Citations

554 Background: Atezo/Bev is the 1 st -line standard for advanced hepatocellular carcinoma (aHCC). Optimal 2 nd -line therapy post-Atezo/Bev remains undefined. This study evaluates continuation of atezolizumab with a MKI versus MKI alone in the 2 nd -line setting. Methods: This multicenter, randomized phase II trial enrolled patients with unresectable aHCC who progressed on Atezo/Bev. Patients were randomized 2:1 to atezolizumab plus MKI (cabozantinib or lenvatinib; Arm A) or MKI alone (Arm B). Stratification factors included MKI choice, viral etiology, and alpha-fetoprotein levels. Dual primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and safety. With 84 death and 89 PFS events, from 122 patients, this trial had 80% power to detect a hazard ratio (HR) of 0.556 in OS and HR of 0.571 in PFS with a one-sided type I error (alpha) of 0.05 for each endpoint. Results: Twenty patients were accrued across 5 U.S. centers, between 01/2022 and 03/2025, before early closure due to slow accrual. Eighteen received treatment (Arm A: n=13; Arm B: n=5). Baseline characteristics: median age 68 yr, extrahepatic 56%, Hep B+ 0%, Hep C+ 33%, NASH 33% and CP A (5 to 6) 100%. MKIs used were cabozantinib (Arm A: 6/13; Arm B: 4/5) and lenvatinib (Arm A: 7/13; Arm B: 1/5). Median follow-up was 28.0 months (mo), with 14 deaths reported. Median (95% CI) OS were 13.9 (7.1-Not Estimable [NE]) and 6.2 (5.1-NE) mo (Arm A and B respectively); and that of PFS 4.3 (2.3-NE) and 4.1 (3.7-NE) mo. ORR was 7.7% (1/13) in Arm A (responder received lenvatinib) and 0% (0/5) in Arm B. Grade ≥3 adverse events (at least possibly related) occurred in 46.2% of Arm A and 60.0% of Arm B patients. G3+ events occurring in >10% of patients included hypertension, fatigue, anorexia, and ALT elevation in Arm A; and hypertension, hallucination, nausea, hypomagnesemia, hypokalemia, mucositis, AST increased and colitis in Arm B. Conclusions: In this limited cohort, continuation of atezolizumab with MKI showed relative activity and manageable safety in aHCC post-Atezo/Bev. The AE profile for atezo/MKI is consistent with the known profile of respective agents. These findings support further investigation of immunotherapy-based combinations in the 2nd-line setting. Clinical trial information: NCT05168163 .

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).

126 Background: NNT/NNH analyses can estimate the magnitude of benefit vs harm of therapeutic agents and can inform clinical decision making. We quantified the benefit/risk profile of fruquintinib (F; a highly selective, oral inhibitor of all 3 VEGFRs) vs other later-line mCRC monotherapies. Methods: Six phase 3 randomized (2:1), placebo (P)-controlled trials (F: FRESCO, FRESCO-2; regorafenib [rego]: CONCUR, CORRECT; TAS-102: TERRA, RECOURSE) were identified. NNT (average number of pts needing treatment to prevent 1 additional death/progression event) for overall survival (OS) and progression-free survival (PFS) was calculated as the inverse of difference in survival function between treatment and P. NNH (average number of pts needing treatment for 1 additional pt to have an adverse event; AE) for treatment-emergent AEs (TEAEs) was calculated as the inverse of absolute risk increase relative to P. Low NNTs and high NNHs suggest a more favorable treatment profile. Results: F had the lowest NNT (most favorable) for 6-month OS (FRESCO-2) and PFS (FRESCO) vs rego and TAS-102 (Table). F had the highest NNH (most favorable) for grade ≥3 TEAEs, palmar-plantar erythrodysesthesia (PPE; FRESCO-2), and fatigue (FRESCO). TAS-102 (TERRA) had the highest NNH for diarrhea, followed by F (FRESCO-2). Consistent with mechanism of action of anti-VEGFRs, F and rego had lower NNHs for hypertension (HTN) vs TAS-102 (TERRA). F (FRESCO) had the lowest NNH for discontinuation due to TEAEs. Conclusions: In this cross-trial comparison, F had the lowest NNT for OS (FRESCO-2) and PFS (FRESCO/FRESCO-2), indicating survival benefit. F had the highest NNHs for grade ≥3 TEAEs, PPE (FRESCO-2), and fatigue (FRESCO), indicating a low risk profile. The analysis highlights fruquintinib as a favorable treatment for pts with mCRC. Clinical trial information: NCT02314819 , NCT04322539 , NCT01584830 , NCT01103323 , NCT01955837 , NCT01607957 . NNT/NNH (95% CI) for mCRC treatments.* F Rego TAS-102 FRESCO NCT02314819 N=416 FRESCO-2 NCT04322539 N=691 CONCUR NCT01584830 N=204 CORRECT NCT01103323 N=760 TERRA NCT01955837 N=406 RECOURSE NCT01607957 N=800 6-month OS 6.5(5.5–8.1) 5.3(4.8–5.9) 5.9(NA) 9.8(NA) 14.1(NA) 7.2(NA) 6-month PFS 4.2(3.7–4.8) 4.4(3.9–5.1) 5.0(NA) 9.1(NA) 7.1(NA) 7.2(NA) Grade ≥3 TEAEs 2.4 (2.0–3.1) 8.1 (5.0–22.5) 2.6 (2.0–3.7) 2.5 (2.2–3.0) 2.8 (2.3–3.6) 5.9 (4.1–10.2) TEAE leading to discontinuation 10.8 (6.7–28.5) NA † (18.0–NA) 12.5 (6.2–NA) 17.5(11.3–39.2) 250.0 (15.3–NA) 50.0 (22.9–NA) PPE 2.2 (1.9–2.5) 6.0 (4.8–8.0) 1.4 (1.3–1.7) 2.6 (2.2–3.0) NA (NA) NA (46.0–NA) HTN 2.4 (2.0–3.0) 3.6 (3.0–4.5) 5.3 (3.6–9.5) 4.5 (3.7–5.8) 14.3 (10.0–25.2) NA (NA) Diarrhea 5.1 (3.8–7.4) 7.3 (5.2–12.3) 6.2 (4.3–11.4) 3.8 (3.2–4.8) 7.9 (5.7–13.0) 5.0 (3.9–6.9) Fatigue 32.5 (10.3–NA) 25.8 (10.1–NA) 10 (5.3–80.3) 5.3 (3.8–8.4) 7.4 (5.0–13.9) 8.3 (5.4–18.1) *All trials except TERRA included best supportive care in both arms. † Lower rate of pts discontinued F vs P due to TEAEs, thus NNH was not applicable (NA).

103 Background: Clinicians spend significant time extracting and synthesizing information to risk-stratify and make adjuvant chemotherapy (AC) recommendations for CRC. By automating parts of this process, LLMs could help reduce documentation burden and variability in decision-making. Methods: We selected 144 stage III, pMMR CRC patients treated at Mayo Clinic (2017–2021). HIPAA-compliant Gemini-2.0-Flash-001 and GPT-4o extracted clinical variables (age, neuropathy grade, pathological stage) from EHRs and generated AC recommendations. Two approaches were compared: (1) a rule-based algorithm with nested if/else statements translating variables into NCCN-based recommendations, and (2) a dynamic LLM agent generating recommendations using a structured prompt informed by NCCN guidelines. Concordance with treating physicians was assessed, with disagreements reviewed by a blinded GI oncologist. Results: The dataset included 144 patients with median age 67 (IQR 66–68), 48.6% female. The LLM pipeline extracted neuropathy grade with 100% accuracy and pathological T/N stages with 99.3% accuracy. Concordance with physician recommendations was 93.1% for the rule-based algorithm and 62.5% for the LLM agent. In discordant cases, blinded adjudication by a GI oncologist favored the algorithm and LLM agent over physicians in most cases (Table 1). Conclusions: This exploratory work shows LLM agents can reliably extract variables and generate evidence-based treatment recommendations for stage III CRC. The high rate of expert preference for LLM recommendations in discordant cases is intriguing but limited by small sample size and possible adjudicator bias. Discordant physician recommendations reflect the complexity of decision-making, including patient preferences, performance status, comorbidities, and subtle findings not fully captured in EHRs. Rather than replacing judgment, we envision LLMs as decision support tools—analogous to an advanced trainee reviewing charts and presenting evidence-based recommendations to the attending physician with ultimate authority. Larger multi-institutional studies with multiple adjudicators are needed to validate these findings and clarify AI’s role in oncology. Patient characteristics, LLM extraction accuracy, and concordance with physician recommendations. Metric Result Total patients 144 Median age (IQR) 67 (66-68) Female (%) 48.6% LLM extraction accuracy – Neuropathy grade 100% LLM extraction accuracy – Pathological T and N stages 99.3% Primary Concordance – Rule-based algorithm vs. physician 93.1% Adjudicator preference of rule-based algorithm over treating physician for discordant cases 100% Concordance – LLM agent vs. physician 62.5% Adjudicator preference of LLM agent over treating physician for discordant cases 82.0%

Abstract Background The increasing reliance on accelerated approvals and surrogate endpoints for Food and Drug Administration (FDA) approvals of gastrointestinal (GI) cancer therapies raises concerns about their clinical benefit and long-term patient outcomes. The shift toward single-arm trials in regulatory decisions further complicates treatment evaluation. Material and Methods This retrospective observational study evaluated all FDA approvals for GI cancer therapies from January 2006 through January 2025. Data were extracted from FDA archives, ClinicalTrials.gov, and PubMed. Approvals were categorized by regulatory pathway (accelerated vs regular), trial design (single-arm vs randomized), and primary endpoint (surrogate vs overall survival [OS]). Clinical benefit was assessed based on OS improvement and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The primary outcome was the proportion of approvals based on surrogate versus OS endpoints. Secondary outcomes included use of single-arm designs, frequency of accelerated approvals, OS gain, and the proportion meeting ESMO-MCBS substantial benefit (score ≥ 4). Results The FDA granted 60 GI cancer drug approvals from 67 trials. Approvals rose from 15 (25%) in 2006-2014 to 45 (75%) in 2015-2025. Single-arm trials increased to 24%, and surrogate endpoints were used in 41.8% (ORR 20.9%, PFS 19.4%). Median OS improvement was 2.1 months (IQR: 1.6-2.65). Only 24.3% of trials met ESMO-MCBS substantial benefit. Of 15 accelerated approvals, 66.7% remained pending, 13.3% received full approval, and 20% were withdrawn. Conclusion Expedited approvals have improved drug access in GI oncology, but modest benefits highlight the need to balance speed with outcomes that truly matter to patients.

Abstract Background This phase 1 study aimed to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary efficacy of rucaparib (RUB), a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, combined with liposomal irinotecan (nal‐IRI) and 5‐fluorouracil (5‐FU) in metastatic gastrointestinal (GI) cancers. RUB targets DNA repair pathways, showing efficacy in tumors with homologous recombination deficiency, such as BRCA mutations. Preclinical data suggest synergy with irinotecan, but overlapping toxicities pose challenges. Methods Eighteen patients with metastatic GI cancers, who previously progressed on at least one systemic therapy, were enrolled. A novel sequential dosing regimen, informed by nal‐IRI pharmacokinetic analysis, was used. Twelve patients were evaluable for dose‐limiting toxicity (DLT) and 12 for response per Response Evaluation Criteria in Solid Tumors v1.1 criteria. Results The MTD was established as RUB 600 mg twice daily, nal‐IRI 50 mg/m 2 , and 5‐FU 2400 mg/m 2 over 46 hours. The objective response rate (ORR) was 33% (4 of 12), and the disease control rate (DCR) was 75% (9 of 12). Common grade 3 adverse events included diarrhea (33%) and neutropenia (25%), with no grade 4/5 events. Responses were notable in patients with somatic ATM and BRCA mutations, especially those with prior platinum exposure. No DLTs occurred at the recommended phase 2 dose. Conclusions This optimized dosing schedule successfully established the MTD for RUB with nal‐IRI and 5‐FU, overcoming prior challenges with PARP inhibitor and irinotecan combinations. The promising ORR and DCR support further evaluation of this regimen in advanced GI malignancies.