Treatment Of Metastatic Colorectal Cancer Research Articles

Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201.

Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Efficacy and safety of toripalimab with fruquintinib in the third-line treatment of refractory advanced metastatic colorectal cancer: results of a single-arm, single-center, prospective, phase II clinical study.

The most effective treatment with immune checkpoint inhibitors (ICIs) is limited to the microsatellite instability high (MSI-H) subgroup of advanced colorectal cancer. ICIs are completely ineffective in microsatellite stabilized (MSS) patients with advanced colorectal cancer. Fruquintinib, a tyrosine kinase inhibitor (TKI) domestically made in China that specifically inhibits vascular endothelial growth factor receptors, is used to treat refractory metastatic colorectal cancer (mCRC). Researches showed that anti-angiogenic therapy combined with immunotherapy induces a long-lasting antitumor immune response. Here, we aimed to evaluate antitumor efficacy and safety of fruquintinib with anti-programmed death-1 (PD-1) antibody toripalimab in Chinese patients with non-MSI-H/mismatch repair proficient (pMMR) mCRC. This was a single-arm, single-center, prospective, phase II clinical trial. A total of 19 MSS patients with refractory or advanced mCRC were enrolled They received fruquintinib (5 mg, orally, once daily for 3 weeks followed by 1 week off in 4-week cycles) and toripalimab (240 mg, intravenously administered on day 1 once every 3 weeks) until disease progression or unacceptable toxicity. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), 1-year PFS rate, disease control rate (DCR), and toxicity were reviewed and evaluated. The Cox regression model was used to analyze the influence on OS and PFS. Among the 19 patients, the median age was 52 years (range, 30-71 years); 4 patients (21.05%) achieved partial response, 10 patients (52.63%) experienced stable disease, and 4 patients (21.05%) experienced progressive disease. The ORR was 21.05%. The median PFS and OS were 5.98 months and 11.10 months, respectively. Patients with peritoneal metastasis received greater benefit from combination therapy, with a longer PFS (P=0.043) in the univariate analysis. The most common treatment-related adverse reactions were fatigue (57.89%), hepatic dysfunction (42.11%) and hypertension (36.84%). No serious adverse effects or adverse effect-related deaths were reported. Our study provides evidence supporting fruquintinib combined with an anti-PD-1 monoclonal antibody have the better effect than fruquintinib alone in the third-line setting for Chinese patients with MSS advanced colorectal cancer. Primary lesion excision and peritoneal metastasis were independent prognostic factors of PFS. Further well-designed, prospective, large-scale studies are needed to validate this outcome.

Fluoropyrimidine-induced hand-foot syndrome and cardiotoxicity: recommendations for the use of the oral fluoropyrimidine S-1 in metastatic colorectal cancer

Fluoropyrimidines (FPs) are an essential part of the majority of systemic regimens in the treatment of metastatic colorectal cancer (CRC). The use of the oral FP S-1 has been approved by the European Medicines Agency as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic CRC in whom it is not possible to continue treatment with another FP due to hand-foot syndrome (HFS) or cardiovascular toxicity (CVT). Subsequently, this indication has been included in the 2022 ESMO guidelines for metastatic CRC. Recommendations for use in daily practice are not available. Based on peer-reviewed published data on the use of S-1 in Western patients with metastatic CRC who switched from infusional 5-fluorouracil (5-FU) or capecitabine to S-1 for reasons of HFS or CVT, recommendations for its use were formulated by an international group of medical oncologists with expertise in the treatment of metastatic CRC and a cardio-oncologist. In patients who experience pain and/or functional impairment due to HFS during treatment with capecitabine or infusional 5-FU, a switch to S-1 is recommended without prior dose reduction of capecitabine/5-FU. S-1 should preferably be initiated at full dose when HFS has decreased to grade ≤1. In patients with cardiac complaints, in whom an association with capecitabine or infusional 5-FU treatment cannot be excluded, capecitabine/5-FU should be discontinued and a switch to S-1 is recommended. These recommendations should guide clinicians in daily practice in the treatment of patients with metastatic CRC with FP-containing regimens.

Living-related partial liver transplantation in unresectable liver metastatic colorectal cancer. A case report

Aim. The purpose of the article is to study the outcome of using living-related partial liver transplantation in the treatment of unresectable liver metastatic colorectal cancer. Case report. A woman, born in 1989, applied to the Medical Center Universal Clinic “Oberig” with a diagnosis of stage IV sigmoid colon cancer pT4N2M1 with synchronous liver metastases after sigmoidectomy and adjuvant chemotherapy. The patient underwent surgical intervention to the extent of right-sided hemihepatectomy with total caudate lobectomy, enucleation of metastases from the left liver lobe, cholecystectomy, extended lymphadenectomy, followed by systemic antitumor therapy. Six months later, according to laboratory and instrumental examinations, the progression of the disease was revealed in the form of new metastases development in the left liver lobe. After a thorough examination, a decision was made to treat the patient by living-related partial liver transplantation. On February 16, 2021, the patient underwent orthotopic transplantation of the left liver lobe from a living-related donor. The patient was discharged on the 31st postoperative day in a satisfactory condition. According to a control MRI after discharge, no signs of disease progression were detected. In the post-transplantation period, the patient developed an acute steroid-resistant rejection requiring antiplatelet immunoglobulin prescription. Three months after discharge, the patient was diagnosed with a high stricture of the bilio-biliary anastomosis, so resections of liver segment IV, hepaticocholedochus, and bihepaticojejunostomy on a defunctionalized Roux loop of the small intestine were performed. In the post-transplantation period, no signs of disease progression were detected, and no special antitumor treatment was used. Conclusions. Liver transplantation is an effective and radical method of treatment for patients with unresectable liver metastatic colorectal cancer.

Development of Multiplex Drop-Off Digital PCR Assays for Hotspot Mutation Detection of KRAS, NRAS, BRAF, and PIK3CA in the Plasma of Colorectal Cancer Patients

The detection of mutations in KRAS, NRAS, BRAF, and PIK3CA has become essential in managing the treatment of metastatic colorectal cancer (CRC) with the approval of new targeted therapies. We developed novel multiplex drop-off digital PCR (MDO-dPCR) assays by combining amplitude-/ratio-based multiplexing with drop-off/double drop-off strategies that allow for the detection of at least the 69 most frequent hotspot mutations in all four genes with only three reactions. We assessed the analytical performance of the assays using synthetic oligonucleotides, which were further validated on plasma cfDNA samples from a large cohort of CRC patients and compared with next-generation sequencing data. The MDO-dPCR assays showed a high sensitivity with a limit of detection ranging from 0.084% to 0.182% in mutant allelic frequency. The screening of plasma cfDNAs from 106 CRC patients identified mutations in 42.45% of them, with a sensitivity of 95.24%, a specificity of 98.53%, and an accuracy of 96.98% for mutation detection, and a strong correlation of measured mutant allelic frequencies compared with next-generation sequencing results. The high sensitivity and comprehensive mutation coverage of the MDO-dPCR assays make them suitable for rapid and cost-effective detection of KRAS, NRAS, BRAF, and PIK3CA mutations in the plasma of CRC patients, and could be useful in early response assessment and longitudinal disease monitoring.

Systemic treatment for metastatic colorectal cancer.

Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and whole-exome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of customized treatment, has resulted in tremendous breakthroughs in DNA sequencing technology in recent years. The appropriate adjuvant treatments for mCRC patients are determined by the tumor stage, presence of high-risk pathologic characteristics, microsatellite instability status, patient age, and performance status. Chemotherapy, targeted therapy, and immunotherapy are the main systemic treatments for patients with mCRC. Despite the fact that these novel treatment choices have increased overall survival for mCRC, survival remains optimal for individuals with non-metastatic disease. The molecular technologies currently being used to support our ability to practice personalized medicine; the practical aspects of applying molecular biomarkers to regular clinical practice; and the evolution of chemotherapy, targeted therapy, and immunotherapy strategies for the treatment of mCRC in the front-line setting are all reviewed here.

Systemic treatment for metastatic colorectal cancer

Systemic treatment for metastatic colorectal cancer

Skin Toxicity as a Predictor of Survival in Metastatic Colorectal Cancer Patients Treated with Anti-EGFR: Fact or Fallacy?

The primary treatment for metastatic colorectal cancer (mCRC) consists of targeted therapy and chemotherapy to improve survival. A molecular target drug with an anti-epidermal growth factor receptor (EGFR) antagonist is recommended when the RAS and BRAF genes are normal. About 50-70% of patients using anti-EGFR antagonists will experience skin reactions. Some studies have shown that severe skin reactions caused by anti-EGFR antagonists may be linked to overall survival (OS) and progression-free survival (PFS), but the results are still uncertain. These data of mCRC patients who underwent anti-EGFR therapy between October 2017 and October 2018 were analyzed retrospectively. A total of 111 patients were included in this study. The survival results showed that gender, age, body mass index, primary tumor site, and recurrence did not significantly affect OS and PFS. However, the first-line anti-EGFR inhibitor treatment was significantly associated with OS (p < 0.001) and PFS (p < 0.001). There was no significant difference in the incidence of acne between males and females in grades 1 and 2, while males have a greater risk in grades 3 and 4 than females (20.3 vs. 4.8%; p-value = 0.041). Skin toxicity was not a predictor of anti-EGFR treatment response in this investigation.

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial

BackgroundThis open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC).MethodsPatients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1–5 and days 8–12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33.ResultsOverall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99–1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55–1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%).ConclusionsFTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC.Clinical trial registrationJapicCTI-173618, jRCTs031180122.

Comparison of the efficacy and safety of fruquintinib and regorafenib in the treatment of metastatic colorectal cancer: A real-world study.

Fruquintinib and regorafenib have been approved for the third-line therapy of metastatic colorectal cancer (mCRC) in China. However, at present, there is a lack of head-to-head clinical trials on the comparison of efficacy and safety between the two drugs. The data of patients with mCRC who were treated with fruquintinib or regorafenib after the standard chemotherapy in Zhejiang Provincial People's Hospital from October 2018 to November 2021 were collected and analyzed. The primary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. The secondary endpoints were the appropriate sequence, objective remission rate (ORR) and disease control rate (DCR) of fruquintinib and regorafenib. A total of 105 patients were enrolled in this study. The ORR of fruquintinib group (n=55) and regorafenib group (n=50) were 6.1% and 2.0%; the DCR were 65.3% and 54.2%, respectively. There was no significant difference in median OS (mOS) and PFS (mPFS) between the two groups (mOS:14.2 vs12.0 months, p=0.057; mPFS:4.4 vs 3.5 months, p=0.150). Combined immunotherapy showed a synergistic effect. The mPFS and mOS of fruquintinib combined with anti-PD-1 therapy were longer than those of fruquintinib monotherapy (mPFS:5.9 vs 3.0 months, p=0.009; mOS:17.5 vs 11.3 months, p=0.008). The mOS of patients treated with regorafenib combined with anti-PD-1 therapy was 14.8 months higher than that of regorafenib monotherapy (p=0.045). When combined with anti-PD-1 therapy, the mPFS and mOS of fruquintinib was significantly longer than regorafenib (mPFS:5.9 vs 3.8 months, p=0.018; mOS:17.5 vs 14.8 months, p=0.044). In the treatment sequence, the OS of patients treated with regorafenib and then fruquintinib was significantly longer than that of the reverse treatment sequence (15.0 vs 8.3 months, p=0.019). The adverse reactions were generally similar, but the incidence of hand-foot syndrome of regorafenib was higher than that of fruquintinib, while fruquintinib was more prone to grade 3 hypertension. Fruquintinib monotherapy showed better disease control rate and objective remission rate in the post-line therapy of metastasis colorectal cancer. Notably, the combination of PD-1 immunotherapy brought the additional effect, especially in the fruquintinib combined with anti-PD-1 therapy. Patients treated with regorafenib and then fruquintinib was significantly longer than that of the reverse treatment sequence. The toxicity of fruquintinib and regorafenib are similar.

Abstract P1-03-04: Visceral fat area as a predictive factor in metastatic HER2 negative breast cancer patients treated by first line chemotherapy with weekly paclitaxel and bevacizumab

Abstract Background Obesity has previously been correlated with poorer survival in both early and metastatic breast cancer. Adipose tissues release proangiogenic factors such as Insulin-like Growth Factor and Vascular Endothelial Growth Factor that may ultimately promote tumor growth. CTscan can be used to measure the visceral fat area (VFA) and the subcutaneous fat area (SFA) on the same section. High VFA has been shown to independently predict poorer outcome in patients given first-line bevacizumab-based treatment for metastatic colorectal cancer and metastatic renal cell carcinoma. The prospective multicenter COMET trial included metastatic HER2 negative breast cancer patients receiving bevacizumab and paclitaxel as fist-line chemotherapy. This study was designed to identify and validate reliable factors to predict benefit of bevacizumab and allow for a more personalized use of this antiangiogenic agent. Our aim was to evaluate the prognostic value of BMI (Body Mass Index), VFA and SFA in the COMET cohort and their impact on the quality of life. Patients and Methods Out of the 510 patients included in the COMET trial from 9/2012 to 3/2016, 480 received bevacizumab and paclitaxel as first-line treatment and 360 had available CTscan data. VFA and SFA were measured retrospectively on the CTscans performed before chemotherapy initiation, at the level of the umbilicus with the patient in the supine position. ImageJ software was used to measure pixels with densities in the -190 HU to -30 HU range in order to delineate the subcutaneous and visceral compartments and to compute the cross-sectional area of each in cm2. These measurements were performed by a radiologist blinded to patients’ characteristics and outcomes. For VFA and SFA, we used a threshold at the median value. VFA and SFA levels were tested for their association with progression-free survival (PFS) and overall survival (OS). The impact on quality of life was based on the Global Health Status, the Physical functioning, the Emotional functioning, Fatigue and Pain scores. Results The mean age at inclusion was 57 years (range: 28-83). At initial diagnosis, the main histological type was invasive ductal carcinoma (n = 247, 80.7%). Most patients had received prior neoadjuvant/adjuvant chemotherapy (n = 245, 68.1%) and a large majority (95.4%) had less than 3 metastatic sites. One hundred and forty patients (46.7%) had histological grade II and 41% had grade III tumors. The majority of the patients had positive hormone receptor tumor (n = 238, 79.3 %) and 62 (20.7%) had triple-negative tumor subtype. The median BMI was 24.7 (range : 17-46). After a median follow-up of 60.6 months (95%CI, 60-61.3), median PFS was 9.5 months (95CI, 8.6-10.3). There was no significant correlation between BMI (p = 0.69), VFA (p = 0.24) or SFA (p = 0.58) and PFS in the univariate analysis. The median OS was 29.6 months (95CI, 25.9-32.4). BMI, VFA and SFA were not correlated with OS. Out of the 360 patients, 328 had available data regarding the quality of life. There was no impact of the VFA or the SFA on the different quality of life scores. Conclusions In our prospective cohort of 360 patients with metastatic breast cancer receiving bevacizumab and paclitaxel as first-line treatment, high VFA or high SFA were not associated with a poorer survival. VFA and SFA had no impact on quality of life. Citation Format: Séverine Guiu, Boris Guiu, Marion Chevrier, Oumar Billa, Christelle Levy, Olivier Trédan, Isabelle Desmoulins, Marc Debled, Jean-Marc Ferrero, Christelle Jouannaud, Anthony Gonçalves, Maria Rios, Marie-Ange Mouret-Reynier, Frédérique Berger, Fatima-Zohra TOUMI, Jérôme Lemonnier, Jean-Yves Pierga, Sandrine Dabakuyo, Sophie Gourgou. Visceral fat area as a predictive factor in metastatic HER2 negative breast cancer patients treated by first line chemotherapy with weekly paclitaxel and bevacizumab [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-03-04.

Middle East and North Africa Registry to Characterize Rate of RAS Testing Status in Newly Diagnosed Patients with Metastatic Colorectal Cancer.

Rat sarcoma virus mutational status guides first-line treatment in metastatic colorectal cancer. This study was a multi center, multi-country ambispective, observational study in the Middle East and North Africa assessing regional rat sarcoma virus testing practices in newly diagnosed patients. The retrospective arm (2011-2014) included adults with metastatic colorectal cancer who had initiated first-line therapy with ≥1 post-baseline visit and survival data. The prospective arm (2014-2019) enrolled newly diagnosed patients with histologically proven metastatic colorectal cancer with ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors, and tissue availability for biomarker analysis. Data look-back and follow-up were 2 years; the rate of RAS mutation was evaluated. RAS testing was ordered for patients in retrospective (326/417) and prospective (407/500) studies. In the former, testing was typically prescribed after first-line treatment initiation, significantly more in patients with stage IV disease (P < .005), resulting in the addition of targeted therapy (41.8% anti-epidermal growth factor receptor, 30.2% anti-vascular endothelial growth factor) in wild-type metastatic colorectal cancer, and significantly impacted the treatment of left-sided tumors (P = .037). In the latter, 58.4% were RAS wild-type; 41.6% were RAS mutant. Non-prescription of RAS testing was attributed to test unavailability, financial, or medical rea sons; predictors of testing prescription were older age, primary tumor in ascending colon, and high tumor grade. RAS status knowledge resulted in the addition of anti-vascular endothelial growth factor (20.4%) or anti-epidermal growth factor receptor therapy (21.2%). Before 2014, RAS testing in patients with colorectal cancer in the Middle East and North Africa was often performed after first-line treatment. Testing is more routine in newly diagnosed patients, potentially shifting early treatment patterns.

A Real-World Comparison of Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer in the United States.

Trifluridine/Tipiracil (TAS-102) and regorafenib are FDA-approved in the United States for treatment of refractory metastatic colorectal cancer (mCRC). FDA approvals of these agents were based on modest improvements in overall survival (OS) compared with best supportive care + placebo in the RECOURSE and CORRECT trials, respectively. This study compared real-world clinical outcomes with the use of these agents. A nationwide deidentified electronic health record-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least 2 lines of standard systemic therapy followed by treatment with either TAS-102 or regorafenib were included for analysis. Kaplan-Meier and propensity score-weighted proportional hazards models were used to compare survival outcomes between groups. The records of 22,078 patients with mCRC were reviewed. Of these, 1,937 patients received at least 2 lines of standard therapy followed by regorafenib and/or TAS-102. Median OS for the TAS-102 alone or prior regorafenib group (n=1,016) was 6.66 months (95% CI, 6.16-7.18 months) compared with 6.30 months (95% CI, 5.80-6.79 months) for regorafenib alone or prior to TAS-102 (n=921; P=.36). A propensity score-weighted analysis controlling for potential confounders did not demonstrate a significant difference in survival between groups (hazard ratio, 0.99; 95% CI, 0.90-1.09; P=.82). A subgroup analysis did not identify any significant differences in outcomes regarding age, performance status, tumor sidedness, microsatellite instability status, or RAS/RAF status. This analysis of real-world data found that OS was similar for patients with mCRC who were treated with TAS-102 compared with regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. A prospective trial comparing TAS-102 and regorafenib would unlikely change current management of patients with refractory mCRC.

Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments.

Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.

Baseline Cytokine Profile Identifies a Favorable Outcome in a Subgroup of Colorectal Cancer Patients Treated with Regorafenib.

Metastatic colorectal cancer is frequently associated with poor clinical conditions that may limit therapeutic options. Regorafenib is a small molecule approved for the treatment of metastatic colorectal cancer, but it is hampered by significative toxicities. Moreover, only a relatively limited number of patients benefit from the treatment. Therefore, the identification of reliable markers for response is an unmet need. Eighteen cytokines, selected based on their prevalent Th1 or Th2 effects, were collected. Peripheral blood samples were gathered at baseline in 25 metastatic colorectal cancer patients treated with regorafenib. Data extracted have been linked to progression-free survival. ROC identified the best cytokines associated with outcome. The relative value of the selected cytokines was determined by PCA. Data analysis identified 8 cytokines (TGF-β, TNF-α, CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21), used to create a signature (TGF-β, TNF-α high; CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21 low) corresponding to patients with a significantly longer progression-free survival. This report suggests that the analysis of multiple cytokines might identify a cytokine signature related to a patient's outcome that is able to recognize patients who will benefit from treatment. If confirmed, future studies, also based on different drugs, using this approach and including larger patient populations, might identify a signature allowing the a priori identification of patients to be treated.

The efficacy of capecitabine as a salvage treatment in metastatic colorectal cancer after prior 5-fluorouracil–included chemotherapies.

54 Background: We aimed to retrospectively analyze the efficacy and toxicity of capecitabine, as a salvage treatment, in metastatic colorectal cancer (mCRC) that progressed after prior standard 5FU included chemotherapies. Methods: From January 1, 2008, to December 31, 2017, patients with mCRC, age ≥ 18, who received capecitabine as third- or fourth-line treatment at five different centers in South Korea, were included. All had disease progression on prior palliative chemotherapies including 5FU, oxaliplatin, and/or irinotecan. Results: A total of 131 patients were analyzed with a median age of 62 (range, 35-87). Almost all patients were exposed to prior 5FU (100%), irinotecan (100%), and oxaliplatin (98.5%). Patients were treated with cetuximab (26.7%), or bevacizumab (45.8%) before capecitabine. The median and mean duration from the last 5FU exposure to capecitabine start were 21 and 67.3 days, respectively (range, 5-1322). The objective response rate (ORR) of capecitabine was 3.6%, and the disease control rate was 30.4%. The median progression free survival (mPFS) and median overall survival (mOS) was 2.77 (95% CI, 2.495-3.045) and 9.60 months (95% CI, 7.625-11.575), respectively. There was a significant difference in efficacy according to the duration from the last 5FU exposure to the time of starting capecitabine. Compared to patients who started capecitabine earlier than 67 days after the last 5-FU administration, those who started capecitabine later than that time showed higher ORR (11.1% vs 1.2%; p-value = 0.043), mPFS (4.430 (95% CI, 2.274-6.586) vs 2.570 months (95% CI, 2.326-2.814); p-value = 0.011), and mOS (14.070 (95% CI, 5.627-22.513) vs 9.500 months (95% CI, 7.370-11.630, p-value = 0.021) (Table). 68.7% patients experienced any grade of adverse events, but only 4.6% complained grade 3 or higher. There was no treatment related death. Conclusions: Capecitabine showed modest antitumor activity with good tolerability in mCRC patients whose disease progressed after oxaliplatin and/or irinotecan. It could be considered as an alternative treatment option for mCRC patients, especially for those who have longer treatment free interval after 5FU based chemotherapies. [Table: see text]

Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

Using a combination of fruquintinib, raltitrexed, and S-1 as a third-line treatment for metastatic colorectal cancer with co-existence of Hodgkin lymphoma: a case report.

Patients with metastatic colorectal cancer (mCRC) beyond second line treatment have a poor prognosis. Fruquintinib, regorafenib, trifluridine/tipiracil (TAS-102), panitumumab and cetuximab combined with single-agent chemotherapy regimens are currently recommended as third-line therapies for patients exhibiting disease progression. Effective late-line therapies for mCRC are urgently needed. The FRESCO randomized clinical trial (RCT) prompts fruquintinib as a third-line treatment in advanced colorectal cancer (CRC). A phase II study in our center reported the efficacy and safety of S-1 plus raltitrexed for the treatment of chemo-refractory mCRC. The combination of the fruquintinib, raltitrexed, and S-1 has not been reported in mCRC. This case report presents a patient with mCRC who received third-line treatment with fruquintinib, raltitrexed, and S-1. A 54-year-old male presenting with hematochezia was admitted to West China Hospital of Sichuan University in June 2017 and underwent surgery for a tumor between the rectum and sigmoid colon. Postoperative pathology identified adenocarcinoma (wild-type RAS/RAF, no PIK3CA mutation), and the patient was diagnosed with mCRC (pathological stage, pT3pN1apM0). The mFOLFOX6 regimen was administered. The patient was subsequently diagnosed with Hodgkin lymphoma in May 2018 and treated with the ABVD regimen after multidisciplinary discussions. Liver metastases (intestinal-type adenocarcinoma) were detected in November 2018, and second-line therapy with the FOLFIRI regimen was initiated in January 2019. Lung metastases were identified in September 2019, so the patient was treated with a combination of raltitrexed, S-1, and fruquintinib. A partial response (PR) was detected in November 2019, and the patient underwent resection of the hepatic lesion on November5, 2020. Computed tomography (CT) images in November 2021 revealed a stable disease; thus, raltitrexed was discontinued, and S-1 and fruquintinib were maintained. The treatment is still responding until the last follow-up (December 2022). The case was characterized by the simultaneous existence of mCRC and Hodgkin lymphoma, which required management by a multidisciplinary team. Third-line therapy with fruquintinib, raltitrexed, and S-1 achieved a PR that permitted surgical resection and enabled a relatively long progression-free survival. The findings suggest that the three agents regimen might be clinically effective as late-line therapy for mCRC.

A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer.

206 Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAMTM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P &lt; 0.001), and between two groups divided at the median: tumor diameter (&gt; 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P &lt; 0.001), carcinoembryonic antigen level (&gt; 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (&gt; 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.

Plasma biomarkers to predict clinical outcomes of FOLFIRI plus ramucirumab (RAM) as second-line treatment for RAS wild-type metastatic colorectal cancer: JACCRO CC-16AR.

177 Background: Angiogenesis-factors (AFs) have been reported as prognostic biomarkers for metastatic colorectal cancer (mCRC). RAS status in circulating-tumor DNA (ctDNA) is considered to be associated with resistance and potential efficacy of re-challenge treatment of anti-EGFR antibody in mCRC with RAS wild-type tumors. However, there were few evidence to prospectively evaluate the dynamic change of AFs and association of RAS status in ctDNA with clinical outcomes in anti-angiogenic therapies after anti-EGFR therapy for mCRC. Methods: Plasma samples were collected at pre-, day 15 after, and post-treatments in the pre-planned biomarker study of the JACCRO CC-16 trial which evaluated 2nd-line FOLFIRI plus RAM after anti-EGFR therapy in mCRC patients with RAS wild-type tumors (UMIN000034885). In 42 enrolled patients (median age, 68-y; ECOG PS 0/1, 31/11; all pts with left-sided tumors; median PFS, 6.8 months; median OS, 21.4 months; ORR, 10.3 %), some AFs (VEGF-A, VEGF-D, PlGF, HGF, IL-8, and angiopoietin-2) and RAS status in plasma were measured using the multiplex assay with Luminex technology and OncoBEAM RAS CRC Kit, respectively. The associations between clinical outcomes and AFs/ RAS status were investigated at timepoint of pre-treatment, using t-test and log-rank test. The median value was used as the cut-off value of AFs for high or low. The associations between AFs and RAS status were investigated using Brunner-Munzel test. Results: AFs and RAS status were evaluable in 38 and 41 patients, respectively. The OS was significantly longer in patients with IL-8 low compared to patients with IL-8 high (32.2 vs. 14.5 months, HR 0.36, p= 0.024). However, there was no difference in PFS between patients with IL-8 high and low. On the contrary, RAS mutations were detected at pre-treatment in 18 (44%) patients: KRAS codon12 83%, codon13 17%, codon61 67%, codon117 6%, codon146 11%, NRAS codon12 39%, codon61 78% in RAS mutations. Median PFS was 6.4 months in patients with RAS mutations in ctDNA, while it was 7.4 months in patients without RAS mutations (p = 0.10). Median OS was significantly longer in patients without RAS mutations compared to patients with RAS mutations (25.4 vs. 14.5 months, HR 0.39, p = 0.024). The ORR was 14.3% and 5.6% in patients without RAS mutations and with RAS mutations, respectively. In an exploratory analysis regarding the relationship between AFs and RAS status, IL-8 level was significantly higher in patients with RAS mutations than those without in ctDNA. Conclusions: This biomarker study demonstrated the associations between clinical outcomes and IL-8/ RAS status in blood before treatment in RAS wild-type mCRC treated with 2nd-line FOLFIRI plus RAM after anti-EGFR antibody therapy. Clinical trial information: UMIN000034885 .