Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study

Abstract

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.

Keywords: (177)Lu-PSMA therapy; Adenoid cystic carcinoma; Prostate-specific membrane antigen; Salivary duct carcinoma; Salivary gland cancer.

Figure 1

Treatment-related adverse events. Figure lists all adverse events possibly, probably, or definitely related to [¹⁷⁷Lu]Lu-PSMA-I&T treatment, sorted based on frequency of occurrence. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Patients were counted once at the highest grade for each adverse event. Abbreviations: ¹⁷⁷Lu: lutetium-177; PSMA: prostate-specific membrane antigen.

Figure 2

Efficacy outcomes. (A) Swimmer plot displaying the time from start of therapy to progressive disease or death (bars), and timepoints of [¹⁷⁷Lu]Lu-PSMA-I&T treatments and confirmed stable disease (signs). (B) Kaplan-Meier estimate of progression-free survival of the AdCC cohort. Abbreviations: ¹⁷⁷Lu: lutetium-177; AdCC: adenoid cystic carcinoma; 95% CI: 95% confidence interval; Lu: lutetium-177; PFS: progression-free survival; PSMA: prostate-specific membrane antigen; SDC: salivary duct carcinoma.

Figure 3

Sum diameter of RECIST target lesions and tumor growth rate before and after [¹⁷⁷Lu]Lu-PSMA-I&T treatment. (A) Sum diameter of RECIST target lesions of all patients. T=0 indicates the start of [¹⁷⁷Lu]Lu-PSMA-I&T therapy. Only imaging timepoints where patients were not on other anticancer therapy are visualized. (B) Sum diameter of RECIST target lesions of patients with CT imaging available both at least six months before and six months after treatment initiation. Pre-therapy timepoints are only visualized from the latest timepoint at least six months pre-treatment. Dashed lines represent the tumor growth rate before treatment. Only imaging timepoints where patients were not on anticancer therapy are visualized. (C) Tumor growth rate before and after treatment of patients with imaging available both at least six months before and six months after treatment initiation. Abbreviations: ¹⁷⁷Lu: lutetium-177; AdCC: Adenoid cystic carcinoma; CT: computed tomography; PSMA: prostate-specific membrane antigen; RECIST: Response Evaluation Criteria in Solid Tumors; SDC: salivary duct carcinoma.

Figure 4

Baseline and evaluation PSMA-PET and CT images of representative cases with stable disease and progressive disease. (A) 70-year old woman with AdCC originating from Bartholin's gland (status post surgery), with metastases in the lungs and the pleurae. At interim evaluation four weeks after the second [¹⁷⁷Lu]Lu-PSMA-I&T treatment cycle and at evaluation three months after the fourth treatment cycle, the size of all metastases was stable (red arrows). The patient had stable disease until 23 months after treatment initiation. (B) 63-year old woman with AdCC originating from Bartholin's gland (status post surgery), with metastases in the lungs, the liver, and the bones. At interim evaluation after the second [¹⁷⁷Lu]Lu-PSMA-I&T treatment cycle, progressive disease was observed. This included growth of the lung metastases (yellow arrows) and the bone metastases (white arrows), and a new liver metastasis (orange arrow). Radioligand therapy was ceased due to the progression. Abbreviations: ¹⁷⁷Lu: lutetium-177; AdCC: Adenoid cystic carcinoma; CT: computed tomography; PET, positron emission tomography; PSMA: prostate-specific membrane antigen.

Figure 5

Scatter plot displaying the correlation between the baseline [⁶⁸Ga]Ga-PSMA-11 PET/CT SUV_mean and the absorbed dose per index tumor lesion. Abbreviations: ⁶⁸Ga: gallium-68; CT: computed tomography; Ga: gallium-68; PET: positron emission tomography; PSMA: prostate-specific membrane antigen; SUVmean: mean standardized uptake value.