durvalumab22. Preclinical studies have demonstrated a relation between the accumulation of radiolabeled PD- (L)1 antibodies with PD-L1 expression, thereby distinguishing between tumors with different PD-L1 expression levels13,14. The first two clinical trials also reported an association between radiolabeled PD-L1 antibody uptake and PD-L1 expression 18,19. However, we did not find such a correlation. Of note, our analysis was performed on a subset of patients using archival tissue biopsies, as fresh histologic prove was not mandatory for study inclusion. Besides sampling error due to small tumor samples, correlating (archival) biopsies to PET-imaging remains challenging due to the heterogenous and dynamic expression levels of PD-L1. Also, in comparison to previous studies, the PD-L1 staining and scoring procedures differed 29,30. A previous study in 22 patients with metastatic NSCLC, triple negative breast cancer and bladder cancer treated with atezolizumab, above median gm [89Zr]Zr-atezolizumab SUV max was associated with improved overall and progression free survival 18. Furthermore, both [89Zr]Zr-nivolumab (anti PD-1) and 18F-BMS-986192 (anti PD-L1) SUVpeak were correlated to nivolumab treatment response in 13 NSCLC patients. However, two other studies using [89Zr]Zr-DFO-durvalumab and [89Zr]Zrpembrolizumab in NSCLC patients, showed a trend but no significant correlation between traceruptake and durvalumab respectively pembrolizumab treatment efficacy 22,31, which is more in line with our data. The early termination of the study resulted in a lower number of included patients. Potentially, more patients could have resulted in a significant correlation. We also evaluated the correlation between tumor metabolism and ICI response, as performed in previous studies 32,33. Our data suggests that particularly [18F]FDG total lesion glycolysis may identify poor durvalumab responders upfront. A potential explanation could be that patients with more extensive disease have already undergone extra steps in the immune escape route. 5
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