Lutetium-177-PSMA-I&T

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [⁶⁸Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [¹⁷⁷Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUV_max on [⁶⁸Ga]Ga-PSMA-11 PET/CT above liver SUV_mean. Patients were planned to receive four cycles ~ 7.4 GBq [¹⁷⁷Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [¹⁷⁷Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [¹⁷⁷Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

Metastatic castrate resistant prostate cancer (mCPRC) remains an aggressive form of prostate cancer that no longer responds to traditional hormonal treatment alone. Despite the advent of novel anti-androgen medications, many patients continue to progress, and as a result, there is a growing need for additional treatment options.

Lutetium-177 (¹⁷⁷Lu) - PSMA-617 has become one of the new frontline treatment options for refractory metastatic castrate resistant prostate cancer after the failure of novel anti-androgen therapy and chemotherapy. Lu-177 has been used in real-world prospective trials and is now becoming utilized in newer phase III clinical trials. Here, we present a comprehensive overview of the current literature, covering retrospective studies, prospective studies, and clinical trials that established Lutetium-177-PSMA-617 (¹⁷⁷Lu-PSMA-617) for the treatment of mCRPC.

¹⁷⁷Lu - PSMA-617 has been approved for treatment of mCRPC based on positive phase III studies. While this treatment is tolerable and effective, biomarkers are necessary to determine which patients will benefit. In the future, radioligand treatments will likely be utilized in earlier lines of therapy and potentially in combination with other prostate cancer treatments.