Advanced Colorectal Cancer Research Articles

First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with advanced colorectal cancer: Safety and efficacy results from a phase I study.

3593 Background: The prognosis of advanced colorectal cancer (CRC) is poor with limited treatment options available. IBI363 is a PD-1/IL-2α-bias bispecific antibody that specifically activate PD-1(+)CD25(+) tumor specific T cells while sparing PD-1(-)CD25(-) bystander T cells, and activate peripheral regulatory T cells to protect the body from autoimmunity. Herein, we report the safety and efficacy of IBI363 in patients (pts) with advanced CRC in a phase I study. Methods: Eligible pts with locally advanced or metastatic CRC who failed or intolerant to standard treatment were enrolled and received IBI363 intravenously at dose levels ranging from 100 ug/kg to 3 mg/kg every week (QW), every two weeks (Q2W) or every three weeks (Q3W). The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), etc. per RECIST v1.1. Results: As of December 22, 2023, a total of 68 pts (males: 55.9%, median age: 55.5 years, ECOG PS 1: 50.0%, liver metastasis: 61.8%; previous treatment ≥3 lines: 76.5%; previous immunotherapy: 27.9%) were recruited and received IBI363 treatment including 24 pts at 600 ug/kg Q2W and 20 pts at 1 mg/kg Q2W. Microsatellite stable (MSS)/proficient mismatch repair (pMMR) was presented in 57 (83.8%) pts and microsatellite status of the remaining 11 (16.2%) pts were unknown. Median follow up time was 5.3 months (95%CI: 4.4-6.9). Treatment emergent adverse events (TEAEs) were reported in 65 (95.6%) pts including grade ≥3 TEAEs in 22 (32.4%) pts. Common TEAEs (≥20%) were arthralgia (35.3%), anemia (32.4%), pyrexia (22.1%) and hypoalbuminemia (20.6%). Treatment related adverse events (TRAEs) were reported in 62 (91.2%) pts including grade ≥3 TRAEs in 16 (23.5%) pts. Immune related adverse events (irAEs) were reported in 22 (32.4%) pts including grade ≥3 irAEs in 4 (5.9%) pts. Serious TRAE were reported in 12 (17.6%) pts. TRAEs leading to treatment interruption and discontinuation were reported in 25 (36.8%) and 2 (2.9%) pts. No TRAE leading to death was reported. Pts with at least 1 post-baseline tumor assessment were included in efficacy evaluable set. In all evaluable pts (n=63), overall ORR was 12.7% (95%CI: 5.6-23.5). In pts with liver metastasis (n=38), ORR was 13.2% (95%CI: 4.4-28.1). In pts with PD-L1 CPS ≥1 (n=13), ORR was 30.8% (95%CI: 9.1-61.4), and DCR was 76.9% (95%CI: 46.2-95.0). The median DoR was not reached. A prospective cohort of CRC pts with PD-L1 CPS ≥1 has been initiated. Further details and data will be updated at the meeting. Conclusions: IBI363 showed acceptable tolerability and manageable safety profiles in pts with advanced CRC. Preliminary efficacy of IBI363 was observed, particularly in pts with PD-L1 CPS ≥1. Clinical trial information: NCT05460767 .

A phase 2 study evaluating response and biomarkers in patients with microsatellite stable (MSS) advanced colorectal cancer (CRC) treated with nivolumab/relatlimab.

3554 Background: Lymphocyte-activation gene 3 (LAG-3) is an immunosuppressive signal, impairing T effector (Teff) activation. Pre-clinical studies suggest LAG-3 inhibition promotes anti-tumor immunity by enhancing Teff function. Correlative studies linked increased LAG-3 levels with reduced overall survival (OS) in CRC. These data prompted optimism that combined LAG-3/PD-1 inhibition might promote anti-tumor responses in MSS CRC. Methods: We conducted a phase 2 study of nivolumab (Nivo) (aPD1)/relatlimab (Rela) (aLAG3) in patients with previously treated advanced MSS CRC. This study enrolled patients onto 1 of 3 arms. Arms A and B used a Composite PD-L1 and acellular Mucin (CPM) score to define patients as CPM(+) in Arm A (CPM≥ 15%) and CPM(-) in Arm B (CPM< 15%). Patients in Arm A and B received Nivo 480mg/Rela 160mg IV q4 weeks. Arm C enrolled patients without biomarker selection who received Nivo 480mg/Rela 960mg or Rela 480mg/Nivo 480mg. The primary endpoint was objective response, and each arm was powered to detect an objective response rate (ORR) of ≥20%. Results: Fifty nine evaluable patients were enrolled (Arm A: 12, Arm B: 15, Arm C: 32). Patient characteristics and responses are outlined. Treatment was well tolerated with no new safety signals over aPD1 alone. Three (5%) patients achieved a partial response (PR), 6 (10%) stable disease (SD), and 50 with progression of disease (PD) as best response. The median progression-free survival was (Arm A: 2.2 mo., Arm B: 2.8 mo., Arm C: 2.6 mo.) while median OS was (Arm A: 4.3 mo., Arm B: 14.2 mo., Arm C: 12.4 mo.). In N=6 patients with lung-only metastases, 2 (33%) experienced a PR, and 1 (17%) a SD, for a clinical benefit rate of 50%. The trial incorporated translational correlates. We will report mass cytometry on PBMCs, RNAseq on baseline biopsies, and imaging mass cytometry on pre- and on-treatment biopsies. Conclusions: This combination did not meet the primary endpoint of 20% ORR for any of the 3 cohorts, but there was intriguing possible activity in patients with lung only metastases, consistent with emerging data. Clinical trial information: NCT03642067 .

Association between anxiety, depression, and symptom burden in patients with advanced colorectal cancer: A multicenter cross‐sectional study

AbstractObjectivesPatients with advanced colorectal cancer (CRC) have multiple concurrent physical and psychological symptoms. This study aimed to explore the relationship between anxiety, depression, and symptom burden in advanced CRC.MethodsA multicenter cross‐sectional study was conducted in 10 cancer centers from geographically and economically diverse sites in China. A total of 454 patients with advanced CRC completed the Hospital Anxiety and Depression Scale and the MD Anderson Symptom Inventory. Multiple regression analysis was applied to explore the relationship between anxiety, depression and symptom burden.ResultsAbout one‐third of the patients showed symptoms of anxiety or depression. Patients with anxiety or depression reported significantly higher symptom burden than those without (p < 0.001). Patients with anxiety or depression reported a higher proportion of moderate‐to‐severe (MS) symptom number than those without (p < 0.001). About 52% of the patients with anxiety or depression reported at least three MS symptoms. The prevalence of MS symptoms was ranging from 7.3% (shortness of breath) to 22% (disturbed sleep), and in patients with anxiety or depression was 2–10 times higher than in those without (p < 0.001). Disease stage (β = −2.55, p = 0.003), anxiety (β = 15.33, p < 0.001), and depression (β = 13.63, p < 0.001) were associated with higher symptom burden.ConclusionsAnxiety and depression in patients with advanced cancer correlated with higher symptom burden. Findings may lead oncology professionals to pay more attention to unrecognized and untreated psychological symptoms in symptom management for advanced cancer patients.

Updated efficacy and safety results from the phase Ib/II study of surufatinib combined with camrelizumab and chemotherapy in patients with advanced colorectal cancer.

e15547 Background: Preclinical and clinical data have demonstrated the synergistic anti-tumor effects of surufatinib, a novel VEGFR1-3, FGFR and CSF-1R inhibitor, in combination with immune checkpoint inhibitors (ICIs)/chemotherapy. A phase Ib/II, open-label study (NCT04929652) was conducted to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced colorectal cancer (CRC). In the phase Ib part, this combination showed favorable safety and efficacy profile, which was presented at ASCO 2023 in poster format (#255). Here, we reported the updated results from the phase Ib and phase II dose escalation part together. Methods: In the phase Ib, pts with CRC received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m2, d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). It had been reported in phase Ib that surufatinib 300 mg QD was defined as the recommended phase 2 dose (RP2D). In phase II dose expansion part, a further 36 pts were treated with the same regimen. The primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: As of Jan 18, 2024, 30 CRC pts (median age 57) were enrolled in the study with 12 pts in the phase Ib part and 18 pts in the phase II part. 70% were male and 23% had ECOG PS 1. 24/30 (80%) pts were positive for KRAS, NRAS or BRAF mutations. Among the 30 efficacy evaluable pts, the ORR was 30.0% (95% CI 14.7–49.4; 9 PR) and DCR was 93.3% (95% CI 77.9–99.2; 28 PR+SD). Pts with RAS/BRAF mutations were more likely to achieve better responses (9 PR in 24 pts, ORR-37.5%). After a median follow-up time of 11.1 months, the median PFS was 6.34 months (95% CI 4.57-9.23) and median OS was not mature. The most common grade 1-2 treatment related adverse events (TRAEs) (≥35%) were diarrhea (70%), fatigue (40%), anemia (36.7%), proteinuria (36.7%) and nausea (36.7%). Eleven pts experienced at least one grade 3 or 4 TRAEs. Grade 3 or 4 TRAEs occurred in > 1 pt included diarrhea (n = 3, 10%) and neutrophil count decreased (n = 2, 6.7%). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF demonstrated promising anti-tumor activity in pts with advanced CRC, with a manageable safety profile. Expansion enrollment is ongoing and updated information will be presented. Clinical trial information: NCT04929652 .

52P Phase Ib study of pembrolizumab and XL888 in patients with advanced colorectal cancer

52P Phase Ib study of pembrolizumab and XL888 in patients with advanced colorectal cancer

Application and evaluation of fecal SDC2 gene methylation in the diagnosis and treatment of colorectal cancer.

e15541 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by regulating cell adhesion, tissue differentiation and angiogenesis. The aim of this study is to verify the sensitivity and specificity of fecal SDC2 gene methylation in the detection of colorectal cancer, find the dominant population who can benefit from this detection, expand its clinical application scenarios, and explore its role in the evaluation of the efficacy and prognosis of patients with advanced colorectal cancer. Methods: A total of 72 patients diagnosed with colorectal cancer were included in the study. The methylation level of SDC2 gene in feces of patients was detected by fluorescence PCR. We evaluated sensitivity and specificity and assessed associations between fecal SDC2 methylation levels, fecal occult blood tests, characteristics of the lesions on colonoscopy, and clinical practice. The critical value of reaction solution A was 10.0, and the critical value of reaction solution B was 10.5. When the Ct value of any tube of reaction solution A or B was less than the critical value, it was judged as "positive". Results: Data from 72 patients were evaluated, with a sensitivity of 89.1% (41/46 95%CI 0.798 to 0.985) for patients with untreated colorectal cancer. The sensitivity of SDC2 methylation detection was 46.2% (12/26 95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference in the detection rate of SDC2 methylation between the two groups was statistically significant (P < 0.001). Among the 46 untreated patients with colorectal cancer, 32 patients with positive SDC2 gene methylation received radical surgery, and 30 of them (93.75%) turned to SDC2 gene methylation negative after surgery. Patients who achieved clinical benefit (CR+PR+SD) found reduced SDC2 gene methylation levels in the stool.There was no significant difference in the methylation level of SDC2 gene between colorectal cancer patients with different fecal occult blood test results (-, +, ++, +++) (P = 0.564)、different lesions (ascending colon, transverse colon , descending colon , sigmoid colon, and rectal) (P = 0.179)、different stages (stage I, II, III, IV) (P = 0.828)、different types (infiltrative, ulcerative, protruding) (P = 0.629), and different sizes of lesions (≤ 5cm, 6-9cm, ≥10cm) (P = 0.644). Conclusions: The high sensitivity of fecal SDC2 gene methylation in detecting untreated CRC patients may help make colonoscopy a screening method only for those at high risk of developing CRC. It may help to evaluate the efficacy of radical surgery, predict the recurrence of colorectal cancer and monitor the efficacy of palliative treatments for colorectal cancer. This work was supported by Shanghai Shenkang Project (No.SHDC2022CRT009).

Efficacy and safety of chidamide in combination with serplulimab and standard third-line treatments in advanced colorectal cancer: A single arm, exploratory phase 2 trial.

TPS3637 Background: The efficacy of third line and subsequent treatments for advanced colorectal cancer (mCRC) is suboptimal, and the available drug options are limited. Approximately 95% of mCRC patients belong to the type of satellite stability (MSS), which often shows poor response to single immunotherapy. Previous clinical trials have preliminarily demonstrated that the potential application of combining anti-angiogenesis drugs with immune checkpoint inhibitors (ICIs) in mCRC. Chidamide is an isoform selective inhibitor of histone deacetylase (HDAC). Studies have shown its synergistic effect with PD-1 monoclonal antibody in anti-tumor activity. Therefore, we aim to conduct further investigations centered on the combination of Chidamide+Serplulimab+standard third-line treatments in mCRC. Methods: This prospective, open-label, single-arm, exploratory multi-center clinical trial has been planned to enroll 30 patients with advanced CRC who have progressed after two lines of standard therapies. The key inclusion criteria are: pathologically confirmed colorectal malignancy; age ≥18 years, regardless of gender; estimated survival ≥3 months; ECOG score 0-1; at least one measurable lesion according to iRECIST criteria; requiring third-line or beyond treatment and no prior treatment with PD1 monoclonal antibody, regorafenib/fruquintinib or TAS-102±bevacizumab; adequate major organ function; and signed informed consent and good compliance, agreeing to cooperate with survival follow-up. Enrolled patients receive Chidamide (20mg twice a week), Serplulimab (3mg/kg on day 1 every two weeks), and standard third-line treatments (TAS-102 35mg/m² twice daily on days 1-5 and 8-12 of a 28-day cycle ± bevacizumab 5mg/kg on day 1 every two weeks or regorafenib 120mg daily or fruquintinib 5mg daily for three weeks followed by one week off ).The primary endpoints are safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate(DCR), PFS rate at 6 months and 12 months, OS rate at 6 months and 12 months, DCR, quality of life score(QoL), and nutritional score PG-SGA. As of February 2024, eight patients have been enrolled in the study. Trial registration number: ChiCTR2300077213. Clinical trial information: ChiCTR2300077213.

Single-center retrospective analysis of second-line treatment with regorafenib in patients with advanced colorectal cancer among the COVID-19 pandemic.

e15552 Background: Regorafenib targets multiple tyrosine kinases that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, We retrospectively analyzed the efficacy and safety of regorafenib alone or combined with chemotherapy/immunotherapy in the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. Methods: Individual patient data from Peking University Third Hospital were analyzed retrospectively from January 2020 to September 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The median age of 31 patients was 65 years, the median PFS was 6 months (1–21 months), and the median OS was 20 months (3–38 months). PFS tended to be prolonged with regorafenib plus capecitabine or immunotherapy in 12 subjects versus regorafenib alone in 19 subjects (8 months vs. 4 months, P = 0.306), with no statistical difference, and so did OS (27 months vs. 15 months, P = 0.899).The analysis of PFS (2.5 months vs. 7 months vs. 4 months, P = 0.164) and OS (13 months vs. 28 months vs. 20 months, p = 0.417) in patients with liver, lung, or abdominal/peritoneal metastases at the initiation of treatment demonstrated poor survival prognosis in patients with liver metastasis. Multivariate analysis showed that regorafenib combined with capecitabine or immunotherapy (wald = 5.766, p = 0.016) and non-liver metastasis (wald = 4.223, p = 0.040) were independent prognostic factors for PFS in the second-line treatment. Adverse drug reactions (ADRs) mainly included hand-foot skin reactions (HFSRs), fatigue, hypertension, and proteinuria, due to which 3 subjects discontinued the treatment. The incidence of Grade 3/4 ADRs was 19.3%, 16.9%, 12.9%, and 9.6%, respectively. Conclusions: Regorafenib alone or combined with chemotherapy/immunotherapy is safe and feasible in the second-line treatment for advanced colorectal cancer, and therefore further prospective studies can be conducted to explore combination therapies.

Impact of colorectal cancer screening on the incidence of advanced stages of the disease in the United States: An analysis of 181,442 patients.

10524 Background: Routine cancer screening, in addition to identifying early-stage cancers, aim to delay the time of diagnosis of the advanced stage. The impact of screening on the incidence of advanced colorectal cancer (aCC) in real-world settings is unknown. Methods: Data of adults aged 50–74 years with regional/distant stage (advanced) colorectal cancer diagnosed between 2004 and 2020 was obtained from the Surveillance, Epidemiology, and End Results Plus Data, 17 Research Plus Registries. The age-standardized incidence rates (ASIR) and annual percentage change (APC) were used to compare incidence trends stratified by sex, race/ethnicity, area of residence, and tumor site. Results: Among 181,442 cases of aCC, 56.6% were male, 117 847 (65%) were Non-Hispanic White (NHW), 23 419 (12.9%) were Non-Hispanic Black (NHB), 22 402 (12.4%) were Hispanics, 15 787 (8.7%) were Non-Hispanic Asian or Pacific Islander (NHAPI), 1564 (0.9%) were Non-Hispanic American Indian/Alaska Native (NHAIA), and 423 (0.2%) were of unknown race, respectively. In 123 609 cases (68.1%), the tumor site was in the colon, in the rectum in 41 395 cases (22.8%), and in the recto-sigmoid junction in 16 438 cases (9.1%). From 2004 to 2020, overall ASIR of aCC decreased (APC, -1.87%: -2.37 to -1.40), especially in females (APC, -2.05%: -2.53 to -1.55 vs. male: APC, -1.84%: -2.36 to -1.29), and metropolitan residents (APC, -2.01%: -2.57 to -1.43 vs. non-metropolitan: APC, -1.36%: -1.78 to -0.92). Notably, NHB showed the greatest decrease (APC, -2.56%: -3.01 to -2.06) followed by NHW (APC, -1.95%: -2.44 to -1.47), NHAPI (APC, -1.80%: -2.25 to -1.32) and Hispanics (APC, -1.29%: -1.85 to -0.64). There was no significant change in the ASIR among NHAIA. Furthermore, the ASIR of advanced colonic (APC, -2.66%: -3.18 to -2.14) and recto-sigmoid cancers (APC, -2.35%: -2.91 to -1.65) declined, but advanced rectal cancer increased (APC, 0.58%: 0.18 to 0.98) over the same period. Conclusions: This study highlights the positive impact of colorectal cancer screening in reducing aCC incidence rates in across genders, residential areas, and racial groups/ethnicities including minority populations. While there may be other contributing factors, increased awareness and use of screening may account for the overall declining aCC incidence rates over the almost 20-year study period. Further research is essential to identify factors contributing to the screening program's limited impact on the NHAIA population and advanced rectal cancers. [Table: see text]

Early [18F]FDG PET/CT response evaluation after a single dose of anti-EGFR therapy as a predictive biomarker for treatment benefit in patients with advanced colorectal cancer.

Early [¹⁸F]FDG PET/CT response evaluation after a single dose of anti-EGFR therapy as a predictive biomarker for treatment benefit in patients with advanced colorectal cancer.

82P Interplay of high-risk human papillomaviruses and Epstein-Barr virus in advanced colorectal cancer

82P Interplay of high-risk human papillomaviruses and Epstein-Barr virus in advanced colorectal cancer

Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer.

Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.

The Role of Matrix Metalloproteinase-2 (MMP2) in Colorectal Cancer Progression: Correlation With Clinicopathological Features and Impact on Cellular Processes.

Background Colorectal cancer (CRC) is a prevalent and deadly disease characterized by significant molecular complexity. Matrix metalloproteinase-2 (MMP2) has been implicated in cancer progression due to its role in extracellular matrix degradation, yet comprehensive studies linking MMP2 expression to CRC progression and its molecular mechanisms remain needed. Methodology This study involved 90 CRC patients, with tumor and adjacent normal tissues analyzed via immunohistochemistry (IHC) to assess MMP2 expression. The human CRC cell line SW480 was treated with an MMP2 inhibitor, ARP100, and evaluated for changes in cell migration, invasion, proliferation, and apoptosis using various assays, including MTT, wound-healing, transwell, caspase activity, and western blot analysis. Results High MMP2 expression was significantly associated with advanced tumor stages, lymph node involvement, and metastasis in CRC patients. Compared to normal tissues, MMP2 expression was markedly higher in cancerous tissues. Inhibition of MMP2 in SW480 cells resulted in reduced migration, invasion, and proliferation, and induced apoptosis, evidenced by increased caspase 3 and 9 activities and higher levels of cleaved caspase proteins. Conclusion Elevated MMP2 expression is correlated with advanced CRC and aggressive tumor characteristics. MMP2 inhibition can suppress CRC cell invasiveness, migration, and proliferation while promoting apoptosis, suggesting its potential as a therapeutic target in CRC treatment.

First-in-human trial of M9140, an anti-CEACAM5 antibody drug conjugate (ADC) with exatecan payload, in patients (pts) with metastatic colorectal cancer (mCRC).

3000 Background: CEACAM5 is a cell surface protein with limited expression in adult healthy tissues, but high expression in various adenocarcinomas, particularly in CRC (>90% of pts). M9140 is the first anti-CEACAM5 ADC with a topoisomerase 1 inhibitor (Top1i) payload (exatecan). The ß-glucuronide linker connecting the M9140 antibody backbone to the payload is highly stable in circulation (drug-to-antibody ratio=8). In preclinical models, M9140 has demonstrated strong potency, antitumor activity, and a bystander effect. Methods: This Phase 1 trial (NCT05464030) investigated the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of M9140 as monotherapy (Q3W [Day 1 of 21-day cycles]; IV) in adults with CRC (ECOG PS ≤1) who had received ≥2 prior lines of treatment. The primary objectives of Part 1A were to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE). Results: At data cutoff (19 Jan 2024), 40 pts from the US, EU, and Japan were treated across 7 dose levels (DLs): 0.6 mg/kg, 1.2 mg/kg (n=3, each), 2.4 mg/kg (n=7), 2.6 mg/kg (n=4), 2.8 mg/kg (n=12), 3.0 mg/kg (n=4), and 3.2 mg/kg (n=7, including 3 pts with primary G-CSF prophylaxis). Most pts were heavily pretreated (80% had ≥3 lines of prior treatment; 100% received irinotecan). Overall, 6 pts experienced dose-limiting toxicities (DLTs); the majority were hematological adverse events at DLs 3.0 and 3.2 mg/kg; 1 patient (at 2.8 mg/kg) experienced a Grade 5 sepsis. The most frequently reported Grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia in 16 (40.0%) pts, thrombocytopenia and anemia in 11 (27.5%) pts each, and WBC decreased in 10 (25.0%) pts. No events of ocular toxicity/interstitial lung disease (ILD) were reported. The best objective response per RECIST v1.1 was partial response (PR) in 4 (10.0%) pts (3 confirmed) (all at DLs ≥2.4 mg/kg); stable disease (SD) in 17 (42.5%), including 6 (15.0%) lasting for ≥100 days and progressive disease (PD) in 6 (15.0%) pts. For a total of 13 (32.5%) pts, the best overall response was not evaluable, including 6 (15.0%) who had no on-treatment tumor assessment yet. The preliminary median progression-free survival (PFS) was 6.7 months (95% CI: 4.6, 8.4). As of data cutoff, 15 (37.5%) pts are continuing treatment. Based on the safety, tolerability, preliminary clinical activity, PK, and PK/pharmacodynamics modeling data, 2.8 mg/kg was declared as the MTD, and 2.4 mg/kg and 2.8 mg/kg were chosen as the RDEs and have been taken forward into a randomized expansion study. Conclusions: M9140 demonstrated encouraging activity in heavily pretreated pts with advanced CRC, with a manageable and predictable safety profile. Contrary to approved ADCs with Top1i payloads, no ILD or ocular toxicities were observed. Evaluation of M9140 in mCRC continues in the dose expansion part of this study. Clinical trial information: NCT05464030 .

46P Efficacy and safety of fruquintinib plus capecitabine as first-line treatment in patients (pts) with advanced metastatic colorectal cancer (mCRC) ineligible for intravenous chemotherapy: Early outcome report of a two-stage, single armed, phase II study

46P Efficacy and safety of fruquintinib plus capecitabine as first-line treatment in patients (pts) with advanced metastatic colorectal cancer (mCRC) ineligible for intravenous chemotherapy: Early outcome report of a two-stage, single armed, phase II study

Efficacy of treatment with traditional Chinese patent medicine (Fufang E'jiao Syrup) for cancer-related fatigue in patients with advanced cancer: A randomized, double-blinded, placebo-controlled, multicenter trial.

12053 Background: There is ongoing interest in finding effective drugs for cancer-related fatigue (CRF) in advanced cancer patients, although studies have had mixed results. Fufang E'jiao Syrup (FFEJS), a traditional Chinese patent medicine, has shown promise in alleviating CRF. This trial aims to investigate whether FFEJS could reduce fatigue and improve quality of life in advanced cancer patients. Methods: This prospective, multicenter, double-blinded, placebo-controlled trial was implemented at 29 hospitals in China, enrolling 611 advanced non-small cell lung cancer, colorectal cancer, and gastric cancer patients with Visual Analogue Scale for Fatigue ≥ 4 points. The study was conducted between September 23, 2019 and April 7, 2022, with a final follow-up on May 25, 2022. Participants were randomized to receive FFEJS (20 ml, 3 times per day) or a matching placebo orally for six weeks. The safety assessments were extended until the fourth week after the trial ended. The primary outcome was the change in total mean score (range: 0 [no fatigue] to 10 [extreme fatigue] points) on the Revised Piper Fatigue Scale-Chinese Version (RPFS-CV) from baseline to week 6. Secondary outcomes include quality of life (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F) and adverse events. FFEJS were compared with the placebo group using a linear mixed model. Results: Among 611 patients randomized (FFEJS: 303 and placebo: 308; 210 non-small cell lung cancer [34.4%], 201 colorectal cancer [32.9%], 200 gastric cancer [32.7%]; mean [SD] age, 62.8 [9.3] years; 413 [68.3%] man; mean [SD] baseline RPFS-CV total mean score, 4.86 [1.30] points), 503 (82.3%) completed the primary end point. By the end of week 6, the FFEJS group achieved normal fatigue levels (RPFS-CV < 4) compared to the placebo group (FFEJS: 3.78 vs Placebo: 4.39, adjusted mean difference 0.59 points [95% CI, 0.45 to 0.76 points]; P < .001). The adjusted mean difference for a favorable shift to a higher FACIT-F total score at week 6 comparing FFEJS with placebo was 2.77 points (97.36 vs 94.23 points; [95% CI, 0.56-4.96 points]; P = .02). There was no difference in adverse events occurrence between FFEJS and the placebo groups (110 [20%] vs 122 [18%], P = .38). Conclusions: In this randomized clinical trial among advanced cancer patients with CRF, FFEJS reducedfatigue severity and improved quality of life compared to placebo. Research is needed to assess the mechanism, clinical effect, and long-term safety of FFEJS for CRF in advanced cancer patients. Clinical trial information: NCT04147312 .

Clinical performance of fecal calprotectin, lactoferrin, and hemoglobin for evaluating the disease activity of IBD and detecting colorectal tumors.

Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers. In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors. Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer. Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone.

Preclinical development of ATR04-484, an auxotrophic strain of Staphylococcus epidermidis, for the topical treatment of epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity.

e24074 Background: Agents targeting the EGFR-mediated signaling pathway are commonly used for the treatment of advanced lung, pancreatic, colorectal, and head and neck cancers. Significant dermal toxicities, which occur in up to 90% of patients treated with EGFR inhibitors (EGFRis) and other therapies inhibiting downstream signaling pathways, may be disruptive to a patient’s quality of life and adherence to therapy. Inhibition of the EGFR pathway may suppress host defenses and lead to opportunistic pathogenic colonization or infection. EGFRi-induced dermal toxicity is associated with elevated levels of Staphylococcus aureus and IL-36γ. ATR04-484 is a topical ointment containing S. epidermidis strain SE484, isolated from a healthy human volunteer that was selected for its ability to inhibit S. aureus and IL-36γ . Methods: Reconstructed human epidermis (RHE) and ex vivo pig skin were used to measure the effect of ATR04-484 on S. aureus in therapeutic and prophylactic settings with S. aureus added prior to or after ATR04-484, respectively. To evaluate the anti-inflammatory effects of ATR04-484, IL-36γ levels were measured on untreated RHE and RHE treated with erlotinib alone or in combination with ATR04-484. 104 colony-forming units (CFU) of methicillin-resistant (MRSA) or methicillin-sensitive (MSSA) S. aureus were used. Toxicology was assessed by measuring cell viability in three in vitro toxicology assays: the eye irritant potential was tested on 3D reconstituted human cornea-like epithelium (RhCE), the skin irritant potential of the strain in the ointment was assessed on 3D RHE, and the skin corrosive potential was evaluated on RHE. Results: ATR04-484 comparably inhibited growth of both MRSA and MSSA in therapeutic and prophylactic settings. In a therapeutic setting, ATR04-484 inhibited MRSA growth by 1 log (90%) compared to untreated MRSA in both RHE and pig skin. In a prophylactic setting, ATR04-484 inhibited MRSA growth by approximately 5 logs on RHE and 2 logs on pig skin. Additionally, application of ATR04-484 reduced IL-36γ to a level comparable to untreated RHE. The effect was dose-dependent; application of 109CFU/cm2 of ATR04-484 showed more potent IL-36γ reduction compared to 108 CFU/cm2. The three toxicology assays indicate that ATR04-484 does not cause irritation or corrosion. Conclusions: In these preclinical studies, ATR-04-484 showed a promising preclinical profile for the treatment of EGFRi-induced dermal toxicity by significantly reducing S. aureus growth, completely ameliorating IL-36γ levels, and showing no safety concerns.

Efficacy of trifluridine/tipiracil in 3rd or 4th line of treatment in patients with advanced or metastatic colorectal cancer: A real-world data analysis with subgroups exploration.

e15576 Background: Patients with unresectable mCRC can achieve long-term overall survival (OS) thanks to modern systemic treatment and subsequent lines of therapy. With effective 1st, 2nd and next lines of therapy, their condition often allows further lines of treatment. Since publication of RECOURSE study, one of the most frequently used drugs in the 3rd or 4th line is trifluridine/tipiracyl (FTD/TPI). There is limited data on optimal selection of patients in order to obtain the greatest therapeutic gain with the least toxicity. The aim of this study was to find and define groups of patients who would benefit most from this treatment in a real-world mCRC patient population. Methods: Consecutive patients with unresectable or metastatic colorectal cancer (mCRC) started treatment with FTD/TPI between 1/Sep/2019 and 31/Dec/2023. Clinical factors including age, gender, primary location of colorectal cancer, BRAF, RAS and MSI-H status, ECOG performance status, baseline CEA level, location of metastases, response to treatment and AEs occurrence were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Jan/2024. Results: 822 medical records of patients with mCRC were analyzed. In total 261 patients treated with FTD/TPI were enrolled. 204 (78%) patients were treated with FTD/TPI in 3rd line (L3) and 57 (22%) in the 4th line (L4). Patients with RASmt were statistically more numerous in the L3 group; no other statistically significant differences in baseline characteristics was found between L3 and L4 groups. Estimated median OS (mOS) was 10.2 and 14.4 months in L3 and L4 group, respectively; no statistical significance was found between them (p = 0.0866; HR = 1.34, Cl 95% 0.9-1.9). Estimated median PFS (mPFS) was 7.4 and 4.6 months in L3 and L4 group, respectively, and statistically significant differences in mPFS was found in the L3 group in comparison to L4 (p = 0.0079; HR = 0.65, Cl 95% 0.5-0.9). Disease progression (PD) was found in 187 (92%) and 50 (88%) patients in the L3 and L4 group, respectively. PD was most common reason for discontinuing therapy. Most frequent serious AEs of grade 3 or higher were diarrhea, neutropenia and weakness. There were no grade 5 AEs and toxicity rarely led to discontinuation of FTD/TPI therapy. 102 (39%) patients were qualified for next line sequential systemic treatment after L3 or L4. Conclusions: Patients with mCRC who were treated with FTD/TPI in the 3rd line had better PFS than patients treated in 4th line, but mOS was statistically non-significantly better in L4 than L3, which requires further analysis. FTD/TPI is an effective therapy in subsequent lines of treatment for mCRC patients with acceptable toxicity.

51P Phase II dose expansion study of DSP107, a first-in-class fusion protein targeting CD47 and 4-1BB, in combination with atezolizumab in patients with advanced MSS colorectal cancer

51P Phase II dose expansion study of DSP107, a first-in-class fusion protein targeting CD47 and 4-1BB, in combination with atezolizumab in patients with advanced MSS colorectal cancer