Kuo, Phillip H.

Abstract Purpose: Prostate-specific membrane antigen (PSMA)–directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule. Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging. Results: 99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc–EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer–like morphology. Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

TPS272 Background: Prostate-specific membrane antigen (PSMA)-targeting positron emission tomography (PET) radiopharmaceuticals enable early detection of metastatic and recurrent prostate cancer (PCa). High urinary radioactivity of some PSMA-PET agents can affect interpretation of scans in the pelvic region (prostate/prostate bed [PB]; pelvic lymph nodes [PLN]). 18 F-Piflufolastat and 18 F-flotufolastat are FDA-approved, mainly renally cleared, diagnostic PSMA-PET agents; data suggest 18 F-flotufolastat has lower urinary radioactivity than 18 F-piflufolastat, but no clinical differences have been confirmed by head-to-head intra-patient studies. The present study will directly compare the urinary radioactivity of 18 F-piflufolastat with 18 F-flotufolastat in men with low prostate-specific antigen (PSA) biochemical recurrence (BCR) of PCa after radical prostatectomy (RP). Methods: This multicenter, prospective, intra-patient comparator study will include men (≥ 18 years old) with low PSA (≤ 0.5 ng/mL) BCR of PCa who have had RP ≥ 6 months before enrollment (with undetectable PSA post surgery) and are due to have routine 18 F-piflufolastat PET. Men who have had prior 18 F-piflufolastat PET or salvage therapy, or with conditions affecting urinary output, will be excluded. Eligible patients will undergo 18 F-piflufolastat PET followed by 18 F-flotufolastat PET ≥ 24 hours but ≤ 10 days later. No diuretic will be administered for scanning purposes. Each radiopharmaceutical will be administered as a single intravenous bolus per approved US prescribing information (USPI). Scanning (with the same scanner for both scans) will start 50–90 minutes post injection of 18 F-piflufolastat and 50–70 minutes post injection of 18 F-flotufolastat. Each patient will be their own control. The primary endpoint will be difference in mean standardized uptake value (SUV mean ) between 18 F-piflufolastat and 18 F-flotufolastat as assessed in volumes of interest drawn on the urinary bladder. Secondary endpoints for both agents will include detection rates: at the patient level (overall; by baseline PSA); for local recurrences in PB subregions; and for PLN lesions. For secondary endpoints, PET scans will be interpreted per product-specific USPI by 2 specially trained, blinded, central readers (a third reader will adjudicate disagreements). Safety will be monitored until 24 hours after the second scan. Around 60 men will be screened and ≥ 52 with evaluable PET scans for both agents will be included in the primary analysis. The primary endpoint will be assessed for normality and a difference in SUV mean will be tested using 2-sided paired tests (Wilcoxon signed-rank test [non-normal]; t-test [normal]). All further endpoints, including safety, will be summarized descriptively. The trial has been open for enrollment since 10/24. Clinical trial information: NCT06604442 .

Abstract INTRODUCTION The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as “rarely appropriate,” “uncertain,” or “appropriate.” Ratings were performed separately for amyloid and tau PET as stand‐alone modalities. RESULTS For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. DISCUSSION AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease. Highlights A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.

AbstractBackgroundThe Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients.MethodThe Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate.ResultAs an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer’s disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered “Appropriate” to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered “Appropriate” to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD.ConclusionThe updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape.

Abstract Background Suspicious F-18 fluciclovine PET/CT findings for osseous metastases from prostate cancer (PC) were targeted for core needle biopsy. We correlated the maximum standardized uptake value (SUVmax) of biopsied lesions, with biopsy results, other diagnostic outcomes, and blood and tissue molecular analysis (TMA). Material and Methods Patients with castrate resistant prostate cancer (CRPC) were recruited from a university oncology clinic. SUVmax, histology, blood, and TMA were correlated. Results Fifteen patients were enrolled and 12 underwent bone biopsies. Fifty percent of bone biopsies demonstrated malignancy. Higher SUVmax was associated with positive biopsies for adenocarcinoma (P = .003), and lesions with SUVmax ≥ 5.1 were all positive for malignancy. Significant correlation between blood and somatic TMA (P = .002) was also found. Conclusion Higher uptake of F-18 fluciclovine was associated with higher predictive value for osseous metastasis on biopsy. There was a significant correlation between blood and TMA.

5002 Background: In the phase 3 VISION study, gallium (68Ga) gozetotide (68Ga-PSMA-11) PET/CT imaging was used to determine eligibility for lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617). Given that 177Lu-PSMA-617 targets PSMA, we assessed the association between quantitative PSMA imaging parameters and treatment outcomes. Methods: In VISION, adults with mCRPC with ≥ 1 PSMA-positive (+) and no PSMA-negative lesions meeting the exclusion criteria were enrolled. In this sub-study, the association between imaging data from pre-enrollment 68Ga-PSMA-11 PET/CT scans of pts in the 177Lu-PSMA-617 group and clinical outcomes was assessed. Imaging data meeting quality requirements were analyzed for 548/551 pts. PSMA expression was quantified by 5 PET parameters: PSMA+ lesions by region, mean standardized uptake value (SUVmean), maximum SUV (SUVmax), PSMA+ tumor volume, and tumor load (PSMA+ tumor volume × SUVmean). Parameters were extracted from the whole body and 4 regions. Association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response was assessed. Results: Most pts (92.7%) had PSMA uptake in bone. In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed (whole-body data shown in Table). Higher whole-body SUVmean was associated with improved clinical outcomes; pts in the highest quartile (SUVmean: rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (< 6.0; < 5.7), respectively. Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis. Conclusions: Higher SUVmean is strongly associated with improved outcomes with 177Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68Ga-PSMA-11 PET/CT scan to identify pts who will benefit from PSMA-targeted radioligand therapy.[Table: see text]

Osteosarcoma (OS) is a malignant bone tumor which is found primarily in adolescents, with the distal femur as the most common location. OS with a jaw primary is present in only about 10% of cases and the risk of recurrence is considered to be decreased in the jaw versus other primary locations. We present a unique case of a patient with localized OS of the jaw with an isolated recurrence in her bone marrow almost 5 years after completion of initial treatment.