PurposeOctreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety.MethodsTwo studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries.ResultsMedian duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61–2.03]; OCT30, RR = 1.09 [95% CI, 0.70–1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28–3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69–3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia.ConclusionsThe results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.
85 Background: In the VISION trial, targeted radioligand therapy with 177Lu-PSMA-617 significantly prolonged radiographic progression free survival (rPFS) and overall survival when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA)-PET-positive metastatic castration-resistant prostate cancer. There was a higher incidence of treatment-emergent adverse events (TEAEs) with 177Lu-PSMA-617 + SoC vs SoC. However, treatment exposure was more than three times longer in the 177Lu-PSMA-617 + SoC arm and thus relative toxicity may have been overestimated. A post hoc analysis of the relationship between exposure and frequency of TEAEs was performed to facilitate comparison of rates between arms. Methods: In this international, open-label study, adult patients previously treated with ≥ 1 androgen receptor pathway inhibitors and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, ≤ 6 cycles) + SoC or SoC. Safety was a secondary endpoint. TEAEs (regardless of causality) were reported from start of randomized treatment for up to 30 days after last treatment administration (including SoC) or 1 day before subsequent anticancer treatment, whichever occurred first. Overall TEAE incidence was adjusted for treatment exposure by calculating incidence per 100 patient treatment-years (PTY). The analysis was performed for the first occurrence of TEAEs. Results: Exposure-adjusted incidence of any grade, grade ≥ 3 and selected TEAEs are listed in the table. There was similar exposure-adjusted incidence of gastrointestinal events and fatigue and higher exposure-adjusted incidence of musculoskeletal and renal events with SoC compared with 177Lu-PSMA-617 + SoC suggesting an association with treatment exposure rather than 177Lu-PSMA-617. Dry mouth, dry eye and acute myelosuppression maintained a higher incidence, confirming relationship with 177Lu-PSMA-617 treatment. Conclusions: The adjusted safety analysis, accounting for a longer safety observation due to longer rPFS in patients receiving 177Lu-PSMA-617, reveals a comparable incidence of TEAEs between arms. This confirms a favorable risk/benefit profile of 177Lu-PSMA-617 added to SoC in this patient population. Clinical trial information: NCT03511664. [Table: see text]
5047 Background: In the phase 3 VISION study, lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) + protocol-permitted standard of care (SoC) improved clinical benefit and was generally well tolerated despite a higher rate of adverse events (AEs) than SoC alone. Here we assess AE incidence by exposure to 177Lu-PSMA-617. Methods: VISION was an international, open-label study of 177Lu-PSMA-617 in adults with PSMA-positive mCRPC previously treated with ≥ 1 androgen receptor pathway inhibitor and 1–2 taxane regimens. Patients received 177Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤ 6 cycles) + SoC or SoC alone. rPFS and OS were primary endpoints; safety was a secondary endpoint. AE analysis by exposure to 177Lu-PSMA-617 was carried out in pre-specified subgroups. 177Lu-PSMA-617 cycle duration was generally ̃6 weeks and cycle 6 duration was until the earliest date of subsequent treatment, and date of last administration of randomized treatment (including SoC) + 30 days. The cycle of onset in which an AE first occurred in a patient at maximum grade was assessed. Results: The median duration of cycle of onset for cycles 1 to 5 was 6 weeks; for cycle 6, it was 26.6 weeks (Table). Of the 529 patients in the 177Lu-PSMA-617 group, 240 (45.4%) received ≤ 4 cycles and 289 (54.6%) received 5–6 cycles of treatment. In patients who received ≤ 4 or 5–6 cycles, 234 (97.5%) and 285 (98.6%) treatment-emergent AEs (TEAEs); 100 (41.7%) and 92 (31.8%) serious TEAEs; 205 (85.4%) and 246 (85.1%) treatment-related AEs; and 13 (5.4%) and 6 (2.1%) fatal TEAEs, respectively, were observed. Number of TEAEs and serious TEAEs by cycle of onset are shown in the Table. Conclusions: Over 50% of patients with mCRPC received 5–6 cycles of 177Lu-PSMA-617. For cycles 1–5, TEAEs occurred at every cycle, with similar frequency. More TEAEs were observed in cycle 6, reflecting its longer median duration than other cycles. Clinical trial information: NCT03511664. [Table: see text]
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