782 Background: FOLFIRINOX is a preferred regimen for borderline and locally advanced pancreatic ductal adenocarcinomas (PDAC). Stereotactic body radiotherapy (SBRT) is promising for local disease control, and predictive markers are needed to define when FOLFIRINOX followed by SBRT is of clinical benefit. Methods: Two single-arm, phase 2 trials for borderline resectable PDAC (BRPC) and locally advanced PDAC (LAPC), were conducted at the Yale Smilow Cancer Hospital from 8/2017 – 1/2019 (NCT03099265) and 9/2019 – 9/2023 (NCT03991962). Patients received 8-12 cycles of FOLFIRINOX followed by SBRT (33 Gy in 5 fractions). Radiographic and biochemical responses (CA19-9) were assessed by a multi-disciplinary team for surgical eligibility. Endoscopic ultrasound strain elastography with core biopsies were performed pre-treatment, post-FOLFIRINOX, and post-SBRT to determine the strain ratio (tumor stiffness) and PDAC molecular subtype, respectively. The primary endpoint was 9-month progression-free survival (PFS). Additional endpoints included median PFS, median overall survival (OS), patterns of recurrence, tumor stiffness (assessed by elastography strain ratio), and PDAC molecular subtype (assessed by K17 IHC test). Results: Twenty patients (10F, 10M, median age 64) were enrolled. Thirteen had BRPC and seven had LAPC. Twelve (60%) patients received FOLFIRINOX + SBRT and three (15%) underwent surgery on protocol. Nine-month PFS was 36% (95% CI, 19-68%, expected was 50% based on LAP07). Median PFS was 8 months (95% CI, 5.8-32.4), and median OS was 13.2 months (95% CI, 9-59). The median follow-up was 72.5 months. Overall response rate was 25% with 5 partial responses. Locoregional-only recurrences were rare (10%), with most recurrences occurring at distant sites (40%) or locoregional sites (20%), indicating favorable local disease control. One patient died of oxaliplatin-related pneumonitis. Pre-treatment tumor stiffness was higher in BRPC vs. LAPC (30.5 vs. 11.4, p = 0.04), and stiffer tumors were mainly basal-like molecular subtype ( p = 0.06). Higher pre-treatment tumor stiffness had a non-significant increased risk of death (adjusted for stage, HR 3.85, 95% CI 0.79–18.84, p = 0.09), such that BRPC with higher pre-treatment stiffness exhibited survival outcomes comparable to that of locally advanced tumors. In contrast, among CA19-9 responders, tumors that became stiffer with chemotherapy had a non-statistical improved overall survival relative to tumors that became softer (HR 0.39, 95% CI 0.07-2.04, p = 0.26). Conclusions: FOLFIRINOX followed by SBRT achieved local disease control in PDAC. Tumor stiffness and molecular subtype emerged as potential biomarkers of response and prognosis, warranting validation in larger studies. Early trial closure from the COVID-19 pandemic and censoring of exceptional responders prior to SBRT likely contributed to the inferior observed outcomes. Clinical trial information: NCT03099265 , NCT03991962 .

PURPOSECancer clinical trial enrollment remains critically low at 5%-7% of adult patients despite exponential growth in available trials. Manual patient-trial matching represents a fundamental bottleneck, whereas current artificial intelligence (AI) and machine learning patient-trial matching systems lack data standardization and compatibility across health systems. We developed and validated a semiautomated clinical trial patient matching (CTPM) tool to improve recruitment efficiency and scalability.METHODSWe created a hybrid rules-based and natural language processing (NLP)-based pipeline that automatically screens patients using structured and unstructured electronic health record data standardized to the Observational Medical Outcomes Partnership (OMOP) common data model. CTPM performance was first evaluated on one metastatic colorectal cancer (CRC) trial by comparing CTPM accuracy and efficiency to manual chart review. Following the single-trial validation, we then implemented the system across 29 clinical trials spanning multiple cancer specialties and phases.RESULTSFor the single CRC trial, CTPM achieved 94% retrospective and 88% prospective accuracy, matching gold standard clinical chart review with 100% sensitivity. Implementation reduced chart review workload 10-fold and screening time by 41% (3.1 to 1.8 minutes per chart) for those patients who did undergo review. Since September 2022, the system has screened 98,348 patients across 29 trials, identifying 825 eligible candidates and facilitating 117 patient enrollments with 9%-37% consent rates.CONCLUSIONThis AI and NLP tool demonstrates improved efficiency in clinical trial recruitment by enabling research teams to focus on qualified candidates rather than exhaustive chart reviews. The OMOP-based framework supports scalability across health systems, with potential to address enrollment challenges that limit patient access to clinical trials.

Baseline CDH17 expression levels across colorectal cancer (CRC) and non-CRC tumors in patients treated with BI 905711 monotherapy (NCT04137289 study) as percent positive staining (A) and H-score intensity (B). Dots represent all biopsies assessed for CDH17 positivity or H-score, including samples from a small number of patients with two biopsies. The dotted line in A represents 90% CDH17 positivity by IHC.

Pharmacokinetic parameters for BI 905711 as monotherapy (NCT04137289)a.

BACKGROUND:A growing population of older adult cancer survivors faces competing cancer and noncancer health risks. There are limited real-world data on recurrence patterns beyond 5 years post-treatment. METHODS:This was a SEER-Medicare retrospective cohort study of patients aged ≥66 with stage I-III breast, colon, or rectal cancer who received definitive surgery and survived ≥5 years from diagnosis without recurrence or second primary malignancy. Late recurrence (5-10 years postdiagnosis) was identified using a validated algorithm to detect treated recurrence in Medicare claims. Demographic and clinical characteristics collected at cancer diagnosis were assessed as predictors of late treated recurrence using restricted mean survival time (RMST) regression. RESULTS:The sample included 12 859 breast, 17 329 colon, and 4427 rectal cancer survivors. The cumulative incidence of late treated recurrence 5-10 years postdiagnosis was 5.0% in breast, 4.4% in colon, and 8.0% in rectal cancer survivors. In all cohorts, stage was associated with shorter RMST. The absolute risk difference between stage I and III was greatest in breast (2% vs 18.1%), followed by rectal (5.2% vs 10.3%) and colon (2.7% vs 6.7%) cancer survivors (P < .001 for all cohorts). Although their effect on RMST was modest (<5%), higher grade, node-positive, and ER-positive disease in breast, left-sided tumors in colon, and radiation in rectal cancer were associated with late treated recurrence. Across all cohorts, the incidence of other-cause mortality (24.1%-34.0%) exceeded cancer-specific mortality (2.9%-6.2%). CONCLUSIONS:Late treated recurrence in older long-term survivors is uncommon, but risk remains elevated 5 years postdiagnosis in those with more advanced stage.

3553 Background: Homozygous loss of the MTAP gene ( MTAP loss) is an emerging biomarker guiding investigational use of PRMT5 and MAT2A inhibitors in a wide variety of tumor types, including CRC. Detecting copy number changes, including homozygous losses, in solid tumors is often challenging and requires robust assay and analytic pipeline especially when the amount of extracted DNA is small. In clinically advanced CRC, small endoscopic and needle-based biopsies are often used for diagnosis, imposing significant limitations on immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) required for treatment selection and clinical trial enrollment. We assessed whether liquid biopsy (LBx) CGP could provide treatment-relevant information on MTAP loss compared to tissue biopsy (TBx) CGP for patients with CRC. Methods: Hybrid capture-based CGP was performed on 46,173 clinically advanced CRC (stage III, IV) TBx cases using the FoundationOne CDx assay and on 9,049 LBx cases using the FoundationOneLiquid CDx assay. Tumor fraction (TF) for each LBx sample was determined using assessments of aneuploidy and variant allele frequencies, as previously described. Results: MTAP loss was detected in 498 (1.08%) TBx cases. For LBx, detection of MTAP loss increased with higher TF, with detections observed only at TF ≥5% (Table 1). With TF ≥5%, the frequency of MTAP loss detection was comparable to or exceeds that observed with TBx. Regarding complete vs partial MTAP exon loss, TBx and LBx showed similar patterns, with complete loss of all 8 MTAP exons observed in 85.7% of TBx cases and 84.5%-89.8% in LBx cases, increasing in higher TF levels. Conclusions: LBx emerges as a promising tool for detecting MTAP loss in clinically advanced CRC, with MTAP loss detection rates approaching those of TBx when LBx TF is ≥5%, while detection is limited at lower TF levels. Incorporation of LBx for MTAP loss detection may expand patient access to biomarker-driven clinical trials involving PRMT5 and MAT2A inhibitors for patients with clinically advanced CRC when sufficient tissue for tissue-based CGP is not feasible. MTAP loss detected by TBx and LBx in clinically advanced CRC. Cohort (cumulative)* MTAP no loss MTAP loss MTAP loss frequency TBx (n=46173) 45675 498 1.08% LBx TF ≥0% (100% of LBx, n=9049) 9002 47 0.52% LBx TF ≥1.0% (62.7% of LBx) 5624 47 0.83% LBx TF ≥5.0% (48.7% of LBx) 4359 47 1.07% LBx TF ≥10.0% (41.5% of LBx) 3712 46 1.22% LBx TF ≥20.0% (31.5% of LBx) 2812 38 1.33% LBx TF ≥30% (24.8% of LBx) 2214 29 1.29% *TF thresholds represent cumulative subsets of the LBx cohort.

Maximum percentage change from baseline in the sum of target lesion diameters in study NCT04137289.

BACKGROUND:Anaplastic lymphoma kinase (ALK) fusions are established oncogenic drivers and therapeutic targets in multiple malignancies, including non-small cell lung cancer, but are rare in colorectal cancer (CRC). Although ALK fusions in CRC have been associated with sensitivity to ALK inhibitors, their broader genomic context remains incompletely defined. We aimed to characterize the prevalence, clinicogenomic features, and therapeutic implications of ALK fusions in advanced CRC. MATERIALS AND METHODS:Comprehensive genomic profiling using hybrid capture-based next-generation sequencing was performed on 56 206 advanced CRC tumors to identify alterations, including ALK fusions. Microsatellite instability (MSI)/mismatch repair (MMR) status, tumor mutational burden (TMB), genomic ancestry, COSMIC trinucleotide signatures, and homologous recombination deficiency (HRD) signatures were derived from sequencing data. PD-L1 expression was assessed by immunohistochemistry. RESULTS:ALK fusions were identified in 63 tumors (0.1%). Compared with ALK fusion-negative CRC, ALK fusion-positive (ALKfus+) tumors demonstrated enrichment for MSI-high/MMR-deficient status and high TMB, with numerically higher PD-L1 expression. In contrast, canonical CRC driver alterations were markedly depleted, including KRAS, APC, and PIK3CA mutations. CONCLUSIONS:ALK fusions define a rare but biologically distinct subset of CRC characterized by frequent MSI-high/MMR-deficient status and a unique genomic landscape. These findings support comprehensive genomic profiling to identify ALK fusions in CRC, which may inform the use of ALK-directed therapies, and highlight the frequent co-occurrence of MSI-high disease within this subgroup.

PURPOSE:The antibody-drug conjugate Temab-A comprises the c-Met-targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload, adizutecan. A first-in-human phase I study (ClinicalTrials.gov identifier: NCT05029882) of Temab-A in patients with advanced solid tumors whose disease has progressed is currently ongoing. We report results from all patients in the dose escalation and the monotherapy metastatic colorectal cancer (mCRC) dose expansion. METHODS:Temab-A was administered intravenously once every 3 weeks as a monotherapy starting at 1.6 mg/kg in dose escalation. In mCRC dose expansion, patients with confirmed BRAF wild-type, microsatellite stable/mismatch repair-proficient mCRC were randomly assigned to 1.6 mg/kg, 2.4 mg/kg, or 3.0 mg/kg Temab-A once every 3 weeks. Primary end points included safety, pharmacokinetics, recommended phase II dose of Temab-A monotherapy, and Temab-A efficacy in patients with mCRC. RESULTS:In total, 57 patients received ≥1 dose of Temab-A in dose escalation; 3.0 mg/kg once every 3 weeks was established as the maximum tolerated dose. Collectively, in dose escalation and dose expansion, 122 patients with mCRC received Temab-A (dose escalation, N = 29; randomized dose optimization expansion, N = 93). All patients experienced ≥1 treatment-emergent adverse event; the most frequent were gastrointestinal (78%) and hematologic (71%) toxicities. Treatment-related discontinuations and deaths were infrequent (10% and 3%, respectively). Across all doses in patients with mCRC, overall response rate was 15.6% (95% CI, 9.6 to 23.2), disease control rate was 74.6% (95% CI, 65.9 to 82.0), and duration of response was 5.9 months (95% CI, 4.1 to 10.5); responses were more frequent at doses of 2.4 mg/kg and 3.0 mg/kg once every 3 weeks. Median progression-free survival was 4.6 months (95% CI: 4.0, 5.4), and median overall survival was 10.4 months (95% CI, 8.9 to 13.1). CONCLUSION:Temab-A at 2.4 mg/kg once every 3 weeks has a tolerable and manageable safety profile, with promising antitumor activity.

Summary of efficacy data for BI 905711 as monotherapy or combination therapy in patients with available data.

Individual pharmacokinetic parameters of cycle 3 based on ADA status in monotherapy study.

Abstract Purpose: Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited. Patients and Methods: The phase II ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti–PD-1 mAb), FOLFOX, and bevacizumab (EZFB) versus regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens. Results: From September 21, 2021, to September 12, 2022, 112 patients were randomized 2:1 to EZFB (n = 75) or regorafenib (n = 37). As of November 13, 2023, the median survival follow-up was 20.4 months. The primary endpoint of progression-free survival (PFS) was improved with EZFB (6.2 months) versus regorafenib [2.1 months; hazard ratio (HR), 0.27; 95% confidence interval (CI), 0.17–0.43; nominal P < 0.0001], as was the secondary endpoint of overall survival (OS; EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37; 95% CI, 0.22–0.63; nominal P = 0.0003). The confirmed overall response rate was 17% (90% CI, 10.6%–26.1%) with EZFB and 3% (90% CI, 0.1%–12.2%) with regorafenib. Treatment-emergent adverse events (TEAE), grade ≥3 TEAEs, and TEAEs leading to discontinuation of all study treatments were reported in 99%, 82%, and 5% of the EZFB arm and in 87%, 49%, and 17% of the regorafenib arm, respectively. Conclusions: EZFB significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile. Further investigation is warranted, given the clinically meaningful improvements in PFS and OS.

Full criteria for DLTs following treatment with BI 905711 as A) monotherapy (NCT04137289) or B) combination therapy (NCT05087992). Any of the following AEs were classified as DLTs, unless unequivocally due to underlying malignancy or an extraneous cause.

Colorectal cancer peritoneal metastases (CRC-PM) are highly aggressive and present distinct therapeutic challenges. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have emerged as potential therapeutic approaches, but their roles remain controversial following recent clinical trials. This review summarizes the evolving landscape of CRC-PM management, including diagnostic challenges, conflicting views of CRS and HIPEC, systemic therapies and new treatment approaches, overview of recent and ongoing landmark clinical trials, and discussion of variations in societal and global guideline recommendations.

BACKGROUND:Mutations in genes encoding proteins involved the DNA damage response (DDR) occur in up to 20% of patients with cancer. It is unknown whether poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, alone or in combination with ATR or AKT inhibitors, have histology-agnostic clinical efficacy in tumors with DDR mutations or PI3K/AKT pathway mutations, respectively. METHODS:The Olaparib Combinations (OLAPCO) trial enrolled patients in treatment arms based on next-generation sequencing results. In cohorts 1 and 2, patients with tumors harboring DDR mutations received either the PARP inhibitor olaparib or olaparib and the ATR inhibitor ceralasertib. In cohort 3, patients with tumors with PI3K-AKT pathway alterations or ARID1A mutations received olaparib and capivasertib. The primary end point was overall response rate (ORR) at 16 weeks assessed by the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS:Sixty-six patients were treated, including 26 on olaparib monotherapy, 24 on olaparib and ceralasertib, and 16 on olaparib and capivasertib. Among all patients treated, the ORR was 6.1% and the clinical benefit rate was 31.2% with a median duration of benefit (DoB) of 11 months. Among seven patients with platinum- and PARP inhibitor-resistant high-grade ovarian serous cancer in the olaparib and ceralasertib arm, one had a partial response and four had stable disease with a median DoB of 10 months. No unexpected toxicities were observed. CONCLUSION:The study failed to meet its primary end point of ORR. DDR and homologous recombination repair defects are not consistently actionable with olaparib as monotherapy or in combination with other targeted therapies in a histology-agnostic manner.

Abstract Purpose: BI 905711, a TRAILR2/cadherin-17 (CDH17) bispecific antibody, demonstrated preclinical apoptotic pathway activation and antitumor activity. Two phase Ia/Ib studies tested BI 905711 monotherapy (NCT04137289) or combination therapy (NCT05087992) in advanced, refractory gastrointestinal (GI) cancers. Patients and Methods: Both studies aimed to determine the maximum tolerated dose (MTD; phase Ia) and recommended phase II dose (RP2D)/recommended dose for expansion (RDE; phase Ib). In phase Ia, patients received BI 905711 monotherapy (0.02–4.8 mg/kg) or 0.6 to 1.2 mg/kg plus biweekly folinic acid (leucovorin), 5-fluorouracil, and irinotecan (FOLFIRI) and bevacizumab. Phase Ib assessed selected doses and regimens given biweekly or weekly (3 weeks on and 1 week off). Safety, efficacy, and pharmacokinetics/pharmacodynamics were evaluated. Results: In NCT04137289, 110 patients [median age 61 years; 80% with colorectal cancer; median of three prior therapies (range, 1–6)] received monotherapy. No dose-limiting toxicities (DLT) occurred, MTD was not reached, RP2D was not determined, and 48.2% of patients had treatment-related adverse events (TRAE), most commonly nausea (16.4%). In 104 response-evaluable patients, 22.1% achieved stable disease (SD). In NCT05087992, 12 patients with colorectal cancer (median age 54.5 years) received combination treatment. Two patients reported DLTs, MTD was not reached, and the selected RDE was 0.6 mg/kg plus biweekly FOLFIRI and bevacizumab. Most patients (91.7%) had TRAEs, including decreased appetite (33.3%), alanine transaminase increased, aspartate transaminase increased, and diarrhea (25% each). Eleven patients (91.7%) achieved SD. Pharmacokinetic/pharmacodynamic data indicated linear dose exposure and ≥2-fold activation of plasma caspase 3/7. Conclusions: In heavily pretreated patients with GI tumors, BI 905711 monotherapy or with FOLFIRI plus bevacizumab displayed a manageable safety profile and limited clinical activity. Significance: Translating preclinical activity of TRAILR2 agonists into the clinic has been hampered by severe hepatotoxicity. BI 905711, a bispecific antibody against TRAILR2 and CDH17, was developed to enhance efficacy and reduce hepatotoxicity. Two phase 1 studies (NCT04137289 and NCT05087992) demonstrated tolerability and minimal hepatotoxicity, dose-proportional pharmacokinetics, and increased markers of target engagement. Antitumor activity was limited. These data show that BI 905711 has reduced TRAIL-related hepatotoxicity in the clinic.

Abstract Purpose: Circulating tumor DNA (ctDNA) is prognostic for patients with metastatic appendiceal and colorectal cancer (CRC), however, its impact on therapy considerations and surgical candidacy is unclear. Current randomized trials are exploring approaches to locoregional therapy for management of multi-site oligometastatic disease. We investigate the role of ctDNA-guided locoregional therapies in the management of peritoneal metastases (PM) with or without multi-site disease. Methods: The study cohort included high-grade appendiceal or CRC patients with single site (peritoneum) or multi-site metastases (peritoneum plus liver, lung, or distant lymph node involvement) who had curative intent surgical interventions for PM between 2023-2025. ctDNA testing was performed in the pre- and post-operative setting. Univariate and multivariate analysis of demographics, pathological, and ctDNA dynamics were performed. Overall survival (OS) was analyzed using Kaplan-Meier (KM) curves to evaluate prognostic impact of ctDNA status and presence of multi-site disease. Results: Of the 61 patients in the study, 67% (n=41) had CRC and 33% (n=20) had high-grade appendiceal cancer. Median postoperative follow up was 18 months with 82% of patients alive at last follow up. Prior to surgery, 33% (n=17) of patients were ctDNA positive with 13% clearing their ctDNA postoperatively initially. However, none of these patients maintained durable negative ctDNA as all converted back to ctDNA positive within 6 months. Of those with negative ctDNA preoperatively, 32% converted to ctDNA positive postoperatively - including 91% converting to positive within 1 year. Patients with ctDNA negative status preoperatively had KM-estimated 2-year OS of 91.2%. History of multi-site disease was present in 39% (n=24) of patients at time of surgery including 50% (n=12) with active multi-site disease and 50% (n=12) with previously treated disease. KM-estimated 2-year OS was excellent for ctDNA negative patients regardless of multi-site disease involvement (2-year OS = 83.3%) or peritoneal-only metastases (2-year OS = 95.6%). Conclusion: This study analyzed the prognostic impact of ctDNA status and multi-site disease for patients with PM from CRC or appendiceal cancer who underwent locoregional therapy. ctDNA appears to be prognostic in patients undergoing curative intent surgical resection for peritoneal metastases. Furthermore, patients with multi-site disease who have negative ctDNA and undergo surgery for peritoneal metastases appear to have survival comparable to patients with peritoneal only metastases. With variable approaches and conflicting guidelines for the management of patients with PM and oligometastatic disease, ctDNA could augment treatment selection, surgical eligibility, and clinical trial enrollment. Citation Format: Justin M. Bader, Kelsey LaBella, Nicole Aguirre, Kwasi Ofori, Princy Gupta, Anup Sharma, Huxley Smart, Alexander Kim, Robert Tseng, SANGWON YUN, Michael Cecchini, Raghav Sundar, Kiran Turaga. Prognostic impact of ctDNA status and multi-site disease burden for patients with peritoneal metastases from appendiceal or colorectal cancer [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 6444.

Pharmacokinetic parameters (AUC0–336 and Cmax) after infusion of BI 905711 (0.02–4.8 mg/kg) during cycles 1 and 3 of (A) monotherapy study (NCT04137289) and (B) combination study (NCT05087992). Ia, study phase Ia; Ib, study phase Ib; Q2W, every 2 weeks. For numbers of evaluable patients in cycles 1 and 3, refer to Table 4.