P4, N=200, Not yet recruiting, The First Affiliated Hospital of Wenzhou Medical University; The First Affiliated Hospital of Wenzhou Medical University

P4, N=30, Not yet recruiting, The First Affiliated Hospital of Zhengzhou University; The First Affiliated Hospital of Zhengzhou University

P1/2, N=62, Recruiting, Sun Yat-sen University Cancer Center; Sun Yat-sen University Cancer Center

Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. Additionally, our findings revealed that macrophages represent a significant source of thymidine phosphorylase expression, comprising over 40% of the expressing cells, in human colorectal cancer, thereby contributing to chemoresistance.

The number of patients with prior regorafenib treatment was 14 in the TAS-102 with bevacizumab group and 5 in the TAS-102 alone group. The combination of TAS-102 and bevacizumab resulted in a better survival outcome than TAS-102 monotherapy, consistent with previous studies. This analysis supports the use of the combination of TAS-102 and bevacizumab as the best therapeutic option for patients with refractory metastatic colorectal cancer in clinical practice.

Favorable prognostic factors revealed in the multivariate analysis of overall survival (OS) were: <3 prior lines of treatment (p = 0.02), good to moderate histological differentiation (p = 0.0003), CEA < 5 ng/L (p = 0.0227) and SII ≤ 550 (p = 0.0001). Our study indicated that pre-treatment SII may be clinically useful for selecting likely responder patients and assessing the prognosis for mCRC patients treated with TT.

P1, N=19, Active, not recruiting, OHSU Knight Cancer Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Sep 2024

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...Capecitabine (CAP) + BEV is recommended in these patients...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.

P2, N=42, Active, not recruiting, Roswell Park Cancer Institute | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2023 --> Jul 2024

P2; Trial completion date: May 2029 --> Sep 2024 | Trial primary completion date: May 2025 --> Sep 2024

P1/2, N=48, Active, not recruiting, Gruppo Oncologico del Nord-Ovest | Recruiting --> Active, not recruiting

P2, N=73, Not yet recruiting, UNICANCER | Trial completion date: Jun 2028 --> Oct 2028 | Initiation date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2026 --> Oct 2026

In summary, our study identified PCDH9 as a tumor suppressor in breast cancer and highlighted TAS-102 as a potential therapeutic option for tumors with low PCDH9 expression or deficiency. The specific interaction between TAS-102 and PCDH9 warrants further exploration, providing deeper insights into its mode of action in treating PCDH9-deficient breast cancer.

P2, N=23, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

P2, N=102, Completed, Academic and Community Cancer Research United | Trial completion date: Apr 2024 --> Jul 2024 | Active, not recruiting --> Completed

P2, N=40, Recruiting, UMC Utrecht

P3, N=430, Completed, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Trial primary completion date: Dec 2023 --> Jul 2024 | Active, not recruiting --> Completed

P2; N=30 --> 0 | Not yet recruiting --> Withdrawn | Trial primary completion date: May 2024 --> May 2025

P2, N=36, Not yet recruiting, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

P=N/A, N=20, Not yet recruiting, Renji Hospital, Shanghai Jiaotong University School of Medicine; Renji Hospital, Shanghai Jiaotong University School of Medicine

P=N/A, N=110, Recruiting, Chang Gung Memorial Hospital

P2, N=200, Recruiting, First Affiliated Hospital of Wenzhou Medical University

TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.

LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.

P2, N=7, Completed, AHS Cancer Control Alberta | Not yet recruiting --> Completed | N=20 --> 7 | Trial completion date: Aug 2027 --> Jul 2023

P1, N=45, Recruiting, Roswell Park Cancer Institute | Trial primary completion date: Jul 2024 --> Sep 2026

P2; N=84 --> 12

P2; Recruiting --> Suspended

P1, N=45, Recruiting, Roswell Park Cancer Institute | Trial completion date: Feb 2026 --> Apr 2027 | Trial primary completion date: Jun 2025 --> Jul 2024

PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796).

P2; N=15 --> 25 | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

P2, N=52, Active, not recruiting, Borstkanker Onderzoek Groep | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Sep 2023 --> Jan 2024

P2, N=28, Active, not recruiting, The University of Hong Kong | Recruiting --> Active, not recruiting | Trial completion date: Nov 2023 --> Dec 2024 | Trial primary completion date: May 2023 --> Mar 2024

P2, N=35, Active, not recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings.

To our knowledge, this is the largest primarily US-based cohort of mCRC treated with FTD-TPI to be reported. KRAS G12 mutation, but not KRAS G13 mutation, was associated with shorter rwOS and ToT compared to KRAS WT, despite enrichment of TP53 and BRAF mutations in the KRAS WT group. This finding is consistent with previously published analyses of large randomized prospective trials of FTD-TPI in mCRC and further support KRAS mutation status as a predictive biomarker in this setting.

Research Funding: MD Anderson Cancer Center, Houston, TXGuardant Health Inc., Redwood City, CA...Background: Identifying non-responders to expensive salvage therapies with modest benefits and substantial treatment related adverse events (TRAEs) (e.g. regorafenib [Reg] or TAS102 [Tas] in mCRC) is key to precision care... In the first prospective study of clinical utility of monitoring ctDNA in mCRC, baseline ctDNA was strongly prognostic for clinical benefit from salvage therapies in mCRC. Adjusted for this prognostic impact, ΔctDNA between C1D1 and C1D15 was predictive of clinical outcomes. Efforts are needed to establish novel signatures, optimal cutoffs/intervals for assessing ctDNA response in mCRC, tailored to pts and their therapy.

It is possible to identify MRD+ pts through screening during surveillance and enroll them onto therapeutic trials. Preliminary results suggest that treatment with TAS-102 is effective in inducing ctDNA clearance in the short term, and in doing so, may prolong DFS for pts receiving additional therapy compared to the SC. However, without evidence of persistent clearance this is unlikely to result in an increased cure fraction.

P1/2, N=26, Recruiting, Wangxia LV

Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded.

P2, N=23, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Mar 2024 --> Jul 2024

P1, N=26, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jul 2023 | Trial primary completion date: Dec 2023 --> Jul 2023