In metastatic colorectal cancer (mCRC), the BRAFV600E mutation subtype is one of the subtypes with the worst prognosis. The long-term abnormal activation of multiple signaling pathways caused by the BRAF V600E mutation is closely related to the formation of BRAF inhibitor resistance and drug-resistant tumor cell subpopulations. These factors significantly impact the survival and prognosis of CRC patients. Therefore, treating mCRC patients with the BRAFV600E mutation, particularly in later stages, is challenging. We reported a case of an mCRC patient with the BRAF V600E mutation in the primary and metastatic tumors. After the failure of second-line treatment, this patient received a combination therapy including immunotherapy (tislelizumab), radiotherapy, and targeted therapy (fruquintinib). Through comprehensive imaging evaluations and continuous monitoring of tumor markers, we were astonished to observe that the patient has achieved and maintained a complete response (CR) for over 12 months. This case supports the efficacy of combination therapy in mCRC patients with the BRAF V600E mutation.

The relative dose intensity (RDI) of cytotoxic agents affects cancer patients' clinical outcome, especially in the curative setting. Poor data are available in metastatic colorectal cancer (mCRC) and with specific regard to the use of the triplet FOLFOXIRI.

We performed a pooled analysis of the phase III TRIBE and TRIBE2 studies comparing FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev in order to assess the prognostic impact of the RDI (<80 % versus ≥80 %) during the first 8 cycles of induction treatment of both the triplet and the doublet regimens.

Overall, 282/581 (49 %) and 404/580 (70 %) of patients treated with FOLFOXIRI/bev and doublets/bev, respectively, received RDI≥ 80 %. Patients receiving RDI≥ 80 % had more favorable clinical condition and tumor-related prognostic features. RDI≥ 80 % was associated with higher ORR (62 % vs 53 %, OR: 1.44, 95 %CI:1.13 - 1.82; p = 0.0026), and longer PFS (11.5 versus 10.0 months; HR: 0.80, 95 %CI: 0.71 - 0.91; p < 0.001) and OS (27.9 versus 22.2 months; HR: 0.75, 95 %CI: 0.65 - 0.85; p < 0.001). These results were confirmed in multivariable models (p < 0.001). Similar ORR (58 % vs 56 %, OR: 1.09, 95 %CI: 0.81-1.48; p = 0.57), PFS (10.8 versus 10.0 months; HR:0.96, 95 %CI: 0.83-1.12; p = 0.63) and OS (22.9 versus 24.9 months; HR:1.07, 95 %CI: 0.90-1.26; p = 0.46) were observed between patients treated with FOLFOXIRI/bev receiving RDI< 80 % and those treated with doublets/bev receiving RDI≥ 80 %. These results were confirmed after stratification for unbalanced baseline characteristics between these subgroups (stratified pORR=0.55; pPFS=0.70; stratified pOS=0.33). As expected, patients in the RDI< 80 % group experienced a higher incidence of severe chemo-related adverse events (72 % vs 34 %, p < 0.001).

Maintaining an adequate RDI in the first-line therapy of mCRC improves patients' clinical outcomes. Since there is no benefit from chemotherapy intensification in the case of low RDI, the secondary prophylaxis of chemotherapy-related severe adverse events might be preferrable rather than individual agents' dose reductions.

We first evaluated thecost-effectiveness of the FOLFOXIRI plus bevacizumab versus mFOLFOX6 plusbevacizumab as the first-line treatment of metastatic colorectal cancer fromhealthcare system perspective.

A partitioned survivalmodel was developed to assess the costs and effects of FOLFOXIRI plusbevacizumab versus mFOLFOX6 plus bevacizumab. Health outcomes weremeasured in quality-adjusted life years (QALYs), and incrementalcost-effectiveness ratios (ICERs). The evaluation of the Chinese healthcarepayer perspective was performed across a lifetime horizon, encompassing directmedical expenses.

The estimated cost for FOLFOXIRI plus bevacizumab treatment was 9306.364USD, which was higher than 8218.436 USD estimated for mFOLFOX6 plusbevacizumab, leading to an ICER of 1961.857 USD per QALY. One-way sensitivityanalysis suggested the body surface area (BSA), the cost of irinotecan,and the cost of fluorouracilhad the largest impact on the ICER. The cost-effectiveness acceptability curvesshowed the probability of FOLFOXIRI plus bevacizumab being cost-effective was100% at a threshold of 12 300 USD per QALY.

FOLFOXIRI plus bevacizumab hadan economic advantage compared to mFOLFOX6 plus bevacizumab as the first-line treatment ofmetastatic CRC in China.

DXd (Exatecan derivative), a novel TOPO-I inhibitor, exhibits high membrane permeability and an efficient bystander effect, serving as a critical cytotoxic drug component in antibody-drug conjugates (ADCs). However, its poor stability, high toxicity and non-ionizable structure limit its clinical applications. Basic/acid/metal coordination modifying strategy offers a potential solution to remotely load non-ionizable drugs into liposomes. However, achieving an optimal balance between therapeutic efficacy and safety remains a major challenge. In this study, DXd was used as a model compound to design and synthesize a series of weakly basic derivatives (DXdd), incorporating various basic moieties linked via alkyl chains of different lengths. The alkyl chain length significantly influenced both the chemical stability and antitumor activity of DXdd. Among them, DXdd with four alkyl chains (DXdd-4PA) demonstrated potent antitumor efficacy with minimal acute and cumulative toxicity. Subsequent optimization of the liposome size loaded with DXdd-4PA revealed that 80 nm was optimal for cancer therapy. Overall, this work provides a valuable framework for the rational design of non-ionizable drugs suitable for remote loading into liposomes, and enhances the translational potential of DXd-based therapeutics.

Circulating tumor DNA variations (∆ctDNA) were reported to be associated with treatment efficacy in metastatic colorectal cancer (mCRC). The present study evaluated ∆ctDNA according to first-line treatment intensity.

Patients from two prospective ctDNA collections were divided into Group ≤ 2 drugs and Group ≥ 3 drugs. ∆ctDNA were analysed from baseline to cycle 3 or 4 (C3-4) according to three predefined subgroups: ∆ctDNA ≥ 80%_ undetectable, ∆ctDNA ≥ 80%_ detectable, and ∆ctDNA < 80%. Impact of ∆ctDNA on progression-free survival (PFS) and overall survival (OS) were analysed.

Pretreatment ctDNA was detected in 129/152 (84.9%) of patients. A ∆ctDNA ≥ 80%_undetectable was more frequent in Group ≥ 3 than ≤ 2 drugs (respectively 51.5% vs. 32.7%, p = 0.015). Patients with ∆ctDNA ≥ 80%_undetectable had longer survival than other ∆ctDNA subgroups, in Group ≥ 3 drugs (mPFS 11.5 vs 7.8 vs 6.3 months, p = 0.02: mOS 30.2 vs 18.1 vs 16.4 month, p = 0.04) and in Group ≤ 2 drugs (mPFS 8.4 vs 6.0 vs 5.3 months, p = 0.05; mOS 29.6 vs 14.6 vs 14.6 months, p = 0.007).

Early ∆ctDNA are associated to treatment intensity in first line mCRC with a significant impact on prognosis.

Bevacizumab shows inter-individual pharmacokinetic variability, with an exposure-response relationship in metastatic colorectal cancer (mCRC) patients. This study explores whether a double dose of bevacizumab, compared to a standard dose, increases efficacy in mCRC patients treated with bevacizumab-based chemotherapy as first-line therapy and who have a low initial trough concentration of bevacizumab. PHARBEVACOL is a multicenter, randomized, double-blind, two-parallel group trial. All patients will receive first-line bi-weekly 5 mg/kg bevacizumab-based chemotherapy and those with low initial bevacizumab concentrations (≤15.5 mg/L) will be randomized to either continue the standard dose (5 mg/kg every 14 days) or receive a double dose (10 mg/kg every 14 days). The primary objective is to evaluate the effect of doubling dose on progression-free survival (PFS). During a screening phase, the first serum trough concentration will be measured on day 14, before the second infusion of bevacizumab. We hypothesize a 40 % PFS in the control group at 9 months versus 60 % in the study group, corresponding to a hazard ratio of 0.56. With 80 % power, a 5 % two-sided type I error, and a minimum 12-month follow-up, 116 patients need to be included. Since only 50 % of screened patients will be eligible for randomization, approximately 244 patients will be screened. Recruitment is scheduled to begin in February 2025.

We have made steady gains in improving overall survival in patients with metastatic, unresectable, colon cancer in the last 5 to 10 years. The backbone of systemic treatment for most patients remains combination chemotherapy, but the field is becoming increasingly biomarker driven, with exciting new targeted therapies on the horizon. This review is organized in sections corresponding to currently relevant biomarkers in colon cancer and will summarize first-, second-, and third-line standard of care for metastatic, unresectable, colon cancer. The last section is intended to introduce the reader to promising agents and novel therapeutic strategies currently under investigation.

Irinotecan is a critical anticancer drug used to treat metastatic colorectal cancer and advanced pancreatic ductal adenocarcinoma by obstructing topoisomerase 1; however, it can cause minor-to-severe and life-threatening adverse effects. UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms increase the risk of irinotecan-induced neutropenia and diarrhea. Hence, screening for UGT1A1 polymorphisms before irinotecan-based chemotherapy is recommended to minimize toxicity, whereas liposomes offer the potential to deliver irinotecan with fewer side effects in patients with pancreatic ductal adenocarcinoma. This review presents a comprehensive overview of the effects of genotype-guided dosing of irinotecan on UGT1A1*28 and UGT1A1*6 variants, incorporating pharmacogenomic research, optimal regimens for metastatic colorectal and pancreatic cancer treatment using irinotecan, guidelines for toxicity reduction, and an evaluation of the cost-effectiveness of UGT1A1 genotype testing.

To improve prognosis of patients with synchronous colorectal liver metastasis (CRLM), we constructed a nomogram model to improve outcome through risk stratification and decision support.

The 389 CRLM patients (273 training set and 116 validation set at a ratio of 7: 3) receiving systematic chemotherapy and synchronously resection with/without radiofrequency ablation (RFA) were retrospectively investigated. Overall survival (OS) and recurrence free survival (RFS) were mainly endpoint. A normo-gram model was conduct. The receiver operating characteristic (ROC) curve, decision curve analysis (DCA), C-index and calibration curve were performed to assess stablity and efficacy of model. The prognosis was evaluated based on Kaplan-Meier (KM) curve.

A total of 389 CRLM patients were included. The median OS and RFS times were 70.20 months (95% CIs: 57.73, 82.68) and 11.70 months (95% CIs: 9.75, 13.65), respectively. These patients were divided into training set and validation set at a ratio of 7: 3. In training set, 1, 3, and 5-year survival rate of OS was 97.38%, 71.18%, and 54.56% as well as RFS was 52.57%, 22.65%, and 21.12%, respectively. Cox model showed that hospital day, R0 resection, RFA, only neoadjuvant chemotherapy and CRS score were independent prognostic factors for CRLM patients. The patients were divided into high-risk group and low-risk group based on cut-off value of score calculated by model. The KM curves were statistically different between two groups (P < 0.01). The ROC curve, DCA and calibration curve showed a good prediction efficacy. the C-index of OS and RFS were 0.72 and 0.68, respectively, which were also verified in the validation set (OS, 0.71; RFS, 0.65).

A good prediction model was developed and validated to assess the prognoses of CRLM patients. Systematic chemotherapy and R0 resection could benefit patients' survival and improve prognosis.

The global burden of colorectal cancer (CRC) continues to rise, with elderly populations disproportionately affected. Despite oxaliplatin's established role in first-line metastatic CRC (mCRC) therapy, its clinical utility in older adults remains debated due to concerns over efficacy, toxicity, and survival outcomes. This meta-analysis evaluates the therapeutic benefits and risks of oxaliplatin-based regimens in elderly patients with mCRC, with emphasis on tumor response, survival endpoints, and treatment-related toxicities.

We systematically reviewed PubMed, Web of Science, Cochrane Library, and Chinese databases (CNKI, Wan Fang) through November 2024 for randomized controlled trials (RCTs) comparing oxaliplatin-based chemotherapy to non-oxaliplatin regimens in patients aged ≥65 with mCRC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), complete response (CR), partial response (PR), disease control rate (DCR), and grade 3-4 adverse events. Data were pooled using random- or fixed-effects models in STATA 14.0 based on heterogeneity (I² statistic). Subgroup analyses explored heterogeneity sources, including chemotherapy combinations (e.g., bevacizumab, panitumumab).

Seven RCTs (1,839 patients) met inclusion criteria. Oxaliplatin significantly improved tumor response rates versus control regimens: ORR (OR 2.18, 95% CI 1.75-2.72; P<0.001), CR (OR 2.57, 1.11-5.97; P=0.028), and PR (OR 1.69, 1.28-2.22; P<0.001). No significant survival benefit was observed for OS (HR 0.97, 0.86-1.08; P=0.58) or PFS (HR 0.90, 0.79-1.01; P=0.07), though trends favored oxaliplatin. Grade 3-4 neutropenia (RR 1.84, 1.32-2.57), diarrhea (RR 2.01, 1.45-2.78), and sensory neuropathy (RR 3.12, 1.98-4.91) were more frequent with oxaliplatin. Subgroup analysis attributed DCR heterogeneity (I²=66%) to regimen differences, with reduced variability in bevacizumab/pantiumumab-combined subgroups.

This analysis demonstrates oxaliplatin's capacity to enhance tumor response in elderly mCRC patients, potentially alleviating symptoms and improving quality of life. However, the absence of significant survival gains underscores the complex interplay between tumor biology and therapeutic resistance. Mechanistically, chemotherapy-driven clonal selection may favor residual resistant subpopulations, as evidenced by liquid biopsy studies linking tumor evolution to disease progression. While toxicity profiles were manageable, the elevated risk of neurotoxicity and myelosuppression necessitates vigilant monitoring in this vulnerable cohort.

Oxaliplatin-based first-line therapy provides clinically meaningful tumor response improvements in elderly mCRC patients, though survival advantages remain elusive. Treatment decisions should balance response benefits against toxicity risks, prioritizing individualized strategies informed by geriatric assessments and molecular profiling. Future trials must integrate biomarker-driven approaches (e.g., ctDNA monitoring, RAS/RAF stratification) to optimize therapeutic precision in aging populations.

The optimal therapeutic strategy for metastatic microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC) remains uncertain. This multicenter retrospective study compared the efficacy and safety of pembrolizumab monotherapy versus bevacizumab combined with modified FOLFOX6 (mFOLFOX6) in this molecularly defined population.

Consecutive patients with metastatic MSI-H/dMMR CRC treated with pembrolizumab or bevacizumab plus mFOLFOX6 at two tertiary centers (2017-2024) were analyzed. Dual primary endpoints included overall survival (OS) and progression-free survival (PFS); secondary endpoints encompassed incidence of grade ≥3 treatment-emergent adverse events (AEs).

Among 58 eligible patients (PE: n=30; BF: n=28), the PE cohort demonstrated a significantly higher objective response rate (ORR) compared to the BF cohort (XX% vs XX%, p=0.030) after a median follow-up of 18.0 months (IQR: 1.0-24.0). Survival analyses revealed superior outcomes in the PE cohort, with a median OS of 12.0 months (95% CI: 10.2-14.1) versus 8.8 months (95% CI: 7.1-9.6) in the BF cohort (HR=0.55, 95% CI: 0.29-0.56; p=0.02). Similarly, median PFS was prolonged in the PE cohort (7.0 months, 95% CI: 5.3-9.3) relative to the BF cohort (3.7 months, 95% CI: 2.2-5.4; HR=0.46, 95% CI: 0.24-0.89; p<0.001). No statistically significant intergroup differences were observed in grade ≥3 treatment-emergent AE rates.

Pembrolizumab monotherapy significantly improved survival over bevacizumab-based chemotherapy in metastatic MSI-H/dMMR CRC, with a manageable safety profile. These results reinforce PD-1 inhibitors as first-line therapy for this population, while highlighting tumor mutation burden (TMB) and tumor burden as critical biomarkers for personalized strategies.

Background/Objectives: Worldwide, colon cancer is a major cause of cancer-related mortality, with an increasing incidence influenced by genetic, environmental, and lifestyle factors. Despite advances in diagnosis and personalized treatments, challenges remain in improving patient prognosis, particularly in metastatic colorectal cancer (mCRC). Bevacizumab (BEV), a monoclonal antibody, is widely used in colorectal cancer treatment. This study aimed to analyze adverse events associated with BEV compared with other therapies based on data from the EudraVigilance (EV) database. Methods: A descriptive and disproportionality analysis was conducted on signals reported in the EV database related to BEV. The study included comparisons with other antineoplastic treatments, such as chemotherapy, targeted therapy, and immunotherapy. Patient demographics, severity of adverse drug reactions (ADRs), and distribution patterns were analyzed to assess the safety profile of BEV in colorectal cancer treatment. Results: The majority of the signals for BEV were from patients aged 18-64 years (39.42%) and 65-85 years (34.08%). Hypertension, thromboembolism, proteinuria, and gastrointestinal disorders have been the most frequently reported. Serious ADRs, including gastrointestinal perforations, hemorrhage, and arterial thromboembolism, were observed in 93.74% of Individual Case Safety Reports. BEV was associated with a higher likelihood of vascular and endocrine disorders compared with chemotherapy and other targeted therapies. Immunotherapy was linked to increased immunological ADRs, while BEV demonstrated fewer immune-related toxicities. Conclusions: Continuous monitoring is necessary to optimize patient management, particularly in elderly patients or those with cardiovascular comorbidities. Understanding BEV's safety profile allows for better personalization of treatment strategies, minimizing risks while enhancing therapeutic outcomes.

The aim of this study was to evaluate the cost-effectiveness of FOLFOXIRI/FOLFOXIRI compared with mFOLFOX6/FOLFIRI in first-line and second-line chemotherapy for metastatic colorectal cancer (mCRC) from the perspectives of the USA and China, respectively, and provide a decision-making basis for clinical selection of these two regimens.

The study used a decision-analytic Markov model to simulate the process of mCRC, including three distinct health states: progression-free survival, progressive disease and death. Clinical data were derived from the TRIBE2 trial.Costs and utilities were obtained from local public databases and literature. One-way sensitivity analyses and probabilistic sensitivity analysis were also performed to explore the parameters' uncertainty in this study.

The main included patients were histologically confirmed colorectal adenocarcinoma.

First-line and second-line treatment with either FOLFOXIRI/FOLFOXIRI or mFOLFOX6/FOLFIRI.

Costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon as primary outcomes.

Patients treated with the FOLFOXIRI/FOLFOXIRI regimen produced 0.08 QALYs in the USA while 0.04 QALYs in China compared with the mFOLFOX6/FOLFIRI regimen. The final ICERs for FOLFOXIRI/FOLFOXIRI were US$5127.70 per QALY and US$30 478.33 per QALY in the USA and China, which are below the willingness-to-pay (WTP) thresholds. In the USA, when the WTP was US$100 000 for each QALY gained, the probability was nearly 99.6% that the FOLFOXIRI/FOLFOXIRI treatment was cost-effective. In China, when the WTP was US$36 053.01 (3 × GDP) for each QALY gained, the probability was nearly 54.7% that FOLFOXIRI/FOLFOXIRI treatment was cost-effective.

Patients with mCRC treated with FOLFOXIRI/FOLFOXIRI as first-line and second-line chemotherapy may improve health outcomes and expend financial resources more efficiently than mFOLFOX6/FOLFIRI whether in China or the USA, which benefits not only individual survival but also the health care system from a value perspective.

The use of interventions such as major liver and lung resection, radiofrequency ablation and transarterial chemoembolization in the management of metastatic colorectal cancer (mCRC) is now relatively commonplace in clinical practice. However, the evidence base regarding these treatments is limited with a lack of high-quality data from randomised controlled trials (RCTs). The aim of this study was to understand the challenges associated with conducting RCTs in advanced mCRC and to identify potential strategies to overcome them, with a view to improving trial design and delivery in this setting.

A qualitative study was undertaken with professionals involved in mCRC trials. Participants were identified using trial registries to identify relevant trials. Individual semi-structured, in-depth qualitative interviews were undertaken online using a topic guide. The principles of thematic content analysis were used for data analysis.

Twelve participants were recruited to the study from six trials; three of the trials had completed, two were either terminated or no longer recruiting and one was open to recruitment. Four major themes were identified, and themes were further subdivided to identify specific challenges and solutions to overcome them. The four themes identified were as follows: trial-related processes, organisational/structural challenges, trial design considerations, and stage IV (metastatic) colorectal cancer-specific factors. Significant challenges were described in relation to funding, ethical approval processes, equipoise, patient preferences, logistical issues in trial delivery, and the advanced nature of mCRC including disease progression and palliative care.

There are a range of strategies which could be implemented to improve the delivery of future trials in this complex setting, from the initial development of a trial through to trial setup, recruitment and follow-up.

The treatment landscape for metastatic colorectal cancer (mCRC) has evolved into a continuum of care with an essential role for biomarkers and molecular subgroups. Treatment guidelines are primarily based on trial results; however, populations and outcomes differ from clinical practice. To support the interpretation of trial results and to assist in tailored patient counseling, we evaluated real-world treatment patterns and outcomes according to RAS/BRAF status. We included all patients diagnosed with BRAFV600E-mutated mCRC in 2015-2020, participating in the Prospective Dutch Colorectal Cancer cohort study, plus a 1:2 random selection of patients with RAS-mutated and double wild-type mCRC. We evaluated differences in administered lines of treatment (LOTs), local treatment, attrition rates, treatment duration, progression-free survival (PFS) and overall survival (OS). 178 BRAFV600E-mutated, 221 RAS-mutated, and 174 double wild-type patients were included. Of BRAFV600E-mutated patients, 26% received ≥3 LOTs, compared to 42% and 47% of the RAS-mutated and double wild-type patients, respectively (p = .002). Local treatment was performed in 25% of BRAFV600E-mutated, 43% of RAS-mutated, and 49% of double wild-type patients (p < .001). Median OS from diagnosis was 15.4, 24.1, and 32.6 months, respectively (p < .001) and loss of prognostic value of RAS/BRAF was observed from the 3rd LOT onwards (p = .17 and p = .54). This paper provides a comprehensive overview of the treatment landscape of mCRC per RAS/BRAF status in daily clinical practice. The observed substantial treatment heterogeneity within and between molecular subgroups underlines the importance of collecting real-world data to address post-trial knowledge gaps and to optimize individualized counseling for all mCRC patients.

BRAF V600E mutations are identified in 10 % of metastatic colorectal cancer (mCRC) cases. In this project, we evaluated the clinicopathologic features and natural history of patients with BRAF mutant (BRAF-mt) mCRC prior to era of BRAF targeted therapy.

This is a retrospective project evaluating patients with diagnosed with mCRC with an identified BRAF V600E mutation between January 1, 2015 and December 31, 2021 seen at the Ottawa Hospital Cancer Centre prior to the approval of cetuximab and encorafenib in Canada. Demographic, clinical, and cancer characteristics were collected from the medical records. Outcomes of interest included overall survival (OS) and time to next therapy (TNT).

71 patients were included. The median age was 69 years, 37 (52 %) patients were females, and 19 (27 %) were mismatch repair deficient (dMMR). Median OS was 12.9 months with 21 (30 %) patients living greater than 2-years. Signet ring histology (HR=7.27, p < 0.001), peritoneal metastasis (HR=2.29, 0.003), distant lymphatic metastasis (HR=2.70, p < 0.001), brain metastasis (HR=2.86, p < 0.048) and metastatectomy (HR=0.17, p < 0.001) were associated with OS. Forty-six (65 %) patients received first-line systemic therapy, 14 (20 %) second-line and 2 (3 %) third-line. Median duration of therapy was 8.5 months for first-line, 5.5 months for second-line and 1.5 months for third-line.

Real world data demonstrates that patients with BRAF-V600E mCRC have poor clinical outcomes with traditional systemic therapies. Only a minority of patients received second- or third-line systemic treatments, highlighting the importance of ongoing research evaluating incorporation of targeted therapy in first-line treatment.

FOLFOXIRI plus bevacizumab (BEV) is an option for first-line treatment of metastatic colorectal cancer (mCRC). However, there is no consensus on the optimal treatment strategy when disease progresses. The EFFORT open-label, multicenter, single-arm phase II study investigated whether FOLFIRI plus aflibercept retains activity after progression of FOLFOXIRI plus BEV treatment.

The patients with unresectable mCRC who failed first-line FOLFOXIRI plus BEV received FOLFIRI plus aflibercept. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). Angiogenic biomarkers were measured before treatment initiation.

From April 2019 to May 2021, 35 patients were enrolled and 34 were analysed in the FAS population (men, 18; median age, 63 years [range: 32-78]). The primary tumor was left-sided in most cases (23/34), 23 patients were RAS mutant, 3 patients had BRAF V600E mutation and 27 patients had liver metastases. The primary end-point was met with a median PFS of 4.3 months [80% confidence interval [CI] 3.7-5.1]. Median overall survival was 15.2 months [95% CI 8.9-22.7]. Per RECIST, there were 1 complete response, 4 partial responses, 21 stable diseases and 8 disease progressions. Overall response rate was 14.7% [95% CI 5.0-31.1], and disease control rate was 76.5% [95% CI 58.8-89.3]. Responses were more common in patients with high VEGF-C, low VEGF-D and low PlGF levels before treatment.

FOLFIRI plus aflibercept, administered after failure of FOLFOXIRI plus BEV, is effective and has a manageable safety profile. This regimen may be a useful second-line treatment option for these patients.

Patients 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.

Patients (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).

As of December 30, 2020, median (m)PFS was 5.68 months (95% CI, 4.67-7.13) with 4mg/kg q1w versus 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) versus 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.

KH903 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.

A phase I study of FOLFIRINOX3-bevacizumab (bFOLFIRINOX3)defined the RP2D for irinotecan at 70 mg/m² and showed promising activity. This phase II trial aimed to evaluate the efficacy of bFOLFIRINOX-3 in chemorefractory metastatic colorectal cancer (mCRC).

In phase II, chemorefractory mCRC were enrolled. The regimen tested consisted of bevacizumab (5 mg/kg), folinic acid(400 mg/m²), 5-fluorouracil (2400 mg/m² for 46 h), oxaliplatin (85 mg/m²) and irinotecan (70 mg/m² administered before and after infusion of 5-fluorouracil). The primary endpoint was efficacy defined by 2-month progression-free survival(PFS). Secondary endpoints included objective response, median PFS, overall survival (OS) and toxicity.

32 patients were enrolled (October 2018 to December 2022); median age 62.5 years (range 32-78). The majority had been treated with several previous lines of chemotherapy (median 3, range [1-8]). Median follow up was 12 months (range [1.5-12]). Two-month PFS was 96.9%. Best objective response rate (ORR) was 28.1%. Median PFS was 9.4 months (95%CI [6.9;11.5]) and median OS was not reached (95% [11.6; NR]). Grade 3 adverse events occurred in 81.2%; mostly diarrhea (37.5%) and neutropenia (12.5%). Grade 3 diarrhea consistently resolved after irinotecan dose reduction. The most common drug-related adverse events (all grades) were diarrhea (96.9%), fatigue (68.8%), nausea (68.7%), anemia (56.3%), peripheral neuropathy (53.4%) and thrombopenia (40.6%).

The combination of bFOLFIRINOX-3 yielded 2-month PFS of 96.9% and best ORR of 28.1%, and was well tolerated. These results are promising in chemotherapy refractory mCRC and provide a rationale for future randomized phase III trials.

NCT03795311 (clinicaltrials.gov).

Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), identifying a subgroup of patients who derive modest benefit from standard treatments and have extremely poor prognosis. The evolution of molecular profiling and the implementation of next generation sequencing in the evaluation of a patient with BRAF-mutated mCRC has currently led to the discovery of actionable alterations. Targeting multiple pathways of resistance in BRAF-mutated mCRC may be the most efficacious route. Then, over a short period of time, the treatment landscape BRAF-mutated mCRC patients has shifted dramatically. Finally, novel treatment strategies are available. This review will discuss on currently approved treatments for BRAF V600E mutated mCRC and will try and portray the changing landscape in this setting in the era of targeted molecular therapy.

SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs).

Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 intravenously once per day on days 1 and 8 of a 21-day cycle).

Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28).

The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.

The mutation of the KRAS (Kirsten rat sarcoma virus) gene is a prevalent genetic alteration in metastatic colorectal cancer (mCRC). According to previous research, this mutation significantly affects clinical outcomes and quality of life (QOL). This research investigated the association between KRAS mutant status and various aspects of QOL in mCRC patients.

This case-control study involved 90 admitted patients with mCRC. The patients were either mCRC with positive KRAS mutants (case group) or those without the mutation (control group). The KRAS mutation status of each patient was determined using standard molecular testing. The QOL was evaluated through validated questionnaires from the European Organization for Research and Treatment of Cancer (EORTC), including QLQ-C30 and the QLQ-CR29 questionnaire for colorectal cancer patients. Differences in QOL between the groups and the association of QOL with the odds of KRAS mutation were analyzed using appropriate statistical tests.

Patients in the wild-type KRAS group had significantly higher scores on the global health status (GHS) of the QLQ-C30 scale compared to those with a KRAS mutation [(64.26 ± 4.63 vs. 49.63 ± 4, crude; p = 0.019, adjusted; p = 0.024). The mean score of the social functioning scale of the KRAS mutation group was significantly higher than the wild-type [(40 ± 5.84 vs. 24.81 ± 4.39, crude; p = 0.040, adjusted; p = 0.021)]. Based on the QLQ-CR29 questionnaire, average QOL scores were suboptimal for both groups but insignificant. Further, both crude and adjusted analyses showed that KRAS mutation odds were significantly linked to improved social functioning [(crude; OR = 1.013; P = 0.044), (adjusted; OR = 1.017; P = 0.019)] and negatively associated with GHS [(crude; OR = 0.983; P = 0.022), (adjusted; OR = 0.982; P = 0.022)].

The study revealed a low QOL in mCRC, a notable difference in social functioning, and the GHS among patients with and without mutations. Further research is needed to develop targeted interventions to enhance QOL in patients with KRAS mutation.

Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine-tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine-tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRASG12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium.

In patients with colorectal cancer and unresectable liver-only metastases (CRLM), treatment with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) plus irinotecan (FOLFOXIRI) and bevacizumab vs FOLFOX/folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab increased progression-free survival, response, and R0/R1 resection/ablation rates, as well as toxic effects in RAS/BRAFV600E-variant and/or right-sided tumors. FOLFOX/FOLFIRI-panitumumab vs FOLFOX/FOLFIRI-bevacizumab increased response at the cost of more toxic effects in RAS/BRAFV600E wild-type, left-sided tumors.

To present long-term outcomes of treatment with FOLFOXIRI plus bevacizumab vs FOLFOX/FOLFIRI plus bevacizumab and FOLFOX/FOLFIRI plus panitumumab vs FOLFOX/FOLFIRI + bevacizumab.

The randomized phase 3 CAIRO5 trial included patients with initially unresectable CRLM in 46 Dutch centers and 1 Belgian center between November 2014 and January 2022. A liver expert panel repeatedly evaluated resectability.

Patients with RAS/BRAFV600E-variant and/or right-sided tumors randomly received FOLFOX/FOLFIRI-bevacizumab (group 1) or FOLFOXIRI-bevacizumab (group 2), and those with RAS/BRAFV600E wild-type, left-sided tumors received FOLFOX/FOLFIRI-bevacizumab (group 3) or FOLFOX/FOLFIRI-panitumumab (group 4). Adjuvant chemotherapy (ACT) after complete local treatment was recommended but not standard.

Overall survival (OS) was analyzed as a secondary outcome. Other outcomes were post hoc analyses.

A total of 530 patients (327 male [62%] and 203 female individuals [38%]; median age, 62 [IQR, 54-69] years) were randomized: 148 in group 1, 146 in group 2, 118 in group 3, and 118 in group 4. The median OS in group 1 was 23.6 (95% CI, 20.1-27.5) vs 24.1 (95% CI, 21.0-30.9) months in group 2 (hazard ratio [HR], 0.90; 95% CI, 0.70-1.17; P = .44), and 39.9 (95% CI, 30.7-44.6) in group 3 vs 38.3 (95% CI, 35.3-51.3) months in group 4 (HR, 0.95; 95% CI, 0.68-1.32; P = .75). OS was longest after complete local treatment without early (≤6 months) recurrence (64.3 months; 95% CI, 57.6 to not reached) and salvage local treatment options after early recurrence (58.9; 95% CI, 47.3 to not reached), followed by patients without salvage local treatment after early recurrence (30.5; 95% CI, 24.4-33.4) and with incomplete local treatment (28.7; 95% CI, 25.9-38.3), and worst in patients with continued unresectability (18.3; 95% CI, 15.7-20.0). After confounder adjustment, ACT was associated with longer OS (HR, 0.66; 95% CI, 0.44-0.98) and relapse-free survival (HR, 0.65; 95% CI, 0.48-0.88) and less early recurrence without salvage local treatment (odds ratio, 0.46; 95% CI, 0.25-0.85).

These results support using FOLFOX/FOLFIRI-bevacizumab for patients with initially unresectable CRLM irrespective of RAS/BRAFV600E status and tumor sidedness. Patients with complete local liver treatment with salvage local treatment in case of early recurrence had the longest OS. ACT might be considered for these patients.

ClinicalTrials.gov NCT02162563.

Relative dose intensity (RDI) is a measurement of chemotherapy (CT) dose defined as the actual dose received divided by the standard calculated dose during a set period. The study objective was to assess the impact of a RDI ≥ 80% on response and survival of patients treated in first line CT by FOLFOXIRI or FOLFIRINOX ± Bevacizumab (BV) for an unresectable metastatic colorectal cancer (mCRC).

It was a retrospective, non-interventional, multicenter study calculating RDI from the first cycles of CT to the first CT-scan evaluation (CT-scan1). Objective response and disease control rates (ORR and DCR), progression-free survival (PFS) and overall survival (OS) were compared between patients with RDI ≥ 80% and <80% and results were adjusted for age, gender, ECOG, tumor location, number of metastatic sites, RAS and BRAF status, the CT regimen, the use of BV, the delay from C1 to CT scan1.

Among 152 screened patients, 100 met inclusion criteria, with a mean (± standard deviation) age at 59.0 (± 10.7) years. The ECOG performance status was 0-1 in 96 (96%) patients; metastases were synchronous in 95 (95%), RAS and BRAF were mutated in 60 (60%) and 22 (22%), respectively. ORR was observed in 51 (51%) at CT-scan1 with median PFS and OS of 10.5 and 21.9 months, respectively. A RDI ≥ 80% was observed in 44 (44%) patients without impact on ORR (ORa: 1.04, 95% CI: 0.37 to 2.89, p = 0.94) but was significantly associated to improved PFS and OS with HRa 0.50 (95%CI: 0.29 to 0.87, p = 0.013) and 0.52 (95% CI: 0.29 to 0.91, p = 0.023), respectively.

Our results suggest a low level of FOLFOXIRI or FOLFIRINOX +/- BV exposure in first-line mCRC is associated with a significant trend on PFS and OS.

Colorectal cancer is the second leading cause of cancer death in Latin America (LA) with a projected 65.4% increase by 2040. Up to 10% of metastatic CRC (mCRC) patients in LA had an activating BRAF mutation. In clinical trials, targeted therapies for BRAF-V600E mutated mCRC have improved patient outcomes. However, in LA, BRAF-V600E testing and treatment of positive patients remains variable. To address this need, the Americas Health Foundation convened a meeting of LA experts on BRAF-V600E mCRC to develop treatment recommendations. The expert panel addressed the current landscape of BRAF-V600E mCRC testing, diagnosis and treatment in the region and identified significant limitations. Local guidelines, multidisciplinary boards, and tumor genotyping are among the recommendations. The panel also made first-line, second-line and surgery recommendations for patients after diagnosis.

FOLFOXIRI plus bevacizumab is a standard first-line chemotherapy for patients with metastatic colorectal cancer (mCRC). However, due to the severe toxicities, this regimen is not widely used. There is limited data on the real-world efficacy and safety.

We conducted a retrospective analysis of clinical data from mCRC patients who received FOLFOXIRI plus bevacizumab as first-line chemotherapy at 31 institutions. The initial dose was standardized according to the TRIBE regimen. Induction therapy was defined as a combination of oxaliplatin, irinotecan, and fluorouracil.

Out of 104 patients who met the criteria, the median age was 58 years (range, 16-72). 81% of patients had an eastern cooperative oncology group performance status (PS) of 0. An initial dose reduction was observed in 63% of patients. The median number of preplanned induction therapy cycles was 12 (range, 4-12). The completion of scheduled induction therapy cycles was observed in 45% of patients, with treatment-related toxicities being the main reason for discontinuation (63%). The median progression-free survival and overall survival were 12.8 months (95% CI, 10.6-15.0) and 27.9 months (95% CI 21.6-34.2), respectively. The objective response rate and disease control rate were 63.7% and 98.9%, respectively. The R0 resection rate was 21.2%. The main grade 3 or higher toxicities were neutropenia (51%), febrile neutropenia (10%), and nausea/vomiting (5%). No treatment-related deaths were observed.

In a real-world clinical setting, FOLFOXIRI plus bevacizumab demonstrated efficacy and safety comparable to previous clinical trials.

Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined.

In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated.

In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively.

Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.

Bevacizumab induces muscle atrophy by changing the gene expression level of muscle tissue. Quantitative computed tomography (QCT) enables precise measurement of various body compositions, including muscle area.

A total of 102 patients with metastatic colorectal cancer (mCRC) undergoing first-line chemotherapy based on bevacizumab were enrolled at thirst Affiliated Hospital of the University of Science and Technology of China. Their body compositions were measured respectively 1 month before and 1 month after the treatment.

Treatment-related decline in skeletal muscle index and visceral fat infiltration significantly affect patient prognosis.

A predictive model constructed by integrating changes in body composition with patient clinical characteristics effectively predicts the 9-month progression-free survival (PFS) of patients with mCRC.

Patients with BRAF 600E mutated mCRC are associated with specific clinicopathological features and poor prognosis. The relative efficacy of first-line FOLFOXIRI triplet chemotherapy or doublet chemotherapy combined with bevacizumab in patients with BRAF 600E mutated mCRC remains controversial.

BRAF V600E-mutated mCRC patients from 3 institutions were included. The clinicopathological characteristics of the enrolled patients were analyzed. Overall survival (OS) of patients was divided into 4 fractions, including 0-25%, 25-50%, 50-75%,75-100% by quartile method. Patients with OS ranging from 0 to 25% were defined as the poor prognosis group, and patients with OS ranging from 75 to 100% were defined as the good prognosis group. A propensity score matching (PSM) analysis was performed to balance the baseline characteristics of patients treated with doublet chemotherapy and triplet chemotherapy combined with bevacizumab. Survival and tumor response of the two regimens were evaluated.

A total of 125 patients with BRAF V600E-mutated mCRC were enrolled. The median OS of BRAF V600E-mutated mCRC was 14.9 months and the median PFS of first-line therapy was 6.1 months. According to the multivariate analysis and the difference in baseline characteristics between the poor prognosis group and the good prognosis group, poor differentiation and liver metastasis were negative independent prognostic factors for OS in patientsx with BRAF V600E-mutated mCRC. Patients treated with first-line triplets had a longer OS than those treated with doublets both before PSM (17.4 months vs. 13.4 months, p = 0.022) and after PSM (17.4 months vs. 10.4 months, p = 0.004). There was no significant benefit between triplet-drug group and doublet-drug group for PFS, ORR and DCR. Subgroup analysis showed that patients in the triplet-drug group had a better prognosis with the following favorable factors: age ≤ 60 years old, PS score of 0-1, liver metastases and multiple organ metastases.

The overall prognosis of BRAF V600E mutant mCRC patients is poor. Poor differentiation and liver metastases were negative independent prognostic factors for OS. First-line triplet-drug therapy was associated with better OS, especially in patients with good physical condition and high tumor burden.