Pernot, Simon

4213 Background: Elraglusib (9-ING-41), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has multimodal antitumor activity. In the international, open-label, randomized phase 2 1801 Part 3B study, elraglusib plus gemcitabine/nab-paclitaxel (GnP) was evaluated in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), with patients randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (mOS) and 1-year survival. The GnP control arm demonstrated shorter mOS than contemporary randomized trials (7.2 months vs 9.2 months in NAPOLI-3 and 9.7 months in PASS-01), driven by higher early mortality (0–2 months: 23.1% vs 10.1% in NAPOLI-3). Given balanced randomization, similar early mortality was inferred in the elraglusib/GnP arm, prompting post-hoc analyses to contextualize efficacy and identify factors associated with early death. Methods: Efficacy and safety were summarized descriptively. Time-to-event endpoints were analyzed using Kaplan–Meier estimates, log-rank testing, and Cox proportional hazards models. Response rates were compared using the Cochran–Mantel–Haenszel test. Post-hoc subgroup, sensitivity, and machine-learning–based multivariate analyses explored clinical, demographic, and biomarker correlates of survival and early mortality. Results: In the full randomized population (elraglusib/GnP n=155; GnP n=78), elraglusib/GnP improved mOS by 2.9 months versus GnP (10.1 vs 7.2 months; HR 0.62; 95% CI 0.46–0.84; p=0.01), with 1-year survival rates of 44.1% versus 22.3%. Among patients receiving ≥1 full treatment cycle, mOS was 12.5 months with elraglusib/GnP and 8.5 months with GnP, comparable to contemporary registrational trials. Across multiple post-hoc sensitivity analyses—including evaluable patients, those matched to NAPOLI-3 baseline tumor burden, patients treated in the EU (early mortality 4%), and those achieving ≥20% CA19-9 decline within the first 1–2 cycles—elraglusib/GnP consistently demonstrated a ≥4-month OS advantage. Early death was associated with low baseline albumin (<3 g/dL), high CA19-9 (>800 U/mL), high tumor burden, and KRAS, TP53, and CDKN2A co-mutations. Conclusions: The elevated early mortality in the GnP control arm reflects enrollment of a heterogeneous, real-world mPDAC population with less restrictive eligibility than recent registrational trials. Post-hoc analyses identify key clinical and molecular drivers of early death and confirm a consistent survival benefit with elraglusib/GnP. These hypothesis-generating findings directly inform eligibility criteria, stratification, and endpoint assumptions for the planned phase 3 trial. Clinical trial information: NCT03678883 .

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)

Background Tumors with mismatch repair deficiency (MMRd) classically display concomitant loss of MLH1/PMS2 or MSH2/MSH6 on immunohistochemistry (IHC) with microsatellite instability-high (MSI-High) status on molecular testing. Nevertheless, a different phenotype can occur in up to 15% of MMRd tumors (unusual phenotype). Data on the efficacy of immunotherapy in this population remain scarce. Methods We conducted a retrospective study within the IMMUNODIG MSI cohort including patients with advanced gastrointestinal MMRd tumors treated with immune checkpoint blockade in the real-world setting. We selected patients with both IHC and MSI assays data available. Unusual MMRd tumors were classified into four distinct groups: (1) isolated loss of PMS2 or MSH6 with MSI-H (isolated/MSI-H), (2) complex loss of MMR proteins with MSI-H (complex/MSI-H), (3) loss of one or more MMR proteins without MSI-H (MMRd-IHC/microsatellite stability (MSS) or MSI-low (MSI-L)), and (4) four MMR proteins retained with MSI-H (retained IHC/MSI-H). Results Out of 759 patients in the IMMUNODIG-MSI cohort, 571 patients met inclusion criteria. Of these, 90 (15.8%) had an unusual phenotype (47 isolated/MSI-H, 19 complex/MSI-H, 16 MMRd-IHC/MSS or MSI-L and 8 retained IHC/MSI-H). Compared with classical phenotypes, patients with a tumor harboring an unusual phenotype had a younger age at treatment (p=0.005), increased RAS mutation (p=0.005), reduced BRAF p.V600E mutation rates (p<0.001), a higher proportion of Lynch syndrome (p<0.001) and a higher prevalence of non-colorectal cancers (p=0.021). After a median follow-up of 28.1 months (mo), there was a significant difference in progression-free survival, with median values of not reached, 66.4 mo, 37.2 mo, 18.3 mo and 5.5 mo for complex/MSI-H, isolated/MSI-H, classical, retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L subgroups, respectively (p<0.001). Notably, objective response rates were 59.1%, 58.7%, and 63.2% for complex/MSI-H, isolated/MSI-H and classical contrasting with 50% and 25% for retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L, with no complete response observed in the latter two. Conclusion Our findings underscore the need for dual testing and advocate for the presence of both MMRd-IHC and MSI-H for optimal immunotherapy response. Of note, complex MMR aberrations and isolated PMS2/MSH6 losses with MSI-H may represent promising candidates for enhanced immunotherapy efficacy.

3569 Background: Immune checkpoint inhibitors (ICIs) are a standard treatment for gastrointestinal (GI) cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). However, around 50% of patients develop resistance to ICIs, during treatment or after discontinuation. In these patients, the efficacy of reuse an ICI in patients progressing during a previous ICI (rechallenge), or in patients who progressed after discontinuation (reintroduction), remains unknown. The INFLATE study evaluates the efficacy of ICI reuse in patients who progressed on or after discontinuing ICI. Methods: This is a multicenter international retrospective study from the IMMUNODIG cohort, including patients from 34 centers in France, the United States, Italy, Belgium and Spain. All patients received ICI for dMMR/MSI GI cancer. We analyzed patients who had progressed following initial ICI (ICI-1) and subsequently received a rechallenge or a reintroduction with ICI (ICI-2), either monotherapy (mono-ICI) or biotherapy (bi-ICI). Results: A total of 77 patients were included, receiving bi-ICI (N = 34) or mono-ICI (N = 43) during ICI-2. The majority (76%) had a metastatic colorectal cancer. The reason for discontinuing ICI-1 was disease progression in 53% of cases, end of treatment in 15%, toxicity in 5% and other reasons in 26%. Patients who discontinued ICI-1 due to progression received MONO-ICI-2 in 29% of cases and BI-ICI-2 in 71%, whereas those who stopped for other reasons received MONO-ICI-2 in 86% and BI-ICI-2 in 14% of cases. Efficacy results are shown in Table 1. The ORR and DCR were 26% and 79% with MONO-ICI-2, and 16% and 71% with BI-ICI-2. Among patients who discontinued ICI-1 due to progression, BI-ICI-2 (N = 29) achieved an ORR and DCR of 8% and 65%, with a median PFS of 5.5 months (95%CI 4.07-10.4). These outcomes were 17%, 67%, and 3.7 months (95%CI 2.37-NA), respectively, with MONO-ICI-2 (N = 12). For patients who discontinued ICI-1 for reasons other than progression, BI-ICI-2 (N = 5) achieved an ORR and DCR of 60% and 100%, with a median PFS not reached (95%CI 11.5-NR), while MONO-ICI-2 (N = 31) achieved 29%, 82%, and 14.2 months (95%CI 11.2–NR), respectively. Conclusions: This is the first multicenter real-world study evaluating ICI reuse in dMMR/MSI GI cancers. In patients who discontinued ICI for reasons other than progression, reintroduction of ICI therapy upon progression achieves tumor control in 85% of cases. In cases of progression on mono-ICI, Bi-ICI re-challenge achieve tumor control in two-thirds of cases and might be to consider in some patients. ORR % DCR % PFS median (95%CI) OS median (95%CI) Overall N=77 21 76 7.65 months(5.5–11.5) 27.6 months(22.2–55.7) Discontinued ICI-1 due to Progression N=41 11 68 5.03 months(3.7–8.05) 26.7 months(21.1–NR) Discontinued ICI-1 for Other Reasons N=36 33 85 14.22 months(11.24–NR) 27.6 months(22.2–NR)

4006 Background: Elraglusib (9-ING-41) is a first-in-class inhibitor of GSK-3ß, which may mediate drug resistance, EMT, and damaged DNA and tumor immune response in advanced cancer. In pancreatic cancer models in mice, elraglusib combined with chemotherapy enhanced anti-tumor effects and survival. In a single-arm clinical study, elraglusib/GnP showed antitumor activity and prolonged survival in pts with mPDAC. Methods: Pts with previously untreated mPDAC were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP in an open-label phase 2 study. The primary endpoint was 1-yr OS in the primary analysis set. Upon study completion, mOS will be the primary endpoint once survival distributions are compared after the 12-month follow-up using log-rank analysis. Secondary endpoints included DCR, ORR, mPFS, and TEAEs/TRAEs. The planned sample size was 207 evaluable pts (130 for elraglusib/GnP and 77 for GnP), assuming 1-yr OS of 55% with elraglusib/GnP and 35% with GnP to achieve 80% power with a chi-square test at a 2-sided 5% α. For OS, nonparametric log-rank test was used with statistical significance at p-value < 0.048. Cytokine/chemokine correlative biomarker assays were performed. The study completed enrollment in February 2024. Results: As of November 15, 2024 (preliminary data cut-off date), 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. Median (range) CA 19-9 levels were 1568 U/mL (1 to 381,904 U/mL) in the elraglusib/GnP arm and 1590 U/mL (2 to 501,000 IU/mL) in the GnP arm. The 1-yr OS rate was 43.6% with elraglusib/GnP vs 22.5% with GnP (z-test p = 0.002); the mOS was 9.3 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.63; log rank p = 0.016; see Table). 38.1% of pts on elraglusib/GnP and 19.2% on GnP are censored, with the majority at > 10 months OS. Several biomarkers appear to be predictive for OS including IFNβ and PD-L1. The most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment in > 60% of patients (vs 9% with GnP). Grade ≥3 TEAEs occurred in 89.7% of pts on elraglusib/GnP and 80.8% on GnP. Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 51.6% (vs 29.5%), anemia 24.5% (vs 29.5%), and fatigue 16.1% (vs 5.1%). Conclusions: The preliminary results showed a statistically significant benefit for 1-yr OS and mOS and favorable trends for ORR and DCR with elraglusib/GnP over GnP, with manageable safety profile. The mOS for GnP is lower relative to MPACT and NAPOLI-3 but comparable to recent real-world meta-analyses, explained by advanced disease burden and higher mortality rate in the first 4 months in our study. Topline analysis (April 2025) and correlative biomarker analysis predictive for OS will be presented. Clinical trial information: NCT03678883 . Preliminary efficacy results. Elraglusib/GnPn=155 GnPn=78 1-year OS, %z-test p=0.002 43.6 22.5 mOS, moHR=0.63; log-rank p=0.016 9.3 7.2 Events, n (%) 96 (61.9) 63 (80.8) mPFS, moHR=0.91; p=NS 5.6 4.9 Events, n (%) 128 (82.6) 70 (89.7) DCR, % 42.6 33.3 ORR, n (%) 43 (27.7) 16 (20.5)

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.