In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225Ac-hG250 and 177Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225Ac-hG250, 25 kBq 225Ac-hG250, and 13 MBq 177Lu-hG250 compared to untreated control (p < 0.05). Non-tumor-bearing mice that received single-dose treatment with 15 or 25 kBq 225Ac-hG250 showed weight loss at the end of the experiment (day 126), and immunohistochemical analysis suggested radiation-induced nephrotoxicity. These results demonstrate the therapeutic potential of CAIX-targeted α-therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity.

Purpose In this phase I study, we evaluated the safety, biodistribution and dosimetry of [89Zr]Zr-DFO-girentuximab (89Zr-girentuximab) PET/CT imaging in patients with suspicion of clear cell renal cell carcinoma (ccRCC). Methods Ten eligible patients received an intravenous administration of 37 MBq (± 10%) of 89Zr-girentuximab at mass doses of 5 mg or 10 mg. Safety was evaluated according to the NCI CTCAE (version 4.03). Biodistribution and normal organ dosimetry was performed based on PET/CT images acquired at 0.5, 4, 24, 72 and 168 h post-administration. Additionally, tumour dosimetry was performed in patients with confirmed ccRCC and visible tumour uptake on PET/CT imaging. Results 89Zr-girentuximab was administered in ten patients as per protocol. No treatment-related adverse events ≥ grade 3 were reported. 89Zr-girentuximab imaging allowed successful differentiation between ccRCC and non-ccRCC lesions in all patients, as confirmed with histological data. Dosimetry analysis using OLINDA/EXM 2.1 showed that the organs receiving the highest doses (mean ± SD) were the liver (1.86 ± 0.40 mGy/MBq), the kidneys (1.50 ± 0.22 mGy/MBq) and the heart wall (1.45 ± 0.19 mGy/MBq), with a mean whole body effective dose of 0.57 ± 0.08 mSv/MBq. Tumour dosimetry was performed in the 6 patients with histologically confirmed ccRCC resulting in a median tumour-absorbed dose of 4.03 mGy/MBq (range 1.90–11.6 mGy/MBq). Conclusions This study demonstrates that 89Zr-girentuximab is safe and well tolerated for the administered activities and mass doses and allows quantitative assessment of 89Zr-girentuximab PET/CT imaging in patients with suspicion of ccRCC. Trial registration NCT03556046—14th of June, 2018

The use of heated sterile water leads to significantly less fogging events than the use of ResoClear impregnation wipes, resulting in an improved continuity of the surgery without differences in operating time and costs.

LBA602 Background: The increasing detection of renal masses presents a significant patient management challenge. Diagnostic options include cross-sectional imaging, which cannot reliably differentiate benign and malignant renal masses, and biopsy, which is invasive and subject to sampling errors. These limitations highlight the unmet need for accurate noninvasive techniques to guide patient management. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell renal carcinoma (ccRCC). Radiolabeled 89Zr-DFO-girentuximab (TLX250-CDx) is highly specific for CAIX and can aid differentiation between ccRCCs and other renal lesions. The ZIRCON study evaluated the performance of TLX250-CDx PET/CT for detection of ccRCC in adult patients with indeterminate renal masses (IDRM). Methods: ZIRCON was an open-label, multicenter clinical trial. Patients with an IDRM (≤ 7 cm; tumor stage cT1) who were scheduled for partial nephrectomy within 90 days from planned TLX250-CDx administration were eligible. Enrolled patients received a single dose of TLX250-CDx IV (37 MBq ± 10%; 10 mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (± 2 days) prior to surgery. Blinded central histology review determined ccRCC status. The coprimary objectives were to evaluate both the sensitivity and specificity of TLX250-CDx PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with IDRM ≤ 4 cm (cT1a). Other secondary objectives included positive and negative predictive values, safety, and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be > 70% and 68% respectively for ≥ 2 independent readers to declare the study successful. Results: 300 patients received TLX250-CDx; mean age was 62 ± 12 y; 71% were males. Of 288 patients with central histopathology of surgical samples, 193 (67%) had ccRCC, and 179 (62%) had CT1a; Of 284 evaluable patients included in primary analysis, the average across all 3 readers for sensitivity and specificity was 86% [80%, 90%] and 87% [79%, 92%] respectively for coprimary endpoints; and 85% [77%, 91%] and 90% [79%, 95%] respectively for key secondary endpoints. For all readers, the lower boundaries of 95% CI for coprimary and key secondary endpoints were > 75%. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%, respectively. Of 263 treatment-emergent adverse events (TEAEs), 2 TEAEs were treatment related. Conclusions: This study confirms that TLX250-CDx PET/CT is well tolerated and can accurately and noninvasively identify ccRCC, with promising utility for designing best management approaches for patients with IDRM. Clinical trial information: NCT03849118 .

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4554 Background: Conventional tools (eg, CT, MRI, biopsy) have limitations for characterizing renal mass histology; approx. 25% of patients with an indeterminant renal masses (IDRM) <4cm undergo surgery for benign disease. Accurate noninvasive techniques to risk stratify the IDRM remains an unmet need. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell renal carcinoma (ccRCC). Radiolabeled 89Zr-DFO-girentuximab is highly specific for CAIX and can aid differentiation between ccRCCs and other renal lesions. ZIRCON evaluated the performance of 89Zr-DFO-girentuximab PET/CT for detection of ccRCC. Methods: In this open label, multicenter trial, patients with an IDRM (≤7cm; cT1) who were scheduled for partial nephrectomy within 90 days from planned 89Zr-DFO-girentuximab administration were eligible. Enrolled patients received a single dose IV (37 MBq±10%; 10mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (±2d). Blinded central histology review determined ccRCC status. The co-primary objectives were to evaluate both the sensitivity and specificity of 89Zr-DFO-girentuximab PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with IDRM ≤4cm (cT1a). Other secondary objectives included positive and negative predictive values, and evaluation of safety and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be >70% and 68% respectively for ≥2 independent readers to declare the study successful. Results: 300 patients received 89Zr-DFO-girentuximab (mean age, 62±12y; 71% Male). Of 288 patients with central histopathology of surgical samples, 193 (67%) had ccRCC, and 179 (62%) had cT1a. Of 284 evaluable patients, the average across all 3 readers for sensitivity and specificity was 86% [80%, 90%] and 87% [79%, 92%] resp. for coprimary, and 85% [77%, 91%] and 90% [79%, 95%] resp. for key secondary endpoints. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%, resp. PET+ ccRCC had higher mean CAIX expression compared with PET- ccRCC patients (p<0.05). Sensitivity and specificity were consistent with masses ≤2cm (n=46) of which, 26 were ccRCC+, 13 ccRCC−, and 3 unevaluable at central histopathology. Of 263 adverse events (AEs) in 124 patients, 2 AEs of mild intensity were treatment related. Conclusions: ZIRCON study confirms 89Zr-DFO-girentuximab PET/CT is a well-tolerated and accurate modality for noninvasive identification of ccRCC in IDRM. This tool could be included in the diagnosis/management of patients with IDRM, limiting unnecessary treatment of benign lesions. Clinical trial information: NCT03849118 .

chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 months with a 1-, 2-, 5-, and 10-year survival of 100%, 83%, 50% and 25%. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible micro-tumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity, or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.