Bevacizumab In Metastatic Colorectal Cancer Research Articles

Cachexia and efficiency of trifluridine/thymidine phosphorylase inhibitor + bevacizumab in metastatic colorectal cancer

In later-line treatment of metastatic colorectal cancer (mCRC), there may be large differences in treatment efficacy depending on cancer cachexia. Recently, the cachexia index (CXI), which was calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio, was developed to evaluate cancer cachexia. We retrospectively examined the CXI of 80 patients who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) + bevacizumab (Bmab) therapy as a later-line treatment for mCRC, and assessed the impact of cancer cachexia on chemotherapeutic efficacy using CXI. Progression-free and overall survival rates were significantly worse in the low CXI group than in the high CXI group, although there were no marked differences in tumor factors, such as the number of metastatic organs or gene mutations, between the two groups. As the cross-sectional area of the iliopsoas muscle was significantly associated with that of the skeletal muscle, the accuracy of the CXI based on the psoas mass index (P-CXI), which is easier to calculate than the SMI, in predicting treatment outcomes was equivalent to that of the CXI based on the SMI (S-CXI). Cancer cachexia is an important factor related to treatment efficacy in later-line treatments, such as FTD/TPI + Bmab therapy.

Cost-Effectiveness Analysis of Bevacizumab Biosimilars Versus Originator Bevacizumab for Metastatic Colorectal Cancer: A Comparative Study Using Real-World Data

ObjectivesMVASI (Amgen) and Zirabev (Pfizer) are 2 of the earliest bevacizumab biosimilars approved for the first-line treatment of metastatic colorectal cancer (mCRC). We aimed to confirm and quantify the real-world cost savings and cost-effectiveness of MVASI and Zirabev relative to originator bevacizumab for patients with mCRC. MethodsWe conducted a population-based, retrospective cohort study in Ontario, Canada, where originator and biosimilar bevacizumab are universally publicly funded. All mCRC patients who received originator bevacizumab between January 2008 and August 2019 or biosimilar bevacizumab between August 2019 and March 2021 were propensity score matched (1:4) to adjust for baseline differences. Total 1-year patient-level costs (CAD) and effects (life years [LY] and quality-adjusted LYs) were calculated from the public health payer’s perspective. Primary outcomes included incremental net monetary benefit and incremental net health benefit (INHB). Sensitivity analyses included a subgroup analysis by biosimilar type (MVASI/Zirabev) and a 2-year analysis. ResultsThe matched cohort included 747 biosimilar cases and 2945 comparators. Bevacizumab biosimilars were associated with an incremental cost of −$6379 (95%CI: −9417, −3537) (ie, cost saving) and incremental effect of 0.0 (95% CI: −0.02, 0.02) LY and −0.01 (95% CI: −0.03, 0) quality-adjusted LYs gained. Incremental net monetary benefit and INHB estimates were $6331 (95% CI: 6245, 6417) and 0.127 LY (95% CI: 0.125, 0.128), respectively, at a willingness-to-pay threshold of $50 000/life year gained, with all estimates indicating the cost-effectiveness of biosimilar bevacizumab. Cost-effectiveness remained consistent across biosimilar brand subgroups and 2-year sensitivity analyses. ConclusionBevacizumab biosimilars demonstrated real-world cost savings while providing similar survival benefit as originator bevacizumab, confirming the initial expectations of their implementation and supporting health system sustainability.

QUATTRO-II randomized trial: CAPOXIRI+bevacizumab vs. FOLFOXIRI+bevacizumab as first-line treatment in patients with mCRC

The QUATTRO-II trial examined the efficacy and safety of capecitabine+oxaliplatin+irinotecan (CAPOXIRI)+bevacizumab (BEV) vs. 5-fluorouracil+folinic acid+oxaliplatin+irinotecan (FOLFOXIRI)+BEV in metastatic colorectal cancer (mCRC). In this phase II study (ClinicalTrials.gov: NCT04097444; jRCTs041190072), patients were randomized (1:1) to FOLFOXIRI+BEV or CAPOXIRI+BEV. The induction treatment in the FOLFOXIRI+BEV/CAPOXIRI+BEV arms was continued for 8/6 cycles (maximum 12/8 cycles if feasible), and the maintenance treatment was 5-fluorouracil/leucovorin+BEV or capecitabine+BEV at the investigators' discretion. The primary endpoint was progression-free survival (PFS), with the two arms deemed equivalent if the hazard ratio (HR) of the point estimate was 0.80<HR<1.25. Secondary endpoints were overall response rate (ORR), overall survival (OS), incidence of adverse events (AEs), and patient-reported outcomes. Overall, 51 and 52 patients were randomized to FOLFOXIRI+BEV and CAPOXIRI+BEV, respectively. The study met itsprimary endpoint; PFS at median follow-up of 23.7 months was 10.6 months (95% confidence interval [CI], 7.7-13.3) in the FOLFOXIRI+BEV arm vs. 10.9months (95% CI, 9.3-14.3) in the CAPOXIRI+BEV arm (HR1.114 [0.80<HR<1.25], p= 0.654). In the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms, the 2-year OS rate (95% CI) was 65.5% (49.5%-77.6%) vs. 74.3% (59.8%-84.2%), and the ORR (95% CI) was 76.5% (62.5%-87.2%) vs. 84.6% (71.9%-93.1%). Major (grade ≥3) AEs in the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms were neutropenia (68.6% vs. 40.4%), febrile neutropenia (9.8% vs. 11.5%), diarrhea (7.8% vs. 17.3%), and appetite loss (7.8% vs. 17.3%). CAPOXIRI+BEV was well tolerated with reduced hematological toxicity and efficacy comparable to those of FOLFOXIRI+BEV, providing a potentially convenient first-line treatment alternative to FOLFOXIRI+BEV in patients with mCRC. Chugai Pharmaceutical Co., Ltd.

The Safety and Effectiveness of Bevacizumab in Metastatic Colorectal Cancer With Unresectable Metastases: A Real-Life Study From the South of Morocco.

Background Colorectal cancer constitutes a significant public health challenge, despite remarkable strides made in the last two decades, particularly in the medical management of metastatic stages. Notable progress has been achieved through targeted therapies such as anti-epidermal growth factor receptors or anti-angiogenic antibodies, as well as advancements in surgical approaches for hepatic metastases. This study seeks to assess the efficacy and safety of bevacizumab plus chemotherapy in individuals with metastatic colorectal cancer. Methodology This is an observational, cross-sectional, retrospective study of all patients who were followed up for metastatic colorectal cancer with unresectable metastases and were treated with bevacizumab in combination with standard chemotherapy from January 2010 until December 2019 in the medical oncology department of the Centre Hospitalier Universitaire (CHU) Souss-Massa of Agadir. Results Of the total 162 cases, 117 (72%) had metastatic disease, and 45 (28%) progressed to metastatic disease after initial treatment. The median age of the patients was 55 years (range = 23-79 years) with a sex ratio of 1.1 (M/F). The tumor was located in the left colon in 135 (83.3%)patients. The results represented adenocarcinoma in 137 (84.6)cases and mucinous subtype in 23 (14.19) cases. The three most common sites of metastasis were the liver (99, 61.1), peritoneum (67, 41.3), and lung (33, 20.3). In the first line, allpatients received bi-chemotherapy plus bevacizumab, i.e., fluorouracil, oxaliplatin, and leucovorin in 34 (20.9%) patients; capecitabine plus oxaliplatin in 88 (54.3%) patients; leucovorin, fluorouracil, and irinotecan in 17 (10.4%) patients; andcapecitabine plusirinotecan in 23 (14.1%) patients. Response after first-line treatment was progression in 74 (45.7) cases, stability in 42 (25.9) cases, partial response in 35(21.6) cases, and complete response in 11 (6.8) cases. Nine (6%) patients were able to benefit from surgical resection of metastatic lesions. Overall, 77 (47%)patients received second-line chemotherapy, i.e., 5-FU with irinotecan in 40 (51.8%)cases or with oxaliplatin in 30(38.8%) cases. Two patients developed undesirable side effects under bevacizumab (hypertension). The median progression-free survival and median overall survival of the study cohort were 9 months and 14 months, respectively. Nevertheless, patients who underwent primary tumor resection (p = 0.048), those with right‑sided tumors (p = 0.022), those who received a higher number of treatment cycles (p = 0.020), and those who received maintenance treatment (p = 0.001) had a longer median overall survival. Conclusions Chemotherapy combination with bevacizumab is considered as the cornerstone of metastatic colorectal cancer treatment in our region. With the new healthcare and social security systems, easier access to expensive treatments and molecular pathology tests is currently available. It is important to highlight that real-world data can offer valuable insights into the daily clinical practice of medical oncology.

High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer.

To improve the prognosis of patients with metastatic colorectal cancer (mCRC), investigating predictive biomarkers of their prognosis and chemotherapeutic responsiveness is necessary. This study aimed to analyze the clinical significance of serum proteinase-3 (PRTN3) as a predictor for prognosis and chemosensitivity, especially to bevacizumab therapy, in mCRC. This single-center retrospective observational study enrolled 79 patients with mCRC in our hospital and 353 patients with colorectal cancer in the TCGA database. Preoperative serum PRTN3 levels were measured using an enzyme-linked immunosorbent assay. The clinicopathological characteristics and prognosis according to serum PRTN3 levels were then evaluated. PRTN3 expression in tumor and stromal cells was evaluated immunohistochemically. The impact of PRTN3 levels on angiogenesis and bevacizumab sensitivity was evaluated using the tube formation assay. Serum PRTN3 levels were an independent poor prognostic factor for progression-free survival (PFS) (hazard ratio, 2.082; 95% confidence interval, 1.118-3.647; P=0.010) in patients with mCRC. Similarly, prognostic analysis with TCGA data sets showed poorer overall survival in patients with PRTN3 expression than that in patients without PRTN3 expression, especially in patients with stage IV. Immunohistochemical analysis of resected specimens revealed that stromal neutrophils expressed PRTN3, and their expression level was significantly correlated with serum PRTN3 levels. Interestingly, the effectiveness of first-line chemotherapy was significantly poorer in the high serum PRTN3 level group. High serum PRTN3 was significantly associated with poor PFS (hazard ratio, 3.027; 95% confidence interval, 1.175-7.793; P=0.0161) in patients treated with bevacizumab, an anti-angiogenic inhibitor. The tube formation assay revealed that PRTN3 administration notably augmented angiogenesis while simultaneously attenuating the anti-angiogenic influence exerted by bevacizumab therapy. Serum PRTN3 levels could be a novel predictive biomarker of PFS of first-line chemotherapy, especially for bevacizumab therapy, in patients with mCRC.

Gastrointestinal perforation associated with bevacizumab in metastatic colorectal cancer.

To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab. We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation. All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Impact of Cardiovascular Comorbidities on the Effectiveness and Safety of Bevacizumab in Older Patients with Metastatic Colorectal Cancer.

Cardiovascular comorbidities are not contraindications of bevacizumab for metastatic colorectal cancer. We aimed to evaluate the impact of cardiovascular comorbidities before bevacizumab treatment on overall survival and cardiovascular safety in older patients with metastatic colorectal cancer. A 2009-2015 cohort of patients with metastatic colorectal cancer aged ≥65 years administered first-line bevacizumab was extracted from the French healthcare reimbursement claims database. Baseline heart failure, hypertension, and venous/arterial thromboembolic events were identified. The 36-month overall survival rate was evaluated using the Kaplan-Meier method, and the impact of cardiovascular comorbidities on the 36-month overall survival using a time-dependent, multivariable, Cox proportional hazards model. The 36-month cumulative incidence of cardiovascular events, and the impact of cardiovascular comorbidities on the likelihood of cardiovascular events were evaluated using the Fine and Gray model, with death as a competing risk. We included 9222 patients (56.4% male; median age 73 years). Two-thirds (66.7%) had baseline cardiovascular comorbidities. The median 36-month overall survival was 20.4 [95% confidence interval (CI) 19.9-21.0] and 21.8 [95% CI 21.1-22.6] months in patients with and without cardiovascular comorbidities, respectively. Age ≥75 years, dependency in activities of daily living, radiotherapy, and another targeted therapy were identified as death risk factors, but not cardiovascular comorbidities. At 36 months, cardiovascular events had occurred in 60.2% [95% CI 58.9-61.4] and 44.1% [95% CI 42.3-45.9] of patients with and without cardiovascular comorbidities. Baseline venous thrombosis, female, three or more cardiovascular medications, another targeted therapy, and more than six bevacizumab injections were identified as risk factors for cardiovascular events. In clinical practice, cardiovascular comorbidities before administering bevacizumab to older patients with metastatic colorectal cancer impacted the cardiovascular safety, but not overall survival. Unless they limit functional independency, older patients with cardiovascular comorbidities should be treated with bevacizumab under close monitoring.

Real-world evidence of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer using an administrative claims database in Japan

Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard therapies for refractory metastatic colorectal cancer (mCRC). No results of large real-world data directly comparing FTD/TPI + bevacizumab (BEV) with FTD/TPI or REG monotherapy have been reported. We evaluated the efficacy and safety of FTD/TPI + BEV in a real-world setting. This retrospective study used a Japanese claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Eligible patients were aged 20 years and over with a diagnosis of mCRC, and received their first dose of FTD/TPI or REG from 2014 to 2021. The primary endpoint was overall survival (OS) in a propensity score matching (PSM) population in which PSM was carried out by matching using a 1 : 1 ratio for the FTD/TPI+ BEV group and the control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were carried out using the inverse probability treatment weighted (IPTW) approach and the analysis in the all eligible population. Secondary endpoints included time to treatment discontinuation (TTD), incidence of adverse events, and post-treatment. Eligible population was 2369 for the FTD/TPI+ BEV group and 9318 for the control group. The PSM population was 1787 for each group. Median OS (mOS) was longer in the FTD/TPI+ BEV group compared to the control group [17.0 versus 11.6 months, hazard ratio (HR)= 0.70, P < 0.001] in the PSM population. Similarly, mOS was longer for the FTD/TPI+ BEV group compared to that for the control group in IPTW analyses and in the all eligible population (both HRs= 0.68). Median TTD was 3.3 months for the FTD/TPI+ BEV group and 1.8 months for the control group in the PSM population (P < 0.001). Real-world data showed that FTD/TPI+ BEV was significantly associated with OS and TTD compared to FTD/TPI or REG. In clinical practice, FTD/TPI+ BEV can be a favorable regimen for refractory mCRC.

SO-22 Gut microbiome composition as predictor of the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the AtezoTRIBE study

SO-22 Gut microbiome composition as predictor of the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the AtezoTRIBE study

Gut microbiome composition as predictor of the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the AtezoTRIBE study.

3534 Background: Gut microbiome has emerged as a biomarker of clinical benefit to immune-checkpoint inhibitors (ICI) but no data are available in metastatic colorectal cancer (mCRC). The AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to FOLFOXIRI plus bevacizumab (bev) prolongs progression-free survival (PFS), but this benefit is limited for patients with proficient mismatch repair (pMMR) tumors. Here, we aimed at investigating the potential predictive role of microbiome in identifying mCRC patients able to achieve benefit from ICI. Methods: AtezoTRIBE was a phase II trial in which 218 mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (arm A) or FOLFOXIRI/bev/atezo (arm B). Stools were prospectively collected. Metagenomic (MG) data from whole genome sequencing (WGS) at level of species genome bins (SGBs) were analysed by linear models corrected for clinical and tumor-related parameters and fold-ratios. We defined as responders (R) those patients who experienced a PFS ≥ 12 months. Results: Stool samples were collected at baseline for 171 (78%) patients (55 in arm A and 116 in arm B) but only 163 were available for MG. Patients with deficient MMR (dMMR) tumors (N = 10) showed significantly lower MG diversity than pMMR ones (N = 148) harboring oral bacteria and pathobionts whose intrinsic immunogenicity has not been demonstrated. Regarding pMMR mCRC patients, baseline microbiome composition was not significantly different according to the treatment arm. The microbiome diversity was not significantly different between R and not-R in both arms, but specific immunogenic SGBs (Lachnospiraceae family members) were over-represented in R treated in arm B. Veillonellaceae and pathobionts were associated with poor prognosis and/or differential benefit from the addition of atezo. Fusobacterium nucleatum was associated with a poor prognosis, also in arm B. Conclusions: This is the largest prospective analysis showing that SGBs may be useful as a biomarker of potential benefit or detrimental effect from atezo in pMMR mCRC patients. Our results prompt the design of microbiota-centered diagnostic tests to identify pMMR mCRC patients more likely to benefit from ICI-based therapeutic strategies. Clinical trial information: NCT03721653 .

A Systematic Review and Meta-Analysis of Trifluridine/Tipiracil plus Bevacizumab for the Treatment of Metastatic Colorectal Cancer: Evidence from Real-World Series.

Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials. A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected. Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination. The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.

Real-world effectiveness and safety of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer: A retrospective observational study using an administrative database.

44 Background: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard of care for refractory metastatic colorectal cancer (mCRC). Several phase II trials of FTD/TPI plus bevacizumab (BEV) have been conducted, showing promising efficacy with manageable safety, and it is widely used for patients with refractory mCRC in Japan. No result has been reported for large-scale real-world data directly comparing FTD/TPI plus BEV with FTD/TPI or REG monotherapy. Here, we evaluated the efficacy and safety of FTD/TPI plus BEV in real-world clinical practice. Methods: We used a nationwide claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan) in Japan. Eligible patients were aged 20 years or older in mCRC who received their first dose of FTD/TPI or REG between May 2014 and January 2021. The primary outcome was overall survival (OS) in a propensity score matching (PSM) population that was performed matching using a 1:1 ratio for FTD/TPI plus BEV and control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were performed using the inverse probability treatment weighted (IPTW) approach and the analysis in all eligible population. Main secondary outcomes were OS for subgroups, time to treatment discontinuation (TTD), adverse events (assessed in all eligible population), and post-treatment. Results: The eligible population was 2,369 for FTD/TPI plus BEV and 9,318 for control group (FTD/TPI: 6,500 and REG: 2,818). The PSM population was 1,787 for FTD/TPI plus BEV and 1,787 for control group (FTD/TPI: 1,252 and REG: 535). Median OS (mOS) was 17.0 months for FTD/TPI plus BEV and 11.6 months for control group (HR: 0.70; 95% CI: 0.63–0.78; P &lt; 0.001) in PSM population. Similarly, mOS was longer for FTD/TPI plus BEV compared to that for control group in IPTW analyses (HR: 0.68; 95% CI: 0.65–0.71; P &lt; 0.001) and in all eligible population (HR: 0.68; 95% CI: 0.63–0.73; P &lt; 0.001). In all eligible population, mOS were 17.6 months for FTD/TPI plus BEV and 12.6 months for control group (FTD/TPI: 12.9 months and REG: 12.1 months). Median TTD was 101 days for FTD/TPI plus BEV and 56 days for control group in PSM population (Wilcoxon rank-sum test P &lt; 0.001). The incidence of hand-foot syndrome was significantly higher in REG compared with that in FTD/TPI plus BEV (Fisher's Exact test P &lt; 0.001. Leukopenia incidence was significantly higher in FTD/TPI plus BEV than that in REG (Fisher's Exact test P &lt; 0.001. Granulocyte colony-stimulating factor was administered to 20.6%, 16.5%, and 1.1% of patients in FTD/TPI plus BEV, FTD/TPI, and REG, respectively. Conclusions: The real-world data showed that FTD/TPI plus BEV had significantly longer OS and TTD than FTD/TPI or REG in mCRC. Thus, FTD/TPI plus BEV may be a favorable regimen for refractory mCRC in clinical practice.

Use of FOLFOXIRI plus bevacizumab in metastatic colorectal cancer (mCRC): An age-stratified analysis.

64 Background: As the incidence of early-onset mCRC continues to rise, evidence is emerging for the use of more aggressive treatment in the front-line setting in patients aged &lt; 50 years (yrs). Although the superior efficacy of the multiagent chemotherapy FOLFOXIRI+bevacizumab (triplet+bev) over doublet regimens (FOLFOX or FOLFIRI+bev) is well documented, it is commonly associated with increased toxicity. Contemporary data are needed on triplet+bev use by age group in the US, which may help tailor treatment in patients with early-onset mCRC. Methods: This was a retrospective, observational cohort study using Optum Oncology Electronic Health Records data between 2010 and 2021. Use of triplet+bev and subsequent treatments were reported by age group (18–49, 50–64, ≥65 yrs) among newly diagnosed patients with mCRC. Baseline demographic and clinical characteristics data for patients receiving triplet+bev and regorafenib as a subsequent treatment were collected. Results: Among 36,053 eligible patients with mCRC diagnosed between 2010 and 2021, 13.8% were aged 18–49 yrs, 36.4% 50–64 yrs, and 49.8% ≥65 yrs at the time of diagnosis. The proportion of patients receiving triplet+bev was higher in age groups 18–49 yrs (4.0%) and 50–64 yrs (3.4%) vs ≥65 yrs (1.5%). Between 2010 and 2020, the proportion of patients receiving triplet+bev changed from 1.5% to 4.2% in age group 18–49 yrs, from 3.1% to 2.6% in 50–64 yrs, and from 1.1% to 1.2% in ≥65 yrs. Over a median 20-month follow-up period, 58.0% of patients in age groups 18–49 and 50–64 yrs, and 53.7% of patients in age group ≥65 yrs, received a new treatment after triplet+bev. In the overall cohort, the most common new treatment after triplet+bev was regorafenib (20.7%), received by 18.2% of patients in age group 18–49 yrs, 22.7% in 50–64 yrs, and 19.2% in ≥65 yrs. Other new subsequent treatments in the overall cohort included trifluridine/tipiracil (17.1%) and cetuximab (16.3%), with a similar trend seen among all age groups. Across age groups, triplet+bev recipients were more likely to be male, obese, resident in the Midwest or Northeast, and have distant metastases, and less likely to have colorectal surgical resection prior to mCRC diagnosis. Patients in age group 18–49 yrs subsequently receiving regorafenib were more likely to be obese and less likely to have Charlson Comorbidity Index ≥3, distant metastases, and colorectal surgical resection before mCRC diagnosis vs those who did not receive regorafenib. Conclusions: Our study shows that, recently, triplet+bev use has increased in patients with mCRC, particularly in those aged &lt; 50 yrs. Chemotherapy-free treatments may be an option for these patients beyond the first-line setting. While regorafenib is typically used in third or later lines, these real-world data suggest it is often a preferred option following triplet+bev treatment.

Trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer: results of a systematic review and meta-analysis.

Trifluridine/tipiracil plus bevacizumab (FTD/TPI + BEV) has shown efficacy and tolerability in refractory metastatic colorectal cancer (mCRC). Because randomized controlled trial (RCT) data comparing FTD/TPI + BEV with FTD/TPI are lacking, this meta-analysis evaluated outcomes with both regimens. Electronic databases, congress proceedings (past 3 years), trial registries, systematic review bibliographies, gray literature, and guidelines through June 2021 were searched for RCTs, non-RCTs, and prospective observational studies involving >20 previously treated patients with mCRC receiving FTD/TPI + BEV or FTD/TPI. Absolute and relative disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse event (AE) rates, and discontinuation rates due to AEs were evaluated using fixed-effects and random-effects models. Study quality, heterogeneity, and publication bias were assessed. In all, 29 of 875 screened publications were selected (26 studies: 5 RCTs, 11 non-RCTs, and 10 prospective observational studies). One RCT compared FTD/TPI + BEV with FTD/TPI. FTD/TPI + BEV versus FTD/TPI had a higher absolute DCR [64% (6 studies; n = 289) versus 43% (10 studies; n = 2809)], median PFS [4.2 (5 studies; n = 244) versus 2.6 (6 studies; n = 1781) months], 12-month PFS [9% (5 studies; n = 244) versus 3% (6 studies; n = 1781)], median OS [9.8 (5 studies; n = 244) versus 8.1 (6 studies; n = 1814) months], and 12-month OS [38% (5 studies; n = 244) versus 32% (6 studies; n = 1814)]. Grade ⩾3 febrile neutropenia, asthenia/fatigue, diarrhea, nausea, and vomiting rates were similar (1%-7%). Grade ⩾3 neutropenia rate was higher with FTD/TPI + BEV than with FTD/TPI [43% (6 studies; n = 294) versus 29% (12 studies; n = 7139)]. Discontinuation rates due to AEs were similar [8% (5 studies; n = 244) and 7% (10 studies; n = 3724)]. Low study quality, heterogeneity, and/or publication bias were detected in certain instances. Despite fewer patients treated with the combination, this meta-analysis consistently suggested that FTD/TPI + BEV provides benefits over FTD/TPI in refractory mCRC and has similar safety, except for more frequent grade ⩾3 neutropenia.

Real-world utilization and acceptance of biosimilar bevacizumab in metastatic colorectal cancer in India

Background: To describe the patient characteristics and usage pattern of biosimilar bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in India.Methods: This real-world, retrospective analysis included adult patients receiving biosimilar bevacizumab between April 2021 and March 2022.Results: A total of 1125 patients with mCRC who received biosimilar bevacizumab-based chemotherapy were included. The mean age at diagnosis was 57.8 years. Majority of the patients were males (71%) and belonged to the age groups of 41-76 years. The primary tumor site was right colon (52.6%) followed by left colon (29.2%) and rectum (17.3%), and tumor grade was reported as high in most (88.7%) of the patients. Majority of the patients received biosimilar bevacizumab-based chemotherapy as first-line therapy (61.3%), followed by second-line (31.9%) and third-line therapy (6.8%). In combination with biosimilar bevacizumab, FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) was the most commonly administered chemotherapy regimen (42.9%), followed by CAPOX (capecitabine and oxaliplatin, 26.5%) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan, 22.8%).Conclusions: Biosimilar bevacizumab-based chemotherapy is being widely used in real‑world clinical setting in India for the management of patients with mCRC.

An immune-related gene expression profile to predict the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the phase II randomized AtezoTRIBE study.

3581 Background: The phase II randomized AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to first-line FOLFOXIRI plus bevacizumab (bev) prolongs PFS of mCRC patients, but benefit is limited among patients with proficient mismatch repair (pMMR) tumours. Among these patients, identifying a subgroup able to achieve benefit from immune-checkpoint inhibitors is a crucial challenge of translational research. To this end, we investigated the potential predictive role of an immunomodulatory gene expression signature (IO score), measuring the presence of infiltrating inflammatory cells and differentiated stromal microenvironment. Methods: AtezoTRIBE was a phase II comparative trial in which mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (control arm) or FOLFOXIRI/bev/atezo (experimental arm). RNA was obtained from FFPE blocks of tumour specimens collected at baseline from 142 (65%) out of 218 enrolled patients. RT-qPCR was performed using DetermaIO™, to assess mRNA expression of a targeted panel of 27 genes. The established pan-cancer IO score and threshold were applied to dichotomize tumours as IO-positive (IO+) or IO-negative (IO-). Results: IO score was successfully determined in 122 (86%) cases, and 33 tumours were defined as IO+ (27%). No differences in terms of baseline clinical and molecular features were observed between IO+ and IO- tumours. Patients with IO+ and IO- tumours showed similar PFS (median PFS: 14.4 vs 13.6; HR 0.84 [95%CI: 0.53-1.33], p = 0.468). An interaction between IO status and treatment effect was reported (p for interaction = 0.066), with higher PFS benefit in favour of the experimental arm among patients with IO+ tumours (HR 0.39 [95% CI:0.15-1.02]) than among those with IO- tumours (HR 0.83 [95% CI 0.50-1.35]). A similar trend was observed in the pMMR subgroup (n = 110) (IO+ tumours: HR for PFS 0.47 [95% CI 0.18-1.25]; IO- tumours: HR for PFS 0.93 [95% CI 0.56-1.55]) (p for interaction = 0.139). No differences in terms of ORR were reported between arms according to the IO status. Conclusions: The investigated immunomodulatory signature (IO score) may be helpful to predict benefit from the addition of atezolizumab to first-line FOLFOXIRI/bev in metastatic colorectal cancer, also in the cohort of pMMR tumours. Our results support the hypothesis that a deeper characterization of tumour immune microenvironment may help identifying mCRC patients more likely to benefit from ICI-based therapeutic strategies. These findings are worthy of further investigation in independent cohorts.

Real-world experience on the efficacy and tolerability of biweekly trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer.

3584 Background: Trifluridine/tipiracil (TAS-102) is currently approved as third-line treatment in metastatic colorectal cancer (mCRC). However, there is paucity of real-world data on the tolerability and efficacy with biweekly dosing as monotherapy or in combination with bevacizumab. In this study, we present our center’s experience with biweekly TAS-102 with or without bevacizumab in mCRC patients (pts). Methods: We performed a single center retrospective observational study of pts receiving TAS-102 between 2018 and 2021. Results: A total of 83 pts were included (53 men, 30 women), with a median age of 64 years. Majority of pts were treated with TAS-102 in the 3rd-line (48.2%) and 4th-line (28.9%) setting. Almost all (94.0%) were of ECOG ≤ 1 at the initiation of treatment. The mean number of cycles administered was 3.8 and bevacizumab (5mg/kg on Day 1, every 2 weeks) was used in combination with TAS-102 in 18 pts (21.7%). Majority of pts (84.3%) were given TAS-102 using the biweekly regimen (35mg/m2 BD, on Day 1-5 and 15-19, q28 days) rather than standard regimen (35mg/m2 BD, on Day 1-5 and 8-12, q28 days) following a change in institutional practice. Fifteen pts (18.1%) had their initial dose reduced to 30mg/m2 BD at prescriber's discretion. Median PFS and OS were 2.37 and 10.15 months, respectively. In terms of tolerability, fatigue (any grade, 42.2%) and neutropenia (any grade, 44.6%) were the two most common adverse events reported. Grade 3 or higher neutropenia and febrile neutropenia were 16.9% and 3.6%, respectively. Dose reduction during treatment was required in 15 pts (18.1%), dose delay in 31 pts (37.3%) and six pts (7.2%) discontinued treatment due to toxicity. More than half (54.2%) had at least an additional line of therapy (regorafenib, clinical trials or re-challenge previous chemotherapy agents) following disease progression with TAS-102. Conclusions: We report the largest real-world experience with biweekly TAS-102. Our pts treated with TAS-102 had comparable median PFS to the RECOURSE cohort but with significantly better OS as more than half continued to receive treatment. Biweekly dosing of TAS-102 with or without bevacizumab is well tolerated with significantly lower rates of Grade 3 neutropenia compared to the published data in the literature.

Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study

BackgroundAn optimal treatment strategy using oxaliplatin and bevacizumab for metastatic colorectal cancer has not been defined. We investigated whether the sequential treatment using fluoropyrimidines with bevacizumab followed by the addition of oxaliplatin at first progression was better than a combination treatment using fluoropyrimidines and oxaliplatin with bevacizumab. MethodsIn the sequential treatment, the escalation from fluoropyrimidines plus bevacizumab to fluoropyrimidines plus oxaliplatin with bevacizumab was recommended in case of progressive disease. Time to failure of strategy was the primary end-point, whereas the secondary end-points were overall survival, progression-free survival, overall response rate and safety. ResultsThree hundred patients with previously untreated metastatic colorectal cancer were randomised to receive either the sequential treatment (n = 151) or the combination treatment (n = 149). The sequential treatment was superior to the combination treatment about time to failure of strategy (15.2 months; 95% CI, 12.5–17.2 months vs. 7.8 months: 95% CI, 6.3–9.5 months; P < 0.001). However, the median overall survival was 27.5 (95% CI, 24.4 to 32.7) months in the sequential treatment and 27.0 (95% CI, 22.8 to 36.0) months in the combination treatment (hazard ratio, 0.92; 95% CI, 0.66 to 1.28; P = 0.61). The overall response rate was 33.1% in the sequential treatment arm and 51.7% in the combination treatment. ConclusionsThe findings support the extension of the sequential treatment starting from fluoropyrimidine plus bevacizumab to selected patients who do not need an objective response to the threatening disease.

Predictive value of vascular endothelial growth factor polymorphisms for maintenance bevacizumab efficacy in metastatic colorectal cancer: an ancillary study of the PRODIGE 9 phase III trial.

Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. We evaluated the impact of SNPs of VEGF-A, VEGF receptors (VEGFR-1, VEGFR-2), and hypoxia inducible factor-1α (HIF-1α) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype (n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7-17.1)] (p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1-42.8) versus 22.5 (95% CI: 18.6-24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2-11.3) versus 9.2 (95% CI: 8.71-10.1)], and duration of the first CFI [4.6 (95% CI: 1.6-13.3) versus 4.14 (95% CI: 0.5-29.0) months, p = 0.3]. Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.