Survival Benefit of Crossover Administration of Regorafenib and Trifluridine/Tipiracil Hydrochloride for Patients With Metastatic Colorectal Cancer: Exploratory Analysis of a Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study (REGOTAS)

Background: The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study.Patients and Methods: We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD).Results: A total of 550 patients (cohort A, n = 252; cohort B, n = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9–10.9 months) vs. 5.2 months (95% CI, 4.4–6.0 months), P < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47–0.72; P < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B.Conclusions: Our study revealed prolonged survival in patients treated with REG and TFTD. Therefore, all active agents, including REG and TFTD, should be made available to mCRC patients.

Targeting Thymidine Phosphorylase With Tipiracil Hydrochloride Attenuates Thrombosis Without Increasing Risk of Bleeding in Mice

Objective: Current antiplatelet medications increase the risk of bleeding, which leads to a clear clinical need in developing novel mechanism-based antiplatelet drugs. TYMP (Thymidine phosphorylase), a cytoplasm protein that is highly expressed in platelets, facilitates multiple agonist-induced platelet activation, and enhances thrombosis. Tipiracil hydrochloride (TPI), a selective TYMP inhibitor, has been approved by the Food and Drug Administration for clinical use. We tested the hypothesis that TPI is a safe antithrombotic medication. Approach and Results: By coexpression of TYMP and Lyn, GST (glutathione S-transferase) tagged Lyn-SH3 domain or Lyn-SH2 domain, we showed the direct evidence that TYMP binds to Lyn through both SH3 and SH2 domains, and TPI diminished the binding. TYMP deficiency significantly inhibits thrombosis in vivo in both sexes. Pretreatment of platelets with TPI rapidly inhibited collagen- and ADP-induced platelet aggregation. Under either normal or hyperlipidemic conditions, treating wild-type mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even at high doses, TPI has a lower bleeding side effect compared with aspirin and clopidogrel. Intravenous delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited thrombosis. Dual administration of a very low dose of aspirin and TPI, which had no antithrombotic effects when used alone, significantly inhibited thrombosis without disturbing hemostasis. Conclusions: This study demonstrated that inhibition of TYMP, a cytoplasmic protein, attenuated multiple signaling pathways that mediate platelet activation, aggregation, and thrombosis. TPI can be used as a novel antithrombotic medication without the increase in risk of bleeding.

Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy

RationaleMost of the current anti-platelet drugs inhibit platelet function permanently and have systemic side effects, including thrombocytopenia and hemorrhage. We previously found that thymidine phosphorylase (TYMP), a platelet cytoplasmic protein, facilitates multiple agonist induced platelet activation and enhances thrombosis. A specific TYMP inhibitor, namely, tipiracil hydrochloride (TPI), has been approved by the U.S. Food and Drug Administration for clinical use as an auxiliary drug making it possible to be repositioned as an anti-platelet medicine.ObjectiveWe aimed to test the hypothesis that TPI is a novel and safe anti-platelet drug by examining its role in platelet activation and thrombosis using both in vitro and in vivo studies.Methods and ResultsBy co-expression of TYMP and Lyn or Lyn-SH3 domain tagged with glutathione S-transferase, we showed the direct evidence that TYMP binds to the SH3 domain in its partners. TYMP haplodeficiency is sufficient to inhibit thrombosis in vivo regardless of gender. TPI treatment rapidly inhibited collagen- and ADP-induced platelet aggregation, which copied the phenotype of TYMP deficient platelets. Under both normal and hyperlipidemic conditions, treating wild type (WT) mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even administered above the effective dose, TPI has a lower bleeding side effect compared to aspirin and clopidogrel. Most importantly, intravenously delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited the growth of developing thrombi. Dual administration of very low dose of aspirin and TPI also dramatically inhibited thrombosis without disturbing hemostasis.ConclusionThis pharmacological study demonstrated that TYMP participates in multiple signaling pathways in platelet and plays a mechanistic role in regulating platelet activation and thrombosis. TPI, a specific TYMP inhibitor, would be a novel safe anti-platelet and anti-thrombosis medicine.

Survival impact on regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) for patients with metastatic colorectal cancer: Single institutional experience.

43 Background: Regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) demonstrated overall survival (OS) benefit in patients (pts) with metastatic colorectal cancer (mCRC) in the CORRECT and RECOURSE phase III trials. In Japan, REG and FTD/TPI have been approved in 2013 and 2014, respectively. However, little is known about survival impact on these agents in the real-world setting. Therefore, the aim of this retrospective study was to evaluate the effects of REG and FTD/TPI in pts with mCRC. Methods: We collected medical records from consecutive 1142 pts who had been initiated with first-line chemotherapy for mCRC from 2008 to 2016 at National Cancer Center Hospital East. The survival outcomes were compared between pts from 2008 to 2011 (cohort A) and those from 2012 to 2016 (cohort B). This study excluded pts who have not been refractory or intolerant to standard chemotherapy including fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR antibody if KRAS exon 2/ RAS wild-type tumors. Results: A total of 590 pts were analyzed (cohort A; N = 236 and cohort B; N = 354). More patients received at least one of REG or FTD/TPI in cohort B (16.1% vs. 59.9%, p < 0.001). The time from initiation to end of standard chemotherapy was comparable between the two cohort (20.0 vs. 17.5 months, p = 0.266). With a median follow-up period of 34.9 months, salvage-line OS (sOS) after standard chemotherapy was significantly longer in cohort B (4.8 vs. 6.6 months, p = 0.001), while there was only a favorable trend in cohort B in terms of OS from start of first-line treatment (27.3 vs. 28.5 months, p = 0.516). In cohort B, pts who sequentially received both of REG and FTD/TPI showed longest sOS (median, both of REG and FTD/TPI; 11.3 months, either REG or FTD/TPI; 7.0 months, neither REG nor FTD/TPI; 3.1 months). Conclusions: Our study showed that REG and FTD/TPI led to prolongation of sOS in the real-world setting, indicating the importance of strategies which make all active agents available to pts with mCRC.