Ferone, Diego

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Grant Recipient; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. G. Fidan Yaylali: None. M. Doknic: Speaker; Self; Pfizer, Inc., Novo Nordisk, Merck, Sandoz. E. Isaeva: None. A. Dreval: None. A. Gilis-Januszewska: None. E. Gezer: None. I. Bancos: Advisory Board Member; Self; Diurnal, Spruce, Neurocrine, Adrenas, Sparrow, Corcept, HRA Pharmaceuticals, Recordati, Xeris, AstraZeneca, Novo Nordisk. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is a rare, serious disorder characterized by overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). There is a need for new, convenient therapies that provide effective disease control. CAM2029 is a novel subcutaneous octreotide depot designed for convenient once-monthly self-administration (ready-to-use syringe or injection pen). In a 24-week, Phase 3 trial (ACROINNOVA 1), CAM2029 was superior to placebo at attaining IGF-1 response (≤upper limit of normal [ULN] at week 22/24: 72.2% vs 37.5%; P=0.0018) in patients with acromegaly previously controlled under standard of care (SoC; octreotide long-acting repeatable [LAR]/lanreotide Autogel). Here, we report interim data from another Phase 3 trial of CAM2029 (ACROINNOVA 2; NCT04125836), focusing on the “New to CAM2029” subgroup of patients whose acromegaly was either controlled or uncontrolled under SoC. Methods: This 52-week, Phase 3, open-label trial (with a 52-week extension) enrolled patients who had received CAM2029 or placebo in ACROINNOVA 1 (reported separately) and “New to CAM2029” patients who were adequately or inadequately controlled (IGF-1 ≤2x ULN) on a stable dose of octreotide LAR/lanreotide Autogel for ≥3 months (data reported here). In the main part of the trial, new patients received once-monthly CAM2029 20 mg for up to 52 weeks. The primary endpoint was adverse events (AEs). Secondary endpoints included (i) the proportion of patients with IGF-1 ≤1x ULN (weeks 50/52 mean), (ii) the change from baseline in IGF-1, and (iii) the combined IGF-1 and GH response. Baseline values reflected SoC treatment. Data cutoff: May 23, 2023. Results: Eighty-one new patients were enrolled (mean age 51.8 years; 59.3% female). No new or unexpected safety signals were observed. The most common treatment-emergent AEs were injection site erythema (n=22) or swelling (n=13), and headache (n=12). AEs were mostly mild (grade 1/2); there were no serious or Grade 3 treatment-related AEs attributed to CAM2029. IGF-I response increased from 14.8% at baseline SoC (12/81) to 33.3% (20/60 patients with available data) at weeks 50/52. The estimated increase in IGF-1 response (linear probability model) from baseline at week 52 was 21.9% (95% CI: 9.6, 34.1). Biochemical control for both IGF-1 and GH improved over time: 30.0% of patients (18/60) had a combined IGF-1 and GH response at the end of the main part of trial, vs 11.7% (7/60) at baseline. Conclusion: CAM2029 was well tolerated with a safety profile consistent with that of SoC. Biochemical control rates improved from SoC baseline over 52 weeks of CAM2029 treatment in the “New to CAM2029” patients. These findings reinforce the efficacy and safety of CAM2029 in patients with acromegaly, including patients with uncontrolled disease with current SoC treatment (octreotide LAR/lanreotide Autogel). Presentation: 6/1/2024

4131 Background: NETTER-2 (NCT03972488) is the first randomized study to evaluate radioligand therapy ([177Lu]Lu-DOTA-TATE; hereafter 177Lu-DOTATATE) at first line (1L) in patients (pts) with advanced, well-differentiated higher grade (G2 and G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Significant improvements in progression-free survival and objective response rate (ORR) were observed for pts receiving 177Lu-DOTATATE. This sub-analysis of NETTER-2 assessed safety and time to response (TTR). Methods: Eligible pts (n=226) were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki67 ≥10% and ≤55%) advanced GEP-NETs and were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq every 8 weeks [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during 177Lu-DOTATATE treatment then Q4W (177Lu-DOTATATE arm), or 60 mg octreotide LAR Q4W (control arm). Hematologic adverse events (AEs) and laboratory toxicities were scored according to CTCAE grade. Response was assessed centrally based on conventional imaging (RECIST 1.1 criteria). Results: The AE pattern in the 177Lu-DOTATATE arm was consistent with the established safety profile. Among laboratory abnormalities, grade 3/4 decreases in lymphocytes (38.1% vs 2.7%), leukocytes (4.1% vs 0), neutrophils (3.4% vs 0), platelets (2.0% vs 0) and hemoglobin (1.4% vs 2.7%) were observed in 177Lu-DOTATATE (n=147) and control (n=73) arms, respectively; median time to first occurrence of hematologic toxicities was 4.4 months among pts with immediate hematotoxicities. These events were transient and manageable. There was no notable difference in infection rates between treatment arms (31.3% 177Lu-DOTATATE and 27.4% control). One case of myelodysplastic syndrome was observed (177Lu-DOTATATE arm ~14 months after first cycle). Five fatal AEs occurred during the randomized treatment period; all considered unrelated to treatment and attributed to GEP-NET progression. AEs leading to 177Lu-DOTATATE dose interruption, reduction and discontinuation occurred in 14 (9.5%), 2 (1.4%) and 3 (2.0%) pts, respectively. Among 65 responders in the 177Lu-DOTATATE arm (ORR 43 %), median TTR (Q1, Q3) was 5.7 months (4.1, 8.3). Most responses occurred during the 4-cycle treatment with 177Lu-DOTATATE. Conclusions: In pts with advanced G2 and G3 (Ki67 ≥10% and ≤55%) GEP-NETs treated with 177Lu-DOTATATE at 1L the most common hematologic toxicity was lymphopenia, but infection rates were similar vs control. With a median TTR of 5.7 months, most responses to 177Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177Lu-DOTATATE and supports its use at 1L for this pt population. Clinical trial information: NCT03972488 .

LBA588 Background: Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor. Methods: Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS. Results: Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p < 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p < 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm). Conclusion: 177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488 .