(S-048) Exposure-Response Analyses of Dato-DXd in patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer

Zoey Tang – AstraZeneca; KyoungSoo Lim – AstraZeneca; Yu Jiang – AstraZeneca; Neelima Denduluri – AstraZeneca; Nana Rokutanda – AstraZeneca; Darlington Mapiye – AstraZeneca; Yuzhuo Pan – Daiichi Sankyo; Ying Hong – Daiichi Sankyo; Song Ren – AstraZeneca; Pavan Vajjah – AstraZeneca; Megan Gibbs – AstraZeneca; Diansong Zhou – AstraZeneca

Objectives: Typically, tissue uptake, expressed in TPR, is reported from a 89Zr-mAb PET study. Nonspecific antibody catabolism and the residualizing property of 89Zr hamper the use of tissue uptake as a measure for target mediated uptake. Moreover, non-linear plasma kinetics may result in variable tissue exposure and thus in variable tissue uptake. Therefore, we propose to report uptake as tissue over plasma ratio additionally corrected for nonspecific antibody catabolism (cTPR). We introduce an organ specific but time independent baseline tissue over plasma ratio (bTPR), which is the expected tissue over plasma ratio in the absence of target mediated uptake. Target mediated uptake is then evident from a cTPR value higher than bTPR.

Methods: We analyzed retrospectively tissue uptake reported for three 89Zr-mAb studies. The method of correction for non-specific uptake due to antibody catabolism requires the net rate of irreversible 89Zr uptake due to nonspecific antibody catabolism [1, 2], total tissue exposure to 89Zr-mAb (the area under the plasma time concentration curve, obtained from blood sampling) and a single PET scan taken more than 24h post injection.

Results: For 89Zr-Cetuximab, 38% of spleen uptake at 144h post injection is due to nonspecific antibody catabolism (median, n = 7). Furthermore, it ranges between 27 and 63% due to interindividual variability in tissue exposure. Patients are ranked differently for total compared to corrected 89Zr-mAb uptake, leading to the risk of invalid conclusions from PET studies if based on total uptake.

Conclusions: 89Zr-mAb PET uptake should be reported as tissue over plasma ratio corrected for nonspecific antibody catabolism.

Citations: [1] Jauw YWS, O’Donoghue JA, Zijlstra JM, Hoekstra OS, Menke-van der Houven van Oordt CW, Morschhauser F, et al. 89Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo. J Nucl Med Off Publ Soc Nucl Med. 2019 Dec;60(12):1825–32.
[2] Wijngaarden JE, Jauw YWS, Zwezerijnen GJC, De Wit-van Der Veen BJ, Vugts DJ, Zijlstra JM, et al. Non-specific irreversible 89Zr-mAb uptake in tumours: evidence from biopsy-proven target-negative tumours using 89Zr-immuno-PET. EJNMMI Res. 2024 Feb 15;14(1):18.

Keywords: Positron Emission Tomography