Citations

Abstract Background Synthetic control arms (SCAs) derived from historical trial data can complement randomized controlled trials (RCTs), particularly in oncology where feasibility, ethical, and cost constraints may limit conventional trial designs. However, their validity for overall survival (OS) remains uncertain. We evaluated the feasibility and limitations of constructing SCAs from the ARCAD metastatic colorectal cancer (mCRC) database across multiple treatment lines. Methods Seven landmark RCTs representing first-, second-, and third-line settings were selected. External control arms were constructed from ARCAD individual patient-level data using propensity score matching based on key clinical and biological variables from a validated ARCAD prognostic score, with adjustment for geographic region and time era when needed. A prespecified two-step benchmarking framework assessed: (1) control-arm OS reproducibility and (2) virtual trial comparisons between matched synthetic controls and original RCT experimental arms. Agreement was evaluated using hazard ratios (HRs) and Z-tests. Results A total of 28,022 patients met the inclusion criteria. ARCAD-derived SCAs were successfully constructed for all selected RCTs and closely reproduced control-arm OS. After matching, baseline characteristics were well balanced, with minimal differences between included and excluded patients. Virtual trials showed concordant treatment-effect estimates with the original RCTs, with a median absolute HR deviation of 0.05 and no significant differences by Z-tests (P>.05). Survival outcomes were consistently reproduced across treatment lines. Conclusion ARCAD-derived SCAs reliably reproduced control-arm OS and benchmark treatment-effect estimates from landmark RCTs in mCRC. Despite limitations related to residual confounding and missing data, this framework supports benchmarking, trial design, and exploratory analyses when conventional control arms are impractical.

Abstract Purpose Traditional adverse event (AE) reporting in oncology trials focuses on the single worst CTCAE grade, which may underrepresent chronic or recurrent toxicity burden. We applied a longitudinal toxicity framework to compare toxicity profiles of chemotherapy with or without cetuximab in metastatic colorectal cancer. Patients and Methods We pooled two randomized first-line trials in the ARCAD database. AEs examined were diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis. Outcomes included grade ≥3 AE, time to first occurrence of maximum grade, early onset (≤6 weeks), and AEL, a normalized measure of cumulative toxicity burden over treatment. Analyses were adjusted for chemotherapy backbone, ECOG performance status, sex, primary tumor location, dose reduction, and treatment duration. Results Compared with Chemotherapy alone (n = 564), Chemotherapy plus cetuximab (n = 738) was associated with higher grade ≥3 rash (21% vs 0.5%; adjusted odds ratio [OR] 49.89, 95% CI 15.8–157.4), higher rash AEL (0.257 vs 0.069; adjusted mean difference 0.22, 95% CI 0.21–0.23), and more frequent early-onset maximum rash (67% vs 34%; adjusted OR 4.28, 95% CI 2.72–6.74). Rash AEL remained higher with cetuximab within maximum-grade strata. HFS showed higher grade ≥3 risk and overall AEL with cetuximab, but no within-grade AEL difference, indicating higher overall HFS burden reflected grade distribution rather than within-grade chronicity. No consistent differences were observed for other AEs. Conclusions Incorporating onset timing and AEL distinguished persistent toxicity burden from isolated peak events. This framework may support comparative tolerability assessment when chronic toxicity burden is central to decision-making.

e15557 Background: In metastatic colorectal cancer (mCRC), systemic chemotherapy can enable conversion surgery in a subset of patients with initially unresectable disease. Although R0 resection considered a key determinant of long-term survival, its clinical impact across heterogeneous trial populations and treatment strategies remains insufficiently defined. We aimed to clarify the survival benefit of R0 resection after first-line chemotherapy using large-scale individual patient data. Methods: Using the ARCAD database, which comprises 67 randomized clinical trials and approximately 47,000 patients, we conducted a pooled analysis of individual patient data from six first-line randomized clinical trials (COIN, COIN-B, 03-TTD-01, ATOM, SOFT and PARADIGM) for which data on R0 resection were available. Patients with initially unresectable mCRC and available surgical data were categorized into three groups: R0 resection, non-R0 resection, and no surgery. All R0 cases were included, comprising liver-only, lung-only, combined liver and lung metastases, and peritoneal dissemination or other metastatic sites. Overall survival (OS) and progression-free survival (PFS) were evaluated using multivariable Cox proportional hazards models adjusted for age, sex, and performance status. Pre-specified subgroup analyses examined the consistency of outcomes according to tumor response, metastatic site, primary tumor sidedness, RAS status, and targeted therapy class. Results: Among 4,445 eligible patients, 263 underwent R0 , 233 underwent non-R0 resection, and 3,949 received no surgical intervention. The R0 resection group comprised patients with liver-only metastases (n = 176), lung-only metastases (n = 23), and combined liver and lung metastases (n = 27). R0 resection was associated with significantly improved OS and PFS compared with both non-R0 resection and no surgery. These survival benefits were consistently observed across key clinical subgroups, including patients achieving complete or partial response to chemotherapy, those with liver or lung metastases, left- and right-sided primary tumors, and both RAS wild-type and mutant disease. Importantly, the benefit of R0 resection was maintained irrespective of anti-EGFR– or anti-VEGF–based first-line therapy. Conclusions: R0 resection following systemic chemotherapy is strongly associated with durable survival benefits in patients with initially unresectable mCRC across diverse clinical settings. These findings support the pivotal role of conversion strategies and highlight the importance of multidisciplinary evaluation to identify appropriate candidates for curative-intent resection.

PURPOSE Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy. METHODS A total of 22,957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability–high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data. RESULTS In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically RAD51 (43.0 v 36.3 months; P < .005) and BLM (42.9 v 34.2 months; P < .005). Similar associations were observed for RAD51 (28.1 v 22.9 months; P = .02) and BLM (29.1 v 23.2 months; P < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low BLM expression was associated with improved OS (41.5 v 22.4 months; HR = 0.52; P = .002), whereas RAD51 showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden. CONCLUSION Low BLM RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low RAD51 expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.

Abstract Introduction: The HER2-targeted doublet, tucatinib and trastuzumab, recently received FDA approval for previously treated HER2-positive metastatic colorectal cancer (mCRC). While the intensity of HER2 IHC staining and ERBB2 amplification have been proposed as potential markers of response, our understanding of the role of the tumor microenvironment remains limited. Methods: The phase II MOUNTAINEER Trial (NCT03043313) enrolled patients for tucatinib plus trastuzumab based on HER2 positivity (IHC or NGS amplification). Patients from cohort A with available HER2 IHC and H&E slides were included in this analysis. Previously validated AI-based models (Lunit SCOPE uIHC and SCOPE IO) were used to quantify the percentage of HER2 3+ stained tumor cells (AI-H3+) and the densities of tumor infiltrating lymphocytes (TILs) in the cancer epithelium (iTIL) and stroma (sTIL). Results: The analyzed cohort (N=30) had an objective response rate (ORR) of 43.4% and median progression-free survival (PFS) of 8.0 months. AI-H3+ percentage showed a strong, dose-dependent association with an ORR of 57.1%, 66.6%, and 80.0% for tumors with AI-H3+ ≥10% (n=14), ≥25% (n=12), and ≥50% (n=10), respectively. This benefit extended to PFS, with the ≥50% cohort reporting a PFS HR of 0.17 (P=0.002) compared to tumors with AI-H3+ &lt;50%. Tumors with below median iTIL or sTIL had significantly shorter PFS. Notably, tumors with sTIL density in the bottom quantile had an ORR of 0% and PFS HR of 4.40 (P=0.002) despite including cases with high AI-H3+. TIL densities and AI-H3+ percentage were not correlated. Conclusion: These findings confirm AI-quantified HER2 intensity as a marker of response and suggests the importance of TILs, which may have a role through immunogenic cell death. Stratification by HER2 and TIL may be an approach to consider as this regimen progresses into the first-line setting. Citation Format: Mitsuho Imai, John H. Strickler, Woochan Hwang, Kara Bonneau, Andrew B. Nixon, Jongchan Park, Chang Ho Ahn, Tanios Bekaii-Saab, Takayuki Yoshino. HER2 expression and tumor-infiltrating lymphocytes predict response to tucatinib plus trastuzumab in HER2-positive metastatic colorectal cancer (MOUNTAINEER): Exploratory analysis of a multicenter, Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7735.

776 Background: Surgery is the only potentially curative option for PC. However, only a minority of patients (pts) undergo resection with current perioperative (periop)-chemotherapy (CT). In the absence of phase III trials, selection between mFOLFIRINOX and gemcitabine/nab-paclitaxel (gem-nab) is based on limited evidence. We assessed whether NGS–based tumor profiling can guide tailoring of CT. Methods: pts with resected PC (resectable, borderline resectable, and downstaged locally advanced) that underwent Tempus xT, xF (DNA), and/or xR (RNA) testing were selected (89% tissue, 11% blood). Most samples (73%) were collected post-CT. Samples were stratified by KRAS status into KRAS -mutated ( KRAS mut) and KRAS wild-type ( KRAS wt). PD-L1 IHC was reported as tumor proportion score (TPS). Primary endpoint was median overall survival (mOS) defined from CT initiation to death with censoring of pts alive at the last follow-up or at a study cutoff of 5 years. Secondary endpoint was molecular profiling by KRAS status. Pearson chi-square and Wilcoxon rank-sum tests were used for descriptive comparisons; univariate Cox regression and log-rank tests (p<0.05) for survival. Results: We included 1,325 pts (median age 66 years [IQR 59–72]) with resected PC [stage II (15%), stage III (12%) and stage I (10%), unknown (62%)]. 95% had adenocarcinoma. Pts received neoadjuvant (50%), neoadjuvant plus adjuvant (26%), neoadjuvant with indeterminate adjuvant allocation (13%) or adjuvant CT (11%). First-line periop-CT was mFOLFIRINOX in 73% and gem-nab in 27% (median duration 4.3 months (mo) [range, 2.6–6.7]). KRAS mutations were present in 75% (G12X 91%: G12D 44%, G12V 34%, G12R 21%, G12C <1%). mOS was 26.7 mo (95%CI, 22.4-35.7) in the total cohort; KRAS mut pts showed a clinically meaningful worse mOS compared to KRAS wt [24.1 vs 35.7 mo; HR 1.61 (95%CI, 0.98 - 2.63); p=0.06]. In the KRAS G12D pts, mFOLFIRINOX showed a trend towards longer mOS compared to gem-nab [17.79 vs 14.53 mo; HR 0.75, (95% CI, 0.56 - 1); p=0.050]; no significant differences were observed in other KRAS subgroups. Compared to KRAS wt, KRAS mut pts were enriched for TP53 (76% vs 22%; p<0.001), SMAD4 (28% vs 5.8%; p<0.001), CDKN2A (33% vs 8.5%; p<0.001), MTAP deletions (7.7% vs 1.2%; p<0.001), and chromatin-regulator alterations ( ARID1A 7.8% vs 1.2%; p<0.001; KMT2C 2.5% vs 0.6%; p=0.034). KRAS wt pts were enriched for BRAF V600E (1.5% vs 0%; p<0.001). PD-L1 TPS ≥1% was more frequent in KRAS mut compared to KRAS wt (11.0% vs 8.1%; p=0.033). Conclusions: KRAS status does not predict benefit from mFOLFIRINOX vs gem-nab in resected PC. Interestingly, resected PC showed a higher prevalence of KRAS wt compared to the metastatic setting. KRAS status is associated with distinct profiles of potentially targetable co-alterations. These findings may suggest the integration of genomic profiling in clinical trials to develop biomarker-driven tailored strategies in the early stage.

679 Background: DNA-damaging agents improve outcomes in metastatic pancreatic cancer (mPC) with homologous recombination repair (HRR) deficiency, albeit use is limited to 6-9% of patients (pts) with BRCA1/2 or PALB2 mutations. We hypothesized that BRCA/PALB2 wildtype mPC may exhibit platinum sensitivity driven by altered HRR gene expression. We correlated HRR gene RNA profiles with real-world overall survival (rwOS) following first-line (1L) platinum therapy (PT). Methods: Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database was used to identify mPC pts with wildtype somatic BRCA1/2 and PALB2 who had Tempus xT DNA and xR RNA testing. RNA-seq data were normalized to correct for assay/batch effects, quantified as transcripts per million (TPM) and reported as log2(TPM+1) for 17 HRR genes and GATA6 . Pts were classified as high and low expressors based on the top and bottom quartile gene expression. Pts were grouped as PT-treated (received 1L PT) or PT-naïve (never received PT). Real world overall survival (rwOS) was calculated from 1L start to death or loss to follow up. Risk set adjustment was applied to mitigate immortal time bias. Median rwOS was estimated using Kaplan-Meier and univariate Cox models. A multivariate Cox Proportional (CoxPh) model included PT use, RAS status, and expression of genes (as continuous variables). Results: Among 1,068 pts, the median age was 66 years and 609 (57%) received 1L PT. In low RAD51 expressors, PT-treated pts (n=136) had significantly longer rwOS than PT-naïve (n=112): 11.4 months (95% CI, 7.8–13.8) vs 8 months (95% CI, 5.5–9.0); p=0.028. In contrast, in high RAD51 expressors, rwOS was similar between PT-treated (n=150) and PT-naïve (n=97): 7.9 vs 6.9 months (p=0.236). High GATA6 expression was also associated with improved rwOS in PT-treated pts vs PT-naïve: 13.5 vs. 9.3 months; p=0.011. In multivariate analysis, increased GATA6 expression remained a positive predictor of rwOS (HR 0.82; 95% CI, 0.76–0.88; p<0.001), and high RAD51 expression was associated with shorter rwOS with PT (HR 1.18; 95% CI, 1.01–1.39; p=0.043). Conclusions: In BRCA/PALB2 wt mPC, transcriptomic profiling identified low RAD51 and high GATA6 expression as predictors for improved rwOS when treated with PT. Integrating these biomarkers may improve development of DNA-damaging therapies beyond canonically defined HRD. Hazard ratios of mPC mortality by selected HRR genes estimated by multivariate CoxPh models. HR 95% CI p value 1L PT (vs PT-naïve) 0.87 0.75, 1.00 0.054 BRCA1 1.15 0.98, 1.35 0.079 BRCA2 0.89 0.77, 1.04 0.14 GATA6 0.82 0.76, 0.88 <0.001 NBN 0.97 0.81, 1.15 0.7 RAD51 1.18 1.01, 1.39 0.043 RECQL4 0.94 0.84, 1.04 0.2 Any RAS mutation 1.43 1.14, 1.81 0.002

599 Background: Biliary tract cancers (BTC) remain aggressive malignancies with limited treatment options. Alterations in PIK3CA are implicated in tumor progression across solid tumors, but their prognostic impact in BTC remains unclear. We investigated the association of PIK3CA alterations(alt), alone and in combination with TP53 and ARID1A , with survival outcomes in advanced BTC. Methods: We conducted a retrospective analysis of 1,079 patients with advanced BTC treated with first-line chemotherapy (CT) or chemoimmunotherapy (CIO) across three sites in the USA, Japan, and Brazil. Genomic profiling was performed using next-generation sequencing on tissue and/or liquid biopsy samples. Survival outcomes were estimated by Kaplan-Meier analysis, with comparisons by log-rank testing and hazard ratios (HR) derived from Cox regression models. Results: PIK3CA alterations were identified in 11% (123/1,079) of patients. The median age at diagnosis was 68 yrs (range, 20–79), with 50% (62/123) female. The most common primary site was intrahepatic in 43.1% (53/123) while majority of patients received CT only 92.5% (111/123). When analyzed with TP53 , 68 pts had PIK3CA/TP53 co-alterations(co-alt), 501 had TP53 alt, 55 had PIK3CA alt alone, and 455 had neither PIK3CA nor TP53 alt (WT/WT). Overall survival (OS) was significantly worse in patients with PIK3CA alt, particularly in the setting of TP53 co-alt. Median OS (mOS) was 22.6 months(m) (95% CI, 20.4–24.8) for PIK3CA/TP53 WT, 15.9 m (95% CI, 11.6–18.5) for PIK3CA alt /TP53 WT, 14.6 m (95% CI, 13.1–19.5) for PIK3CA alt/ TP53 alt, and 17.1 m (95% CI, 15.5–18.8) for TP53alt/PIK3CA WT (p<0.001). In analyses with ARID1A , 32 pts had PIK3CA/ARID1A co-alt, 91 had ARID1A alt only, 120 had PIK3CA alt only, and 836 were WT/WT. PIK3CA/ARID1A co-alt tumors had a mOS of 12.8 m (95% CI, 9.1–NE) compared with 19.3 m (95% CI, 18.1–20.9) in PIK3CA WT /ARID1A WT (p=0.009). Multivariate analysis identified PIK3CA alt (hazard ratio [HR] 1.37, 95%CI 1.09–1.72; p=0.008), PIK3CA alt/ TP53 alt (HR 1.52 95% CI, 1.11–2.07; p=0.008), ARID1A alt/ PIK3CA WT (HR 1.40, 95% CI 1.08-1.82, p=0.011), and metastatic status (HR 1.82, 95% CI 1.52-2.19, P<0.001) as independent prognostic factors for shorter OS. Conclusions: In advanced BTC, PIK3CA alt were associated with significantly worse overall survival, particularly when co-occurring with TP53 or ARID1A alt. These findings establish PIK3CA as a prognostic biomarker of poor outcome and highlight the need to explore PI3K-targeted therapeutic strategies in BTC.

593 Background: TP53 and CDKN2A are the most frequently mutated tumor suppressors in BTC, each linked to poor outcomes. Their co-alteration remains unexplored due to the current single-gene classification. Methods: This is an international multicenter study involving 35 institutions across 3 continents (North America, Asia, South America). Genomic profiling was performed on tissue or blood samples using NGS. Patients (pts) were categorized as wild-type (wt) TP53/ wt CDKN2A (WT/WT) (42%), mutated (mut) TP53 /wt CDKN2A (45%), wt TP53 /mut CDKN2A (5%), mut TP53 /mut CDKN2A (8%). Associations between TP53 / CDKN2A status , clinical and genomic features were evaluated using Chi-squared/Kruskal-Wallis tests adjusted for multiple comparisons. Overall survival (OS) from start of first-line systemic therapy was analyzed by Kaplan–Meier and multivariate Cox regression (covariates: age, sex, stage, primary site, first-line treatment, TP53/CDKN2A status), p or q<0.05. Results: We included 1079 pts with BTC. Median age 66 years with intrahepatic BTC (46%), gallbladder cancer (25%), extrahepatic BTC (22%), undefined (6%), ampullary cancer (< 1%). Most had de novo metastatic disease (54%), followed by recurrent (38%) and locally advanced disease (8%). Treatment regimens included chemotherapy (87%), chemo-immunotherapy (12%) and immunotherapy alone (<1%). The most frequently actionable genes were HER2 (8%), IDH1 (7%), BRAF (6%), FGFR2 fusions (4%), MSI-High (H) (3%). HER2 alterations were prevalent in mut TP53 /wt CDKN2A vs WT/WT (11 vs 4%, q = 0.002). IDH1 alterations were more frequent in WT/WT vs TP53 mut/wt CDKN2A (10 vs 4%, q < 0.001). FGFR2 fusions were more common in wt TP53 /mut CDKN2A vs WT/WT (17 vs 6%, q < 0.001), mut TP53 /mut CDKN2A (17 vs 3%, q = 0.001) and mut TP53 /wt CDKN2A (17 vs 1%, q < 0.001). MSI-H was enriched in mut TP53 /mut CDKN2A vs wt TP53 /mut CDKN2A (11 vs 2%, q = 0.035), mut TP53 /wt CDKN2A (11 vs 3%, q = 0.002) and WT/WT (11 vs 2%, q < 0.001). TMB-H was more prevalent in mut TP53 /mut CDKN2A vs mut TP53 /wt CDKN2A (16 vs 8%, q < 0.001) and WT/WT (16 vs 3%, q < 0.024). There was no significant difference in ORR, DCR and PFS among the four groups. mut TP53 /mut CDKN2A had the shortest median OS, while WT/WT had the longest (Table). Only 14% of mut TP53 /mut CDKN2A received regimens including immunotherapy. Conclusions: mut TP53 /mut CDKN2A represents a high-risk subset enriched with MSI-H and TMB-H pts, underscoring the need to prioritize the development of immunotherapy strategies. TP53 / CDKN2A status is prognostic, stratifying patients into distinct survival groups and supporting NGS use in the first-line setting. mOS (months) (95% CI) HR (95% CI) P-value WT/WT 21.4 (19.0-24.4) reference wt TP53 /mut CDKN2A 17.3 (12.4-25.9) 1.16 (0.79-1.71) 0.442 mut TP53 /wt CDKN2A 17.4 (16.0-19.2) 1.21 (1.01-1.45) 0.040 mut TP53 /mut CDKN2A 13.8 (11.5-18.1) 1.54 (1.13-2.09) <0.001