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Background: In the pivotal phase III RECOURSE trial, trifluridine/tipiracil (FTD/TPI) improved progression-free and overall survival (PFS, OS) of patients with pre-treated metastatic colorectal cancer (mCRC). Subsequently, the TALLISUR trial provided post-authorisation efficacy and safety data and patient-reported outcomes on quality of life (QoL) in a German patient cohort. The present analysis reports the final data on efficacy, safety and QoL and investigates the impact of baseline characteristics and associated prognostic subgroups on outcome. Methods: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). To assess the primary endpoint, QoL, EORTC QLQ-C30 questionnaires were employed. Secondary endpoints included QoL assessed through EQ-5D-5L questionnaires, OS, PFS and safety. Additionally, 3 subgroups were defined according to a post-hoc analysis of the RECOURSE trial: best, good and poor prognostic characteristics (BPC, GPC, PPC). Patients with < 3 metastatic sites at inclusion and/or ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC patients without liver metastasis at inclusion were considered to have BPC. All remaining patients were considered to have PPC. Results: Of 195 patients, 186 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. Treatment with FTD/TPI was associated with maintained QoL. For all patients, median OS was 6.9 months (95% CI 6.1 – 8.3) and for the defined subgroups (BPC n = 20 vs GPC n = 65 vs PPC n = 121) 12.2, 7.9 and 6.8 months (95% CI 6.0 – 18.2, 6.2 – 13.3, 5.4 – 8.1). The most frequent TEAEs were neutropenia (29.6%), anaemia (24.7%) and nausea (23.7%). Febrile neutropenia occurred in 1.1%. Conclusions: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression, but also with maintained QoL. Independent of other baseline characteristics such as ECOG performance status and age, low metastatic burden and indolent disease were factors associated with favourable outcome. Clinical trial registration: EudraCT-Number 2017–000292-83, first registration 19/06/2017. [ABSTRACT FROM AUTHOR]

Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. Patients and methods: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). Results: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. Conclusions: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum. METHODS: A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization. RESULTS: The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26–44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169). DISCUSSION: GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population. [ABSTRACT FROM AUTHOR]

Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1‐3, fibroblast growth factor receptor 1‐3 and platelet‐derived growth factor receptor‐a/‐b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC‐C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC‐C is a randomised controlled, double‐blinded, phase II trial in mCRC patients that received a first‐line non‐oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1‐d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty‐three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32‐1.30; P =.2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48‐2.23; P =.9387; DCR: F + P: 50% vs F + N: 66,7%; P =.2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second‐line therapy of mCRC. What's new?: Anti‐angiogenic agents frequently are used in combination with fluorouracil‐based doublet chemotherapy for metastatic colorectal cancer (mCRC) following failure of first‐line therapy. Prolonged use of existing angiogenesis inhibitors, however, fuels the development of resistance, necessitating a search for more effective anti‐angiogenic agents. Here, the authors examined the novel angiogenesis inhibitor nintedanib in combination with modified FOLFOX in second‐line treatment of mCRC. Nintedanib plus mFOLFOX was associated with only modest improvements in survival, a result potentially impacted by slow patient accrual in the trial. Adverse events were comparable to other combination therapies for mCRC, indicating general clinical safety for nintedanib plus mFOLFOX. [ABSTRACT FROM AUTHOR]

Treatment of metastatic colorectal cancer (CRC) has continuously improved over the last decade. However, disease monitoring remains underdeveloped and mostly dependent on imaging e.g. RECIST 1.1 criteria. The genetic landscape of individual cancers and subsequently occurring treatment-induced evolution remain neglected in current surveillance strategies. Novel biomarkers demand minimally invasive and repetitive tracking of the cancer mutagenome for therapy stratification and to make prognostic predictions. Carcinoembryonic antigen (CEA), a routinely used tumor marker for CRC, does not meet these goals and thus prevents its use as a reliable monitoring tool. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, may bypass the limitations of currently available biomarkers and could be a tool for noninvasive disease monitoring. Here, total cfDNA levels differentiated a cohort of metastatic CRC patients from healthy controls. Furthermore, we correlated cfDNA during chemotherapy of 27 stage IV patients with clinical parameters to establish its prognostic and predictive value. Indeed, cfDNA levels in chemotherapy naive patients correlate with the tumor burden and CEA values at diagnosis and increase upon disease progression during 1st and 2nd line treatment. Moreover, we confirm the possibility of cfDNA-based genotyping of KRAS to early detect the emergence of resistance during chemotherapy. These data indicate that repetitive quantitative and mutational analysis of cfDNA might complement current treatment standards but may have also limited value in some patients. [ABSTRACT FROM AUTHOR]