scholarly journals PD-L1 Expression on Circulating Tumour Cells May Be Predictive of Response to Regorafenib in Patients Diagnosed with Chemorefractory Metastatic Colorectal Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6907
Author(s):  
Lucrezia Raimondi ◽  
Filippo Maria Raimondi ◽  
Laura Di Benedetto ◽  
Giuseppe Cimino ◽  
Gian Paolo Spinelli
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tyrosine Kinases ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Tumour Cells ◽  
Circulating Tumour Cells ◽  
Multikinase Inhibitor ◽  
The Third ◽  
Third Line

Regorafenib, targeting a broad range of receptor tyrosine kinases (RTKs), is an oral multikinase inhibitor which improves the progression-free survival (PFS) and overall survival (OS) of patients diagnosed with chemorefractory metastatic colorectal cancer (mCRC), making an immunosuppressive tumour microenvironment. The correlation between PD-1/PD-L1 expression and RTKs inhibition has been studied in several tumour types but has not been analyzed extensively in mCRC in the era of regorafenib. In this study, using liquid biopsy, we evaluated the opportunity to reveal if PD-L1 expression on circulating tumour cells (CTCs) could serve as a predictive biomarker of response and clinical benefit in patients treated with regorafenib as the third line of treatment. We analyzed a cohort of forty chemorefractory metastatic colorectal cancer patients, of whom twenty-six KRAS mutated, treated with regorafenib, all as the third line of treatment. Blood samples were collected from patients prior to treatment and longitudinally four and eight weeks after initiation of therapy. CTCs were identified using multiparametric flow cytometry; therefore, PD-L1 expression was evaluated. Objective responses were defined following the RECIST criteria v.1.1. Moreover, focusing on peripheral blood biomarkers, we found that high platelet-to-lymphocyte ratio (PLR) was an independent prognostic indicator of poor OS. For the first time, our study showed the usefulness of sequential assessments of CTCs as a non-invasive real-time biopsy to evaluate PD-L1 expression in patients diagnosed with mCRC and treated with regorafenib. Our analysis suggests that by assessing PD-L1 expression on CTCs, we could predict who will benefit from regorafenib, offering highly individualized treatment plans.

scholarly journals Therapeutic Targeting of the Tumour Microenvironment in Metastatic Colorectal Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 2067
Author(s):  
Rhynelle S. Dmello ◽  
Sarah Q. To ◽  
Ashwini L. Chand
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Liver Metastasis ◽  
Metastatic Colorectal Cancer ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Cellular Interactions ◽  
Circulating Tumour Cells ◽  
Therapeutic Targeting ◽  
Colorectal Cancer Patients

Liver metastasis is the primary contributor to the death of patients with colorectal cancer. Despite the overall success of current treatments including targeted therapy, chemotherapy, and immunotherapy combinations in colorectal cancer patients, the prognosis of patients with liver metastasis remains poor. Recent studies have highlighted the importance of the tumour microenvironment and the crosstalk within that determines the fate of circulating tumour cells in distant organs. Understanding the interactions between liver resident cells and tumour cells colonising the liver opens new therapeutic windows for the successful treatment of metastatic colorectal cancer. Here we discuss critical cellular interactions within the tumour microenvironment in primary tumours and in liver metastases that highlight potential therapeutic targets. We also discuss recent therapeutic advances for the treatment of metastatic colorectal cancer.

Tumor bulk as a prognostic biomarker and predictor of benefit from anti-EGFR therapy in patients with metastatic colorectal cancer: Analysis of 476 patients from the ARCAD Clinical Trials Program.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 108-108
Author(s):  
Benjamin Adam Weinberg ◽  
Manel Rakez ◽  
Benoist Chibaudel ◽  
Tim Maughan ◽  
Richard Adams ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Performance Status ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Wild Type ◽  
Cox Models ◽  
Study Results

108 Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]

scholarly journals The combination of TAS-102 and bevacizumab as the third line chemotherapy for metastatic colorectal cancer (TAS-CC3 Study)

2018 ◽  
Vol 29 ◽  
pp. viii157
Author(s):  
H. Kamiyama ◽  
Y. Yoshida ◽  
H. Yoshida ◽  
C. Kosugi ◽  
K. Ishibashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
The Third ◽  
Third Line ◽  
Line Chemotherapy

scholarly journals Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Wei Yu ◽  
Qiaomeng Tao ◽  
Yufeng Zhang ◽  
Fengming Yi ◽  
Long Feng
Keyword(s):  
Colorectal Cancer ◽  
Adverse Reactions ◽  
Advanced Colorectal Cancer ◽  
Cox Regression ◽  
Combined Therapy ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Free Survival ◽  
The Third ◽  
Third Line

Background. The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. Methods. We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan–Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). Results. The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0–272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment ( p = 0.005 ). Lung metastasis was a negative factor in combined therapy ( p = 0.032 ). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy ( p = 0.034 ). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 ( p = 0.034 ). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. Conclusions. Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy.

scholarly journals Practical considerations in the use of regorafenib in metastatic colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592095686
Author(s):  
Fotios Loupakis ◽  
Lorenzo Antonuzzo ◽  
Jean-Baptiste Bachet ◽  
Feng-Che Kuan ◽  
Teresa Macarulla ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Metastatic Colorectal Cancer ◽  
Treatment Options ◽  
Daily Practice ◽  
The Third ◽  
Appropriate Treatment ◽  
Third Line ◽  
Line Setting ◽  
Physician Patient

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.

scholarly journals Aflibercept in the Treatment of Metastatic Colorectal Cancer

2012 ◽  
Vol 6 ◽  
pp. CMO.S7432 ◽  
Author(s):  
Tzu-Fei Wang ◽  
Albert Craig Lockhart
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
The Third ◽  
Common Cancer ◽  
The Us

Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept.

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