Bekaii-Saab, Tanios S.

399 Background: The standard of care for resectable GEA adenocarcinomas is perioperative chemotherapy with the FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) regimen. Recent studies investigating the addition of checkpoint inhibitors (CPIs) to perioperative chemotherapy have shown mixed results. An NMA can leverage both direct and indirect comparisons to evaluate the relative efficacies of available regimens in this setting. Methods: MEDLINE, EMBASE, Scopus, Web of Science and CENTRAL were searched until August 27th, 2025. Eligible studies included phase 3 randomized trials evaluating perioperative or neoadjuvant chemotherapy +/- CPIs ± radiation in resectable GEA. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Hazard ratios and 95% confidence intervals (CIs) were estimated using a frequentist NMA framework. Results: Fifteen trials including 8072 patients were analyzed. For DFS, perioperative durvalumab + FLOT (dFLOT) ranked highest (P-score = 0.99), followed by FLOT (P-score = 0.84) (HR for dFLOT vs. FLOT was 0.71, 95% CI 0.58-0.86). dFLOT also ranked higher than perioperative pembrolizumab + cisplatin and fluorouracil/capecitabine (KN-585), though this comparison was not statistically significant (HR 0.65, 95% CI 0.40-1.04). Compared with CROSS, dFLOT showed superior DFS (HR of 0.48, 95% CI 0.36-0.63). For OS, dFLOT ranked the highest (P-score=0.95) and was superior to CROSS (HR 0.57, 95% CI 0.42-0.77). While dFLOT appeared favorable versus FLOT (HR 0.78, 95% CI 0.62-0.98), this finding was primarily driven by MATTERHORN, which did not meet its prespecified OS significance boundary (P = 0.03 vs threshold P < 0.0001), and the proportional hazards assumption was violated. Similarly, no significant OS difference was observed between dFLOT and the KN-585 arms (HR 0.75, 95% CI 0.45-1.23). Conclusions: In this NMA, perioperative FLOT remained the benchmark regimen for resectable GEA. dFLOT has shown promising early results, ranking the highest for DFS and showing favorable, but not statistically definitive OS trends in comparison to FLOT. Importantly, the network enabled indirect comparisons not tested in head-to-head trials, demonstrating that dFLOT ranked above pembrolizumab+CF/CX (KN-585) without reaching statistical significance, and also outperformed CROSS. However, these findings should be interpreted with caution, as they are primarily driven MATTERHORN data in which OS did not cross the prespecified threshold and proportional hazards assumptions were violated. Perioperative immunotherapy combinations appear promising, but final MATTERHORN results and further confirmatory studies are needed before dFLOT can be considered as a new standard of care.

392 Background: PAC+RAM is the standard second-line therapy for advanced GEA. However, PAC-related neuropathy is a major challenge, particularly since many pts have pre-existing neuropathy from prior platinum exposure. An effective “neuropathy-free” regimen remains an unmet need. We evaluated FTD-TPI+RAM as an alternative to PAC+RAM. Methods: This multi-center, randomized, phase II study enrolled GEA pts who progressed on or were intolerant to fluoropyrimidine+ platinum therapy. Pts were randomized to FTD-TPI+RAM (Arm A) or PAC+RAM (arm B) at a 1:1 ratio. The primary endpoint was progression-free survival (PFS), defined as time interval between randomization date and the date of disease progression or death; Secondary endpoints included overall survival (OS) and adverse events (AEs). The design hypothesized non-inferiority (NI) of Arm A to Arm B with a NI margin of hazard ratio 1.19. 90 PFS events from 116 pts provide 80% power with a one-sided alpha of 0.15. The interim futility analysis, conducted in December 2024 with 20 events, did not cross the futility boundary (Z statistic ≥ 1.172 ) and continued enrolling pts. The trial closed enrollment in March 2025 due to slow accrual. At the time of interim analysis, 20 events had occurred and the Z statistic was 0.4532. Final analysis included the 29 pts that were eligible, consented, randomized, and received any protocol treatment. Results: Among 29 pts (15 Arm A; 14 Arm B), baseline characteristics were balanced (in Arms A vs B, median age 64 vs 63; 80% vs 85.7% male; 86.7%% vs 78.6% White; 80% vs 78.6% ECOG 1). At data freeze of 8/4/2025, 26 PFS events were reported. Median PFS was 3.2 vs. 3.9 months in Arm A vs. Arm B (HR 1.37, 95% CI 0.61-3.02). NI was not demonstrated (Z =0.34, threshold for NI<-1.036). Median OS was 8.4 vs. 10.7 months, in Arms A and B, respectively. Grade ≥3 AEs occurred in 93% (Arm A) vs 71% (Arm B) with hematologic AEs occurring more frequently in Arm A than Arm B (53% vs 29%). Peripheral sensory neuropathy (any grade) occurred more frequently in Arm B (86%) vs. Arm A (47%). Conclusions: Although NI was not achieved due to early closure and small sample size, FTD-TPI+RAM was relatively safe and associated with less neuropathy compared with PAC+RAM. This regimen warrants further evaluation for pts in whom neuropathy limits taxane use. Clinical trial information: NCT04660760 .

380 Background: KRAS amplifications (amp) occur in ~2% of solid tumors, representing a high unmet need for effective targeted therapies. BI3706674 binds to GDP-bound KRAS and locks KRAS protein in an inactive form. In preclinical models, BI3706674 has shown potent inhibition of KRAS-amp tumors. Methods: This is a Phase Ia/b trial (NCT06056024) to explore the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of BI 3706674 in patients (pts) with unresectable or metastatic KRAS wild type amp or KRAS G12V mutated (mut) solid tumors. The trial aimed to define the maximum tolerated dose (MTD). Pts (ECOG 0 -1) received BI 3706674 daily per os at 50 - 1200 mg doses. Dose escalation (DE) was guided by a Bayesian logistic regression model. This report focuses on KRAS wt amp pts from Phase Ia (DE). Results: As of 31 July 2025, 46 pts had received BI 3706674. Pts (n=15/46) with KRAS wt amp tumors had upper gastrointestinal tract (uGI) cancer [n=9: gastric (GAC;n=5), oesophageal (EAC; n=2), gastroesophageal junction (GEJC; n=2) cancers], Cholangiocarcinoma (n=1), colorectal (CRC; n=4), and ovarian (OC; n=1) cancers. Pts were treated at 200 mg (n=2), 400 mg (n=1), 800 mg (n=5), 1200 mg (n=7) doses; males: n=11; ECOG 1: n=10; median age - 62 years (range 38–83); median number of prior treatment lines was 3 (range 1-6). AEs were reported in 15 pts (100%), including 12 pts (80%) with treatment-related AEs (TRAE). High-grade AEs (Grade 3-5) were reported in 10 pts (66.7%), including 4 pts (26.7%) with TRAEs. SAEs were reported in 7 pts (46.7%), including 2 pts (13.3%) with TRAEs. The most-frequent AEs were mostly low-grade (Grade 1-2) diarrhoea (10 pts, 66.7%), nausea (10 pts, 66.7%), and vomiting (9 pts, 60.0%), often reported as TRAE. Two dose limiting toxicities were observed in 1200 mg group: nausea (Grade 3) and vomiting (Grade 3). MTD was not reached. BI 3706674 PK parameters followed the predicted non-linear PK model; dose dependent systemic exposure reached plateau at 800 mg. 12/15 pts with KRAS wt amp tumors, including 10/12 pts in 800 – 1200 mg groups, were efficacy evaluable; Disease control rate (DCR) was 58.3% (7/12 pts): 3/ 12 pts with partial response (PR), 4/12 had stable disease (SD), 5/12 pts - disease progression (PD). In 800 – 1200 mg groups 1 - OC, 2 – CRC pts achieved SD. PK/PD/efficacy correlation data is pending. Conclusions: BI 3706674 showed a tolerable safety profile and clinical efficacy in pts with KRAS amp tumors. Study results provide clinical proof of concept. KRAS wt amp is a druggable target and KRAS-targeting treatment is active in KRAS wt amp uGI cancer pts. Clinical trial information: NCT06056024 . Anticancer activity of BI 3706674 in efficacy evaluable pts with KRAS wt amp tumors. All pts, 200 – 1200 mg, N=12 Pts with uGI cancers,800 – 1200mg, N=7 ORR, n (%) 3* (25%) 3* (43%) SD, n (%) 4 (33.3%) 1 (14%) DCR, n (%) 7 (58.3%) 4 (57%) PD, n (%) 5 (41.7%) 3 (43%) *Tumor shrinkage: -60.3%, -34% and 34.3%.

373 Background: Recent studies have demonstrated encouraging outcomes with neoadjuvant ICIs in pts with localized deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) GEC, prompting discussions around the feasibility of nonoperative management (NOM). However, current evidence is largely from phase 1 and 2 clinical trials with limited sample sizes. Thus, the efficacy and safety of neoadjuvant ICI in this pt population remain subject to ongoing debate. Methods: We conducted a systematic review and meta-analysis of prospective and retrospective studies evaluating neoadjuvant ICIs in pts with localized dMMR/MSI-H GEC according to the PRISMA guidelines. The primary outcomes were pathological complete response (pCR) and complete clinical response (cCR) rates. cCR was defined as no evidence of residual disease on tumor-specific imaging and on endoscopy with biopsy. Secondary outcomes included major pathologic response (MPR) rates and the incidence of grade 3–4 immune-related adverse events (irAEs). Proportions with 95% confidence intervals (CI) were used to pool event rates for occurrence of cCR, pCR, MPR and grade 3-4 irAEs. The DerSimonian and Laird random-effects model was used. NOM was assessed as part of the qualitative analysis. Results: 20 studies comprising 396 pts treated with neoadjuvant ICIs were included. Three studies utilized double ICI blockade (PD-1/ PD-L1 inhibitor plus CTLA-4 inhibitor), while the remaining studies primarily utilized monotherapy with a PD-1 inhibitor, with or without chemotherapy. Overall, 320 (81.0%) underwent surgical resection. The pooled pCR rate was 41.6% (95% CI, 33.1%–50.8%), cCR 63.8% (95% CI, 45.6%–78.8%), and MPR 64.2% (95% CI, 49.1%–76.9%). The pooled incidence of grade 3–4 irAEs was 5.1% (95% CI, 0.6%–12.2%). Subgroup analysis showed higher pCR with ≥3 months versus <3 months of ICI (50.2% [95% CI 42.2–58.3] vs 28.4% [18.9–40.2]; χ²=8.69, p=0.003). Forty-four pts were managed with NOM, two experienced early local regrowth over median follow-up ranging from 11.5 to 28 months. Conclusions: Neoadjuvant ICI therapy appears to be a safe and effective therapeutic strategy for pts with localized dMMR/MSI-H GEC. Neoadjuvant ICI exposure for ≥3 months seems to yield higher pCR rates than <3 months. The high and prolonged cCR rates support the nonoperative strategy in selected patients with dMMR/MSI-H GEC.

158 Background: PIK3CA mutations are common in CRC and may be a negative prognostic factor. INAVO is a potent and selective PI3Kα inhibitor that also promotes mut p110α degradation. BEV and CETUX are standard treatment (tx) components for RAS mut and RAS -wildtype (wt) mCRC, respectively. The Phase I/Ib INTRINSIC open-label umbrella study (NCT04929223) evaluates targeted therapies in biomarker-selected mCRC subpopulations. We report INAVO + BEV and INAVO + CETUX results. Methods: Patients (pts) with PIK3CA mut, RAS mut mCRC received INAVO (9 mg oral once daily) + BEV (intravenous [IV] 15 mg/kg every 3 weeks). Pts with PIK3CA mut, RAS wt mCRC received INAVO + CETUX (IV 400 mg/m 2 then 250 mg/m 2 weekly thereafter). Primary endpoint: confirmed objective response rate (cORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), and safety. Progression-free survival (PFS) and overall survival (OS) were exploratory. Results: At the clinical cut-off dates, 16 pts were enrolled in the BEV arm; 35, in the CETUX arm. Most had ≥2 metastatic sites at enrollment (n = 16 [100%] and 30 [85.8%], respectively) and ≥2 prior lines of metastatic therapy (16 [100%] and 28 [80.0%]). In the BEV arm, 3 pts (18.8%) had no prior BEV. In the CETUX arm, 25 pts (71.4%) had no prior CETUX; 17 (48.6%) had prior anti-EGFR therapy. All pts in the BEV arm and 34 in the CETUX arm were evaluated for efficacy and safety. Median follow-up was 9.4 months (mo; interquartile range: 5.5–14.4) and 12.6 mo (8.9–16.6), respectively. Efficacy is shown in the Table. All pts had adverse events (AEs); 15 (93.8%) and 34 (100%), respectively, had tx-related AEs (TRAEs); 5 (31.2%) and 12 (35.3%), grade 3–4 TRAEs; 2 (12.5%) and 11 (32.4%), serious AEs. One grade 5 AE (infusion-related reaction) occurred (CETUX arm). Dose reduction/interruption due to AEs occurred in 12 (75.0%) and 27 (79.4%) pts; tx withdrawal due to AEs, in 0 and 4 (11.8%) pts, respectively. Hyperglycemia was the most common AE, TRAE, and AE leading to dose reduction/interruption in both cohorts. Hypertension was observed more frequently with BEV; dermatitis acneiform and dry skin, with CETUX. Conclusions: INAVO + BEV and INAVO + CETUX showed encouraging efficacy in pts with PIK3CA mut mCRC, with no new or unexpected safety signals. Clinical trial information: NCT04929223 . INAVO + BEV(n = 16) INAVO + CETUX(n = 34) cORR, all PR, n (%) 1 (6.3) 7 (20.6)* SD, n (%) 10 (62.5) 17 (50.0) Progressive disease, n (%) 3 (18.8) 9 (26.5) Missing/NE, n (%) 2 (12.5) 1 (2.9) mDoR, mo (90% CI) 7.7 (NE) 4.4 (4.2–5.3) DCR, n (%) 11 (68.8) 15 (44.1) mPFS, mo (90% CI) 4.2 (2.8–6.8) 3.5 (2.8–4.4) mOS, mo (90% CI) 11.0 (8.5–14.5) 12.8 (10.7–13.8) CI, confidence interval; m, median; NE, not evaluable; PR, partial response; SD, stable disease. *3 pts with PRs received prior anti-EGFR therapy; 1 had a best prior response of SD (last dose 233 days before study tx) and 2 had best prior responses of PRs (last doses 134 and 171 days before study tx).