428 Background: Circulating tumor DNA (ctDNA) analysis enables detection of minimal residual disease (MRD), offering potential for improved risk stratification and guidance for adjuvant chemotherapy (ACT). We evaluated the clinical utility of tumor-informed ctDNA analysis for postoperative MRD assessment in stage II–III gastric cancer (GC). Methods: This sub-study of the ongoing EXODOX trial (NCT04787354), a phase III randomized study comparing reduced-duration versus standard 6-month XELOX as ACT in patients with pathologic stage II–III GC after curative resection, investigated ctDNA MRD using the CancerDetect assay (IMBdx, Inc.). This tumor-informed bespoke panel (BSP) was generated by whole-exome sequencing of tumor tissue and paired white blood cells, identifying up to 100 patient-specific variants. Whole blood (20 mL) was collected at five postoperative time points: 3–10 weeks (P0), 6 months (P1), 12 months (P2), 18 months (P3), and 24 months (P4). MRD positivity was defined as detection of ≥2 BSP variants in plasma. Results: This analysis included 68 patients enrolled between May 2022 and March 2025. ctDNA MRD was assessed at P0 (n=64), P1 (n=50), P2 (n=36), P3 (n=27), and P4 (n=15). Median age was 66 years (range, 39–96); 45 patients (66.2%) were male; all had adenocarcinoma; 54 patients (79.4%) had stage III disease. At P0, MRD positivity was 43.8% (28/64), with a median of 7 somatic mutations per patient (range, 2–94). MRD positivity was significantly higher in stage III versus stage II patients (52.0% vs. 14.3%, P=0.015). MRD clearance after ACT occurred in 40.0% (8/20) of patients who were ctDNA-positive at P0. Conversely, 5 (19.2%) of 26 patients who were initially ctDNA-negative converted to positive, resulting in an overall positivity rate of 34.0% (17/50) at P1. MRD positivity rates were 27.8% at P2, 25.9% at P3, and 13.3% at P4. After a median follow-up of 13.3 months, 11 patients (16.2%) experienced recurrence. ctDNA positivity was significantly associated with worse recurrence-free survival (RFS) at P0 (HR, 15.8; 95% CI, 2.0–123.4; P=0.01), P1 (HR, 5.5; 95% CI, 1.1–27.4; P=0.04), and P2 (HR, 24.5; 95% CI, 2.6–234.0; P=0.01). Patients who converted from positive to negative after ACT had RFS comparable to those with persistent negativity, while patients with persistent positivity had the poorest outcomes (HR, 11.6; 95% CI, 2.3–58.1; P<0.01). Conclusions: In stage II–III GC, postoperative MRD detected by ctDNA was strongly associated with recurrence risk. MRD clearance after ACT was associated with outcomes similar to persistent negativity, supporting the clinical utility of ctDNA MRD in guiding ACT decisions. Continued follow-up is underway to validate these findings.

Leptomeningeal carcinomatosis (LMC) from gastric cancer is rare but carries a poor prognosis, and its risk factors and clinical presentation remain unclear. Among 3850 patients treated with palliative chemotherapy, those with pathologically or cytologically confirmed LMC were included. Responsiveness to intrathecal methotrexate (IT-MTX) was defined as a malignant cell count < 1/μL on ≥ 2 consecutive cerebrospinal fluid analyses. Survival outcomes were compared across subgroups with different clinical presentations. During a median follow-up of 13.7 months, LMC was diagnosed in 0.8

11500 Background: GIST, the most common mesenchymal malignancy of the gastrointestinal tract, is commonly driven by activating KIT mutations. Despite therapeutic advances, treating advanced GIST with KIT tyrosine kinase inhibitors (TKIs) remains challenging due to emergence of heterogeneous resistance mutations inadequately addressed by current approved therapies. Bezuclastinib, an oral, selective type 1 TKI, in combination with sunitinib, a type 2 TKI, inhibits common primary and secondary resistance mutations in advanced KIT -mutant GIST. The Peak study evaluated efficacy and safety of bezuclastinib + sunitinib vs standard second-line sunitinib monotherapy in patients with advanced GIST who received prior imatinib therapy. Methods: Peak was a multipart study: dose confirmation (Part 1a), 2 drug-drug interaction (DDI) assessments (Part 1b; DDI substudy), and a randomized phase 3 (Part 2; abstract focus). Patients were randomized 1:1 to bezuclastinib 600 mg once daily (QD) + sunitinib 37.5 mg QD (n=204) or sunitinib 37.5 mg QD (n=209). Primary endpoint was blinded independent central review (BICR)-assessed median progression-free survival (mPFS). Key secondary endpoints were objective response rate (ORR) per BICR and overall survival (OS). Crossover to combination was permitted at BICR-confirmed progression. Results: Patients (N=413) were randomized to either bezuclastinib + sunitinib or sunitinib monotherapy; median (range) age, 63 (30-88) years; 59.6% and 14.0% had activating KIT mutations in exons 11 only and 9 only, respectively. The combination significantly improved mPFS (HR, 0.50; 95% CI, 0.39-0.65; P<0.0001). mPFS was 16.5 months (95% CI, 13.8-19.2) for the combination vs 9.2 months (95% CI, 7.2-11.0) for monotherapy. ORR significantly improved with the combination vs monotherapy (46% vs 26%; risk difference, 20%; 95% CI, 10.6-28.6; P<0.0001). As of Sep 30, 2025, OS data remain immature. Incidence of adverse events (AEs) was similar between arms. Grade (Gr)≥3 AEs were comparable, with no significant increase in common sunitinib-associated AEs. Higher rates of Gr≥3 ALT/AST elevations and anemia were observed with the combination and were manageable with dose modification. ALT/AST elevations led to bezuclastinib dose reductions in 13.2% and discontinuations in 1.5% of patients in the combination arm; all Gr3 hepatic AEs resolved; no Gr4 events occurred. Additional treatment-emergent AEs leading to discontinuation of either drug in >1 patient in the combination arm were neutropenia (2.9%) and diarrhea (1%). No treatment-related AEs led to death in the combination arm. Conclusions: Combined KIT inhibition with bezuclastinib + sunitinib significantly improved mPFS vs sunitinib monotherapy, reducing the risk of progression or death by 50% and increasing ORR from 26% to 46%. The combination was well tolerated with no new safety findings. Clinical trial information: NCT05208047 .

SHR-A1811, an antibody‒drug conjugate consisting of the anti-HER2 antibody trastuzumab conjugated via a cleavable linker to a topoisomerase I inhibitor payload, demonstrated substantial antitumor activity in patients with heavily treated HER2-expressing or mutated advanced solid tumors. The main analysis was reported, and this is a long-term follow-up of the HORIZON-X trial (NCT04446260). This global, multicenter, first-in-human, phase 1 trial enrolled patients aged ≥ 18 years with unresectable, advanced, or metastatic HER2-expressing or mutated solid tumors refractory or intolerant to standard therapies across 38 hospitals. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every three weeks. The primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. From September 7, 2020, to June 4, 2024, 396 patients with a median of three prior treatment regimens (IQR 2-5) received SHR-A1811. As of March 12, 2025, the median follow-up was 17.1 months for HER2-positive breast cancer, 10.6 months for HER2-low expressing breast cancer, and 4.3 to 8.2 months in non-breast cancers. The safety profile remained consistent with that of previous reports. Grade 3 or higher treatment-related adverse events occurred in 261 patients (65.9%), and any grade interstitial lung disease was observed in 10 patients (2.5%). The median progression-free survival was 25.0 months (95% CI 17.2-33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2-13.8) for HER2-low expressing breast cancer, and 3.5 to 17.2 months for non-breast tumors. This final analysis further confirmed the long-term efficacy and favorable safety profile of SHR-A1811 among heavily prior-treated advanced solid tumors, reinforcing its potential as an effective HER2-targeted therapy.

TPS4250 Background: Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), has demonstrated significant survival benefit in advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJA) in the phase 3 SPOTLIGHT and GLOW trials, validating CLDN18.2 as a therapeutic target. The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with surgery followed by adjuvant S-1 for patients with resectable locally advanced gastric cancer (LAGC). Building on this evidence, we designed NEOCLAUD to evaluate whether adding zolbetuximab to neoadjuvant DOS chemotherapy, followed by adjuvant zolbetuximab/S-1, improves outcomes in patients with CLDN18.2-positive LAGC. Methods: This open-label, multicenter, phase Ib/II trial will enroll up to 57 patients with newly diagnosed, resectable G/GEJA positive for CLDN18.2 (≥75% moderate–strong membranous staining by VENTANA 43-14A). Eligible patients must have clinical stage T3–4/N0 or T2–4/N+ disease (AJCC 8th), ECOG 0–1, and no distant metastasis. Primary endpoints are recommended phase II dose (RP2D) (phase Ib) and the pathologic complete regression (pCR) rate (phase II). Phase Ib uses a 3+3 design to determine the RP2D. Phase II will test whether adding zolbetuximab increases the pCR rate from 10% (historical control) to 25%; the primary endpoint will be met if ≥8/40 patients achieve pCR (A’Hern single-stage design, α = 0.05, power = 80%). Secondary endpoints include PFS, OS, objective response rate, disease control rate, R0 resection rate, and safety. Exploratory endpoints include artificial intelligence-based histopathology modeling, spatial transcriptomics, single-cell RNA sequencing, and circulating tumor DNA minimal residual disease analysis. Neoadjuvant therapy consists of zolbetuximab 800 mg/m² on cycle 1 day 1 (C1D1) followed by 600 mg/m² on C2D1/C3D1, with DOS (docetaxel 50 mg/m², oxaliplatin 100 mg/m² IV D1; S-1 40 mg/m² PO BID D1–14) every 3 weeks ×3 cycles. Surgery (D2 gastrectomy) is performed 1–4 weeks post-neoadjuvant therapy. Adjuvant therapy (initiated 3–8 weeks post-surgery) includes zolbetuximab 600 mg/m² D1/D22 Q6W ×8 cycles plus S-1 PO D1–28 Q6W ×8 cycles. Enrollment has been ongoing since February 2025 across multiple sites in Korea. Clinical trial information: NCT06732856 .

e15018 Background: SHR-A1904, a novel CLDN18.2 targeted ADC, showed promising antitumor activity in pretreated CLDN18.2-positive gastric/gastroesophageal junction cancer (GC/GEJC) in a China-only phase 1 trial (Nat Med. 2025; NCT04877717). Here, we report a 2-part multicenter global study assessing SHR-A1904 in patients (pts) with CLDN18.2-expressing advanced solid tumors (NCT05277168). Methods: During dose escalation (DE), pts with CLDN18.2-expressing (H score ≥1 by central lab IHC) advanced relapsed or refractory (R/R) solid tumors were enrolled to receive SHR-A1904 at 0.6–6.0 mg/kg (Q3W IV) in an i3+3 design. During dose optimization (DO), pts with CLDN18.2-positive (≥50% of cells with 2+ or 3+ staining) advanced R/R GC/GEJC were enrolled to receive SHR-A1904 at 6.0 and 8.0 mg/kg. The primary endpoints were DLT and safety in DE, and efficacy and safety in DO. Exploratory subgroup analyses in Asians vs non-Asians were done at 3.6 mg/kg (the minimal effective dose) or higher. Results: As of Dec 1, 2025, 51 pts were enrolled from Australia, South Korea, the United States, and Moldova, including 41 with GC/GEJC, 9 with pancreatic cancer, and 1 with lung adenocarcinoma. 42 pts received SHR-A1904 at 3.6 mg/kg or higher, 24 of whom were Asian. All pts had prior therapy (≥2 lines, 72.5%). The median follow-up was 6.7 mo (range, 0.2–27.9). During DE, 1 DLT (grade 3 vomiting) occurred at 6.0 mg/kg. Among all pts, TRAEs were reported in 48 (94.1%) pts; the most common were nausea (66.7%), vomiting (52.9%), and fatigue (23.5%). Grade ≥3 TRAEs and serious TRAEs occurred in 21 (41.2%) and 9 (17.6%) pts. No TRAEs led to death. In Asians, TRAEs and Grade ≥3 TRAEs occurred in 22 (91.7%) pts and 11 (45.8%) pts; in non-Asians, TRAEs and Grade ≥3 TRAEs occurred in 17 (94.4%) pts and 9 (50.0%) pts. Overall, ORR, DCR, and CBR (CR + PR + SD ≥24 weeks) were 25.5%, 58.8%, and 33.3%, respectively. The median PFS, OS, and DoR were 2.8 mo (95% CI, 1.7–5.4), 9.8 mo (95% CI, 6.7–15.2), and 5.7 mo (95% CI, 2.8–NR), respectively. Exploratory subgroup analyses by race are shown in Table. After a single dose, C max and AUC of SHR-A1904 increased with the dose except the 4.8 mg/kg group. The mean t 1/2 of SHR-A1904 is around 4.3–7.2 days. Conclusions: SHR-A1904 showed tolerable safety and promising antitumor activity in pretreated CLDN18.2-expressing advanced solid tumors. Furthermore, exploratory subgroup analyses by race support global development of SHR-A1904 in both Asians and non-Asians. Clinical trial information: NCT05277168 . Efficacy summary. Overall (N=51) Asians (N=24) # Non-Asians (N=18) # ORR 25.5 (13; 14.3–39.6) 20.8 (5; 7.1–42.2) 44.4 (8; 21.5–69.2) DCR 58.8 (30; 44.2–72.4) 66.7 (16; 44.7–84.4) 66.7 (12; 41.0–86.7) CBR 33.3 (17; 20.8–47.9) 20.8 (5; 7.1–42.2) 66.7 (12; 41.0–86.7) DoR, mo 5.7 (2.8–NR) 8.5 (2.9–NR) 5.7 (2.8–NR) PFS, mo 2.8 (1.7–5.4) 2.8 (1.5–5.4) 9.7 (1.9–NR) OS, mo 9.8 (6.7–15.2) 9.8 (5.2–NR) 15.2 (9.0–NR) Data are % (n; 95% CI) or median (95% CI). # at 3.6 mg/kg or higher.

Purpose EP4, a key receptor in the PGE 2 axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. Patients and Methods This multicenter, double-blind, randomized phase 2 study enrolled chemotherapy-naïve patients with HER2-negative unresectable advanced or recurrent G/GEJC. Patients were randomized (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results At the data cutoff, 226 patients were randomized to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio of 0.67; 90% confidence interval, 0.48–0.92; p-value, 0.040 [prespecified two-sided α = 0.10]), with favorable OS at a prespecified analysis with limited follow-up (hazard ratio of 0.60; 95% confidence interval, 0.37–0.96) and ORR (62.0% vs 48.7%). Exploratory subgroup analyses suggested that ONO-4578 regimen provided greater benefit in PD-L1 CPS ≥1, whereas no clear benefit in CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhoea (55.7% vs 45.3%), and anaemia (55.0% vs 34.7%). Conclusion This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase 3 trial.

BACKGROUND:This phase IB/II study assessed safety, pharmacokinetics, and efficacy of alpelisib, a selective PI3Kα inhibitor, plus weekly paclitaxel in patients with PIK3CA-altered metastatic or recurrent gastric cancer (GC). METHODS:In phase IB, patients with advanced solid tumors received alpelisib 250 mg (dose level [DL] 0) or 300 mg (DL1) once daily plus paclitaxel 70 mg/m2 on Days 1, 8, and 15 every 4 weeks to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose (RP2D). In phase II, patients with PIK3CA-altered GC received RP2D, and the primary endpoint was 4-month progression-free survival (PFS). Subjects with diabetes or those with risk factors for diabetes who also had impaired glucose tolerance were excluded. Pharmacokinetic sampling was performed in phase IB at cycle 1, Days 1 (initial dose) and 8 (steady state). RESULTS:In phase IB, MTD was not reached; RP2D was established at DL1. Two patients developed DLTs at DL0 (grade 3 hyperglycemia, diarrhea, and fatigue) and DL1 (grade 3 hyponatremia). Toxicities were consistent with known PI3Kα inhibitor plus taxane combination profiles and were generally manageable. In phase II (n = 9), the 4-month PFS rate was 22.2%, and enrollment was discontinued early for futility; no objective responses were observed, and the median PFS was 2.6 months. Alpelisib exposure, assessed by Cmax and AUC0-24, was within expected ranges, and prior gastrectomy was associated with lower exposure. CONCLUSION:Alpelisib plus paclitaxel was tolerable and pharmacologically feasible with a defined RP2D but showed limited efficacy in PIK3CA-altered GC.

Purpose: Immune checkpoint inhibitor plus chemotherapy is the standard first-line treatment for advanced gastric cancer; however, predictive biomarkers for optimal patient selection remain unsatisfactory. This study was aimed at evaluating the predictive value of tumor mutational burden (TMB) and insertion/deletion (Indel) rate in patients with gastric cancer treated with nivolumab plus chemotherapy. Materials and Methods: This retrospective study included 132 patients with gastric cancer treated with first-line nivolumab plus chemotherapy and 185 patients treated with chemotherapy alone, all of whom had next-generation sequencing data available. The TMB and Indel cut-offs were set at 15.63 mutations per megabase and 18.19%, respectively, as determined based on their ability to best distinguish progression-free survival (PFS) among the patients who received nivolumab plus chemotherapy. Results: PFS was favorable for nivolumab and chemotherapy than for chemotherapy alone in both the high and low TMB groups; nevertheless, survival benefits were observed only in the high Indel group. Among the subgroups defined based on both TMB and Indel rates, the high TMB and high Indel rate subgroup showed the greatest benefit from nivolumab plus chemotherapy compared with that from chemotherapy alone. The benefit of this subgroup remained significant in patients with proficient mismatch repair (MMR) tumors, whose survival outcomes were comparable to those of patients with deficient MMR tumors. Among patients treated with nivolumab plus chemotherapy, high TMB and Indel rate were independently associated with favorable survival outcomes. Conclusions: Thus, Indel rate, particularly in combination with TMB, may be a promising predictive biomarker for gastric cancer. However, further validation of their predictive value is warranted.

4007 Background: Anti-PD-1 antibodies combined with chemo are the standard 1L treatment for HER2-negative G/GEJ cancer. Prostaglandin E 2 (PGE 2 )-EP4 signaling is known to induce immunosuppressive tumor microenvironment, by inducing the differentiation of MDSCs and M2 macrophages, potentially contributing to resistance to immunotherapy. ONO-4578, an EP4 antagonist, is expected to modulate tumor immunosuppression through inhibiting the PGE 2 -EP4 signaling and to enhance the efficacy of anti-PD-1 antibody. The addition of ONO-4578 appeared to augment the efficacy of NIVO in patients with G/GEJ cancer in the previous phase 1 trial. This study aimed to evaluate the efficacy and safety of ONO-4578 combined with NIVO and chemo compared with placebo combined with NIVO and chemo as 1L treatment for patients with unresectable adv/rec G/GEJ cancer. Methods: ONO-4578-08 study is a randomized, double-blind, phase 2 trial conducted in Japan, Korea, and Taiwan. Chemo-naïve patients with HER2-negative adv/rec G/GEJ cancer were randomized in a 2:1 ratio (ONO-4578 group:placebo group), stratified by PD-L1 expression level (CPS < 5 vs CPS≥5), ECOG performance status (0 vs 1), presence of peritoneal metastasis (yes vs no). Patients in each group received ONO-4578 40 mg or placebo once daily, and all received NIVO 360 mg every 3 weeks and chemo (SOX [S-1 + oxaliplatin]/CAPOX [capecitabine + oxaliplatin]). The primary endpoint was investigator-assessed progression-free survival (PFS), powered (two-sided α = 0.10) to detect a HR of 0.65 with 117 events in a planned enrollment of 210 patients; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between December 2023 and September 2024, 226 patients were randomized to each group (150 vs 76 patients). With a median follow-up of 8.5 months, PFS was significantly longer in the ONO-4578 group than the placebo group with a hazard ratio (HR) of 0.67 (90% confidence interval [CI]: 0.48–0.92; P = 0.040; median PFS: 9.0 vs 6.9 months). At a minimum follow-up of 7.4 months, OS favored the ONO-4578 group (median OS: not reached vs 12.7 months; HR: 0.60 [95% CI: 0.37–0.96]). ORR was also higher in the ONO-4578 group (62.0% vs 48.7%). The most common treatment-emergent adverse events (TEAEs) in the ONO-4578 group were diarrhea (55.7% vs 45.3%), anemia (55.0% vs 34.7%), and peripheral sensory neuropathy (50.3% vs 46.7%). Serious TEAEs occurred in 53.7% of patients in the ONO-4578 group and 42.7% in the placebo group. Conclusions: ONO-4578 combined with NIVO and chemo significantly improved PFS compared with placebo combined with NIVO and chemo in treatment-naive patients with HER2-negative unresectable adv/rec G/GEJ cancer with no new safety concerns. Clinical trial information: NCT06256328 .

PURPOSE:EP4, a key receptor in the prostaglandin E2 axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. METHODS:This multicenter, double-blind, randomized phase II study enrolled chemotherapy-naïve patients with human epidermal growth factor receptor 2 (HER2)-negative unresectable advanced or recurrent G/GEJC. Patients were randomly assigned (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), and safety. RESULTS:At the data cutoff, 226 patients were randomly assigned to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio [HR] of 0.67 [90% CI, 0.48 to 0.92]; P = .040 [prespecified two-sided α = .10]), with favorable OS at a prespecified analysis with limited follow-up (HR of 0.60 [95% CI, 0.37 to 0.96]) and ORR (62.0% v 48.7%). Exploratory subgroup analyses suggested that the ONO-4578 regimen provided greater benefit in PD-L1 combined positive score (CPS) ≥1, whereas no clear benefit was observed in those with CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored the ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhea (55.7% v 45.3%) and anemia (55.0% v 34.7%). CONCLUSION:This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase III trial.

OBJECTIVE:In the RATIONALE-305 trial, first-line tislelizumab + chemotherapy (CAPOX ([capecitabine + oxaliplatin] or 5-fluorouracil [5-FU] + cisplatin) significantly improved overall and progression-free survival (PFS) versus placebo + chemotherapy in unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC). This exploratory analysis evaluated the comparative efficacy of tislelizumab + CAPOX versus tislelizumab + CAPOX or FOLFOX (5-FU, leucovorin, oxaliplatin) using a matching-adjusted indirect comparison (MAIC) approach. METHODS:An unanchored MAIC was performed, weighting individual patient data from RATIONALE-305 (tislelizumab + CAPOX) to match the DisTinGuish Part C (tislelizumab + CAPOX or tislelizumab + FOLFOX) aggregate population. After matching, hazard ratios (HRs) for PFS and odds ratios (ORs) for objective response rate (ORR) were calculated in base-case and sensitivity analyses. RESULTS:Baseline characteristics were well balanced post-matching (i.e. weighting). In the base case, compared with tislelizumab + CAPOX, median PFS was numerically longer with tislelizumab + CAPOX or tislelizumab + FOLFOX (7.2 vs. 10.5 months [HR 1.24; 95% CI 0.93-1.65; p = 0.1423]). No statistically significant difference in ORR was observed (48.8% vs. 56.5% [OR, 0.71; 95% CI 0.44-1.15; p = 0.1675], respectively). Sensitivity analyses produced consistent results, supporting the robustness of the base-case findings. CONCLUSIONS:This exploratory analysis found no statistically significant differences in PFS or ORR between tislelizumab + CAPOX and tislelizumab + CAPOX or FOLFOX. Although median PFS was numerically longer with the mixed chemotherapy backbone, these findings are exploratory in nature and warrant further investigation. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, RATIONALE-305 (NCT03777657); DisTinGuish (NCT04363801).

4023 Background: Sone-Ve (AZD0901), an antibody-drug conjugate comprising an anti-CLDN18.2 antibody and monomethyl auristatin E, showed promising antitumor activity and a manageable safety profile in pts with advanced or metastatic gastric/GEJ cancers in the first-in-human study conducted in China. Methods: CLARITY-PanTumor01 is an ongoing, global, phase 2 study (NCT06219941) evaluating Sone-Ve in gastric/GEJ cancers, PDAC, and BTC outside of China. Here we report data for pts with CLDN18.2+ advanced or metastatic gastric/GEJ cancers and ≤2 lines of prior systemic therapy (substudy 1) receiving Sone-Ve 2.2 mg/kg IV Q3W (pts randomized to 1.8 mg/kg are not reported). Primary endpoints were safety and objective response rate (ORR; 30 pts were selected to estimate ORR; lack of efficacy is concluded if ≤6 confirmed responses). Secondary endpoints included duration of response (DoR) and progression-free survival (PFS). Molecular responses (MRs) based on circulating tumor DNA (ctDNA) were evaluated. Results: As of Oct 31, 2025, 67 pts received Sone-Ve 2.2 mg/kg, including 30, 31, and 6 pts from the randomized (RC), paired biopsy (PBC), and Japanese safety (JSC) cohorts, respectively. All pts had adverse events (AEs; grade ≥3 in 34.3% overall, 36.7% of the RC, and 35.5% of the PBC). The most common grade ≥3 AEs were neutrophil count decreased (7.5%), anemia (7.5%), vomiting (6.0%), and nausea (6.0%). Dose reductions were most commonly due to gastrointestinal (GI) AEs and occurred in 40.3% of pts overall, 56.7% of the RC, and 19.4% of the PBC (adoption of a 4-drug antiemetic regimen improved GI tolerability in the PBC). The ORR was 28.4% (95% CI: 18.0–40.7). Median DoR has not yet been reached. Additional data are in the Table. Among evaluable pts, 58.6% (17/29) had sufficient baseline ctDNA levels to enable MR analysis; of these, 10 (58.8%) had at least a partial MR (>50% ctDNA reduction) within 2 cycles of Sone-Ve initiation. Conclusions: Sone-Ve 2.2 mg/kg demonstrated clinically meaningful efficacy and a manageable safety profile consistent with the first-in-human study. ctDNA MRs were observed in over half the evaluable pts. Clinical trial information: NCT06219941 . RC(n=30) PBC (n=31) Total*(n=67) ORR, % (95% CI) † 26.7 (12.3–45.9) 29.0 (14.2–48.0) 28.4 (18.0–40.7) Best overall response, n (%) † Complete response Partial response Stable disease Progressive disease Not evaluable 2 (6.7)6 (20.0)14 (46.7)7 (23.3)1 (3.3) 1 (3.2)8 (25.8)18 (58.1)4 (12.9)0 3 (4.5)16 (23.9)35 (52.2)12 (17.9)1 (1.5) 6-month response rate, % (95% CI) 87.5 (38.7–98.1) NC (NC–NC) 71.9 (39.2–89.1) PFS † Events, n/N (%) Median, months (95% CI) 6-month, % (95% CI) 22/31 (71.0)4.2 (2.9–8.6)44.8 (26.5–61.6) 19/31 (61.3)3.1 (2.8–5.5)30.3 (13.3–49.3) 47/68 (69.1)4.2 (3.0–7.0)39.9 (27.7–51.9) NC, not calculable. *Includes the JSC. † Investigator-assessed per RECIST v1.1.

11501 Background: Most GISTs present with activating KIT mutations (exons 9/11) initially responsive to imatinib, but many progress due to diverse KIT resistance mutations (largely in exons 13/14/17/18). Velzatinib (subject to USAN approval), a novel selective KIT inhibitor, has broad mutation coverage and robust in vitro/vivo preclinical activity in models with mutations relevant to 1 st - (1L) and 2 nd -line (2L) GIST. We present results from StrateGIST 1 evaluating the safety and efficacy of velzatinib in patients (pts) with advanced GIST as 1L or 2L therapy by KIT mutation status. Methods: The study design of StrateGIST 1 has been previously described (Schöffski et al. J Clin Oncol 2024). We present updated safety and efficacy data for 1L and 2L pts by KIT mutation status treated with velzatinib at the recommended phase 1b dose (RP1bD) of 300-mg tablet or exposure-equivalent 400-mg capsule. Results: As of December 15, 2025, 18 pts in 1L and 46 pts in 2L received velzatinib at the RP1bD and were evaluable for the efficacy analysis. In 2L pts, median follow-up (mFU) was 14.7 (95% CI: 12.9, 18.4) mo and median progression-free survival (mPFS) was 13.7 (95% CI: 7.4, 18.4) mo. In 1L, the mFU was 6.4 (95% CI: 1.8, 11) mo, and all pts (18/18) had a reduction in tumor volume, of whom 11 (61%) experienced unconfirmed responses, including 1 complete and 10 partial responses (Table 1). As of the cutoff date, 17 1L pts remained on study treatment. Treatment was well tolerated, with low rates of dose reductions (1L: 0%; 2L: 6%) and withdrawals (1L: 0%; 2L: 4%) due to AEs. Conclusions: Velzatinib exhibited promising activity and tolerable safety as 1L and 2L therapy across clinically relevant KIT mutations for pts with advanced GIST. These data support further study of velzatinib, including in 1L pts, to address the need for therapeutic options with broad coverage of clinically relevant GIST mutations. This study (NCT05489237) is funded by GSK. Clinical trial information: NCT05489237 . Clinical activity and response by mutation status per mRECIST v1.1. a 1Ltotal(n=18) 2Ltotal(n=46) 2LEx 9mutation only(n=8) 2LEx 11mutation only(n=14) 2LEx 11+ATP-binding pocket resistance mutation (13/14)(n=14) 2LEx 11+activation loop resistance mutation (17/18)(n=3) 2LOther(including ≥2 resistance mutations)(n=7) Best overall response, n (%) Complete response 1 (6) 2 (4) 0 1 (7) 0 0 1 (14) Partial response 10 (56) 14 (30) 5 (62) 2 (14) 5 (36) 1 (33) 1 (14) Stable disease 7 (39) 25 (54) 3 (38) 8 (57) 8 (57) 2 (67) 4 (57) Progressive disease 0 5 (11) 0 3 (21) 1 (7) 0 1 (14) Not evaluable 0 0 0 0 0 0 0 Objective response rate, n (%)(95% CI) 11 (61)(35.7, 82.7) 16 (35)(21.4, 50.2) 5 (62)(24.5, 91.5) 3 (21)(4.7, 50.8) 5 (36)(12.8, 64.9) 1 (33)(0.8, 90.6) 2 (29)(3.7, 71) a In an efficacy-evaluable population defined as all pts with ≥1 postbaseline disease assessment or prior clinical progression or death.

Epidermal growth factor receptor (EGFR) amplification remains a controversial therapeutic biomarker. We report outcomes of erlotinib plus bevacizumab (E + B) in patients with EGFR-amplified metastatic solid tumors. Patients with metastatic solid cancer who had progressed after standard therapies and were treated with E + B based on central molecular tumor board recommendations in the KOSMOS trial were included. Only those with an EGFR copy number ≥ 3 were selected. The primary endpoint was the clinical benefit rate (CBR), while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Between February 2021 and April 2024, 25 patients were treated with E + B (median EGFR copy 8.9; range, 3–76). Six tumor types were included, with colorectal cancer being the most prevalent (N = 14), followed by glioblastoma (N = 5), and other types (N = 6). Overall, four partial responses (PR) and seven cases of stable disease (SD) lasting over 16 weeks were observed, resulting in a CBR of 44.0

The gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Between the 1990s and early 2000s, GIST was identified as a tumor characterized by KIT or PDGFRA mutations, resulting in imatinib being established as an effective targeted therapy. However, with advances in molecular diagnostics, approximately 10%-15% of GISTs have been reported to harbor alternative mutations, such as those in the succinate dehydrogenase subunit genes and BRAF, leading to the development of additional targeted therapies. GISTs exhibit a wide spectrum of clinical behaviors, ranging from indolent to highly aggressive, prompting the development of diverse risk classification systems. However, multiple systems remain in use, leading to inconsistent pathologic reports. Moreover, the mitotic counting method-a key factor in risk stratification-has become a major source of confusion among pathologists owing to the adoption of digital pathology and discrepancies between updated international guidelines and outdated reimbursement requirements. These inconsistencies have hindered pathologic reporting and communication between pathologists and clinicians. This review comprehensively overviews the historical background, molecular subtypes, and risk classification systems of GIST, focusing on evolving issues in mitotic rate evaluation and the application of risk classification systems in clinical practice.

4006 Background: Anti-PD-1 antibodies combined with chemotherapy (Chemo) are established as a standard first-line (1L) treatment for HER2-negative gastric/gastroesophageal (G/GEJ) cancer. Nivolumab (NIVO) and ipilimumab (IPI), an anti-CTLA-4 antibody, have complementary mechanisms of action on tumor immunity. Combining NIVO plus Chemo with IPI is expected to suppress disease progression durably and prolong survival, as suggested in other types of tumors. Methods: ATTRACTION-6 is a randomized, phase 3 trial conducted in Japan, Korea, and Taiwan. Previously untreated patients with HER2-negative unresectable advanced or recurrent G/GEJ cancer were randomized 1:1 to receive NIVO 360 mg every 3 weeks, IPI 1 mg/kg every 6 weeks in addition to Chemo (S-1 plus oxaliplatin [SOX] or capecitabine plus oxaliplatin [CAPOX]) or Chemo alone. Randomization was stratified by PD-L1 (CPS≥5 or CPS < 5, indeterminate), ECOG PS (0 or 1), countries (Japan or Korea/Taiwan), and disease status (advanced or recurrent). Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), objective response rate (ORR) per RECIST v1.1 assessed by site investigator, and safety. Results: Between November 2021 and August 2023, 626 patients were randomized 1:1 to the NIVO + IPI + Chemo arm (N = 315) or the Chemo arm (N = 311). At the median follow-up of 31.3 months, the primary endpoint of OS was not met (HR 0.90; 95.8% CI 0.74-1.09; P = 0.267; median OS 15.7 vs 15.8 months). Median PFS was 8.9 vs 7.7 months (HR 0.83; 95% CI 0.69-1.00). Among patients with ≥1 measurable lesion at baseline, ORR was 57.9% vs 38.5%. Grade≥3 adverse events (AEs) and grade≥3 treatment-related AEs occurred in 80.0% and 64.8% in the NIVO + IPI + Chemo arm, respectively, and 62.4% and 42.9% in the Chemo arm, respectively. Treatment-related deaths occurred in 0.3% vs 0%, and the only observed event was gastroenteritis in the NIVO + IPI + Chemo arm. Conclusions: In ATTRACTION-6 study, NIVO + IPI + Chemo did not improve OS compared with Chemo as 1L treatment for patients with HER2-negative unresectable advanced or recurrent G/GEJ cancer. Although toxicity increased with the addition of NIVO and IPI, no new safety signals were observed. Clinical trial information: NCT05144854 .

Background SAR443216 is an engineered human trispecific antibody that targets human epidermal growth factor receptor 2 (HER2)-positive (HER2+) cancer cells and activates T cells via co-engagement of cluster of differentiation (CD)3 and CD28. This first-in-human, dose-escalation study evaluated the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics of SAR443216 in participants with relapsed/refractory (R/R) HER2-expressing solid tumors.Methods In this multicenter, open-label, non-randomized Phase 1 study (NCT05013554), SAR443216 was administered intravenously at dose levels (DLs) of 18–900 µg. Dose escalation occurred within participants using intraparticipant lead-in dosing (2-week and 3-week lead-in cohorts). The primary objective was to determine the maximum tolerated dose (MTD); secondary objectives included PK, immunogenicity, and preliminary clinical activity.Results 40 participants (n≥3 at each DL) were treated with SAR443216. The median treatment duration was ~8 weeks in both 2-week and 3-week lead-in cohorts. Nearly all participants (97.5%) had at least one treatment-emergent adverse event (TEAE), of which 45% were grade ≥3. Most frequent TEAEs were cytokine release syndrome (CRS, 50%), fever (35%), alanine aminotransferase elevation (32.5%), aspartate aminotransferase elevation (27.5%), and infusion-related reactions (IRRs, 27.5%). No severe CRS, IRRs, fever, or pulmonary and cardiac toxicities were observed. Disease control rates were 34.5% in the 2-week and 36.4% in the 3-week lead-in cohorts. Average duration of disease stabilization was 10.48 weeks. Median follow-up time was 3.43 weeks. No objective responses were observed. The MTD was not reached. Dose-dependent PK showed overall consistent PK profiles across DLs. SAR443216 induced serum proinflammatory cytokines and increased multiple T-cell activation markers in peripheral blood mononuclear cells, indicating T-cell activation and target engagement. However, no clear trend in T-cell abundance or activation was observed among tumor-infiltrating T cells or other immune cells.Conclusion These findings indicate that SAR443216 treatment is feasible and well tolerated in participants with R/R HER2+solid tumors. Further evaluation is warranted to fully characterize the efficacy and safety of SAR443216.Trial registration number NCT05013554.