PURPOSE:Standard adjuvant treatment for stage III colorectal cancer (CRC) combines intravenous oxaliplatin with a fluoropyrimidine, either with intravenous 5-fluorouracil with folinic acid oxaliplatin, capecitabine (CAPOX). This study aims to describe the toxicity of these two regimens in patients with a diverting stoma. METHODS:We conducted a retrospective, single-center study of patients with stage III CRC who had a diverting stoma and received adjuvant treatment with either FOLFOX or CAPOX between January 2016 and July 2023. Clinical characteristics and treatment details were extracted from electronic health records. The primary end point was the rate of hospitalization during adjuvant chemotherapy. Secondary end points included treatment compliance and toxicity. RESULTS:A total of 87 patients with CRC and a diverting stoma received treatment with either CAPOX (n = 37) or modified FOLFOX regimen: oxaliplatin, 5-fluorouracil, folinic acid (mFOLFOX6)  (n = 50). No patient had dihydropyrimidine dehydrogenase deficiency. Baseline clinical characteristics were similar between groups. The hospitalization rate was 35% with CAPOX and 18% with FOLFOX (P = .07). Most hospitalizations occurred during the first cycles of adjuvant treatment and were primarily related to digestive toxicities. Higher hospitalization rates with CAPOX were observed across all subgroups, regardless of sex, age, performance status, or renal function. CONCLUSION:Patients with a diverting stoma who receive adjuvant chemotherapy with fluoropyrimidines and oxaliplatin are at higher risk of severe digestive toxicities when treated with the CAPOX regimen. The mFOLFOX6 regimen appears to be safer alternative in this population.

28 Background: CheckMate 8HW (CA209-8HW), a Phase 3, randomized, 3-arm open-label study, evaluated nivolumab monotherapy (nivo: Arm A), nivolumab plus ipilimumab combination therapy (nivo+ipi: Arm B) or investigator’s choice chemotherapy (chemo: Arm C) for the treatment of subjects with deficient mismatch repair/microsatellite instability- high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). The Idylla companion diagnostic (CDx) MSI Test was used as an investigational method, next to an IHC MMR method, to centrally and retrospectively confirm MSI-H status in trial participants enrolled by local MSI-H/dMMR assays. Methods: Clinical utility of the Idylla CDx MSI Test (Idylla) in the intended use population was assessed by evaluating: (1) progression-free survival (PFS) and the corresponding hazard ratio (HR) of nivo+ipi vs. chemotherapy in the 1st line (1L) therapy of mCRC, (2) PFS HR of nivo+ipi vs. nivo in all lines, and (3) objective response rates (ORR) of nivo+ipi and nivo in all lines. Enrollment of patients in the trial was based on local dMMR/MSI-H status per at least one of the three methods (IHC, PCR, NGS), referred as the Clinical Trial Assay positive (CTA+) population. The Idylla test was used at the central laboratory to retrospectively evaluate the patients’ MSI status by testing the submitted tumor specimens. A bridging study between the efficacies of the trial randomized population (CTA+) and the intended use population of the Idylla CDx MSI Test was conducted to demonstrate the clinical utility of the test. Results: Of the 837 CTA+ subjects randomized to all arms, 725 subjects had valid Idylla results by central testing. From the remaining 112 subjects, 7 were tested by the Idylla but resulted in an invalid result and 105 were unevaluable by Idylla as they did not meet the test or other quality requirements. In all CTA+ subjects in 1L, the PFS HR for nivo+ipi (n=200) vs chemo (n=101) was 0.32 (95% CI of 0.22 - 0.45). In comparison, in the CTA+ subjects centrally determined as MSI-H by Idylla, the PFS HR for nivo+ipi (n=147) vs chemo (n=71), in 1L was 0.20 (95% CI: 0.12–0.31). In addition, in CTA+ subjects centrally determined to be MSS by Idylla, the PFS HR of nivo+ipi (n=30) vs chemo (n=15) in 1L was 1.51 (95%CI: 0.68-3.33). In the nivo+ipi vs nivo comparison in all lines of therapy, the PFS HR for centrally determined Idylla MSI-H group (n=504) was 0.60 (95% CI: 0.45–0.80 ) compared to PFS HR of 0.63 (95% CI: 0.51–0.79) in CTA+ (n=705). The ORRs for nivo monotherapy and for nivo+ipi in centrally determined Idylla MSI-H group were 58.7% (95% CI, 52.3, 64.9) and 73.5% (95% CI: 67.7, 78.8), respectively, in all lines of therapy. Conclusions: The Idylla CDx MSI Test can effectively identify MSI-H mCRC patients who may benefit from treatment with nivolumab as a monotherapy and/or treatment with nivolumab in combination with ipilimumab.

3532 Background: In the phase 3 CheckMate 8HW trial, both dual primary endpoints of progression-free survival (PFS) were met for first-line (1L) NIVO + IPI vs chemotherapy (HR 0.21; P < 0.0001) and NIVO + IPI vs NIVO in all lines (HR 0.62; P = 0.0003) in patients (pts) with centrally confirmed (CC) MSI-H/dMMR mCRC. We report explorative subgroup analyses of NIVO + IPI vs NIVO. Methods: The study design was described previously (Andre NEJM 2024). Pts with MSI-H/dMMR mCRC per local testing were enrolled. After randomization, IHC and PCR based tests were used for central confirmation. Results: In all randomized pts, 84% (296/354) in the NIVO + IPI and 81% (286/353) in the NIVO arm had CC MSI-H/dMMR; in 1L pts, 85% (171/202) and 85% (170/201) had CC MSI-H/dMMR, respectively. Median follow-up in all randomized pts was 55.1 (range 24.7–68.5) mo. Pts receiving NIVO + IPI had improved disease control rates vs NIVO in 1L (85% vs 81%, respectively) and all lines (84% vs 76%, respectively). Pts with complete or partial response (CR/PR) or stable disease (SD) on 1L NIVO + IPI had improved PFS vs NIVO. In all lines, pts with CR/PR or SD receiving NIVO + IPI had improved overall survival (OS) vs those on NIVO (Table). Pts receiving NIVO + IPI had improved disease-specific OS vs NIVO (HR 0.47; 95% CI 0.32–0.68). In all lines, pts on NIVO + IPI had improved PFS and OS vs NIVO regardless of the number of sites of metastasis (Table). After treatment, 82% (185/226) of pts on NIVO + IPI were alive and treatment free vs 67% (125/186) on NIVO; 90% (198/220) and 79% (141/178) of pts were alive and systemic treatment free, respectively. In pts surviving ≥4 years, baseline characteristics and incidence of treatment-related adverse events were consistent with the all randomized CC population. Further analyses will be presented. Conclusions: NIVO + IPI demonstrated clinical benefit vs NIVO across subgroups, as shown by numerically increased PFS and OS in pts with CR/PR or SD, and improved PFS and OS regardless of number of metastatic sites. No defining characteristic was identified in long-term survivors vs all randomized CC pts. These results further support NIVO + IPI as a standard of care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . 1L NIVO + IPI(n = 171) NIVO(n = 170) HR (95% CI) mPFS (95% CI), mo CR/PR NR (NE) NR (60.8–NE) 0.82 (0.43–1.54) SD 33.1 (5.8–NE) 9.2 (4.4–22.1) 0.52 (0.24–1.14) All lines (n = 296) (n = 286) mPFS (95% CI), mo 1 metastatic site at BL NR (NE) 60.8 (26.3–NE) 0.51 (0.33–0.77) ≥2 metastatic site at BL 59.2 (38.4–NE) 23.0 (11.8–NE) 0.70 (0.51–0.97) mOS (95% CI), mo CR/PR NR (NE) NR (NE) 0.92 (0.46–1.83) SD NR (35.3–NE) 26.8 (15.7–48.9) 0.43 (0.23–0.80) 1 metastatic site at BL NR (NE) NR (NE) 0.52 (0.31–0.88) ≥2 metastatic site at BL NR (NE) NR (NE) 0.68 (0.46–0.99) BL, baseline; m, median; NE, not estimable; NR, not reached.

Managing unresectable metastatic colorectal cancer (mCRC) requires a comprehensive strategy. While chemotherapy, anti-angiogenic, and anti-epidermal growth factor receptor (EGFR) agents are available, strategy trials are needed to optimize their use and sequencing. The STRATEGIC-1 phase III trial (NCT01910610) was designed to determine the optimal treatment sequence in patients with untreated, unresectable wild-type RAS/BRAFV600E mCRC. Patients were randomized (1:1) to FOLFIRI-cetuximab then mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab then FOLFIRI-bevacizumab followed by EGFR monoclonal antibody +/- irinotecan (arm B). The primary endpoint was the duration of disease control (DDC). Secondary endpoints were overall survival (OS), time to failure of strategy (TFS), progression-free survival (PFS), overall response rate (ORR), salvage surgery rate, safety, and health-related quality of life (HRQoL). Overall, 263 patients (arm A:131, arm B:132) were randomized. After 68.4 months of median follow-up (95% CI, 76.5-98.0), the median DDC was 22.8 months (95% CI, 20.4-28.8) in arm A and 23.5 months (95% CI, 17.9-26.3) in arm B (HR = 1.01, 95% CI, 0.76-1.34; log-rank P = 0.945). The median OS was 40.4 months (95% CI, 32.4-51.1) in arm A and 34.4 months (95% CI, 27.5-42.2) in arm B (HR = 1.30, 95% CI, 0.99-1.72). The ORR was higher in arm A (82.4% versus 65.4%) in the first-line group but not in the second-line group (20.7% versus 16.4%). Adverse events were consistent with the well-known safety profiles. STRATEGIC-1 did not meet its primary endpoint and was inconclusive in identifying the optimal treatment strategy in wild-type RAS/BRAFV600E mCRC.

Background Patients with advanced pancreatic ductal adenocarcinoma (aPDAC) often experience general health decline at diagnosis due to a high-symptom burden. The optimal management of symptoms and/or poor performance status (PS) in these patients remains an unmet medical need. Patients and Methods In this multicenter study, patients with PS≥2 and pathologically confirmed or imaging-suspected aPDAC were included at first oncology visit in a personalized 14-day emergency integrative supportive care program (14-EISCP) to manage pain, nutrition, diagnostics, and stenting procedures. The primary endpoint was the 14-EISCP success in feasibility of planned procedures and clinical benefit defined as post-EISCP PS≤1, ≥5 points improvement in fatigue, pain, global health-related quality of life (HRQoL) scores (EORTC QLQ-C15-PAL), or chemotherapy initiation within 30 days. Results A total of 106 patients were included; 93 evaluable patients considered for primary endpoint analysis (median age: 76 years [68-80], PS3: 20.9%, metastases: 61.3%). The median overall survival was 4.1 months (IC95% 2.6-5.6). The 14-EISCP was successful in 59.1% (n=55) of patients, meeting the primary objective (clinically relevant). The 14-EISCP feasibility was achieved in 70.9% of cases. Post-EISCP clinical benefit was observed in 79.6% of patients, with PS improvement to 0/1 in 13.2%, HRQoL improvement in 23.9%, and chemotherapy initiation ≤30 days in 73.1%. Among evaluable patients, 17.2% received mFOLFIRINOX or gemcitabine-nab-paclitaxel, 35.4% received FOLFOX, 25.3% had gemcitabine or 5-fluorouracil alone, and 22.2% received best supportive care. In patients with PS2 at baseline, the administration of doublet/triplet chemotherapy was associated with improved overall survival compared to single-agent. Discussion These results offer a promising framework for improving outcomes in aPDAC patients, bridging the gap between symptom management and systemic therapy administration. Conclusions In patients with PS≥2 and aPDAC, the personalized 14-EISCP was feasible and lead to meaningful clinical benefit, allowing doublet or triplet chemotherapy in half the patients.

BACKGROUND:Greater toxicity of adjuvant chemotherapy in females has been reported previously, but the impact of patients' sex on chemotherapy (CT)+/-targeted therapies for non-resectable, metastatic colorectal cancer (mCRC) has remained unclear. We compared efficacy and toxicity of first-line chemotherapy, with or without targeted therapies, between male and female mCRC patients. METHODS:Twenty-seven randomized trials from the ARCAD CRC database were included. Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate, toxicity (according to NCI-CTCAE). Analyses were performed within three treatment groups: A) CT alone, B) CT+bevacizumab, and C) CT+epidermal growth factor receptor inhibitor. OS and PFS were estimated using Kaplan-Meier method. Associations with sex were assessed using study-stratified Cox models adjusted for age, performance status, body mass index, and CT backbone. RESULTS:Baseline data from 18,041 patients were analysed; among 15,271 included in outcome analyses, no sex differences in OS or PFS were observed. Adjusted OS hazard ratios (95% confidence interval) for females versus (vs.) males were: A: 1.01 (0.95-1.08, P = .69), B: 0.96 (0.89-1.04, P = .36), C: 0.97 (0.87-1.10, P = .67). Females experienced higher toxicity, including grade 1-4 and 3-4 nausea (71.8% vs. 60.5% and 7.5% vs. 4.8%), vomiting (47.7% vs. 35.5% and 6.6% vs. 4.4%), and neutropenia (52.4% vs. 44.4% and 29.2% vs. 18.8%) (P < .001). Conversely, rash (grade 1-4 and 3-4) was more frequent in males (29.6% vs. 24.3% and 5.1% vs. 3.7%, P < .001). CONCLUSIONS:Despite higher chemotherapy-related toxicity in females, treatment efficacy was similar between sexes. Rash was more common in males, highlighting that patients' sex modulates toxicity profiles in both directions. Strategies to reduce adverse events in female patients are warranted.

INTRODUCTION:Immune checkpoint inhibitors (ICI) are standard for MSI-H/dMMR metastatic colorectal cancer (mCRC). We compared their efficacy and sought subgroups deriving greater benefit from ICI combination. PATIENTS AND METHODS:All patients with MSI/dMMR mCRC treated by anti-PD-1 ± anti-CTLA-4 in the prospective monocenter immunoMSI cohort were analyzed. Treatment choice followed trials availability and regulatory approvals. Main endpoints were progression-free survival (PFS, iRECIST) and overall survival (OS). Landmark analysis at 6 months, restricted mean survival time (τ = 7 years) and piecewise Cox models were used. Interactions were tested in a single Cox model including subgroup terms, treatment, and interaction terms. RESULTS:Among 210 patients, 97 received ICI combination and 113 monotherapy with anti-PD-1. Median follow-up was 4.4 years (4.1 combo; 5.4 mono). About 165 patients (78.5%) received ICI in second line or latter. Combination improved PFS (hazard ratios [HR] 0.48, 95% CI 0.31-0.76) and OS (HR 0.49, 0.29-0.84). RMST was 5.27 versus 3.91 years (+1.36 years, 0.55-2.17). Piecewise HRs showed an early benefit (0-6 months HR 0.32, 0.16-0.66) that attenuated thereafter. Objective responses were 78% versus 60%; progressive disease 5% versus 15%. Interactions were observed for sex (PFS HR 0.21 vs. 0.87 for females vs. males; P-interaction = .0067), liver metastases (0.30 vs. 0.79; 0.0479) and sidedness (0.27 vs. 0.64; 0.0922). CONCLUSION:Dual CTLA-4/PD-1 blockade improved PFS and OS versus anti-PD-1 alone, driven by higher early response rates. Female sex, absence of liver metastases, and left-sided tumor location may predict greater benefit from combination.

BACKGROUND:The selection of biologic therapies in metastatic colorectal cancer (mCRC) is traditionally guided by right-left classification; however, this binary classification may not fully capture heterogeneity in responsiveness to anti-epidermal growth factor receptor (EGFR) therapy. We evaluated whether treatment efficacy varies across detailed anatomical tumour segments. METHODS:Individual patient-level data from 12 randomised controlled trials in the ARCAD database were analysed. Patients with RAS wild-type (RAS-WT) mCRC receiving first-line doublet chemotherapy plus anti-EGFR therapy or bevacizumab were included. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). RESULTS:A total of 2867 patients were included (815 right-sided colon cancer [RSC]; 2052 left-sided colorectal cancer [LSC]). In RAS-WT RSCs, anti-EGFR therapy was not associated with improved OS or PFS versus bevacizumab. In RAS/BRAF-WT RSCs, anti-EGFR therapy was associated with inferior PFS. In contrast, in RAS-WT LSCs, anti-EGFR therapy significantly improved OS and ORR, without a significant difference in PFS. Segment-level analyses (N = 1491) showed no significant heterogeneity within RSCs, although median OS numerically varied across subsites. Within LSCs, the OS benefit was most pronounced in the rectum. CONCLUSIONS:The efficacy of anti-EGFR therapy in mCRC appears to exhibit additional intraregional heterogeneity beyond the conventional right-left classification. These findings suggest that anatomical tumour location may reflect underlying biological differences not fully captured by this binary classification.

Les carcinomes à cellules acineuses du pancréas sont un sous-type histologique rare (environ 1–2 %) des adénocarcinomes pancréatiques. Ces tumeurs se développent à partir des cellules acinaires et peuvent être associées à des contingents neuro-endocrines ou excréto-pancréatiques canalaires. Le diagnostic histologique des tumeurs acinaires repose sur la morphologie et l’immunohistochimie par un marquage immunohistochimique anti-BCL10. La faible prévalence des carcinomes à cellules acineuses pancréatiques rend difficile de mener des études dédiées et leur prise en charge dans les recommandations internationales est similaire à celles des adénocarcinomes canalaires. Les études rétrospectives semblent néanmoins en faveur d’une présentation moins agressive, avec des tumeurs plus volumineuses mais un envahissement ganglionnaire moindre et un pronostic plus favorable que les adénocarcinomes. Les recherches récentes ont également mis en évidence une carcinogenèse différente. Au contraire des adénocarcinomes canalaires, les mutations KRAS sont rarement présentes. En revanche, des altérations du système de recombinaison homologue HRD sont fréquemment mises en évidence (30 % des cas). Dans la plupart des cas, elles sont associées à des mutations germinales, notamment BRCA2, ouvrant la voie à un conseil génétique. D’autres anomalies moléculaires, telles que des altérations de BRAF (environ 3 %) ou une déficience du système MMR (2–4 %), ont également été rapportées. Ainsi, l’identification d’un carcinome pancréatique de type acinaire doit amener à des analyses moléculaires théranostiques complémentaires pour permettre une personnalisation thérapeutique.

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.

Colorectal cancer predominantly affects older adults (ie, those aged 70 years or older). Along with shifting demographic trends, the number of patients with colorectal cancer in this age group is estimated to sharply increase globally over the next few decades. During the past decade, new treatment modalities and systemic therapeutic options have been introduced through well conducted clinical trials that shaped and fundamentally redefined the treatment landscape. However, older adults with reduced physiological reserves, functional impairment, comorbidities, and geriatric syndromes are under-represented in such studies. Yet, for this population, growing evidence for geriatric assessment and management shows patient-centred benefits with the potential to further improve outcomes, parallel to the broadening armamentarium of medical innovations. The purpose of this Review is to summarise the evidence base of the current therapeutic landscape of colorectal cancer and guide management of older adults in daily clinical practice through pragmatic decision making.

TPS264 Background: B7-homolog 3 protein (B7-H3), an immune checkpoint protein, is overexpressed in many types of solid tumors but has limited expression in normal tissues. B7-H3 expression is correlated with tumor progression, metastasis, and poor clinical outcomes across various malignancies. GSK’227 (HS-20093) is a novel antibody-drug conjugate composed of a fully human anti–B7-H3 monoclonal antibody linked to a topoisomerase I inhibitor via a protease-cleavable linker. GSK’227 has shown acceptable safety and promising antitumor activity in an Asian patient (pt) population with advanced solid tumors (NCT05276609; NCT05830123). This study (NCT06885034) will first assess GSK’227 as monotherapy for efficacy, safety, tolerability, PK, and immunogenicity and subsequently in combination therapy, in pts with previously treated advanced, unresectable, gastrointestinal (GI) solid tumors, in a global population. Methods: This Phase 1b/2, open-label, multicenter study will assess early efficacy and safety signals of GSK’227 in pts with advanced, unresectable GI solid tumors. The study will include Cohort A, evaluating two doses (1:1 randomization) of GSK’227 administered 3-weekly (Q3W) in pts with advanced, unresectable colorectal cancer (CRC, sub-cohort CRC-A). The study will also assess two additional doses (1:1 randomization) administered 2-weekly (Q2W) (sub-cohort CRC-B). In parallel, Cohort B will assess a single Q3W dose of GSK’227 in pts with advanced, unresectable pancreatic ductal adenocarcinoma (PDAC). The study has two parts per cohort. Part 1 involves signal seeking (and dose optimization for CRC only) and an optional extension, in which GSK’227 is evaluated as monotherapy. Subsequently, Part 2 (expansion) may evaluate combination treatments with GSK’227. The optional extension component and the expansion part will be guided by the totality of emerging data . Eligible adults must have histologically confirmed advanced, unresectable CRC or PDAC, 1–2 lines of prior treatment (only 1 for PDAC), and ECOG PS of 0–1. Part 1’s primary endpoint is confirmed ORR. Secondary endpoints include unconfirmed ORR, DoR, PFS, safety/tolerability, PK, immunogenicity, and pt-reported AEs/tolerability. Efficacy will be assessed per RECIST v1.1, with imaging every 6 weeks (±7 days) from date of randomization (sub-cohorts CRC-A and CRC-B) or first dose (cohort B) for the first 48 weeks, and then every 12 weeks (±7 days) thereafter. Safety follow-up will be assessed at 30 (±3), 60 (±7), and 90 (±7) days after the last dose. Safety, tolerability, and efficacy analyses will be summarized descriptively; efficacy analyses will also include point estimates with 2-sided 95% CIs. Clinical trial information: NCT06885034 .

MOUNTAINEER was a multicenter, open-label, phase 2 trial (NCT03043313) that evaluated the efficacy and safety of tucatinib plus trastuzumab, a dual HER2-targeted chemotherapy-free regimen. Patients were included if they had chemotherapy-refractory, HER2+, RAS wild-type unresectable or metastatic colorectal cancer. This final analysis reports updated efficacy and safety after a median follow-up of 32.4 months. Of the 84 patients who received tucatinib plus trastuzumab, the confirmed objective response rate was 39.3%; median duration of response was 15.2 months. Median progression-free survival was 8.1 months and overall survival was 23.9 months. Efficacy was relatively similar across central HER2+ testing methods. No clear association of treatment response with co-occurring biomarker alterations was seen. Few patients discontinued treatment due to adverse events; no treatment-emergent deaths occurred. Tucatinib plus trastuzumab showed clinically meaningful efficacy and favorable safety. Efficacy was observed irrespective of central HER2+ testing methods and in patients with heterogeneous tumor biomarker profiles.

BACKGROUND:Immune checkpoint blockers (ICBs) are front-line therapy for mismatch repairdeficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Poor ECOG performance status (PS) is widely recognized as a negative prognostic factor, often leading physicians to avoid treatment. We aimed to assess the effect of ECOG PS on patient outcomes in dMMR/MSI-H mCRC receiving ICBs. METHODS:This is an international multicenter retrospective cohort study of ICBs-naïve dMMR/MSI-H mCRC patients who received ICBs between 2014-2024. Exposure variables included best treatment response and patient characteristics including line of treatment, RAS/BRAF status, single-agent versus doublet ICBs, and metastatic sites. The main outcome was overall survival. Kaplan-Meier analysis was used to analyze the association of best treatment response with overall survival according to ECOG PS of 2-3 and 0-1. RESULTS:The study cohort included 51 dMMR/MSI-H mCRC patients with ECOG PS of 2-3 and 633 patients with ECOC PS of 0-1 that were treated with ICBs. Median follow-up time was 35.3 months (IQR 23.9-54.9) and 49.9 months (IQR 46.7-53.8), respectively. For patients with ECOG PS of 2-3 ORR and DCR rates were 37.3% and 60.8%. Median overall survival (mOS) was 14.4 months - not reached for those who achieved CR/PR and 1.7 months for those whose best response was PD. For patients with ECOG PS of 0-1, mOS was not reached, and ORR was 60.0%. CONCLUSIONS:Patients with dMMR/MSI-H mCRC and ECOG PS 2-3 derive durable benefit from ICBs, mainly among those who achieved CR/PR, and should therfore be considered candidates for ICBs.

Background The optimal management of primary tumor (PT) in microsatellite instability-high metastatic colorectal cancer patients treated with immune checkpoint inhibitors (ICIs) remains unclear. Patients and methods We retrospectively analyzed a prospective, single-center cohort to assess PT outcomes in this setting. Results Among 210 patients, 21% received first-line ICI; we focused on 33 patients (16%) without prior PT resection at ICI initiation. Early progressive disease (<6 months) occurred in 10 patients (5%), with eight deaths (<1 year); two underwent surgery for symptomatic PT. Among the remaining 23 patients (11%) with disease control (≥6 months), 15 had PT resection due to clinical events (n = 5) or for non-symptomatic reasons (n = 10), including seven with pathological complete response and eight with residual tumor. Eight patients had no PT resection, including two with metastatic and/or local progressive diseases. After a median 75-month follow-up, only six patients (3%) remained progression-free with PT in place and no residual endoscopic tumor. Conclusions If PT is left in place at ICI initiation, close monitoring is required due to its specific evolution. Resection may be indicated for symptomatic stenosis. Prospective trials are needed to define the role of endoscopic monitoring and indication of PT resection in first-line ICI.

Anti-PD1 and anti-PD-L1 inhibitors have become central to systemic therapy for solid tumors, reshaping indications and outcomes across multiple tumor types. Their widespread use, however, raises major economic, environmental, and societal challenges. Current regimens - fixed dose, defined frequency, and predetermined duration - are supported by limited clinical and paraclinical evidence. Consistent signals from pharmacokinetic and pharmacodynamic studies, retrospective cohorts and small prospective trials suggest that overtreatment is possible in a significant proportion of patients. In this context, therapeutic de-escalation should be evaluated along three axes: dose reduction, extension of dosing intervals, and adjustment of the total duration of treatment. This review summarizes the current state of knowledge on the pharmacokinetics and pharmacodynamics of checkpoint inhibitors, as well as retrospective and prospective clinical data exploring dose, frequency, and duration de-escalation across different tumor types. It also presents the main trials currently underway to evaluate these strategies and their clinical, economic, and societal impacts.

BACKGROUND:KRAS mutations in metastatic colorectal cancer (mCRC) are a factor of poor prognosis, partly because of associated resistance to anti-EGFR therapies. Liver metastases (LM) were also described as a factor of poor prognosis. This study aims to compare the outcomes of patients treated in third-line setting with placebo or Trifluridine/Tipiracil or regorafenib (TToR) and to assess the impact of LM and KRAS mutations on prognosis. METHODS:Data were pooled from five placebo-controlled randomized trials of the ARCAD CRC database (CORRECT, RECOURSE, CONCUR, TERRA, and J003). Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier estimates and adjusted Cox models. Interaction tests were conducted to evaluate the combined effects of LM and KRAS mutations. RESULTS:The study included 2,207 patients: 1,464 treated with TToR and 743 with placebo. A total of 73% had LM and 51% had KRAS mutations. Patients with LM had significantly lower OS and PFS compared to those without LM in both TToR (HR = 0.48 for OS; HR = 0.55 for PFS) and placebo groups (HR = 0.49 for OS; HR = 0.58 for PFS). Patients with KRAS mutations had worse OS compared to wild-type KRAS in TToR-treated patients (HR = 1.18), but not in placebo-treated patients (HR = 1.03). Interaction tests were not significant between LM and KRAS status in both TToR and placebo groups. CONCLUSIONS:In patients with refractory mCRC, LM are a major poor prognosis factor, while KRAS mutations have no clinically relevant additive impact. These results underline the importance to stratify clinical trials on liver metastases rather than on RAS status in latter lines.

3531 Background: First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) showed PFS benefit vs chemotherapy (chemo) in patients (pts) with MSI-H or dMMR metastatic colorectal cancer (mCRC) in the phase 3 CheckMate 8HW trial. Using post hoc analyses, we examined the association of PFS with single and dual positivity in validated CDx MSI (polymerase chain reaction; PCR) or MMR (immunohistochemistry; IHC) central assays. Methods: Study details were published previously (Andre T et al. NEJM 2024). Pts with unresectable or mCRC with MSI-H or dMMR per local testing were randomized 2:2:1 to NIVO + IPI, NIVO, or chemo. Tumor tissue samples were tested centrally using validated Idylla (CDx MSI PCR; Biocartis) and Dako (CDx MMR IHC; Agilent) assays post randomization. Clinical trial assay positive (CTA+) pts were those with locally diagnosed MSI-H/dMMR mCRC randomized to NIVO + IPI or chemo. PFS and hazard ratios (HR) were evaluated in CTA+ pts; pts positive using a single central assay (CDx MSI or CDx MMR); and pts positive in both central assays (CDx dual positive). Results: Of the 303 pts randomized to 1L NIVO + IPI or chemo, 301 had locally diagnosed MSI-H/dMMR (CTA+; 2 randomized pts missed local testing and were excluded in the analysis). 263 pts had valid CDx MSI results, 284 had valid CDx MMR results; 208 were CDx dual positive (Table); result missingness was mainly due to lack of tissue samples. PFS benefit was noted with NIVO + IPI vs chemo in CTA+ pts (HR, 0.32; Table). Greater PFS benefit with NIVO + IPI vs chemo was seen in pts positive with single CDx MSI or CDx MMR assays (HR, 0.20 and 0.22, respectively), and was consistent with those from CDx dual positive pts (HR, 0.20; Table). Pts with microsatellite stable (MSS) or mismatch repair proficient (pMMR) status were low, so these data should be interpreted with caution (Table). Conclusions: In this post hoc analysis, dual positivity from CDx MSI and CDx MMR assays did not offer greater PFS benefit with 1L NIVO + IPI vs chemo over positivity from a single CDx MSI or MMR assay. Single CDx MSI or CDx MMR assays provided similar PFS benefit with 1L NIVO + IPI vs chemo in pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . NIVO + IPI(n = 202) Chemo(n = 101) HR (95% CI) a n (%) Median PFS (95% CI) n (%) Median PFS (95% CI) CTA+ 200 (99) NR (34.3–NE) 101 (100) 6.2 (4.7–9.0) 0.32 (0.22–0.45) CDx b MSI+: MSI-H 147 (73) NR (38.4–NE) 71 (70) 6.2 (4.7–9.0) 0.20 (0.12–0.31) CDx b MSI−: MSS 30 (15) 1.8 (1.5–5.8) 15 (15) 7.4 (4.0–12.9) 1.51 (0.68–3.33) CDx b MMR+: dMMR 163 (81) NR (38.4–NE) 82 (81) 5.9 (4.4–7.8) 0.22 (0.14–0.34) CDx b MMR−: pMMR 27 (13) 1.8 (1.5–5.8) 12 (12) 11.5 (2.0–NE) 1.39 (0.57–3.40) CDx b : dual positive 139 (69) NR (38.4–NE) 69 (68) 6.2 (4.9–9.2) 0.20 (0.13–0.32) a Cox proportional hazards model stratified by tumor sidedness. b By central assay. NE, not estimable; NR, not reached.

137 Background: The open-label, phase 2 KEYSTEP-008 study (NCT04895722) evaluated pembro-based combinations vs pembro in participants (pts) with chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Methods: Adults with stage IV colorectal adenocarcinoma, locally confirmed MSI-H/dMMR status and ECOG PS 0 or 1 were randomized 1:1 (cohort A) to coformulated quavonlimab (anti–CTLA-4; Qmab)/pembro (25 mg/400 mg) IV Q6W or pembro 400 mg IV Q6W or 1:1:1:1:1 (cohort B) to Qmab/pembro (25 mg/400 mg) IV Q6W, MK-4830 (anti-ILT4) 800 mg + pembro 200 mg IV Q3W, coformulated favezelimab (anti−LAG-3; fave)/pembro (800 mg/200 mg) IV Q3W, coformulated vibostolimab (anti-TIGIT; vibo)/pembro (200 mg/200 mg) IV Q3W, or pembro 400 mg IV Q6W. Pts received treatment for ~2 y. Primary end point: ORR per RECIST v1.1. Secondary end points: DOR and PFS per RECIST v1.1, OS and safety. Results: In cohort A, 121 pts were randomized to Qmab/pembro (n = 60) or pembro (n = 61). In cohort B, 181 pts were randomized to Qmab/pembro (n = 39), MK-4830 + pembro (n = 20), fave/pembro (n = 40), vibo/pembro (n = 41), or pembro (n = 41). Median (range) follow-up was 33.6 mo (19.3-46.0) for cohort A and 20.3 mo (10.9-37.5) for cohort B. In cohort A, ORR (95% CI) was 45% (32-58) with Qmab/pembro and 30% (19-43) with pembro. In cohort B, ORRs (95% CI) were 46% (30-63) with Qmab/pembro, 65% (41-85) with MK-4830 + pembro, 38% (23-54) with fave/pembro, 49% (33-65) with vibo/pembro, and 42% (26-58) with pembro. Additional results are in the table. Grade 3-4 TRAEs occurred in 12% with Qmab/pembro and 8% with pembro in cohort A; and 21% with Qmab/pembro, 0% with MK-4830 + pembro, 20% with fave/pembro, 27% with vibo/pembro, and 20% with pembro, in cohort B; 2 pts with vibo/pembro had grade 5 TRAEs. Conclusions: Pembro-based combinations evaluated in this study showed numerically higher ORR vs pembro alone, but the absolute improvement was modest, especially in the 1L setting. Despite manageable safety, these results do not support further clinical development of these combinations in pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04895722 . Cohort AQmab/pembron = 60 Cohort APembron = 61 Cohort BQmab/pembron = 39 Cohort BMK-4830 + pembron = 20 Cohort BFave/pembron = 40 Cohort BVibo/pembron = 41 Cohort BPembron = 41 ORR (95% CI), % 45 (32-58) 30 (19-43) 46 (30-63) 65 (41-85) 38 (23-54) 49 (33-65) 42 (26-58) DOR, median (range), mo NR (8 to 42+) NR (6 to 44+) NR (4+ to 27+) NR (4+ to 31+) NR (4 to 27+) NR (2+ to 25+) NR (4+ to 34+) PFS, median (95% CI), mo 18 (4-NR) 4 (2-15) NR (12-NR) NR (2-NR) 8 (2-NR) 25 (8-NR) NR (4-NR) PFS HR(95% CI) 0.65 (0.41-1.02) - 0.78 (0.39-1.56) 0.77 (0.33-1.81) 1.18 (0.62-2.26) 0.78 (0.38-1.58) - OS, median (95% CI), mo NR (29-NR) 37 (14-NR) NR (NR-NR) NR (7-NR) NR (21-NR) NR (NR-NR) NR (21-NR) OS HR(95% CI) 0.70 (0.41-1.21) - 0.99 (0.43-2.29) 1.17 (0.45-3.07) 1.02 (0.45-2.32) 0.80 (0.33-1.95) - NR, not reached.

PURPOSE:Routine testing for mismatch repair deficiency (dMMR)/microsatellite instability (MSI) in colorectal cancers is recommended for Lynch syndrome screening, prognosis, and treatment guidance. In the metastatic setting, RAS/BRAF mutations guide treatment decisions. The impact of these mutations on the tumor immune microenvironment (TiME) in MSI/dMMR colorectal cancer is not known. EXPERIMENTAL DESIGN:The study involved retrospective analysis of 448 patients with stage I to IV MSI/dMMR colorectal cancer profiled using next-generation sequencing (Tempus xT DNA sequencing of 595-648 genes at 500x coverage and Tempus xR whole-exome capture RNA sequencing). MSI status was determined by assessing 44 or 239 loci using next-generation sequencing. dMMR was determined using IHC. Tumor mutational burden, tumor neoantigen burden (NTB), PD-L1, immune infiltration, and canonical immune pathways (76 gene set signatures) were analyzed. RESULTS:The median age at diagnosis was 67 years (range, 21-86); 59% of patients were female, and 70% were stage III to IV. Among the 448 patients, 100 (22%) harbored RAS mutations (RASmut), 119 (27%) a BRAFV600E mutation, and 229 (51%) were double wild type. RASmut exhibited lower NTB (median, 12 vs. 15 vs. 16; P = 0.003) and PD-L1 (3.6% vs. 13% vs. 24%; P < 0.001) than BRAFV600E and wild-type tumors, respectively. The RASmut TiME had lower overall inflammation and fewer infiltrating CD8+ T cells than wild-type or BRAFV600E tumors. In contrast, BRAFV600E tumors exhibited hyperproliferative characteristics associated with broad metabolic reprogramming but a similarly inflamed TiME compared with wild-type tumors. CONCLUSIONS:Our data suggest that MSI/dMMR colorectal cancers harboring RASmut are less immunogenic, and the TiME contains a lower inflammatory profile than wild-type or BRAFV600E tumors. Further analysis and validation are required to confirm these findings.