Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.

Charting the Course of Targeted α Therapy With First-in-Human, Postadministration Image-Guided Dosimetry and Response Assessment of 212 Pb-VMT-α-NET in Metastatic Neuroendocrine Tumors.

ABSTRACT: 212 Pb emerges as a compelling in vivo α-particle generator for targeted α therapy due to its favorable half-life ( t1/2 = 10.6 hours) aligning with the biological half-lives of small peptides and its potent α-particle emissions within the decay series. However, one of the challenges with 212 Pb is to perform appropriate image-guided dosimetry. To date, all the data have been extrapolated from its imaging analog, 203 Pb. We present the first-in-human posttherapy image-guided dosimetric estimates of a single cycle of 212 Pb VMT-α-peptide, administered in a 41-year-old woman with an advanced grade 2 NET. The patient also demonstrated partial response on treatment.

Potential Efficacy of 68 Ga-Trivehexin PET/CT and Immunohistochemical Validation of αvß6 Integrin Expression in Patients With Head and Neck Squamous Cell Carcinoma and Pancreatic Ductal Adenocarcinoma.

PURPOSE: αvß6 integrin is exclusively expressed in epithelial cells and is upregulated in many carcinomas, such as pancreatic ductal adenocarcinomas (PDACs) and head and neck squamous cell carcinomas (H&NSCCs). Trivehexin is a recently synthesized trimerized αvß6 integrin selective nonapeptide, which can be labeled with a positron emitter like 68 Ga. This is a pilot study to assess the potential role of 68 Ga-Trivehexin PET/CT in patients with H&NSCC and PDAC and their correlation with αvß6 integrin expression by the tumor tissue on immunohistochemistry (IHC). PATIENTS AND METHODS: Thirty-two patients with suspected H&NSCC (n = 20) or PDAC (n = 12) underwent whole-body 68 Ga-Trivehexin PET/CT and 18 F-FDG PET/CT scans on 2 separate days. All 32 patients underwent biopsy from the tumor site for histopathological diagnosis and IHC for αvß6 integrin expression. The degree of αvß6 integrin expression on IHC was scored using the immunoreactive score and modified 4-point immunoreactive score classification. RESULTS: The 68 Ga-Trivehexin PET images demonstrated increased tracer uptake (mean SUV max 5.9 ± 3.3) in the primary and metastatic lesions with good lesion delineation in 8 out of the 9 cases of PDACs. However, FDG PET showed increased tracer uptake in 7 cases (6.2 ± 2.6). Among various cases of H&NSCC, increased uptakes of 68 Ga-Trivehexin (6.6 ± 4.5) and 18 F-FDG (12.7 ± 6.7) were seen in 17 out of the 18 patients. The 2 cases of inflammatory changes with suspected disease recurrence showed increased tracer uptake in 18 F-FDG PET (7.98 ± 3.1) and no significant uptake in 68 Ga-Trivehexin PET (2.2 ± 0.34).IHC showed higher expression of αvß6 integrins in lesions with higher uptake of 68 Ga-Trivehexin. A higher sensitivity, specificity, and accuracy of 68 Ga-Trivehexin PET over 18 F-FDG PET was seen for detection of primary and metastatic lesions. CONCLUSIONS: 68 Ga-Trivehexin is a promising noninvasive molecular imaging agent for tumors expressing αvß6 integrin, especially in cases where 18 F-FDG PET/CT scan may be suboptimal due to its low uptake, or due to its nonspecific uptake around tumor sites.

Lead-203 VMT-α-Neuroendocrine Tumor Scintigraphy: A Promising Theranostics Agent.

Targeted alpha therapy (TAT) using lead-212 (Pb-212)-labeled peptides presents an attractive option for the treatment of metastatic neuroendocrine tumors (NETs). As Pb-203 presents an accurate diagnostic surrogate to Pb-212, imaging with Pb-203-labelled peptides can be an important prerequisite to assess the feasibility of TAT with Pb-212-labelled agents. Here, we present the imaging data of a patient with metastatic NET with Pb-203 VMT-α-NET, a somatostatin receptor targeting agent, and demonstrate the matching distribution of Pb-203 VMT-α-NET with Ga-68 DOTANOC.