Tipiracil: A Comprehensive Pharmacological and Clinical Monograph on its Evolving Role in Oncology

Section 1: Introduction

1.1 Overview

Tipiracil is a small molecule inhibitor of the enzyme thymidine phosphorylase (TPase, EC 2.4.2.4).[1] It is not administered as a standalone therapeutic agent but serves as an indispensable component of the oral fixed-dose combination antineoplastic drug known as Lonsurf, which is also referred to by its development code, TAS-102.[1] In this combination, Tipiracil is formulated with the cytotoxic thymidine-based nucleoside analog, trifluridine, in a precise molar ratio of 1:0.5 (trifluridine to tipiracil).[1] This specific formulation is designed to overcome the significant pharmacokinetic challenges associated with trifluridine, thereby enabling its clinical utility in oncology.

1.2 The Rationale for Combination Therapy

The development of Tipiracil is a prime example of a successful "drug rescue" strategy, born from the need to solve a fundamental pharmacological problem. Trifluridine, while recognized as a potent cytotoxic agent through its incorporation into DNA, was initially clinically unviable as an oral agent due to its extremely poor pharmacokinetic profile.[5] When administered alone, trifluridine exhibits a very short serum half-life, approximately 12 minutes following intravenous injection, and undergoes extensive and rapid degradation during its first pass through the liver.[6] This catabolism is mediated almost entirely by the enzyme thymidine phosphorylase (TPase), which converts trifluridine into its inactive metabolite, 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY).[1]

This rapid degradation rendered oral administration of trifluridine ineffective, as therapeutic plasma concentrations could not be achieved or sustained. Tipiracil was therefore rationally designed and developed as a potent and specific inhibitor of TPase, with the express purpose of being co-administered with trifluridine.[6] By inhibiting TPase, Tipiracil effectively blocks the primary metabolic pathway of trifluridine, preventing its degradation and dramatically increasing its systemic bioavailability. This strategic pairing transformed a promising but failed compound into a globally approved and clinically impactful oral cancer therapy, highlighting a key paradigm in modern pharmacology: optimizing the pharmacokinetic profile of a known active agent can be as valuable as discovering a new one. This success serves as a powerful proof-of-concept for revisiting other pharmacokinetically flawed compounds that could potentially be rescued with a co-administered inhibitor of their primary metabolic pathway, a strategy with significant implications for improving the efficiency and cost-effectiveness of drug development.

1.3 Thesis Statement and Report Scope

This report will provide an exhaustive analysis of Tipiracil, positioning it not merely as a pharmacokinetic adjuvant but as a molecule with a dual mechanism of action that has been central to the development of a new standard of care in refractory metastatic colorectal cancer (mCRC). The primary function of Tipiracil is to enable the therapeutic efficacy of trifluridine, a role which is complemented by a secondary, pharmacodynamic anti-angiogenic effect. This monograph will present a comprehensive review of Tipiracil's chemical identity, its non-clinical and clinical pharmacology, a detailed analysis of the pivotal clinical trial evidence that has shaped its use, its established safety profile, its global regulatory status, and the evolving landscape of ongoing research exploring its future role in the treatment of mCRC, metastatic gastric cancer (mGC), and other solid tumors.

Section 2: Chemical Identity and Physicochemical Properties

2.1 Nomenclature and Identifiers

For the purpose of unambiguous identification across scientific literature and global regulatory databases, Tipiracil is cataloged under several names and unique identifiers. The hydrochloride salt is the form used in the final drug product.[1]

• Chemical Name: 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione.[1]
• Synonyms: 5-Chloro-6-((2-iminopyrrolidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione; Tipiracilo.[2]
• CAS Number: 183204-74-2 (base); 183204-72-0 (hydrochloride salt).[8]
• DrugBank ID: DB09343.[1]
• PubChem CID: 6323266.[8]
• UNII: NGO10K751P.[1]
• ChEBI ID: CHEBI:90879.[1]
• ChEMBL ID: CHEMBL235668.[1]

2.2 Structural and Molecular Data

Tipiracil is structurally described as a member of the pyrimidone class, specifically a uracil derivative. The core uracil ring is substituted at position 5 with a chloro group and at position 6 with a (2-iminopyrrolidin-1-yl)methyl group. This structure classifies it chemically as a pyrimidone, an organochlorine compound, a carboxamidine, and a member of the pyrrolidines.[1]

• Molecular Formula: C9​H11​ClN4​O2​.[1]
• Molecular Weight:
• Average: 242.66 g·mol⁻¹.[2]
• Monoisotopic: 242.057053323 g·mol⁻¹.[2]
• Chemical Structure Representations:
• SMILES: C1CC(=N)N(C1)CC2=C(C(=O)NC(=O)N2)Cl.[1]
• InChI: InChI=1S/C9H11ClN4O2/c10-7-5(12-9(16)13-8(7)15)4-14-3-1-2-6(14)11/h11H,1-4H2,(H2,12,13,15,16).[1]
• InChIKey: QQHMKNYGKVVGCZ-UHFFFAOYSA-N.[1]

2.3 Physical Properties

The hydrochloride salt of Tipiracil, which is used in the Lonsurf formulation, is a white crystalline powder.[8] Its solubility profile is critical for its formulation as an oral tablet and has been well-characterized.

• Solubility in Water: 5 mg/mL at 20 °C.[8]
• Solubility in Other Solvents: It is soluble in 0.01 M hydrochloric acid and 0.01 M sodium hydroxide. It is slightly soluble in methanol, very slightly soluble in ethanol, and is considered practically insoluble in organic solvents such as acetonitrile, isopropyl alcohol, acetone, diisopropyl ether, and diethyl ether.[8]
• Solubility in Buffers: For research purposes, its solubility in PBS has been noted as 2 mg/mL, though achieving this requires ultrasonic agitation and warming to 60°C.[12]

The following table provides a consolidated summary of Tipiracil's key identifiers and physicochemical properties.

Table 1: Chemical and Physical Properties of Tipiracil
Property	Value / Identifier
IUPAC Name	5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione 1
DrugBank ID	DB09343 1
CAS Number	183204-74-2 (base); 183204-72-0 (HCl salt) 8
Molecular Formula	C9​H11​ClN4​O2​ 1
Average Molecular Weight	242.66 g·mol⁻¹ 2
Appearance (HCl Salt)	White crystalline powder 8
Water Solubility (20°C)	5 mg/mL 8
SMILES	C1CC(=N)N(C1)CC2=C(C(=O)NC(=O)N2)Cl 1
InChIKey	QQHMKNYGKVVGCZ-UHFFFAOYSA-N 1

This table serves as a foundational reference for chemists, pharmacists, and formulation scientists, aggregating data scattered across multiple sources into one definitive summary for research, development, and quality control purposes.

Section 3: Non-Clinical and Clinical Pharmacology

3.1 Mechanism of Action (MoA)

3.1.1 Primary MoA: Thymidine Phosphorylase Inhibition

The central and defining mechanism of action for Tipiracil is its function as a potent and specific inhibitor of the enzyme thymidine phosphorylase (TPase).[1] This enzymatic inhibition is the cornerstone of the Lonsurf combination therapy. TPase is the primary enzyme responsible for the rapid catabolism of trifluridine, breaking it down into its major inactive metabolite, 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY).[1] By directly inhibiting TPase, Tipiracil effectively blocks this extensive first-pass metabolism, a critical step that enables the oral administration of trifluridine and allows it to reach and maintain therapeutic concentrations in the plasma.[6]

3.1.2 Pharmacodynamic Impact on Trifluridine

The clinical consequence of Tipiracil's TPase inhibition is a profound and clinically essential enhancement of trifluridine's systemic exposure. Clinical pharmacokinetic studies have demonstrated that when co-administered with Tipiracil, the bioavailability of trifluridine is dramatically increased. Specifically, Tipiracil causes trifluridine's peak plasma concentration (Cmax​) to increase by approximately 22-fold and its total exposure, as measured by the area under the curve (AUC), to increase by approximately 37-fold compared to when trifluridine is administered alone.[4] This powerful pharmacokinetic potentiation is the key synergistic interaction that underpins the clinical efficacy of the Lonsurf combination product.

3.1.3 Secondary MoA: Indirect Anti-Angiogenesis

Beyond its primary pharmacokinetic role, Tipiracil possesses a secondary pharmacodynamic mechanism that may contribute to its overall anti-tumor activity. The enzyme it inhibits, TPase, is also known to be identical to an angiogenic factor called platelet-derived endothelial cell growth factor (PD-ECGF).[1] In many solid tumors, TPase is overexpressed, and elevated levels are directly associated with increased tumor vascularity (angiogenesis), higher malignancy, and a poorer clinical prognosis.[2] By inhibiting TPase, Tipiracil therefore exerts an indirect anti-angiogenic effect, which may contribute to the overall therapeutic benefit by helping to downregulate the formation of new blood vessels that supply the tumor.[1]

This dual mechanism of action becomes particularly relevant when Lonsurf is combined with bevacizumab, an antibody that directly targets vascular endothelial growth factor (VEGF). This creates a multi-pronged synergistic attack on the tumor. First, trifluridine exerts direct cytotoxic effects by incorporating into tumor cell DNA.[5] Second, Tipiracil enhances trifluridine's bioavailability through TPase inhibition.[8] Third, Tipiracil simultaneously provides an indirect anti-angiogenic effect by inhibiting TPase/PD-ECGF.[1] Fourth, bevacizumab provides a potent and direct anti-angiogenic effect by neutralizing VEGF.[14] Preclinical data further suggest that bevacizumab may "normalize" tumor vasculature, thereby increasing the delivery and phosphorylation of trifluridine within the tumor itself.[14] This "triple-threat" synergy—direct cytotoxicity combined with two complementary anti-angiogenic mechanisms—provides a compelling biological rationale for the clinically meaningful and statistically significant survival benefit observed in the pivotal SUNLIGHT clinical trial.

3.2 Pharmacokinetics (ADME)

The pharmacokinetic profile of Tipiracil has been well-characterized in clinical studies involving patients with advanced solid tumors.

• Absorption: Following oral administration, Tipiracil is absorbed from the gastrointestinal tract with a bioavailability of at least 27%.[5] In cancer patients receiving the standard dose of Lonsurf, peak plasma concentrations ( Tmax​) of Tipiracil are typically reached approximately 3 hours post-dose.[2] Food has a significant effect on its absorption; a high-fat, high-calorie meal can decrease both the peak concentration ( Cmax​) and total exposure (AUC) of Tipiracil by approximately 40%.[5] For this reason, Lonsurf is recommended to be administered with food to ensure consistent exposure.[15]
• Distribution: Tipiracil exhibits very low binding to plasma proteins, with less than 8% of the drug being bound.[2] This low protein binding minimizes the potential for drug-drug interactions arising from displacement from plasma albumin. The apparent volume of distribution ( Vd​/F) for Tipiracil hydrochloride is large, at 333 L, which indicates extensive distribution of the drug into tissues outside of the plasma compartment.[2]
• Metabolism: A key feature of Tipiracil's pharmacokinetic profile is its lack of metabolism by the cytochrome P450 (CYP) enzyme system.[2] It also does not undergo significant metabolism in the liver or by isolated hepatocytes, meaning it avoids extensive first-pass effect.[2] The vast majority of the drug is excreted in its unchanged form. A minor metabolite, 6-hydroxymethyluracil (6-HMU), has been identified in plasma, urine, and feces, but it is formed only to a small extent and is believed to be a product of metabolism by gut microflora rather than hepatic enzymes.[2] This lack of reliance on the CYP450 pathway is a significant clinical advantage. Cancer patients, particularly those with refractory disease, are often on multiple concomitant medications for supportive care and to manage comorbidities. Many of these drugs are substrates, inhibitors, or inducers of CYP enzymes, a major source of clinically significant drug-drug interactions. By avoiding this pathway, Tipiracil has a more predictable pharmacokinetic profile and a substantially lower risk of interactions with a wide range of common medications. This simplifies clinical management, making the regimen safer and easier to administer in a real-world, polypharmacy setting. The primary interaction risk is shifted to the less commonly considered OCT2 and MATE1 transporters.
• Excretion: Tipiracil is eliminated from the body primarily through two routes: approximately 50% of an administered dose is excreted in the feces, and 27% is excreted in the urine.[2] In both routes, the major component recovered is unchanged Tipiracil, with 6-HMU being the main metabolite.[2] The elimination half-life ( t1/2​) of Tipiracil is short, approximately 2.1 hours after a single dose, which slightly increases to 2.4 hours at steady state.[2] Consistent with its short half-life, no accumulation of Tipiracil is observed with the repeated dosing schedule used in clinical practice.[7]

The following table summarizes the key pharmacokinetic parameters for Tipiracil.

Table 2: Summary of Tipiracil Pharmacokinetic Parameters
Parameter	Value
Bioavailability (Oral)	≥27% 5
Time to Peak Plasma Concentration (Tmax​)	~3 hours 2
Plasma Protein Binding	<8% 2
Apparent Volume of Distribution (Vd​/F)	333 L 2
Metabolism	Not metabolized by CYP450 enzymes; minor metabolism to 6-HMU by gut flora 2
Elimination Half-life (t1/2​)	2.1 hours (single dose); 2.4 hours (steady state) 2
Routes of Excretion	Feces (50%), Urine (27%) 2
Food Effect	High-fat meal decreases Cmax​ and AUC by ~40% 5

3.3 Pharmacodynamics and Drug Interactions

The potential for drug-drug interactions with Tipiracil is primarily driven by its reliance on specific transporters for elimination and its mechanism of action as a TPase inhibitor.

• Transporter-Mediated Interactions: In vitro studies have identified Tipiracil as a substrate for two key renal transporters: Solute Carrier Family 22 Member 2 (SLC22A2), also known as Organic Cation Transporter 2 (OCT2), and Solute Carrier Family 47 Member 1 (SLC47A1), also known as Multidrug and Toxin Extrusion Protein 1 (MATE1).[6] This is the most critical pathway for predicting clinically relevant interactions. Drugs that inhibit OCT2 and/or MATE1 can decrease the renal clearance of Tipiracil, leading to increased plasma concentrations and a higher risk of toxicity. Clinicians should monitor for increased Lonsurf-related toxicity when it is co-administered with known inhibitors of these transporters.[13]
• Target-Mediated Interactions: As a potent inhibitor of thymidine phosphorylase, Tipiracil has the potential to interact with other drugs that are substrates for this enzyme. This includes other fluoropyrimidines like capecitabine, floxuridine, and fluorouracil, whose metabolic pathways also involve TPase.[16] Additionally, trifluridine, the partner drug of Tipiracil, requires phosphorylation by thymidine kinase for its activation. This creates a potential for competitive inhibition with other substrates of human thymidine kinase, such as the antiviral drug zidovudine. Co-administration of zidovudine could theoretically decrease the activation and efficacy of trifluridine, and this combination should be avoided if possible.[6]

The following table provides a practical clinical summary of potential drug-drug interactions.

Table 3: Clinically Relevant Drug-Drug Interactions for Tipiracil
Interacting Group	Interacting Drugs	Potential Effect and Recommendation
OCT2 / MATE1 Inhibitors	Cimetidine, Cisplatin, Ciprofloxacin, Apalutamide, Bupropion, Diphenhydramine, Dolutegravir, Famotidine, Pyrimethamine 2	Can decrease renal excretion of Tipiracil, leading to increased plasma concentrations and potential for increased toxicity. Monitor patients for increased adverse reactions. 2
Thymidine Phosphorylase (TPase) Substrates	Capecitabine, Floxuridine, Fluorouracil 16	Tipiracil inhibits the metabolism of these agents, which could alter their efficacy and toxicity profiles. Clinical significance requires careful consideration of treatment sequencing.
Human Thymidine Kinase Substrates	Zidovudine 13	These agents may compete with trifluridine for activation by thymidine kinase, potentially reducing the anti-tumor activity of Lonsurf. Avoid combination if possible. 6

Section 4: Clinical Efficacy in Metastatic Colorectal Cancer (mCRC)

4.1 The Foundation of Monotherapy: The RECOURSE Trial (TPU-TAS-102-301)

The approval and establishment of Lonsurf as a therapeutic option in oncology were founded on the results of the pivotal RECOURSE trial.

• Design: RECOURSE was a large-scale, global, randomized (2:1), double-blind, placebo-controlled Phase III clinical trial. It enrolled 800 patients with metastatic colorectal cancer (mCRC) whose disease was refractory to, or who were intolerant of, all available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as biologic agents targeting VEGF and, for RAS wild-type patients, EGFR.[17] Patients were randomized to receive either Lonsurf (35 mg/m² twice daily on the standard schedule) plus best supportive care (BSC), or placebo plus BSC.[19]
• Primary Endpoint: The primary objective of the trial was to demonstrate an improvement in overall survival (OS).[19]
• Results: The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in OS for patients treated with Lonsurf. The median OS was 7.1 months in the Lonsurf arm compared to 5.3 months in the placebo arm, representing a 1.8-month improvement (Hazard Ratio for death = 0.68; 95% Confidence Interval [CI], 0.58–0.81; p < 0.001).[17] This corresponded to a 32% reduction in the risk of mortality. The trial also met key secondary endpoints, including a significant improvement in progression-free survival (PFS), with a median PFS of 2.0 months for Lonsurf versus 1.7 months for placebo (HR 0.48; p < 0.0001), and a significantly higher disease control rate (DCR) of 44.0% for Lonsurf versus 16.3% for placebo (p < 0.0001).[19]
• Conclusion: The robust and positive results of the RECOURSE trial unequivocally established Lonsurf as a new standard of care for patients with heavily pre-treated, refractory mCRC. These findings provided the basis for its initial regulatory approvals by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[17]

Table 4: Summary of Efficacy Results from the RECOURSE Trial
Endpoint	Lonsurf Arm (n=534)	Placebo Arm (n=266)	Hazard Ratio (95% CI)	p-value
Median Overall Survival (mOS)	7.1 months	5.3 months	0.68 (0.58–0.81)	< 0.001
Median Progression-Free Survival (mPFS)	2.0 months	1.7 months	0.48 (0.40–0.55)	< 0.001
Disease Control Rate (DCR)	44.0%	16.3%	N/A	< 0.0001
Data sourced from.17

4.2 Establishing a New Standard of Care: The SUNLIGHT Trial (NCT04737187)

Following the success of Lonsurf monotherapy, the SUNLIGHT trial was designed to determine if adding an anti-angiogenic agent could further improve outcomes.

• Design: SUNLIGHT was a global, randomized (1:1), open-label, active-controlled Phase III trial. It compared the efficacy and safety of Lonsurf in combination with bevacizumab versus Lonsurf monotherapy in 492 patients with refractory mCRC who had received a maximum of two prior chemotherapy regimens for advanced disease.[23]
• Primary Endpoint: The primary endpoint was overall survival (OS).[24]
• Results: The trial demonstrated a compelling and practice-changing result. The combination of Lonsurf plus bevacizumab led to a statistically significant and clinically profound improvement in OS. The median OS for the combination arm was 10.8 months, compared to 7.5 months for the Lonsurf monotherapy arm (HR 0.61; 95% CI, 0.49–0.77; p < 0.001).[24] This represents a 3.3-month absolute improvement in median survival and a 39% reduction in the risk of death. The combination was also superior for all key secondary endpoints. Median PFS was more than doubled, at 5.6 months for the combination versus 2.4 months for monotherapy (HR 0.44; 95% CI, 0.36–0.54; p < 0.001).[21]
• Conclusion: The SUNLIGHT trial was a landmark study that successfully established Lonsurf plus bevacizumab as a new, superior standard of care for the third-line treatment of patients with refractory mCRC. The magnitude of the survival benefit led to rapid global regulatory approvals for this combination regimen.[23]

Table 5: Summary of Efficacy Results from the SUNLIGHT Trial
Endpoint	Lonsurf + Bevacizumab Arm (n=246)	Lonsurf Monotherapy Arm (n=246)	Hazard Ratio (95% CI)	p-value
Median Overall Survival (mOS)	10.8 months	7.5 months	0.61 (0.49–0.77)	< 0.001
Median Progression-Free Survival (mPFS)	5.6 months	2.4 months	0.44 (0.36–0.54)	< 0.001
Overall Survival Rate at 12 months	43%	30%	N/A
Disease Control Rate (DCR)	76.6%	47.0%	N/A	< 0.001
Data sourced from.21

4.3 Subgroup Analysis of the SUNLIGHT Trial: Consistent Benefit in Diverse Populations

A critical finding from the SUNLIGHT trial was the consistency of the benefit from adding bevacizumab across all clinically relevant, prespecified patient subgroups.[26] This broad applicability reinforces its role as a standard of care. The survival benefit was maintained regardless of:

• Patient Age: A dedicated subgroup analysis examined outcomes in patients aged <65, 65-74, and ≥75 years. The hazard ratios for OS consistently favored the combination arm across all age groups (HRs of 0.65, 0.64, and 0.49, respectively), demonstrating that elderly patients derive a similar or even greater relative benefit from the combination therapy.[32]
• KRAS Mutation Status: The benefit of the combination was observed in patients with both KRAS wild-type and KRAS mutant tumors, indicating that the mechanism of synergy is independent of this key oncogenic driver.[30]
• Prior Bevacizumab Treatment: Importantly, the survival benefit was also seen in the large proportion of patients who had previously received and progressed on a bevacizumab-containing regimen (HR 0.73).[30] This finding provides strong clinical evidence for the "angiogenesis continuum" hypothesis, which posits that tumors may develop resistance but do not become entirely independent of the VEGF pathway. Continuing to suppress this pathway with bevacizumab, even after prior progression, remains a valid and effective strategy when paired with a new cytotoxic backbone like Lonsurf. This has fundamentally changed clinical practice, providing a clear evidence base for re-using bevacizumab in the third-line setting.
• Presence of Liver Metastases (CRLM): A post-hoc analysis evaluated outcomes based on the presence of colorectal liver metastases at baseline. While patients without liver metastases had better overall outcomes in both treatment arms, the addition of bevacizumab to Lonsurf resulted in longer OS and PFS compared to Lonsurf alone in both the group with CRLM and the group without CRLM.[35]

4.4 Real-World Evidence (RWE) and Comparative Effectiveness

Data from real-world clinical practice have largely corroborated the findings from the pivotal randomized controlled trials.

• Corroboration of Trial Data: Multiple retrospective RWE studies conducted in community oncology settings have confirmed the superiority of Lonsurf plus bevacizumab over Lonsurf monotherapy. One large study using the ConcertAI database (n=3,680) found a median real-world OS (rwOS) of 9.4 months for the combination versus 6.4 months for monotherapy (HR 0.68), closely mirroring the results of SUNLIGHT.[36] Another study from Texas Oncology reported a median OS of 11.6 months with the combination versus 6.2 months with monotherapy.[37] Similarly, the REWRITE study, a real-world analysis from Portugal, reported a median OS of 7.9 months with Lonsurf monotherapy, which is highly consistent with the 7.1 months observed in the RECOURSE trial.[38]
• Comparative Effectiveness vs. Regorafenib: Lonsurf and regorafenib are the two primary oral agents approved for refractory mCRC. A large RWE study using the de-identified Flatiron Health database directly compared the two agents as monotherapies. The analysis found no statistically significant difference in OS between patients treated with Lonsurf versus those treated with regorafenib (median OS of approximately 6.6 months vs. 6.3 months, respectively).[39] This suggests that, as monotherapies, the two agents have comparable efficacy in a real-world setting.
• Contradictory Evidence: It is worth noting that not all RWE studies are in perfect alignment. A very small, single-center retrospective study involving only 43 patients did not find a statistically significant improvement in OS or PFS with the addition of bevacizumab.[40] Such findings from small, observational studies are subject to significant selection bias and confounding factors and do not outweigh the robust, high-level evidence from the large, randomized SUNLIGHT trial.

Section 5: Clinical Efficacy in Other Solid Tumors

5.1 Metastatic Gastric and GEJ Adenocarcinoma: The TAGS Trial

The clinical utility of Tipiracil-based therapy extends beyond colorectal cancer. The efficacy of Lonsurf in metastatic gastric cancer (mGC) and adenocarcinoma of the gastroesophageal junction (GEJ) was established in the TAGS trial.

• Design: TAGS was a global, randomized, double-blind, placebo-controlled Phase III trial that enrolled 507 patients with metastatic gastric or GEJ adenocarcinoma who were refractory to at least two prior lines of chemotherapy.[4]
• Results: The trial met its primary endpoint of overall survival. Patients treated with Lonsurf had a significantly longer median OS of 5.7 months compared to 3.6 months for those receiving placebo (HR 0.69; 95% CI, 0.56–0.85; p <.001).[4]
• Conclusion: Based on the positive results of the TAGS trial, Lonsurf received approval from both the FDA and EMA for the treatment of adult patients with mGC or GEJ adenocarcinoma who have been previously treated with at least two prior systemic treatment regimens. This provided an important new therapeutic option for a patient population with limited effective treatments.[1]

5.2 Investigational Uses in Other Malignancies

The favorable safety profile and unique mechanism of action of Lonsurf have prompted its investigation in other tumor types.

• Cholangiocarcinoma: The TRITICC trial (NCT04059562) is an ongoing Phase II pilot study evaluating the efficacy of Lonsurf in combination with irinotecan. This trial is enrolling patients with advanced, non-resectable, or metastatic cholangiocarcinoma or gallbladder carcinoma who have progressed after a prior gemcitabine-based therapy.[42] This represents a rational effort to expand the drug's utility into other challenging gastrointestinal malignancies.
• SARS-CoV-2: In a notable example of potential drug repurposing, some early preclinical computational and in vitro research has suggested that Tipiracil may inhibit SARS-CoV-2 enzymes, specifically the Nsp15 endoribonuclease, by interacting with its uridine binding pocket.[8] While this finding is highly preliminary and has not been translated into clinical studies, it highlights the potential for existing drugs to be explored for novel antiviral applications.

Section 6: Comprehensive Safety Profile and Management

6.1 Adverse Reactions

The safety profile of Lonsurf is well-defined and is characterized primarily by manageable myelosuppression and gastrointestinal toxicities. The profile differs slightly between monotherapy and combination therapy with bevacizumab.

• Primary Toxicities: Across all studies, the most common and clinically significant adverse reactions are hematologic (neutropenia, anemia, thrombocytopenia) and gastrointestinal (nausea, vomiting, diarrhea), along with fatigue and decreased appetite.[5]
• Lonsurf Monotherapy (Pooled Data): In patients receiving Lonsurf as a single agent, the most frequent Grade ≥3 adverse events are neutropenia (38%), anemia (17-18%), and thrombocytopenia (4-5%). Febrile neutropenia, a serious complication of neutropenia, occurs in approximately 3-4% of patients.[17]
• Lonsurf in Combination with Bevacizumab (SUNLIGHT Trial): The addition of bevacizumab to Lonsurf primarily increases the incidence and severity of neutropenia. In the SUNLIGHT trial, Grade ≥3 neutropenia was reported in 52% of patients in the combination arm, compared to 32-38% in monotherapy arms. However, this increase in neutropenia did not translate to a higher rate of febrile neutropenia, which remained very low at 0.4%.[23] This critical observation suggests that while the neutropenia is more common, it is generally manageable and does not lead to a proportional increase in infectious complications. Other common Grade ≥3 events in the combination arm included anemia (5%) and thrombocytopenia (4%).[23]

The following table provides a direct comparison of the most common severe adverse events between the two regimens.

Table 6: Comparison of Grade ≥3 Adverse Events (Lonsurf Monotherapy vs. Lonsurf + Bevacizumab)
Adverse Event	Lonsurf Monotherapy (%)	Lonsurf + Bevacizumab (%)
Neutropenia	38%	52%
Anemia	17%	5%
Thrombocytopenia	4%	4%
Febrile Neutropenia	3%	0.4%
Fatigue	4%	3%
Nausea	1%	1%
Diarrhea	3%	Not Reported as ≥2%
Data compiled from pooled monotherapy studies 19 and the SUNLIGHT combination study.23

6.2 Management of Toxicities

Effective management of adverse events is crucial for maintaining patients on therapy. The prescribing information for Lonsurf provides clear guidelines.

• Hematologic Monitoring: Proactive monitoring is essential. Complete blood counts (CBC) must be obtained prior to the start of each treatment cycle and again on Day 15 of each cycle to detect myelosuppression.[15]
• Dose Modifications: The regimen has well-defined rules for dose interruption and reduction. Treatment should be withheld if the absolute neutrophil count (ANC) falls below 0.5 × 10⁹/L or if platelets drop below 50 × 10⁹/L. After recovery, the dose can be reduced by 5 mg/m² increments for subsequent cycles. A maximum of three dose reductions are permitted, down to a minimum dose of 20 mg/m² twice daily (or 15 mg/m² twice daily for patients with severe renal impairment). Once a dose is reduced, it should not be re-escalated.[15]
• Supportive Care: The use of granulocyte-colony stimulating factors (G-CSF) is a key strategy for managing neutropenia. In clinical trials, G-CSF was used in 14% of patients on monotherapy and 29% of patients on combination therapy with bevacizumab.[23] Standard anti-emetic and anti-diarrheal medications should be administered as clinically indicated to manage gastrointestinal side effects.[5]

6.3 Warnings and Precautions

The Lonsurf label includes several important warnings and precautions for specific risks and patient populations.

• Severe Myelosuppression: This is the most significant warning associated with Lonsurf. It can be life-threatening, and fatal outcomes due to neutropenic infection or sepsis have been reported, although the incidence is low (0.3% to 0.4%).[5]
• Embryo-Fetal Toxicity: Lonsurf is considered genotoxic and can cause fetal harm based on its mechanism of action and findings from animal studies. Therefore, it is not recommended for use during pregnancy. Women of reproductive potential must use effective contraception during treatment and for at least 6 months after the final dose. Men with female partners of reproductive potential must use condoms during treatment and for at least 3 months after the final dose.[5] Breastfeeding is also not recommended during treatment.[5]
• Use in Specific Populations:
• Geriatric Patients: Patients aged 65 years and older have been observed to have a higher incidence of Grade 3 or 4 hematologic toxicities, particularly neutropenia, compared to younger patients.[15] However, the SUNLIGHT trial's subgroup analysis confirmed that the efficacy benefit of the combination regimen is preserved, and the treatment is considered tolerable in this population.[32]
• Renal Impairment: No dose adjustment is needed for mild or moderate renal impairment. However, for patients with severe renal impairment (Creatinine Clearance [CrCl] 15-29 mL/min), a dose reduction of the starting dose from 35 mg/m² to 20 mg/m² is required. This is because exposure to both trifluridine and especially tipiracil is significantly increased in patients with impaired renal function.[7] Lonsurf has not been studied in patients with end-stage renal disease.[46]
• Hepatic Impairment: Lonsurf should not be initiated in patients with baseline moderate or severe hepatic impairment. While no adjustment is needed for mild hepatic impairment, patients with moderate impairment have shown a high incidence of Grade 3 or 4 hyperbilirubinemia.[7]

Section 7: Regulatory History and Dosing Recommendations

7.1 Global Regulatory Landscape

Lonsurf has received approvals from major regulatory bodies worldwide based on the strength of the data from its pivotal Phase III clinical trials.

• U.S. Food and Drug Administration (FDA):
• September 22, 2015: Initial approval for Lonsurf as a monotherapy for the treatment of patients with refractory mCRC, based on the RECOURSE trial.[17]
• February 22, 2019: Approval expanded to include the treatment of adult patients with metastatic gastric or GEJ adenocarcinoma refractory to at least two prior chemotherapy regimens, based on the TAGS trial.[4]
• August 2, 2023: Approval granted for Lonsurf in combination with bevacizumab for the treatment of adult patients with mCRC previously treated with standard therapies, based on the landmark SUNLIGHT trial.[23]
• European Medicines Agency (EMA):
• April 2016: Initial marketing authorisation granted for Lonsurf monotherapy for refractory mCRC, following a positive opinion based on the RECOURSE study.[20]
• ~2019: Indication expanded to include refractory metastatic gastric or GEJ adenocarcinoma, based on the TAGS trial.[4]
• August 1, 2023: The European Commission approved Lonsurf in combination with bevacizumab for third-line refractory mCRC, based on the results of the SUNLIGHT trial.[29]

7.2 Formulation, Dosage, and Administration

• Formulation: Lonsurf is supplied as oral, film-coated tablets. Two strengths are available to allow for precise dosing based on body surface area:
• 15 mg trifluridine / 6.14 mg tipiracil: A white, biconvex, round tablet.[15]
• 20 mg trifluridine / 8.19 mg tipiracil: A pale red, biconvex, round tablet.[15]
• Dosage: The recommended starting dose of Lonsurf, either as monotherapy or in combination with bevacizumab, is 35 mg/m² per dose, calculated based on the trifluridine component. The dose is rounded to the nearest 5 mg increment, and the total dose should not exceed 80 mg per administration.[15] The number and strength of tablets for each dose are determined by the patient's Body Surface Area (BSA).
• Administration Schedule: The calculated dose is administered orally twice daily with food. The dosing schedule follows a 28-day cycle, with treatment given on Days 1 through 5 and Days 8 through 12. This is followed by a 14-day rest period. Treatment continues until disease progression or unacceptable toxicity occurs.[15] Patients are instructed to swallow the tablets whole and not to make up for missed or vomited doses.[15]

Section 8: Future Directions and Expert Conclusion

8.1 The Evolving Research Landscape

The established efficacy and manageable safety profile of Lonsurf, particularly its non-CYP metabolism, make it an attractive and versatile backbone for combination with other novel therapeutic agents.[14] The future of Tipiracil-based therapy lies in exploring these new combinations and expanding its use into earlier lines of therapy and new cancer types. A robust pipeline of ongoing clinical trials reflects this strategy.

• Combination with Chemotherapy: Recognizing that Lonsurf has a different mechanism of resistance than traditional fluoropyrimidines, trials are exploring its combination with other standard cytotoxic agents. The TRITICC trial (NCT04059562) is investigating Lonsurf plus irinotecan in cholangiocarcinoma, while the sequential TASOXIRI trial is testing Lonsurf with alternating oxaliplatin and irinotecan in refractory mCRC.[42]
• Combination with Targeted Therapy: Research is underway to combine Lonsurf with other targeted agents beyond bevacizumab. One active trial is investigating the combination of Lonsurf with talazoparib, a PARP inhibitor, in patients with locally advanced or metastatic colorectal or gastroesophageal cancer, potentially exploiting synthetic lethality in tumors with DNA damage repair deficiencies.[50] Another innovative approach is being tested in a trial combining Lonsurf with XB2001, a monoclonal antibody targeting IL-1α, to modulate the tumor microenvironment and enhance therapeutic response.[51]
• Combination with Immunotherapy: Several trials are evaluating the potential synergy between Lonsurf and immune checkpoint inhibitors. The rationale is that the DNA damage caused by trifluridine may increase tumor antigen release and immunogenicity, which could be potentiated by checkpoint blockade. Active trials are investigating combinations with pembrolizumab and other immunotherapies in various advanced solid tumors.[50]
• Optimizing Treatment Sequences: The optimal sequencing of third-line agents remains an important clinical question. The SOREGATT trial (NCT04450836) is a randomized Phase II study directly comparing the two main sequences: Lonsurf followed by regorafenib versus regorafenib followed by Lonsurf, which will provide critical data to guide clinical decision-making.[52]
• Moving into Earlier Disease Settings: A significant area of future development is the investigation of Lonsurf in earlier stages of cancer, particularly in the adjuvant or minimal residual disease (MRD) setting. NCI-supported trials are currently active, evaluating Lonsurf for the treatment of ctDNA-positive (circulating tumor DNA) Stage II-III colorectal cancer after completion of standard surgery and chemotherapy. Success in this area would represent a major paradigm shift, moving a drug from the refractory metastatic setting to a potentially curative one.[50]

The following table summarizes key ongoing clinical trials that are shaping the future of Tipiracil-based therapy.

Table 7: Summary of Key Ongoing Clinical Trials Involving Tipiracil/Trifluridine
Trial Identifier	Phase	Indication	Combination Agents	Key Question / Rationale
NCT04059562 (TRITICC)	II	Cholangiocarcinoma / Gallbladder Cancer	Irinotecan	Efficacy of Lonsurf + chemotherapy in a new GI malignancy after gemcitabine failure.42
NCT04450836 (SOREGATT)	II	Refractory mCRC	Regorafenib (sequencing)	To determine the optimal treatment sequence between Lonsurf and regorafenib.52
	50		Active	Locally Advanced/Metastatic CRC or GEJ Cancer
	50		Active	ctDNA-positive, Stage II-III CRC
NCT05201352	I/II	Refractory mCRC	XB2001 (anti-IL-1α antibody)	To test if modulating the tumor microenvironment with IL-1 inhibition increases Lonsurf efficacy.51

8.2 Synthesis and Concluding Remarks

Tipiracil is a testament to the power of rational drug design in modern pharmacology. It is far more than a simple pharmacokinetic enhancer; it is a cleverly designed molecule with a dual mechanism of action that successfully resurrected a failed but potent cytotoxic agent, trifluridine. The resulting combination product, Lonsurf, first carved out a critical niche in the oncology armamentarium by providing a modest but significant survival benefit for heavily pre-treated patients with metastatic colorectal cancer, a population with few remaining options.

The subsequent success of the landmark SUNLIGHT trial, which established the superiority of Lonsurf combined with bevacizumab over Lonsurf monotherapy, has fundamentally redefined the third-line standard of care for refractory mCRC. This trial provided robust evidence for the power of multi-targeted synergistic therapy, combining direct cytotoxicity with dual-pathway anti-angiogenic blockade. The consistent benefit observed across diverse and challenging patient subgroups underscores the broad clinical utility of this regimen.

With a well-characterized and manageable safety profile, a lack of clinically significant CYP450-mediated drug interactions, and a growing body of evidence in other malignancies like gastric cancer, Tipiracil-based therapy has proven to be a durable and versatile platform. The ongoing research into novel combinations with immunotherapy, PARP inhibitors, and other targeted agents, coupled with its investigation in earlier, potentially curative disease settings, ensures that Tipiracil will remain a cornerstone of treatment for gastrointestinal cancers and a subject of intense clinical investigation for the foreseeable future. Its journey from a "rescuer" molecule for a single failed drug to a backbone for future combination therapies represents a major and continuing success story in oncologic drug development.

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