Background: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. Methods: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. Results: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAF^V600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. Conclusion: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.

Extended molecular profiling (EMP) is recommended to tailor targeted treatment for advanced cholangiocarcinoma (CCA). However, neither the impact of EMP nor the availability of targeted therapies has been extensively described in a real-world setting. ANITA is an observational (retrospective and prospective) study enrolling 621 patients with CCA from 10 tertiary Italian cancer centers between 2017 and 2023. Current analyses are focused on access to EMP, evolving rates of EMP over time, access to targeted treatments and respective outcomes. Moreover, we explore the prognostic and predictive role of major driver molecular alterations. EMP was performed in 79.9% of patients with advanced CCA. The rate of EMP increased significantly over time (2017-2023: +25.8%). Overall, 139 patients harbored ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I-III alterations, and 18.7% of these patients received matched targeted therapies. No differences were seen in overall survival (OS) and progression-free survival (PFS) according to EMP availability. Patients receiving targeted therapies had the best OS, which was significantly longer than that of patients who did not receive targeted treatments (hazard ratio 0.49, 95% CI 0.28-0.86) or those without EMP available (hazard ratio 0.34, 95% CI 0.21-0.54). Among ESCAT I-III-positive cases, 42 patients had FGFR2 fusions/rearrangements and 59 had IDH1 mutations. After excluding patients treated with targeted therapies, only FGFR2 fusions/rearrangements retained a prognostic association with OS. Despite the increasing availability of EMP in advanced CCA, patient access to targeted therapies remains suboptimal. Our findings demonstrate that targeted treatments can markedly improve OS. Therefore, strategies to increase access to - and accelerate the availability of - targeted therapies are warranted. ANITA is the largest observational, retrospective and prospective, study exploring the impact of molecular profiling and matched targeted treatment in a large cohort of patients with advanced cholangiocarcinoma. While the availability of molecular profiling has increased in recent years, access to targeted therapy is still limited in routine practice. Administration of targeted treatment has a significant impact on overall survival, highlighting the importance of promoting timely and early access to new agents in this disease. ESR-21-21387.

Background: Cisplatin, gemcitabine, and durvalumab combination is a standard first-line treatment for advanced biliary tract cancer. This study aimed to assess the impact of genetic alterations on outcomes in patients with advanced biliary tract cancer treated with cisplatin, gemcitabine, and durvalumab in real-world clinical practice. Methods: Patients with unresectable, locally advanced, or metastatic biliary tract cancer treated with cisplatin and gemcitabine plus durvalumab across 39 centers in 11 countries in Europe, the United States, and Asia were included in this analysis. Results: The cohort included 513 patients with advanced biliary tract cancer. The 5 most frequently altered genes were TP53 (22.1%), KRAS (13.7%), CDKN2A/B (13.6%), ARID1A (12.2%), and IDH1 (9.2%). In multivariate analysis, SMAD4 mutations were associated with improved progression-free survival (PFS) (hazard ratio [HR] = 0.49, P = .018) and overall survival (HR = 0.11, P = .023), while TP53 mutations were linked to worse PFS (HR = 1.62, P = .0047) and TERT mutations to worse overall survival (HR = 8.92, P = .0012). No other genomic alterations were statistically associated with outcomes. Subgroup analysis showed that TP53 mutations negatively affected PFS and overall survival in intrahepatic cholangiocarcinoma, while KRAS mutations were associated with poorer PFS in extrahepatic cholangiocarcinoma. No gene alterations were linked to outcomes in gallbladder cancer. Conclusions: This large-scale analysis, with comprehensive molecular profiling, supports the positive prognostic impact of SMAD4 mutations for PFS and overall survival and highlights the negative prognostic roles of TP53 (PFS) and TERT (overall survival) mutations, providing valuable insights for personalized treatment strategies in biliary tract cancer.

Background & Aims: Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options and a poor prognosis. While first‐line combination therapies have improved outcomes, second‐line treatment remains challenging. Ivosidenib, an IDH1 inhibitor, has shown promise in treating IDH1 mutant CCA, but real‐world data is limited. This study aims to evaluate ivosidenib's efficacy and safety in a large cohort of patients and compare it with second‐line chemotherapy. Methods: This observational, retrospective, multicenter study included patients with advanced IDH1 mutant CCA treated with ivosidenib at 11 European institutions from May 2021 to September 2024. The primary endpoint was progression‐free survival (PFS); the main secondary objectives were overall survival (OS), disease control rate (DCR), overall response rate (ORR) and safety. As a pre‐planned exploratory objective, mPFS and OS of second‐line ivosidenib and FOLFOX/CAPOX were compared by means of inverse probability of treatment weights (IPTW)‐adjusted analysis. Results: The study included 46 patients treated with Ivosidenib; 43.5% received ivosidenib as second line and 56.5% as ≥ third line. Median PFS and OS were 3.7 (95% CI, 2.2–36.5) and 11.5 months (95% CI, 9.5–36.5). DCR was 50.0%. Grade ≥ 3 adverse events occurred in 8.7% of patients. IPTW‐adjusted mPFS was 6.9 months with ivosidenib and 2.1 months with FOLFOX/CAPOX (HR: 0.36, 95% CI, 0.20–0.64, p = 0.0005), while the mOS was 15.9 and 9.0 months with ivosidenib and FOLFOX/CAPOX, respectively (HR: 0.47, 95% CI, 0.23–0.96, p = 0.0405). Conclusion: This study suggests that ivosidenib is a valid option for patients affected by metastatic IDH1 mutant CCA after at least one line of standard treatment.