Treatment Of Colorectal Cancer Research Articles

Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.

194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.

Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in CRC.

261 Background: Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data in CRC, we explore the use of large PDOs collections to characterize ADC efficacy and affinity through systematic mapping of the relationship between target antigen affinity and payload efficacy. Methods: We have assembled a collection of 85 PDOs from colorectal cancer (CRC), generated from primary tumour samples and metastatic biopsies. Patients ranged from 32 to 89 years old and had experienced an average of 1.54 lines of treatment prior to the PDO-generating tissue sampling. Using gene expression levels of well known target antigens such as CEACAM5, ERBB2, MSLN and TROP2 as a proxy for protein concentration, we explore the relationship between the target antigen affinity and the efficacy of a subset of common payloads including topoisomerase and microtubule inhibitors. This allows us to identify the relationship between two of the three main vectors of ADC efficacy in CRC. Results: We show that topoismerase inhibitor and microtubule inhibitor efficacy relates to the RNA expression level of multiple target antigens commonly used in active clinical trials in CRC. These data match the target antigen and payload couples currently under development or approved in the clinic. We are developing a tool to optimize clinical trial design. This approach will allow us to match patients more accurately with the appropriate payload, ensuring a higher likelihood of response. Conclusions: We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC.

Real-world genomic testing performance in colorectal cancer (CRC): The MultiTEAM Systems Framework Precision Oncology Reflex Testing (TEAMSPORT).

108 Background: Genomic testing plays a pivotal role in personalizing treatment for CRC patients. Despite recommendations from NCCN, adoption remains uneven. Research indicates that only 64.7% of patients with metastatic CRC (mCRC) underwent molecular testing nationwide. TEAMSPORT seeks to address this gap by evaluating the feasibility of reflex testing and examining how pathology and oncology teams integrate genomic testing into routine practice. Methods: This quasi-experimental study tracks testing over time. Eligible patients were 18 years or older, with a histological diagnosis of adenocarcinoma, who received treatment at the University of Kansas Health System (TUKHS). Exclusion criteria included patients discharged to hospice after diagnosis, those whose last contact with TUKHS occurred within 30 days of diagnosis, and patients who passed away within 30 days of diagnosis. Testing rates were calculated as the number of tests performed divided by the number of testing opportunities, where "testing opportunities" refer to NCCN-recommended tests based on cancer stage. An intervention to increase adherence to NCCN-recommended testing began in December 2022. Results: From January 2022 to December 2023, 564 colorectal cancer (CRC) cases were eligible for genomic testing, resulting in 1,525 testing opportunities. In localized CRC, testing rates steadily improved, from 92% in January-June 2022 to 98% by July-December 2023 for patients diagnosed outside of TUKHS. At TUKHS, the rates remained high, reaching 100% in the first two periods and staying over 90% in subsequent periods. Patients with mCRC saw similar trends, particularly in the control arm where rates went from 61% to 71%. Specific molecular NCCN-recommended tests were assessed. At TUKHS, testing rates were high for microsatellite instability (MSI - 98%) which is caused by deficiency of the DNA mismatch repair (dMMR) system. Lower testing rates were observed for other markers like KRAS (70%), BRAF (67%) and HER2 (48%). Testing rates were assessed based on primary insurance. At TUKHS, the testing rates for Medicaid patients reached 94%, private insurance patients at 78%, and Tricare/VA at 100%. Outside of TUKHS, Medicaid patients had lower testing rates at 21%, private insurance patients at 74%, and CMS patients at 66%. Time to test by processing lab will be presented at the meeting. Conclusions: Despite the high testing rates for MSI/dMMR, the overall genomic testing in CRC remains imperfect, with lower rates for BRAF and HER2 . This discrepancy may be related to the fact that targeted therapies for BRAF and HER2 are not yet part of first-line treatment for CRC. Causes for the discrepancy in testing rates by primary insurance have yet to be determined. Future research should address these gaps to enhance precision oncology in CRC management.

Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.

217 Background: Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used in therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, and the detailed mechanisms of resistance are not fully understood. The aim is to develop new therapeutic strategies by elucidating the mechanisms of irinotecan resistance. Methods: We used in vitro approach to demonstrate the mechanism of topoI degradation. Immunohistochemistry staining was used to explore the biomarker for irinotecan, Finally, in vivo approach was used to develop a new strategy for irinotecan treatment. Results: Mechanism of topoisomerase I (topoI) degradation: We investigated the molecular mechanism of topoI degradation in detail. After irinotecan administration, double-strand breaks occur in the DNA, activating DNA-PK. This activated DNA-PK phosphorylates the S10 residue of topoI, and BRCA1-BARD1 ubiquitinates the phosphorylated topoI. Eventually, topoI is degraded by the proteasome. Colorectal cancer cell lines where topoI degradation occurred after irinotecan administration showed irinotecan resistance. Development of a biomarker for irinotecan sensitivity: We created a monoclonal antibody that labels the phosphorylated S10 residue of topoI (topoI-pS10). We examined topoI-pS10 expression in colorectal cancer cases with a history of irinotecan treatment. The results showed a sensitivity of 87.5%, accuracy of 70%, positive predictive value of 70.7%, and negative predictive value of 87%, indicating that topoI-pS10 expression could serve as a biomarker for irinotecan sensitivity.Development of new therapeutic strategies: The degradation of topoI, which causes irinotecan resistance, is carried out via the ubiquitin-proteasome pathway. It is expected that combining irinotecan with a proteasome inhibitor, which blocks this pathway, will enhance irinotecan’s effectiveness. When irinotecan was combined with a proteasome inhibitor in irinotecan-resistant colorectal cancer cell lines, cell death occurred at a higher rate compared to when they were not combined. Similar results were observed in experiments using mice. Conclusions: Based on the mechanism of topoI degradation, we developed a biomarker for irinotecan sensitivity and a new therapeutic strategy. This study suggests the potential for further improvements in irinotecan therapy.

Efficacy of plogosertib (CYC149462), a novel orally bioavailable PLK1 inhibitor, on patient-derived models of colorectal cancer.

209 Background: Colorectal cancer (CRC) is the third most common cancer in adults in the United States. Given the relative rapid cell division in cancer cells compared to most normal cells, drugs targeting mitosis and other cell cycle checkpoints are of interest in CRC treatment. One multi-tasking protein in cell division is polo-like kinase 1 (plk1). Plk1 is a serine threonine kinase that is highly expressed during mitosis and involved in a variety of functions, including spindle assembly, chromosome segregation, G2/M transition, and cytokinesis. Encouragingly, its expression is also significantly higher in CRC compared to normal mucosa, which makes it an attractive cancer-specific target in CRC. In this study, we sought to evaluate the efficacy of plogosertib (CYC149462), a novel plk1 inhibitor, in a series of preclinical models of advanced CRC. Methods: Fourteen CRC patient-derived organoids (PDOs) were generated from patients who underwent biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. Diagnosis of CRC is confirmed in PDOs using H&E and IHC. Subsequently, PDOs were treated with plogosertib in a range of concentrations from 256pM to 100µM. Drug screens were performed for standard of care agents 5FU, oxaliplatin, and SN38. Viability was assessed with Cell-Titer Glo (CTG) 72 hours after treatment. Using a matched PDX, mice were treated with vehicle or 40 mg/kg daily of plogosertib via oral gavage for 2 weeks, 5 days per week. Cell cycle analysis was performed by flow cytometry, and localization of DNA during mitosis was done by fluorescence staining. Results: CRC PDOs were more sensitive to plogosertib (CYC149462) than 5FU, and oxaliplatin, with significantly lower IC 50 values (518.86±377.47nM for plogosertib vs. 38.87±45.63µM for 5FU, and 37.78±39.61µM for oxaliplatin respectively (ANOVA, P < 0.05). Subsequently, we validated our findings in vivo using a matched PDX in which plogosertib treatment led to significant tumor growth inhibition compared to vehicle (t-test, p < 0.05) without serious adverse effects. Furthermore, we showed that plogosertib induces dysfunction in alignment of chromosomes and subsequent G2/M cell cycle arrest (p < 0.05). Conclusions: Together, our study shows that pharmacological inhibition of Plk1 using plogosertib represents a promising therapeutic approach for advanced CRC.

A comprehensive update on the potential of curcumin to enhance chemosensitivity in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.

Liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab as second-line therapy in metastatic colorectal cancer (IRIS): A multi-center, single-arm, prospective, phase II study.

195 Background: In patients with advanced colorectal cancer (CRC), the recommended second-line treatment following first-line therapy with oxaliplatin-based regimens is irinotecan-based therapy. Liposomal irinotecan, a novel formulation of traditional irinotecan, has demonstrated potential to enhance efficacy while minimizing toxicity. This study aims to investigate the efficacy and safety of liposomal irinotecan in combination with 5-FU/LV and bevacizumab as a second-line treatment option for metastatic CRC. Methods: This is a multi-center, single-arm, prospective, phase II study. Patients with metastatic CRC who received oxaliplatin-based chemotherapy as first-line treatment were enrolled to receive liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab regimen until disease progression and/or unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 50 patients were enrolled from Jan 2024 to Jul 2024 across 6 sites in China. The median age was 56.5 years (range: 30.0-76.0), with 58.0% male and 36.0% ECOG 0. Among the patients, 38.0% had left-sided colon cancer, 24.0% had right-sided colon cancer, and 38.0% had rectal cancer. As of Sept 14, 2024, 39 patients had at least one tumor assessment and 19 patients were still on treatment. ORR and DCR were 20.5% (8/39, 95% CI: 9.3%-36.5%) and 84.6% (33/39, 95% CI: 69.5%-94.1%), respectively. Eleven patients had disease progression and 5 patients died, and the median PFS and OS were not reached. The relative dose intensity of liposomal irinotecan and 5-fluorouracil were 92.8% (range: 23.6%-109.6%) and 89.5% (range: 13.3%-116.8%), respectively. During treatment, 43 (86.0%) patients had at least one adverse event (AE) and 24 (48.0%) had grade 3-4 AE. Most common (≥ 10%) grade 3-4 AEs were neutropenia (20.0%), leukocytopenia (16.0%) and diarrhea (10.0%). No unexpected toxicities observed in this study. Conclusions: These preliminary results reveled that liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab after oxaliplatin-based treatment for metastatic CRC was well tolerated with encouraging clinical activity, which warrants further follow up. Clinical trial information: NCT06184698 .

Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.

118 Background: Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib. Methods: A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96). Conclusions: This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.

Meta-analysis of phase II/III randomized controlled trials (RCTs) to determine the incidence of hypertension and proteinuria in patients with gastrointestinal (GI) cancers treated with fruquintinib.

119 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors which impedes angiogenesis associated with tumor growth. On November 8th, 2023, the US FDA approved fruquintinib for use as a third-line treatment for metastatic colorectal cancer (mCRC). With the introduction of novel cancer therapies, monitoring for adverse events is critical. This meta-analysis aims to assess the risk of hypertension (HTN) and proteinuria in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive search of MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024, identifying Phase II/III RCTs that employed fruquintinib in GI cancers and reported HTN and proteinuria as adverse effects. The Mantel-Haenszel method was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q-statistic, and a random effects model was applied. Results: Our analysis included 1872 patients, 1131 (60%) of whom received fruquintinib, from three Phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one Phase II RCT. FRESCO, FRESCO-2, and the phase II trials compared fruquintinib to placebo in patients with mCRC. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. The incidence of any-grade HTN was higher in the fruquintinib group, 34.92% vs 7.55% (RR 3.96; 95% CI: 3.05-5.13; P<0.00001); the rate of high-grade HTN was 13.96% vs 1.21% (RR 9.01; 95% CI: 4.67-17.40; P<0.00001). In the mCRC subgroup, incidence of any-grade and high-grade HTN was 43.02% vs 10.45% (RR 3.97; 95% CI: 2.95-5.33; P<0.00001), and 17.28% vs. 1.27% (RR 12.06; 95% CI: 5.19-28.01; P<0.00001), respectively. Incidence of any-grade proteinuria was also found to be statistically significant and higher in the fruquintinib arm in both GI cancer cohort and mCRC subgroup: 27.3% vs 16.19% (RR 1.89; 95% CI: 1.30-2.74; P=0.0008), and 25.22% vs 11.73% (RR 2.29; 95% CI: 1.17-4.51; P=0.02). The rate of high-grade proteinuria was not statistically significant in both cohorts. In GI cancer group, 1.85% vs 0.53% (RR, 2.49; 95% CI: 0.86-7.16; P=0.09), and mCRC subgroup 2.17% vs 0.51% (RR, 2.87; 95% CI: 0.74-11.12; P=0.13). Conclusions: This meta-analysis revealed a higher incidence of any-grade and high-grade HTN with fruquintinib in GI cancer patients, with significant association in the mCRC subgroup. Fruquintinib was also noted to be associated with increased risk of any-grade proteinuria, however, incidence of high-grade proteinuria was not different in patients treated with fruquintinib compared to placebo. Prompt identification and early management of these adverse events are crucial.

Comparison of risk factors, treatment strategy, and outcomes of early- vs. older-onset colorectal cancer within the prospective ColoCare study.

95 Background: The incidence of colorectal cancer among young adults aged 20-49 has continually increased in recent decades. Early-onset colorectal cancer (EOCRC) patients are more likely to be diagnosed at a more advanced stage of disease, have hereditary cancer syndromes, and have different molecular pathological features of disease than later-onset patients. Herein we compare the risk factors, treatment approaches, and responses to treatment of early-onset versus later-onset colorectal cancer within. Methods: The ColoCare Study is a prospective cohort enrolling individuals diagnosed with primary colorectal cancer at six different cancer centers in the United States and one in Germany. Serial questionnaires assess demographic characteristics and symptoms experienced prior to diagnosis, while clinical characteristics (including staging, pathology, treatments given) are abstracted from medical records. Restricting to patients with available age and stage, patients diagnosed <50 years old were labeled as “early-onset” and ≥50yo as “later-onset.” Associations between patient age and characteristics of interest were tested using Fisher’s Exact Test for count data. Results: Of the3,173 patients included in this analysis, 78% were later-onset (mean: 65 years) and 22% were early-onset (mean: 42 years). Demographic data was comparable between the two groups, with 43% being female. Though similar rates of ever alcohol use were seen between the two groups, early-onset patients reported consuming fewer weekly alcoholic beverages than later-onset patients (mean (standard deviation) of 5.5 (6.6) vs. 8.4 (9.3)). Early-onset patients were less likely to have ever smoked tobacco (38% vs 51%, p<0.001) and had lower rates of obesity (27% vs 31%) or overweight (34% vs 40%) than later-onset patients (p<0.001). For stage II/III disease, early-onset patients were more likely to have received chemotherapy and/or radiation treatment compared to later-onset patients (87% vs 70%, p<0.001), though both groups had similar rates of surgery. Despite this, younger patients did not appear to experience better outcomes, with 21% of younger patients experiencing a recurrence or new metastasis during follow-up versus 20% of later-onset patients. Conclusions: The risingincidence of colorectal cancer in early-onset patients does not appear to be explained by traditional risk factors such as alcohol use, tobacco use, or high BMI. Early-onset patients are more likely to receive chemotherapy or radiation, but observed outcomes are notably poorer compared to later-onset patients. Further statistical analysis on specifics of treatments by stage is ongoing.

Phase Ib/II study of fruquintinib plus 5-fluorouracil/leucovorin after progression on fruquintinib monotherapy in metastatic colorectal cancer.

128 Background: Fruquintinib is a standard third-line treatment in metastatic colorectal cancer (mCRC). However, no standard therapeutic regimen is available for mCRC patients who progressed on third-line therapy. Preclinical experiments supported a rationale for combining antiangiogenic therapy and 5-fluorouracil (5FU) in refractory mCRC with evidence for synergy. This open-label phase Ib/II study was designed to determine the safety and efficacy of fruquintinib plus 5-fluorouracil/leucovorin for mCRC patients who progressed on fruquintinib monotherapy. Methods: The enrolled patients would receive fruquintinib at a fixed dose of 4mg once daily (three weeks on, one week off) and 5FU at two dose levels (1800mg/m 2 and 2400mg/m 2 ) CIV 46 hours on day one and day 15, with leucovorin 400mg/m 2 iv 2 hours before 5FU. Treatments were repeated every 28 days. The primary endpoint was determining the recommended phase II dose (R2PD) of 5FU in phase Ib and the six-month OS rate in phase II. Secondary endpoints for phase II included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety. Planned enrollment was 39 patients. Results: No dose-limiting toxicities occurred in the phase Ib dose-escalation study, and the R2PD of 5FU was 2400mg/m 2 . Between April 2020 and June 2024, 24 patients were enrolled in the phase II stage. The median age was 57.5 years old (from 35 to 68), and 58.33% were female. Left-sided colorectal cancer patients accounted for 75%. Sixteen (66.7%) patients harbored KRAS mutation, and one (4%) had BRAF V600E mutation. Regarding the number of lines of systemic therapy, 83.3% received this study regimen as fourth-line therapy and 16.7% as fifth-line or later therapy. As of June 30, 2024, efficacy was assessed in all 24 patients with a DCR of 62.5% (15 stable disease, nine progression disease). The median follow-up time was 16.5 months (95% CI:12.553-20.447). The primary endpoint six-month OS rate was 91.3%, the median PFS was 4.4 months (95% CI: 1.243-7.557), and the median OS was 17.3 months (95% CI: 12.892-21.708). The most common TRAEs were nausea (25%), hand-foot syndrome (16.7%), abnormal liver function (8.3%), and proteinuria (8.3%). One patient experienced grade 3 mucositis. No treatment-related death occurred. Conclusions: Fruquintinib plus 5-fluorouracil/leucovorin regimen preliminarily demonstrated promising efficacy with a tolerable safety profile for mCRC patients despite progression on prior fruquintinib monotherapy. Further investigation into this possible later-line regimen in mCRC is warranted. Clinical trial information: ChiCTR2000032640 .

Nationwide analysis of Medicare expenditure and utilization of EGFR inhibitors from 2018-2022.

112 Background: EGFR inhibitors are used extensively for treatment of metastatic colorectal cancer ranging from first line drugs in combination with chemotherapy to monotherapy for refractory disease. As we increasingly move towards targeted treatments for cancer, financial implications of these drugs must be taken into consideration. In this study we aim to analyze changes in Medicare spending for Cetuximab and Panitumumab to better understand the financial impact of these therapies. Methods: We obtained data from the publicly available Medicare Part D database from Centers for Medicare and Medicaid Services. Data on total spending, total claims, total beneficiaries, average spending per claim, and average spending per beneficiary was extracted from the database. We adjusted the data for 2018 for 2022 using a standard annual inflation rate. Percentage change was calculated using the adjusted data. Results: For Cetuximab, we saw a sharp increase in total spending by 38.77%, from $4,912,903.87 in 2018 to $6,811,781.05 in 2022. The number of claims rose by 31.96%, while the total number of beneficiaries saw a modest increase of 2.44%. Average spending per claim increased by 16.04%, and average spending per beneficiary grew by 49.44%. Panitumumab showed a similar rise in total spending by 43.23%, from $1,594,347.66 in 2018 to $2,283,142.83 in 2022. Claims increased by 25.42%, and beneficiaries grew by 47.83%. Average spending per claim increased by 25.97%, and average spending per beneficiary saw a substantial rise of 65.75%. Conclusions: Our results indicate a significant increase in the financial burden related to EGFR inhibitors. As we move away from chemotherapy and shift our focus to targeted therapies, it is imperative to explore generic alternatives and direct policy changes to ensure equitable access across various racial and socio-economic groups. These findings highlight the need for further research into healthcare policy reforms to ease the burden on our health system. Drug Year Total Spending ($) Total Claims Total Beneficiaries Avg Spending/Claim ($) Avg Spending/Beneficiary ($) Cetuximab 2018 4,912,903.87 551 123 8,072.80 36,163.51 2022 6,811,781.05 727 126 9,369.71 54,061.75 % Change 0.3877 0.3196 0.0244 0.1604 0.4944 Panitumumab 2018 1,594,347.66 5,955 184 242.72 30,714.91 2022 2,283,142.83 7,470 272 305.81 50,736.51 % Change 0.4323 0.2542 0.4783 0.2597 0.6575

Bevacizumab plus mFOLFOX6/FOLFIRI sequential bevacizumab plus capecitabine maintenance in RAS-mutated advanced colorectal cancer: A real-world study of first-line/second-line conversion therapy.

77 B ackground: Currently, the standard first-line/second-line treatment for advanced colorectal cancer with RAS mutations is chemotherapy combined with bevacizumab. Patients with colorectal cancer confirmed maintenance therapy can effectively improve progression-free survival, improve patient quality of life. Therefore, this study aims to evaluate the efficacy and safety of bevacizumab combined with mFOLFOX6/FOLFIRI sequential bevacizumab combined with capecitabine as first-line/second-line conversion therapy for RAS-mutated advanced colorectal cancer. M ethods: This is an open-label, single-center study in previously untreated patients with RAS mutant mCRC. Eligible patients received first-line chemotherapy of bevacizumab (5mg/m 2 ) combined with mFOLFOX6/FOLFIRI for 12 cycles randomly, during which the efficacy was assessed every 4 cycles, then followed by bevacizumab(7.5mg/m 2 ) in combination with capecitabine maintenance therapy which assessed every 2 cycles until disease progression, and then switched to the second-line therapy FOLFIRI/mFOLFOX6 combined with bevacizumab which was assessed every 4 cycles until disease progression or intolerable toxicity. Imaging studies were performed to assess treatment efficacy according to RECIST1.1 criteria, and the primary endpoint was progression-free survival (PFS), including first-line PFS and second-line PFS after progression, and the secondary endpoints included disease response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. R esults: This study recruited 78 subjects from January 2021 to May 2024. As of September 10, 2024, a total of 70 subjects were analyzable for the first-line treatment, of which 6 subjects met the surgical criteria after treatment and achieved NED status; 45 patients reached the first-line PFS endpoint, with a median PFS (mPFS) of 249 days (95% CI: 204.4-293.6), an ORR of 38.6%, and a DCR of 95.7% . Twenty patients entered the first-line maintenance therapy, with a mPFS of 358 days (95% CI: 53.8-662.2). For the second-line treatment, a total of 43 subjects were analyzable, of which 35 patients reached the second-line PFS endpoint, with a second-line mPFS of 171 days (95% CI: 89.8-252.1). 41 subjects underwent at least one efficacy evaluation, with ORR of 14.6% and DCR of 75.6%. The most common grade 3 treatment-related adverse events were neutropenia, leukopenia, anemia, hypertension, diarrhea, and thrombocytopenia. There were no treatment-related deaths. No new adverse events occurred during the entire combination treatment period. C onclusions: This real world study has demonstrated good tolerability and encouraging clinical efficacy, especially with potential implications for treatment planning and management strategies for advanced colorectal cancer with RAS mutations. Clinical trial information: ChiCTR2100042553 .

Efficacy and safety of fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

166 Background: Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290). Methods: Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m 2 , orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance. Conclusions: Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC. Clinical trial information: NCT05659290 .

Updated efficacy and subgroup analysis of first-line serplulimab plus bevacizumab and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

170 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus bevacizumab and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Our previous presentation at the 2024 ASCO Meeting showed the progression-free survival results. Here we present the updated efficacy and safety findings together with subgroup analysis results after a median follow-up of 31.0 months. Methods: A total of 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m 2 ] and oral capecitabine [1000 mg/m 2 ]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: In the phase 2 part, by the data cutoff of June 30, 2024, sustained improvements in PFS (16.6 vs. 10.7 months, stratified HR 0.66, 95% CI 0.37–1.19) and DOR (17.7 vs. 11.3 months, stratified HR 0.45, 95% CI 0.20–0.98) were observed for patients in group A compared to group B in the modified intent-to-treat population (n = 112; two patients in group A did not receive any intended study treatment). 32/55 (58.2%) patients in group A and 35/57 (61.4%) in group B have died. Median overall survival (OS) was 25.6 months in group A and 21.2 months in group B (stratified HR 0.86, 95% CI 0.53–1.42). A trend of PFS and OS benefits was similarly observed for the patients with a microsatellite stable (MSS) status (PFS: 16.8 vs. 10.1 months, stratified HR 0.65, 95% CI 0.33–1.29; OS: 23.5 vs. 20.2 months, stratified HR 0.79, 95% CI 0.45–1.38). 39 (70.9%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related serious TRAEs occurred in 13 (23.6%) patients in group A and 14 (24.6%) patients in group B. Conclusions: With a follow-up duration of 31.0 months, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC patients including those with MSS status alongside a manageable safety profile. The phase 3 part of this study is currently ongoing to further evaluate serplulimab plus bevacizumab and XELOX as a first-line treatment option in mCRC. Clinical trial information: NCT04547166 .

Updated survival results of ZL-IRIAN: Irinotecan plus anlotinib or in combination with penpulimab as second-line treatment of metastatic colorectal cancer.

167 Background: The irinotecan based chemotherapy in combination with bevacizumab had become the standard second-line treatment for metastatic colorectal cancer (mCRC), but the efficacy was limited. Anlotinib, an oral anti-angiogenic tyrosine kinase inhibitor, had initially shown promising clinical effects when combined with chemotherapy in the first-line treatment of mCRC. Whether anlotinib could bring clinical benefit in the second line treatment warrants further exploration. The PD-1 antibody might have partial effects when combined with anti-angiogenic agents with or without chemotherapy in first- and third-line treatment for proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC. Our study was to explore the rationality of anlotinib plus chemotherapy or further combined with a novel anti-PD-1 IgG1 antibody—penpulimab in the second line treatment of mCRC. Methods: This study was an open label, non-randomized, multi-cohorts, phase II prospective clinical trial that included pts with pMMR/MSS mCRC who were eligible for the second-line systemic treatment. Two cohorts were established as follows: Cohort A consisted of anlotinib(10mg daily, d1-10, q2w) + irinotecan (180mg/m d6, q2w) (n = 23); Cohort B consisted of anlotinib (8mg daily, d1-10, q2w)+irinotecan (180mg/m d6, q2w) + penpulimab (200mg, d6, q2w) (n = 23). The primary endpoint was ORR. Secondary endpoints included progress free survival (PFS), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. The ORR was reported at 2024 ASCO, and PFS and OS have been updated in this report. Results: At the cutoff date on August 2024, a total of 23 Pts were enrolled in A cohort, and 23 pts were enrolled B cohort but 21 pts received at least one dose of treatment. The median PFS was 7.87 months (95% CI 5.52-10.22) in A cohort, compared to 7.4 months (95% CI 3.17-11.63) in B cohort, p=0.141. The 6-month, 12-month and 18-month PFS rates in A cohort and B cohort were 69.3% vs 80.7%, 27.5% vs 40.3% and 5.5% vs 22.4%, respectively. The median OS of A cohort was 21.73 months (95% CI 9.43-34.03), compared to 19.17 months (95% CI 11.44-26.90 months) in B cohort, p=0.987. The 12-month and 24-month OS rates in A cohort and B cohort were 64.7% vs 73.1% and 20.2% vs 54.8%, respectively. Safety profile indicated that 65.2% (15/23) and 66.7% (14/21) experienced grade≥3 adverse events in A cohort and B cohort, respectively. Common grade ≥ 3 adverse reactions (≥ 20%) mainly include hypertension (4.35% vs 14.29%), diarrhea (13.04% vs 9.52%), neutrophilopenia (39.13% vs 33.33%), and leukopenia (26.09% vs 9.52%). Conclusions: There was no statistically significant difference in overall efficacy between the two cohorts, but the long-term PFS and OS rates were higher in group B cohort, indicating that immunotherapy may bring long-term survival benefits to certain patients. Clinical trial information: NCT05229003 .

Exploratory study of TAS-102 combined with intermittent administration of fruquintinib in the treatment of third-line metastatic colorectal cancer.

174 Background: Fruquintinib and TAS-102 are two globally recognized standard therapies for mCRC patients who have previously undergone standard chemotherapy. A phase II exploratory study suggested that the combination of TAS-102 and fruquintinib could prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, the benefits are sometimes limited due to tolerability issues associated with continuous dosing. This study aimed to investigate the efficacy and safety of intermittent administration of TAS-102 combined with fruquintinib as a third-line treatment for mCRC patients. Methods: This open-label, single-arm, single-center, exploratory clinical trial enrolled mCRC patients who had failed at least two standard treatment regimens. Eligible patients received oral fruquintinib (3 mg, once daily, on days 1-5 and 8-12) and TAS-102 (35 mg/m², twice daily, on days 1-5) every two weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). Secondary endpoints included OS, PFS , DCR, and safety. Results: From August 2023 to September 2024, 26 eligible patients were enrolled. The median age of the patients was 58 years (range: 19-77), with 61.5% being female. RAS mutations were present in 57.7% of patients, 57.7% had left-sided colon or rectal cancer, 57.7% had liver metastases, and 76.9% had multiple metastases. As of September 10, 2024, 22 patients had undergone at least one tumor assessment, and 12 patients were still on treatment. Among them, 18.2% (4/22) achieved partial response , and 50% (11/22) had stable disease as the best response. Median PFS (mPFS) was 135 days (95% CI: 60.52-209.48). mPFS in RAS-mutant and RAS wild-type patients was 161 days (95% CI: 63.37-258.63) and 135 days (95% CI: 60.20-209.80), respectively, with ORRs of 25% and 12.5%. mPFS in patients with liver metastases (LM) and non-LM was 135 days (95% CI: 45.42-224.58) and 161 days (95% CI: 87.84-234.16), respectively, with ORRs of 14.3% and 25%. mPFS in patients with multiple metastases was 135 days (95% CI: 71.86-198.14), with an ORR of 17.6%. Median OS was not yet mature. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grades 3-4) included leukopenia (76.9%, 11.5%), neutropenia (73.1%, 11.5%), and anemia (53.8%, 7.7%). Non-hematological TRAEs were mostly grades 1-2, including anorexia (46.2%) and fatigue (19.2%). One case of grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusion s: These preliminary results suggest that intermittent administration of TAS-102 in combination with fruquinitinib as a third-line treatment for patients with mCRC reduces hematological toxicity and is well tolerated, with encouraging clinical results. Clinical studies are ongoing. Clinical trial information: ChiCTR2300078241 .

Meta-analysis of phase II/III randomized controlled trials (RCTs) to evaluate the incidence of hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia (PPE) syndrome in patients with gastrointestinal (GI) cancers treated with fruquintinib.

117 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 blocks the angiogenesis associated with tumor proliferation. Recently, the US FDA approved fruquintinib as a third-line treatment for metastatic colorectal cancer (mCRC). As with any other novel cancer therapies, adverse events are always a concern and all patients should be monitored in order to early detect and appropriately treat any adverse events. This meta-analysis aims to assess the risk of HFSR or PPE syndrome in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers mentioning HFSR or PPE as an adverse effect were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients, of whom 1131 (60%) received fruquintinib, from 3 phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and 1 phase II RCT were eligible for evaluation of HFSR or PPE incidence. FRESCO, FRESCO-2, and phase II trials involved patients with mCRC, they compared fruquintinib vs placebo. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, it compared fruquintinib + paclitaxel vs placebo + paclitaxel. The incidence of any-grade and high-grade HFSR or PPE was higher in the fruquintinib group compared to the placebo group, 27.93% vs 3.64% (RR, 7.64; 95% CI: 4.08-14.33; P<0.00001), and 8.5% vs 0% (RR, 26.0; 95% CI: 6.42-105.29; P<0.00001), respectively. In the mCRC subgroup analysis, the higher incidence of any-grade and high-grade HFSR or PPE in the fruquintinib arm was also statistically significant, 29.70% vs 2.55% (RR, 10.27; 95% CI: 5.59-18.88; P<0.00001), and 8.45% vs 0% (RR, 19.34; 95% CI: 3.84-97.36; P=0.0003), respectively. Conclusions: This meta-analysis revealed increased incidence of any-grade and high-grade HFSR or PPE in patients with GI cancers including mCRC treated with fruquintinib. In the FRESCO trial, this association was also shown to confer survival benefit in Chinese patients with mCRC. Prompt identification and providing proper supportive care is crucial in managing this adverse event and ultimately, preserving the patients’ quality of life.

Lysyl oxidase inhibitors in colorectal cancer progression.

The lysine oxidase (LOX) family, consisting of LOX and LOX-like-1-4 (LOXL1-LOXL4), catalyses the cross-linking reaction of collagen and elastin in the extracellular matrix (ECM). Numerous studies have demonstrated that LOX family members are dysregulated in a variety of cancers, including colorectal cancer (CRC), and play a key role in cancer cell migration, proliferation, invasion and metastasis. Targeting LOX family proteins with specific inhibitors has therefore been developed as a new therapeutic strategy for cancer. In this paper, we review the role of LOX enzymes in the development and progression of CRC. In addition, we address recent advances in the development of LOX/LOXL inhibitors, highlighting the potential use of this inhibitor as an effective and complementary treatment for CRC.

The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with colorectal cancer: A network meta-analysis.

The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer. A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS). A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib+Binimetinib+Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy+Cetuximab+Dalotuzumab (Chemo-CET-DAL), Encorafenib+Cetuximab (ENC-CET), and Panitumumab+Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy+Bevacizumab+Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy+Bevacizumab, ENC-CET, Chemotherapy+Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET. In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.