Long-term adverse events and survival of patients with neuroendocrine neoplasms (NEN) receiving peptide receptor radioligand therapy (PRRT) using 225Ac- and 225Ac-/177Lu-labeled (TANDEM) antagonist DOTA-LM3: A retrospective analysis

Introduction: PRRT offers radiomolecular precision medicine for SSTR-positive NEN with favorable toxicity and improved PFS. In resistant cases, ²²⁵Ac is a notable candidate for targeted α therapy. The possibility of using SSTR antagonists like DOTA-LM3 that only minimally internalize into tumor cells and show higher tumor uptake, tumor-to-background ratio and longer retention time, is a significant development in radiotheranostics. This retrospective study assesses ²²⁵Ac-DOTA-LM3 safety in advanced NEN patients, as monotherapy and with ¹⁷⁷Lu as TANDEM. We also evaluate OS and follow-up time.

Methods: Between March 2022 and November 2023, 24 patients (17 men, 7 women; age range 36-67, mean 51.7) received ²²⁵Ac-DOTA-LM3 PRRT based on ⁶⁸Ga-DOTA-LM3 PET/CT findings. Pancreas was the most common primary site (14), followed by small intestine (6), rectum (2), pheochromocytoma (1) and CUP-NEN (1). The ²²⁵Ac administered activity varied according to the number of PRRT cycles per patient. Premedication (antiemetics/dexamethasone) and para-aminohippuric acid for renal protection was administered. PRRT-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.5.0) and assessed focusing on hematological, renal, and hepatic profile.

Results: In total, 38 ²²⁵Ac-DOTA-LM3 cycles were administered over 20 months (14 monotherapies, 24 TANDEM). 12 patients received one cycle, either monotherapy or TANDEM (range 2-20 MBq ²²⁵Ac); 10 patients received two (range 9-30 MBq ²²⁵Ac) and 2 patients three cycles (26 and 32 MBq ²²⁵Ac). Therapy was generally well tolerated with mostly mild and transient acute adverse events: vomiting (7); nausea (6); flare pain (6); flushing (5); diarrhea (2); fatigue (1); hypertension (1). During follow-up three patients died (OS 12-20 months) due to post-surgical complications (one patient) or disease progression after initial response (two patients). 21 patients are still alive (follow-up 2-18 months). At baseline 13 patients had anemia G1 (54.1%), 6 patients anemia G2 (25%) and 1 patient anemia G3 (4.1%). After PRRT the proportion of patients with anemia G2 did not change and with anemia G3 increased to 2 (8.3%). Baseline leucopenia was G1 in 1 patient (4.1%), G2 in 2 patients (8.3%) and G3 in 1 patient (4.1%). After PRRT G1 and G2 leucopenia increased to 3 (12.5%) and the only patient with leucopenia G3 did not worsen. Absolute neutrophil count G3 occurred in one patient about three weeks after TANDEM therapy. Baseline thrombocytopenia G1 and G2 was present in 3 and 1 patient (12.5% and 4.1%), respectively. After PRRT the number of patients with thrombocytopenia G1 increased to 6 (25%), with G2 to 2 (8.3%); one patient showed thrombocytopenia G3 (4.1%) and two patients G4 (8.3%). One patient was diagnosed with acute myeloid leukemia 12 years after the first ⁹⁰Y-DOTATOC PRRT. Baseline creatinine levels were normal in 19 patients (79.1%), 4 patients had renal insufficiency G1 (16.6%) and 1 patient G2 (4.1%). After PRRT 1 patient progressed from G2 to G3 (4.1%) and 2 patients developed renal insufficiency G3 (8.3%). In our cohort, no significant PRRT-related hepatotoxicity was observed: all patients with baseline altered liver profile had hepatic metastases and did not worsen after therapy.

Conclusions: Our retrospective analysis shows that PRRT is relatively safe in terms of long-term toxicity, with transient and mild acute adverse events. Only few patients experienced G3/G4 adverse events: two anemia G3, one ANC G3, three thrombocytopenia G3/G4, one acute myeloid leukemia (3 months after TANDEM and 12 years after initial PRRT), three renal insufficiency G3 (one patient with known neurogenic bladder and recurrent urinary retention; in the other patient, PRRT-related toxicity was excluded by renal biopsy, revealing tubular damage without glomerular disturbances). PRRT with ²²⁵Ac-DOTA-LM3 also showed promising survival outcomes in patients failing treatment with ¹⁷⁷Lu-DOTATATE or ¹⁷⁷Lu-DOTATOC.