Kaván, Petr

TPS646 Background: SSTR-targeted RPT has transformed the treatment landscape for NETs, significantly improving clinical outcomes in phase 3 studies versus other targeted therapies. Nevertheless, disease progression and renal toxicity after treatment highlight the need for further improvement. Use of the α-emitter 225 Ac as the radioactive component has shown promising results in clinical studies: initial data from ACTION-1 suggest promising efficacy for RYZ101, a first-in-class, highly potent α-emitting RPT, in patients with SSTR+ GEP-NETs progressing after 2–4 cycles of 177 Lu-somatostatin analogs. RYZ401 is a cyclic 6-amino acid SSTR-targeting peptide agonist conjugated to a DOTA chelator bound to 225 Ac. Preclinical data have shown an improved therapeutic window versus DOTATATE. RYZ401 has the potential to deliver higher radiation doses to tumors, with improved renal clearance and lower kidney absorbed dose, potentially eliminating the need for amino acid infusion. Methods: RYZ401-101 is a global, multicenter, phase 1, first-in-human, dose-escalation/-expansion study designed to determine the recommended phase 2 dose (RP2D) and optimal treatment regimen, safety and tolerability, and preliminary efficacy of RYZ401 in patients with NETs and other selected solid tumors expressing SSTRs. Key eligibility criteria: histologically confirmed metastatic or unresectable well-differentiated NETs; WHO grade 1–3 (Ki-67 ≤55%); ≥1 SSTR PET-positive measurable lesion; and disease progression after ≥1 prior treatment line. In dose escalation, 6–18 patients will receive escalating doses of RYZ401 (2.0–11.1 MBq IV Q6W × 2–4 cycles); no amino acid co-infusion is planned. In dose expansion, approximately 80 patients will receive RYZ401 at the RP2D, 40 patients with well-differentiated GEP-NETs (cohort A) and 40 with other SSTR+ tumors including non-GEP-NETs (cohort B). Primary endpoints: dose-limiting toxicities in weeks 1–4 of treatment (dose escalation) and safety (dose expansion). Secondary endpoints: safety, pharmacokinetics, and efficacy outcomes (dose escalation and expansion). RYZ401 dosimetry will be evaluated in a sub-study of 10−16 patients. Enrollment is ongoing in the USA. Clinical trial information: NCT07165132 .

761 Background: Glycogen Synthase Kinase-3β (GSK-3β) is a known therapeutic target in cancer including pancreatic adenocarcinoma (PDAC). The combination of elraglusib (9-ING-41), a novel GSK-3 inhibitor, and gemcitabine/nab-paclitaxel (GnP) is being evaluated as first-line therapy for patients with metastatic PDAC (mPDAC). We previously reported topline results indicating that the 1801 Part 3B phase 2 trial (NCT03678883) met its primary endpoint, showing a clinically meaningful survival benefit in patients treated with elraglusib/GnP compared to GnP alone. Here, we examined whether gene mutations correlated with clinical outcomes in mPDAC patients enrolled in this randomized phase 2 trial. Methods: For mutational analysis, archival tumor and/or plasma samples were obtained from 53 (GnP group) and 117 (elraglusib/GnP group) patients with previously untreated mPDAC. Cell-free DNA and/or tumor-extracted DNA were analyzed using the next generation sequencing. The comparison of the response rates was performed with the use of Chi-square tests. Kaplan-Meier survival curves were compared by log-rank (Mantel-Cox) tests. Results: Mutational analysis identified frequently mutated genes (detectable in ≥25% of patients): KRAS (141/170, 83%), TP53 (121/170, 71%), and CDKN2A (56/170, 33%). Mutations in KRAS, TP53, or CDKN2A genes did not correlate with objective response rate. Based on 81% of the recorded death events in the elraglusib/GnP group and 91% in the GnP group (topline data April, 2025), KRAS and TP53 gene mutations were associated with worse overall survival (OS) in patients treated with elraglusib/GnP (p<0.05) but not in GnP-treated patients. The rate of triple (KRAS+TP53+CDKN2A) mutations was significantly higher in the patients with OS<2 months as compared to the patients with OS>2 months in the elraglusib/GnP group (p<0.05) but not in the GnP group. Conclusions: Our preliminary results identified KRAS and TP53 gene mutations as potential predictive biomarkers of clinical outcome in elraglusib/GnP-treated mPDAC patients. Updated OS data and mutational analysis will be included in the final presentation. Clinical trial information: NCT03678883 .

653 Background: Elraglusib (9-ING-41), a novel small molecule inhibitor of GSK-3ß, has a multimodal mechanism of action that enhances chemotherapy cytotoxicity and regulates anti-tumor immune cell response. Elraglusib was evaluated in a randomized, open-label, phase 2 study (NCT03678883) comparing elraglusib/GnP vs GnP in previously untreated mPDAC. Methods: Pts were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP. Primary endpoint was mOS, with 1-yr OS rate estimates summarizing clinical benefit throughout the study. Secondary endpoints were ORR, mPFS, and TEAEs/TRAEs. Pre-dose cytokines, mutational analysis, and immunophenotyping were correlated with outcomes. An oral presentation at ASCO 2025 discussed preliminary data. Results: As of 27 April 2025, the primary analysis set included 155 pts in the elraglusib/GnP arm and 78 pts in the GnP arm, with 52.8% males and 57.5% ECOG PS 1. The 1-yr OS rate was 44.1% with elraglusib/GnP vs 22.3% with GnP; the mOS was 10.1 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.62; p=0.01) with approximately 79% events recorded (25.8% of pts on elraglusib/GnP and 10.3% on GnP were censored with the majority at >12 mo OS). Improved OS with elraglusib/GnP was consistent across all randomized pts and subgroups regardless of liver metastases, ECOG status, or baseline CA 19-9 levels. Most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment (66.5% pts vs 0 with GnP). Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 52.3% (vs 30.8%) and anemia 25.2% (vs 29.5%). No differences in sepsis/febrile neutropenia rates were between arms. RAS , TP53 and CDKN2A co-mutations were associated with worse OS in the elraglusib/GnP arm only (p<0.05). Elevation in pre-dose cytokines including CXCL2 correlated with improved OS in the elraglusib/GnP arm. Additionally, increased CD8+ T cells, granzyme B, and NK cells and reduced MDSCs were observed in elraglusib-treated tumors. Conclusions: A significant benefit for 1-yr OS and mOS and a favorable trend for ORR were observed with the addition of elraglusib to GnP. The mOS was lower in the GnP arm vs historical studies, likely due to early deaths in the first 2 months, but aligns with mOS estimates in the real-world analysis with broad heterogeneous population. Our study included 19.7% pts with albumin <3.0 g/dL and >25% with CA 19.9 levels > 8,000 U/mL. Immune correlates support elraglusib’s immune-modulatory role. Final efficacy data cut-off in Dec 2025 and correlative studies will be presented. Clinical trial information: NCT03678883 . Outcome Elraglusib/GnPN=155 GnPN=78 Primary endpoint: mOS (mo)HR=0.62; log-rank p=0.01 10.1 7.2 Events, n (%) 115 (74.2) 70 (89.7) Primary endpoint: 1-yr OS (%) 44.1 22.3 18-month OS (%) 20.5 4.4 24-month OS (%) 13.2 0 mPFS (mo)HR=0.9; p=NS 5.6 5.1 Events, n (%) 136 (87.7) 75 (96.2) ORR, n (%) 44 (28.4) 17 (21.8)