Treatment Of Metastatic Colorectal Cancer Research Articles

Vascular endothelial growth factor pathway’s influence on bevacizumab efficacy in metastatic colorectal cancer treatment

Vascular endothelial growth factor pathway’s influence on bevacizumab efficacy in metastatic colorectal cancer treatment

Efficacy and safety of regorafenib for the treatment of metastatic colorectal cancer in routine clinical practice: results from a Spanish hospital

IntroductionRegorafenib is indicated as treatment in third-line and beyond in patients with metastatic colorectal cancer.Methods This is a retrospective study of a cohort of patients with mCRC treated with regorafenib in Hospital Universitario Ramón y Cajal, in Madrid, Spain.ResultsWith the aim to assess the efficacy and safety of regorafenib, 91 patients treated between 2013 and 2023 were included. Only 1.1% of patients achieved disease control. Median progression free survival was 2.40 months and median overall survival was 4.76 months. The most frequent adverse events were fatigue and hand-foot skin reaction (59.34% and 28.57%, respectively).DiscussionOur results confirm the safety of regorafenib as treatment of mCRC in real clinical practice. Although our population is less pretreated than in the CORRECT trial, our disease control rate was inferior. This difference may be due to a worse baseline status and a high percentage of hepatic disease showed in our patients.

Comparison of efficacy and safety of regorafenib and anti-EGFR targeted therapy in metastatic colorectal cancer: A retrospective study

Aim. To compare the efficacy of regorafenib and the combination of chemotherapy (CT) with anti-EGFR (cetuximab/panitumumab) in the third-line treatment of metastatic colorectal cancer (mCRC). Materials and methods. A retrospective analysis of a prospective database of patients with mCRC from two clinics in the Russian Federation was conducted. Overall survival was considered the primary efficacy criterion. Additional criteria were progression-free survival (PFS), objective effect (OE), and incidence of toxicity. No statistical hypothesis was assumed. Statistical analysis was performed using SPSS (IBM SPPS Statistics v. 20). Results. The database identified 51 patients with morphologically confirmed left-sided mCRC with wild-type RAS and BRAF genes who received more than two lines of antitumor drug therapy from 2010 to 2021, one of which included anti-EGFR antibodies in the third and subsequent lines of treatment. Thirty patients who received regorafenib in the third line and 21 patients who received CT in combination with anti-EGFR in the third line were selected, of which 7 patients had a history of anti-EGFR use, and 14 patients received anti-EGFR for the first time. The median overall survival from the third line initiation date in the CT group in combination with anti-EGFR was numerically higher (21 months, CI 9.0–32.9 months) than in the regorafenib group (10 months, CI 2.4–17.5 months); p=0.1 by log-rank test (Mantel–Cox test); p=0.2 by Breslow–Wilcoxon test; p=0.3 (Tarone–Ware test). PFS was also higher in the anti-EGFR CT group (6 months, CI 3.8–8.2 months) than in the regorafenib group (3 months, CI 1.2–4.7 months); p=0.05 according to Breslow–Wilcoxon test. OE of third-line therapy was reported in 57.1% (n=12) of patients in the CT with anti-EGFR group and significantly less often in the regorafenib group – 10.3% (n=3) of patients (p=0.001). The toxicity of drug therapy of all grades in the regorafenib group was reported in 86.2% (n=25) of patients, while in the CT anti-EGFR group, it was significantly less common – in 52.4% (n=11) of patients (p=0.01). Conclusion. Compared with regorafenib, combining CT with anti-EGFR agents in the third-line treatment of patients with left-sided mCRC with wild-type RAS and BRAF genes is associated with better PFS and the frequency of OE with significantly less toxicity.

Impact of renal impairment on early development of severe neutropenia with trifluridine/tipiracil treatment for metastatic colorectal cancer.

Trifluridine/tipiracil (FTD/TPI) with or without bevacizumab is an effective treatment for metastatic colorectal cancer (mCRC). As this agent is mainly excreted via the kidney, we aimed to evaluate the impact of renal impairment (RI) on the early development of severe neutropenia, a dose-limiting toxicity and whose development reflects better treatment outcomes, in patients with mCRC treated with FTD/TPI. Patients with mCRC receiving FTD/TPI ± bevacizumab (n = 100) were divided into the RI group (creatinine clearance [CCr] < 90 mL/min) or control group (CCr ≥ 90 mL/min), and retrospectively evaluated. Severe neutropenia during the first two cycles occurred in 57.6% and 34.2% of patients in the RI and control groups, respectively, which was significantly different (P = 0.03) and met our primary endpoint. Furthermore, the incidence during the first cycle also differed significantly (52.5% in the RI group and 17.1% in the control group, P = 0.0004). Multivariate logistic regression analysis suggested that baseline RI and neutropenia were significant risk factors for early severe neutropenia (adjusted odds ratio and 95% confidence interval: 3.07, 1.24-7.59, P = 0.02 for RI, and 9.76, 1.08-88.11, P = 0.04 for neutropenia). In conclusion, our study suggested that patients with RI can exhibit early severe neutropenia during real-world FTD/TPI treatment for mCRC.

New Insights into Colorectal Cancer through the Lens of Precision Oncology and Personalized Medicine: Multi-Omics Helps Aging of Predisposed People.

Recently, there has been a significant evolution in our understanding of the molecular pathways causing the genesis and progression of cancer via the inter-individual variations. Thus, one-size-fits-all methods for cancer treatment have been replaced by precision oncology (PO) targeting individual cancer symptoms, offering increased effectiveness, and decreased safety concerns and cost load. The identification of novel actionable indications, rapid, precise, and comprehensive detection of complex phenotypes in every individual, pioneering clinical trial projects with enhanced response feedback, and widespread availability of innovative targeted anticancer management for every patient are vital for the effective implementation of next-generation precision oncology. Additionally, the emergence of precision medicine has altered the perspective of oncologic biomarkers, drug discovery, drug development, and, improvements for cancer patients. This paper narratively reviewed to identify actionable abnormalities, Genomic profiling of tumors employing clinical next-generation sequencing (NGS) from both tumor tissues and liquid biopsies along with the multi-omics strategies as the key component of PO. Our increasing information on tumor biology, specifically microenvironment and heterogeneity- associated data, would improve our understanding of the resistance of targeted drugs and specific mechanisms of action, as well as help enhance existing metastatic colorectal cancer (mCRC) treatment strategies. Collectively, this paper indicated the current and innovative strategies for prognosis, diagnosis, and treatment of various cancer types based on PO overview with a groundbreaking emphasis on CRC suggesting the integrations of multi-omics, highlighting Genomics, and utilizing AL and ML algorithms with targeted therapies. Notably, these findings can help improve the life-span and ageing of the predisposed people.

Efficacy and Safety of KH903 Plus FOLFIRI as A Second-line Treatment In Unresectable Recurrent or Metastatic Colorectal Cancer: A Randomized Phase 2 Study

BackgroundPatients with recurrent or metastatic advanced colorectal cancer (mCRC) often face the clinical dilemma as this unresectable disease is continuously progressing and endangering the patients’ lives. In the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. MethodsPatients (N=122) were randomized 1:1 to 4mg/kg q1w KH903 or 5mg/kg q2w KH903, and both groups of patients were treated with the fixed regimen of FOLFIRI (every 2 weeks) along with the KH903 therapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were Overall Survival (OS), objective response rate (ORR), and disease control rate (DCR). ResultsAs of December 30, 2020, median (m)PFS was 5.68 months (95% CI,4.67-7.13) with 4mg/kg q1w vs. 5.19 months (95% CI, 4.04, 5.78) with 5mg/kg q2w (HR, 0.76; 95% CI, 0.50-1.16),and mOS was 13.14 months (95% CI, 10.61-19.52) vs. 16.03 months (95% CI, 10.28- NE), respectively (HR, 1.11; 95% CI, 0.65-1.89), The ORR was 15.9% and 11.9% for both groups, respectively, and The DCR for both groups was 85.7% and 83.1%, respectively. Grade 3 or higher treatment-related adverse event rates for both groups were 68.3% vs.52.5%, respectively. ConclusionsKH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents (Avastin®, ZALTRAP®, Cyramza®) and no new safety signals were observed. Micro AbstractIn the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. We demonstrated that KH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents. It was suggested that KH903 in combination with FOLFIRI has shown further clinical development value, and its efficacy and safety can be further confirmed in later clinical trials, providing more options for second-line treatment of metastatic colorectal cancer patients.

Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.

This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC). This multicenter, open-label, single-arm study enrolled patients with KRAS-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC. Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis. Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).

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.

Clinical risk factors of bevacizumab-related hypertension in patients with metastatic colorectal cancer: a retrospective study.

Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, is widely used as a first-line treatment for metastatic colorectal cancer (mCRC), with hypertension being a common adverse effect. However, there is limited data on the predisposing factors contributing to bevacizumab-induced blood pressure (BP) elevation. This study aims to identify clinical risk factors associated with bevacizumab-related hypertension in patients with mCRC. This retrospective study included 178 patients treated between January and June 2020. Demographic data and medical histories were extracted from hospital electronic medical records. Among the 178 patients, 54 (30.3%) developed bevacizumab-related hypertension, with a median onset time of 48days. Univariate and multivariate analyses identified pre-existing hypertension [odds ratio (OR), 3.30; 95% confidence interval (CI), 1.56-6.99] and age ≥60years (OR, 2.04; 95% CI, 1.00-4.17) as independent risk factors for bevacizumab-related hypertension. The area under the receiver operating characteristic (ROC) curve was 0.66 (95% CI, 0.57-0.75, P < 0.001). The median overall survival (OS) for the cohort was 30.53months (95% CI, 22.23-38.84). No significant differences in OS were observed between patients with and without bevacizumab-related hypertension (31.13 vs. 27.87months, P = 0.86). Pre-existing hypertension and age ≥60years are significant clinical risk factors for bevacizumab-related hypertension in mCRC patients. Bevacizumab-related hypertension did not affect overall survival. Clinicians should closely monitor BP within the first 2months of bevacizumab treatment in high-risk patients.

Negative hyperselection beyond RAS: is a key tool for choosing the optimal maintenance treatment in metastatic colorectal cancer?

Negative hyperselection beyond RAS: is a key tool for choosing the optimal maintenance treatment in metastatic colorectal cancer?

Schisandrin C prevents Regorafenib-Induced cardiotoxicity by recovering EPHA2 expression in cardiomyocytes.

Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, has been approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma by the US Food and Drug Administration and European Medicines Agency. However, regorafenib-induced cardiotoxicity increases the risk of mortality. Despite reports that regorafenib can cause mitochondrial dysfunction in cardiomyocytes, the molecular mechanism of regorafenib-induced cardiotoxicity is much less known and there is an urgent need for intervention strategies. Here, we treated mice with vehicle or 200 mg/kg regorafenib daily for 42 days by gavage or treated cardiomyocyte lines with 8, 16 or 32 μM regorafenib, and we found that regorafenib could cause apoptosis, mitochondrial injury and DNA damage in cardiomyocytes. Mechanistically, regorafenib can reduce the expression of EPHA2, which inhibits AKT signaling, leading to cardiomyocyte apoptosis and cardiotoxicity. In addition, we showed that recovering EPHA2 expression via plasmid-induced overexpression of EPHA2 or schisandrin C, a natural product, could prevent regorafenib-induced cardiotoxicity. These findings demonstrated that regorafenib causes cardiomyocyte apoptosis and cardiac injury by reducing the expression of EPHA2 and schisandrin C could prevent regorafenib-induced cardiotoxicity by recovering EPHA2 expression, which provides a potential management strategy for regorafenib-induced cardiotoxicity and will benefit the safe application of regorafenib in clinic.

Clinical Trial Data Review of the Combination FTD/TPI + Bevacizumab in the Treatment Landscape of Unresectable Metastatic Colorectal Cancer.

Recommended first and second line treatments for unresectable metastatic colorectal cancer (mCRC) include fluorouracil-based chemotherapy, anti-vascular endothelial growth factor (VEGF)-based therapy, and anti-epidermal growth factor receptor-targeted therapies. In third line, the SUNLIGHT trial showed that trifluridine/tipiracil + bevacizumab (FTD/TPI + BEV) provided significant survival benefits and as such is now a recommended third line regimen in patients with refractory mCRC, irrespective of RAS mutational status and previous anti-VEGF treatment. Some patients are not candidates for intensive combination chemotherapy as first-line therapy due to age, low tumor burden, performance status and/or comorbidities. Capecitabine (CAP) + BEV is recommended in these patients. In the SOLSTICE trial, FTD/TPI + BEV as a first line regimen in patients not eligible for intensive therapy was not superior to CAP + BEV in terms of progression-free survival (PFS). However, in SOLSTICE, FTD/TPI + BEV resulted in similar PFS, overall survival, and maintenance of quality of life as CAP + BEV, with a different safety profile. FTD/TPI + BEV offers a possible first line alternative in patients for whom CAP + BEV is an unsuitable treatment. This narrative review explores and summarizes the clinical trial data on FTD/TPI + BEV.

Modern strategy of metastatic colorectal cancer treatment (literature review)

Modern strategy of metastatic colorectal cancer treatment (literature review)

Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer

Rap2b, a proto-oncogene upregulated in colorectal cancer (CRC), undergoes protein S-palmitoylation at specific C-terminus sites (C176/C177). These palmitoylation sites are crucial for Rap2b localization on the plasma membrane (PM), as mutation of C176 or C177 results in cytosolic relocation of Rap2b. Our study demonstrates that Rap2b influences cell migration and invasion in CRC cells, independent of proliferation, and this activity relies on its palmitoylation. We identify ABHD17a as the depalmitoylating enzyme for Rap2b, altering PM localization and inhibiting cell migration and invasion. EGFR/PI3K signaling regulates Rap2b palmitoylation, with PI3K phosphorylating ABHD17a to modulate its activity. These findings highlight the potential of targeting Rap2b palmitoylation as an intervention strategy. Blocking the C176/C177 sites using an interacting peptide attenuates Rap2b palmitoylation, disrupting PM localization, and suppressing CRC metastasis. This study offers insights into therapeutic approaches targeting Rap2b palmitoylation for the treatment of metastatic CRC, presenting opportunities to improve patient outcomes.

588P Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study

588P Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study

514MO The efficacy and safety of ivonescimab with or without ligufalimab in combination with FOLFOXIRI as first-line (1L) treatment for metastatic colorectal cancer (mCRC)

514MO The efficacy and safety of ivonescimab with or without ligufalimab in combination with FOLFOXIRI as first-line (1L) treatment for metastatic colorectal cancer (mCRC)

581P mRNA profiling as a biomarker of prognosis and response to first-line treatment in metastatic colorectal cancer: Discovery and validation of a gene expression signature in three randomized trials

581P mRNA profiling as a biomarker of prognosis and response to first-line treatment in metastatic colorectal cancer: Discovery and validation of a gene expression signature in three randomized trials

559P Early changes in circulating tumor DNA (ctDNA) and outcome during systemic palliative treatment for metastatic colorectal cancer: A systematic review and meta-analysis — An initiative under the ctDNA RECIST program

559P Early changes in circulating tumor DNA (ctDNA) and outcome during systemic palliative treatment for metastatic colorectal cancer: A systematic review and meta-analysis — An initiative under the ctDNA RECIST program

Regorafenib combined with immune checkpoint inhibitors versus regorafenib monotherapy as a late-line treatment for metastatic colorectal cancer: a single-center, retrospective cohort study.

Few data are available on metastatic colorectal cancer (mCRC) treated with late-line regorafenib monotherapy or combined with other therapies. This study thus aimed to examine regorafenib combined with immune checkpoint inhibitors (ICIs) compared with regorafenib monotherapy in patients with advanced CRC. This single-center retrospective cohort study included patients with advanced CRC who experienced recurrence and progression after standard first- and second-line treatments treatment from November 2018 to December 2021. The patients received regorafenib plus ICIs or regorafenib monotherapy. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST). Overall survival (OS) and progression-free survival (PFS) were analyzed via multivariate analysis. The combined group and the monotherapy group included 30 and 43 patients, respectively. The median OS (13.7 vs. 10.1 months; P=0.10) and PFS (4 vs. 3.6 months; P=0.32) were not significantly different between the two groups. In males, the median OS was significantly longer in the combined group compared with the monotherapy group (not reached vs. 8.03 months; P=0.02), but the median PFS showed no significant difference (7.23 vs. 3.90 months; P=0.16). There was no significant difference in OS (P=0.71) or PFS (P=0.89) in females. Eastern Cooperative Oncology Group performance status (ECOG PS) 1 [vs. 0; hazard ratio (HR) =3.13, 95% confidence interval (CI): 1.61-6.10; P<0.001] was independently associated with PFS. ECOG PS 1 (vs. 0; HR =3.63, 95% CI: 1.54-8.56; P=0.003) and combined therapy (vs. monotherapy; HR =0.47, 95% CI: 0.22-0.99; P=0.048) were associated with OS. Regorafenib combined with ICIs led to numerically longer PFS and significantly prolonged OS in patients with mCRC compared to regorafenib monotherapy, especially in male patients.

Hazard Ratios and Alternative Effect Measures: AnAppliedIllustration.

Although the limitations of hazard ratios (HRs) for quantifying treatment effects in right-censored data have been widely discussed, HRs are still preferentially reported over other, more interpretable effect measures. This may stem from the fact that there are few applied examples that directly contrast the HR and its interpretation with alternative effect measures. We analyzed data from two randomized clinical trials comparing panitumumab plus standard-of-care chemotherapy (SOCC) with SOCC alone as first- and second-line treatment for metastatic colorectal cancer. We report the effect of treatment with panitumumab on progression-free survival (PFS) using a Cox proportional hazards model to estimate the HR and the Kaplan-Meier estimator of cumulative incidence (risk). Further analyses included examining the cumulative incidence curves; kernel-smoothed, non-parametric hazards curves; fitting the Cox model with a continuous time variable; and estimating restricted mean survival as well as median survival. The HR was 0.82 (95% confidence interval [CI]: 0.71, 0.93), while the risk ratio (or relative risk [i.e., ratio of the cumulative incidence among the treated versus comparator]) was 0.99 (95% CI: 0.96, 1.02). These two measures suggest apparently different conclusions: either a treatment benefit or no effect. Through subsequent analyses, we demonstrated that, while the cumulative incidence of the outcome was similar by the end of follow-up regardless of treatment, the panitumumab treated group experienced longer PFS than those randomized to SOCC. Substantial nonproportional hazards were evident with panitumumab treatment reducing the hazard of progression/mortality during the first ~1.75 years but associated with an increased hazard of progress/mortality thereafter. This example underscores the difficulties in interpreting HRs, particularly in the setting of qualitative violations of proportional hazards, and the value of quantifying treatment effects via multiple effect measures.