This study aimed to identify the most effective first-line treatment for patients with metastatic colorectal cancer based on overall survival, identify the most commonly used treatment, and generate a meaningful ranking among all available treatments based on their relative effectiveness. Researchers used the ANOVA parametrization method to fit the second-order fractional polynomial network meta-analysis with a random-effect model. Using a non-proportional hazards network meta-analysis, 46 treatments were compared by considering a combination of direct and indirect evidence extracted from clinical trial studies. Included in the review were 46 trials involving 21350 patients. Between January 2000 and January 2023, researchers conducted a thorough search through Embase, PubMed/Medline, and Scopus. To undertake a secondary analysis of this data, we recreate individual patient data from published Kaplan-Meier (K-M) survival curves and assess the accuracy of that reconstruction. A random-effects model was used to evaluate the pooled overall survival and hazard ratio with a 95 percent confidence interval. The predicted survival curves for the network meta-analysis showed that GOLFIG and FOLFOX + Cetuximab treatments have higher survival, respectively. Our results provide moderate quality evidence and comparative effective estimates for various available first-line treatments for metastasis colorectal cancer based on network meta-analysis.

Pembrolizumab and other immunotherapies have become central in treating metastatic colon cancer, particularly effective in patients with mismatch repair deficiencies. We report a case involving a man who initially underwent radical surgery for sigmoid colon cancer on April 27, 2011, followed by hepatic tumor resection on September 21, 2017. Post-surgery, he received eight cycles of adjuvant chemotherapy with the CAPEOX regimen and was regularly monitored through CT and MRI scans. On August 24, 2022, liver metastases were detected, and he was diagnosed with Lynch syndrome (LS) due to germline mutation in the MSH2 and EPCAM genes. He commenced treatment with 200mg of pembrolizumab intravenously every three weeks on September 2, 2022, and demonstrated a sustained response. However, after 17 cycles, he developed a treatment related adverse event (TRAE) of pancreatic endocrine dysfunction, leading to type 1 diabetes, managed with subcutaneous insulin injections. After 30 cycles of treatment, no evidence of disease was observed. This case underscores the significant clinical benefits of first-line pembrolizumab in managing hepatic metastasis in colonic carcinoma associated with LS, despite the occurrence of TRAEs. It raises critical questions regarding the optimal duration of immunotherapy following a complete or partial response and whether treatment should be discontinued upon the emergency of TRAEs. Continued research and forthcoming clinical trials with checkpoint inhibitors are expected to refine treatment protocols for LS-associated carcinoma.

BACKGROUND: The impact of sidedness on survival of later-line treatment in patients with metastatic colorectal cancer (mCRC) is undetermined. This study aimed to investigate the association between sidedness and survival among chemotherapy refractory patients with mCRC treated with trifluridine/tipiracil (TAS-102) or regorafenib or both.
METHODS: Patients with mCRC treated with TAS-102 or regorafenib between 2015 and 2020 was retrospectively collected. Patients were stratified into TAS-102 first and regorafenib first, then subdivided into TAS-102 followed by regorafenib (T-R) and regorafenib followed by TAS-102 (R-T) groups. The oncologic outcomes were presented with time-to-treatment failure (TTF) and overall survival (OS).
RESULTS: After matching, 376 TAS-102 patients and 376 regorafenib patients were included for outcomes comparison. TTF had insignificant differences while OS was significantly different between TAS-102 and regorafenib groups. Median TTF and OS were 1.9 months versus 2.0 months (P = .701) and 9.1 months versus 7.0 months (P = .008) in TAS-102 and regorafenib, respectively. The OS benefits were consistent regardless primary tumor location. Subgroup analysis with 174 T-R patients and 174 R-T patients was investigated for treatment sequences. TTF and OS had significant differences in both groups. Median TTF and OS were 8.5 months versus 6.3 months (P = .001) and 14.4 months versus 12.6 months (P = .035) in T-R and R-T groups, respectively. The TTF and OS benefits were persisted regardless primary tumor location.
CONCLUSIONS: TAS-102 first provided a better survival benefit in chemotherapy refractory patients with mCRC across all sidedness. Further prospective studies are warranted to validate our conclusions.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing.
METHODS: We collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs. A control cohort of BRAFm pMMR/MSS mCRC patients treated with encorafenib+cetuximab+/-binimetinib from 2nd line was used.
RESULTS: dMMR/MSI-H (n = 50) BRAFm mCRC patients were more often > 70-year-old, with right-sided primary tumors, without liver but more lymphnode metastases than pMMR/MSS (n = 170). They were treated more frequently beyond 2nd line and 45 % were primary progressors to ICIs. Lower ORR (18 % versus 32 %, p = 0.09) and DCR (60 % versus 73 %, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS patients. After a median follow-up of 14.04 months, no differences in PFS (median 5.13 versus 4.50 months, HR 0.83, 95 %CI: 0.57-1.20, p = 0.31) and OS (median 10.75 versus 9.11 months, HR 0.89, 95 %CI: 0.59-1.32, p = 0.55) were observed.
CONCLUSIONS: Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.

In identifying biomarkers for anticancer drugs, the lack of objectivity in selecting candidate factors makes interpretation difficult. We performed preclinical analysis and a translational validation study to identify candidate biomarkers for regorafenib efficacy in metastatic colorectal cancer (mCRC). Using in silico COMPARE analysis with a human cancer cell line panel, JFCR39, we selected candidate biomarkers whose expression correlates with regorafenib sensitivity. We validated predictive values in mCRC patients receiving regorafenib (discovery, n = 53) and FTD/TPI (control, n = 16). Blood samples were obtained at baseline (BL), before the second cycle (2nd), and at progressive disease (PD), and biomarker levels were measured using ELISA. Our analysis showed that high matrix metalloproteinase (MMP)-14 expression was associated with a high sensitivity to regorafenib. In the discovery cohort, high MMP-14 levels at BL and PD were correlated with tumor shrinkage and longer progression-free survival (PFS). A subsequent analysis of other related factors further indicated that the patients with decreased MMP-9 levels at the 2nd had higher disease control rates, tumor shrinkage, longer PFS, and overall survival than those with increased changes. These findings were not observed in the control cohort. Our study suggests MMP-14 and MMP-9 may serve as prognostic markers for regorafenib and provide insights into novel combination therapies with anti-MMP-9 agents or FTD/TPI.

Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated notable efficacy in treating patients with deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, its clinical application is fraught with challenges and can lead to significant immune-related adverse events (ir-AEs). In this report, we present a complicated case of an mCRC patient with MSI-H and mutations in β2M and LRP1B proteins, complicated by concurrent bacteremia and liver fluke infection, who received first-line anti-PD1 therapy. The patient exhibited a positive response to anti-PD1 treatment, even in the presence of concomitant antibiotic and anti-parasitic interventions. Additionally, the patient experienced immunotherapy-related autoimmune hemolytic anemia (ir-AIHA), a rare hematological ir-AE, which was effectively treated later on. Immunotherapy represents a pivotal and highly effective approach to tumor treatment. Baseline assessment of the MMR and MSI status is a crucial step before initiating immunotherapy, and regular ongoing assessments during the treatment course can facilitate early recognition of any secondary complications, enabling prompt intervention and ensuring optimal therapeutic outcomes. Overall, a multidisciplinary diagnostic and therapeutic algorithm can help maximize the therapeutic benefits of immunotherapy.

BACKGROUND: Primary tumor (PT) sidedness is an established prognostic marker in metastatic colorectal cancer (mCRC) and has a predictive impact on the efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibody [monoclonal antibody (mAb)] in patients with RAS wild-type mCRC. This investigation focuses on patients with BRAFV600E-mutated (BRAFmt) mCRC and examines the efficacy of anti-EGFR mAbs in relation to primary tumor sidedness (PTS).
METHODS: This pooled analysis was carried out using individual patient data from five randomized studies in the first-line setting of mCRC. The population of interest was limited to patients with BRAFmt mCRC and known PTS. For analysis, treatment was stratified into two groups: those treated with anti-EGFR mAbs and those without. Dichotomous variables, such as overall response rate and objective response rate (ORR), were compared using chi-square or Fisher\'s exact test. Time-to-event endpoints [progression-free survival (PFS) and overall survival (OS)] were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. An interaction test was carried out via Cox regression.
RESULTS: A total of 102 patients with BRAFmt mCRC were identified. The type of targeted therapy (anti-EGFR-based versus non-anti-EGFR) did not significantly impact the outcome. However, in patients with left-sided primary tumors, anti-EGFR mAb-based treatment, compared with non-anti-EGFR, was associated with a higher ORR (58% versus 34%; P < 0.01), trended toward improved PFS [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.34-1.13; P = 0.12], and demonstrated prolonged OS (HR 0.38; 95% CI 0.20-0.72; P < 0.01). In patients with right-sided primary tumors, anti-EGFR-based therapy had no effect on ORR (33% versus 36%; P > 0.99), induced inferior PFS (HR 1.97; 95% CI 1.12-3.47; P = 0.02), and trended toward a worse OS (HR 1.76; 95% CI 0.99-3.13; P = 0.05).
CONCLUSIONS: This analysis suggests that PTS has predictive value for the efficacy of anti-EGFR mAb in the first-line treatment of BRAFmt mCRC.

BACKGROUND: Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, inhibits angiogenesis and reduces tumor growth. Serum VEGF-C, lactate dehydrogenase, and inflammatory markers have been reported as predictive markers related to bevacizumab treatment. Programmed cell death ligand 1 (PD-L1) could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis.
OBJECTIVE: To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer (CRC) according to the expression of PD-L1.
METHODS: This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24, 2014 and February 28, 2022, at Samsung Medical Center (Seoul, South Korea). Analysis of patient data included evaluation of PD-L1 expression by the combined positive score (CPS). We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC.
RESULTS: A total of 124 patients was included in this analysis. Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy. While 77% of patients received FOLFOX, 23% received FOLFIRI as backbone first-line chemotherapy. The numbers of patients with a PD-L1 CPS of 1 or more, 5 or more, or 10 or more were 105 (85%), 64 (52%), and 32 (26%), respectively. The results showed no significant difference in progression-free survival (PFS) and overall survival (OS) with bevacizumab treatment between patients with PD-L1 CPS less than 1 and those with PD-L1 CPS of 1 or more (PD-L1 < 1% vs PD-L1 ≥ 1%; PFS: P = 0.93, OS: P = 0.33), between patients with PD-L1 CPS less than 5 and of 5 or more (PD-L1 < 5% vs PD-L1 ≥ 5%; PFS: P = 0.409, OS: P = 0.746), and between patients with PD-L1 CPS less than 10 and of 10 or more (PD-L1 < 10% vs PD-L1 ≥ 10%; PFS: P = 0.529, OS: P = 0.568).
CONCLUSIONS: Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.

Recent advances in immunotherapy using immune checkpoint inhibitors (ICIs) for various cancers have also highlighted a rise in immune-related adverse events, including hepatitis, potentially leading to the discontinuation of treatment. This study aimed to evaluate the prevalence of hepatitis in metastatic colorectal cancer (mCRC) patients undergoing different ICI therapies. An extensive search of PubMed, PubMed Central, and Google Scholar up to November 2023 identified relevant studies. After excluding non-English articles, case reports, reviews, ongoing trials, and studies combining other therapies, five studies qualified for inclusion. Data extraction and statistical analyses were performed using Excel and Comprehensive Meta-Analysis software, respectively. Results from a subgroup analysis indicated that the incidence of hepatitis was comparable among patients treated with PD-1 monotherapy, PDL-1 monotherapy, and combination PD-1 and CTLA-4 therapy, with rates of 2.6%, 2.2%, and 1.7% for any grade and 2.1%, 2.2%, and 1.7% for grade ≥3 hepatitis, respectively. Naive-treated mCRC patients exhibited higher hepatitis rates than those previously treated (3.2% vs 1.6% and 2.6% vs 1.6% for any grade and grade ≥3, respectively). This study underscores the similar risk of hepatitis across different ICI therapies, with an increased incidence in naive-treated mCRC patients.