An Exhaustive Monograph on TAS-102 (Trifluridine/Tipiracil; Lonsurf®): Chemical Profile, Pharmacology, Clinical Efficacy, and Regulatory Status

I. Executive Summary & Introduction to TAS-102 (Lonsurf®)

A. Overview

TAS-102, marketed under the brand name Lonsurf®, is a novel, orally administered combination antineoplastic agent that has emerged as a cornerstone therapy for patients with heavily pre-treated, refractory metastatic gastrointestinal cancers.[1] Its development and approval represent a significant advancement in the management of metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC), offering a new therapeutic option for a patient population with limited alternatives following progression on standard chemotherapeutic and biological regimens.[3]

B. Core Components

The drug product is a fixed-dose combination of two distinct active pharmaceutical ingredients, formulated in a precise molar ratio to achieve a synergistic therapeutic effect.[2] The components are:

• Trifluridine (FTD): A thymidine-based nucleoside analog, specifically α,α,α-trifluorothymidine, which functions as the primary cytotoxic component of the combination. Its mechanism is centered on the disruption of DNA synthesis and integrity.[1]
• Tipiracil (TPI): A specific and potent inhibitor of the enzyme thymidine phosphorylase (TP). Tipiracil is not included for any direct antineoplastic activity of its own; rather, its role is exclusively to modulate the pharmacokinetics of trifluridine, thereby enabling its therapeutic efficacy.[6]

C. Clinical Significance

TAS-102 is indicated for adult patients with mCRC and mGC who have progressed after treatment with established therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF and anti-EGFR biologics where appropriate.[7] The development of TAS-102 is a notable example of strategic pharmaceutical design, specifically the "resurrection" of a promising but previously failed cytotoxic agent through intelligent pharmacokinetic modulation. Trifluridine was originally synthesized in the 1960s, but its clinical development was abandoned due to a prohibitively poor pharmacokinetic profile, characterized by a rapid elimination half-life of approximately 18 minutes following intravenous administration. This rapid clearance was attributed to extensive and swift degradation by the enzyme thymidine phosphorylase (TP).[1] The critical innovation that led to the success of TAS-102 was not the discovery of a new cytotoxic molecule, but the co-formulation of trifluridine with tipiracil. By specifically inhibiting TP, tipiracil shields trifluridine from first-pass metabolism in the liver and gastrointestinal tract, dramatically increasing its oral bioavailability and systemic exposure to therapeutic levels.[1] This successful pairing transformed an otherwise non-viable compound into an effective anticancer drug, a concept explicitly acknowledged by its description as a "resurrected novel Fluoropyrimidine".[4] This unique mechanism of action and resistance profile provides a critical treatment avenue for tumors that have become refractory to conventional fluoropyrimidines like 5-fluorouracil (5-FU).[1]

D. Report Objective

This report provides an exhaustive, expert-level analysis of TAS-102 (Lonsurf®). It aims to synthesize and contextualize the available chemical, pharmaceutical, pharmacological, clinical, and regulatory data into a comprehensive monograph suitable for clinical researchers, medical science professionals, and pharmaceutical analysts. The analysis will cover the drug's fundamental properties, its dual-component mechanism of action, the pivotal clinical evidence supporting its approved indications, its comprehensive safety profile and risk management strategies, and its global regulatory journey, concluding with an expert synthesis of its current clinical positioning and future research trajectories.

II. Chemical, Pharmaceutical, and Formulation Profile

A. Nomenclature and Identification

A precise understanding of the nomenclature and identifiers for TAS-102 and its components is fundamental for accurate scientific communication and regulatory tracking.

• Generic/Chemical Name: The officially recognized name for the combination drug product is trifluridine and tipiracil hydrochloride.[1]
• Code Name: During its development phase, the compound was universally referred to as TAS-102.[5]
• Brand Name: The commercial name under which the drug is marketed is Lonsurf®.[2]
• Synonyms: Various synonyms are used in literature and commercial databases, including Trifluridine-Tipiracil Hydrochloride Mixture and tipiracil hydrochloride mixture with trifluridine.[1]
• Key Identifiers:
• DrugBank Accession Number: DB08937 refers to the TAS-102 combination product.[12]
• CAS Number: 733030-01-8 is assigned to the specific trifluridine and tipiracil hydrochloride mixture used in the final drug product.[1]

B. Chemical Structure and Properties of Components

TAS-102 is an orally bioavailable agent composed of trifluridine and tipiracil hydrochloride, precisely formulated in a fixed molar ratio of 1:0.5.[6] This ratio was determined through preclinical studies in human colorectal cancer xenograft models to provide the optimal balance between maximal antitumor activity and acceptable toxicity.[1]

The chemical formula for the mixture is C10​H11​F3​N2​O5​⋅0.5C9​H11​ClN4​O2​⋅0.5HCl, with a corresponding molecular weight of 435.76 g/mol.[1] It is important to note that some commercial sources may list alternative formulas or molecular weights (e.g., a molecular weight of 871.53 g/mol) [10]; these often correspond to a 2:1 molar ratio representation of the components or a different salt form and should be interpreted with caution. The 1:0.5 molar ratio of trifluridine to tipiracil hydrochloride is the clinically validated and regulatory-approved composition.[5]

Trifluridine (FTD)

• Description: Trifluridine is a fluorinated pyrimidine nucleoside, specifically an analog of thymidine, characterized by a trifluoromethyl group at the 5-position of the uracil base. This substitution is critical to its mechanism of action.[1]
• IUPAC Name: 1--5-(trifluoromethyl)pyrimidine-2,4-dione.[14]
• Chemical Formula: C10​H11​F3​N2​O5​.[14]
• Molecular Weight: 296.20 g/mol.[17]
• CAS Number: 70-00-8.[14]
• DrugBank ID: DB00432.[14]

Tipiracil (TPI) and its Hydrochloride Salt

• Description: Tipiracil is a uracil derivative that functions as a thymidine phosphorylase inhibitor. It is structurally composed of a uracil ring substituted with chloro and (2-iminopyrrolidin-1-yl)methyl groups.[7]
• IUPAC Name (Base): 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione.[19]
• Chemical Formula (Base): C9​H11​ClN4​O2​.[19]
• Molecular Weight (Base): 242.66 g/mol.[19]
• CAS Number (Base): 183204-74-2.[19]
• DrugBank ID (Base): DB09343.[18]
• Hydrochloride Salt (as used in formulation): The active ingredient in the Lonsurf® formulation is the hydrochloride salt of tipiracil, which enhances its stability and solubility properties.
• Chemical Formula: C9​H12​Cl2​N4​O2​ (representing C9​H11​ClN4​O2​⋅HCl).[7]
• Molecular Weight: 279.12 g/mol.[7]
• CAS Number: 183204-72-0.[7]
• DrugBank Salt ID: DBSALT001349.[7]

The distinct chemical properties of each component are summarized in Table 1.

Table 1: Chemical and Physical Properties of TAS-102 Components

Property	Trifluridine (FTD)	Tipiracil (Base)	Tipiracil Hydrochloride (TPI.HCl)
IUPAC Name	1--5-(trifluoromethyl)pyrimidine-2,4-dione 14	5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione 19	5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride 7
CAS Number	70-00-8 14	183204-74-2 19	183204-72-0 7
DrugBank ID	DB00432 14	DB09343 18	DBSALT001349 7
Molecular Formula	C10​H11​F3​N2​O5​ 14	C9​H11​ClN4​O2​ 19	C9​H12​Cl2​N4​O2​ 7
Molecular Weight (g/mol)	296.20 17	242.66 19	279.12 7
Water Solubility (mg/mL)	Not specified; sparingly soluble	Not specified	0.731 7
logP	-0.7 to -0.8	-0.7	-0.21 to -2 7
pKa (Strongest Acidic)	7.9	7.28	7.28 7
pKa (Strongest Basic)	-3.5	11.5	11.55 7
Hydrogen Bond Donors	3 22	3 19	3 7
Hydrogen Bond Acceptors	5 22	4 19	4 7

C. Pharmaceutical Formulation and Handling

• Dosage Forms: Lonsurf® is provided as film-coated oral tablets, available in two strengths to allow for precise, body surface area (BSA)-based dosing. The tablets contain a fixed ratio of the active ingredients [23]:
• 15 mg trifluridine / 6.14 mg tipiracil
• 20 mg trifluridine / 8.19 mg tipiracil
• Storage and Stability: The drug should be stored at controlled room temperature (20°C to 25°C, with excursions permitted to 15°C to 30°C).[25] It is crucial that tablets are kept in their original container, which includes a desiccant packet to protect them from moisture. The stability data submitted for regulatory approval granted a 24-month expiration date. However, if tablets are removed from the original bottle, they should be discarded after 30 days.[23]
• Safe Handling: Lonsurf® is classified as a cytotoxic drug. Therefore, specific handling precautions are necessary to minimize exposure. Caregivers should wear gloves when handling the tablets, and hands must be washed thoroughly after contact. Contaminated waste should be disposed of according to local guidelines for cytotoxic agents.[25]

III. Comprehensive Pharmacological Profile

A. Pharmacodynamics: Mechanism of Action (MOA)

The clinical efficacy of TAS-102 is derived from the sophisticated and synergistic interplay of its two components. Trifluridine acts as the cytotoxic "warhead," while tipiracil functions as its essential pharmacokinetic "shield," allowing the warhead to reach its target.[5]

Trifluridine: The Cytotoxic Warhead

The primary anticancer activity of TAS-102 is exerted by trifluridine through a multi-step process following oral administration:

1. Cellular Uptake and Activation: Trifluridine is actively transported into cancer cells via concentrative and equilibrative nucleoside transporters (CNT1, ENT1, and ENT2).[6] Once inside the cell, it undergoes phosphorylation by the enzyme thymidine kinase (TK) to form trifluridine monophosphate (TF-TMP). Subsequent phosphorylations convert it to its final, active triphosphate form, trifluridine triphosphate (TF-TTP).[6]
2. Primary Mechanism: DNA Incorporation and Dysfunction: The central mechanism of trifluridine's cytotoxicity is the direct incorporation of TF-TTP into the DNA backbone by DNA polymerases, where it substitutes for natural thymidine bases.[1] This event is highly deleterious to the cell. The presence of the bulky and highly electronegative trifluoromethyl group in the DNA helix causes significant structural distortions, leading to DNA dysfunction, strand breaks, and interference with the function of DNA repair enzymes.[1] This widespread DNA damage ultimately triggers cell cycle arrest, primarily during the G2/M phase, and induces apoptosis (programmed cell death).[1] Preclinical studies have demonstrated a direct positive correlation between the extent of trifluridine incorporation into DNA and the magnitude of its antitumor activity, confirming this as its principal mode of action.[6] Furthermore, research indicates that the incorporation of TF-TTP into DNA occurs with greater efficiency than the incorporation of metabolites from 5-FU, potentially contributing to its activity in 5-FU-resistant settings.[6]
3. Secondary Mechanism: Thymidylate Synthase Inhibition: In addition to DNA incorporation, trifluridine, via its monophosphate form (TF-TMP), also exerts an inhibitory effect on thymidylate synthase (TS), the same enzyme targeted by 5-FU.[6] Inhibition of TS depletes the intracellular pool of deoxythymidine monophosphate (dTMP), a necessary precursor for DNA synthesis. However, this TS inhibition is considered a minor contributor to the overall cytotoxic effect of TAS-102, with DNA incorporation being the dominant and clinically defining mechanism.[6]

Tipiracil: The Pharmacokinetic Enhancer

The inclusion of tipiracil in the formulation is a feat of rational drug design aimed at overcoming the inherent pharmacokinetic liabilities of trifluridine:

1. The Pharmacokinetic Challenge: When administered as a single agent, trifluridine is subject to rapid and extensive first-pass metabolism by the enzyme thymidine phosphorylase (TP), which is highly expressed in the liver and gastrointestinal tract.[1] TP catabolizes trifluridine to its major inactive metabolite, 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY), resulting in a very short systemic half-life and insufficient oral bioavailability to achieve therapeutic drug concentrations.[1]
2. The Pharmacokinetic Solution: Tipiracil is a potent and specific inhibitor of thymidine phosphorylase.[6]
3. The Consequence: By co-administering tipiracil with trifluridine, the enzymatic degradation of trifluridine is effectively blocked. This inhibition of TP significantly increases the systemic concentration (Cmax​) and overall exposure (AUC) of trifluridine, thereby enhancing its oral bioavailability and allowing it to reach and maintain therapeutic levels in the plasma and, consequently, within tumor cells.[1] This protective effect is the sole reason for tipiracil's inclusion in Lonsurf®.

Distinction from 5-Fluorouracil (5-FU) and Clinical Implications

The unique mechanism of TAS-102 is fundamental to its clinical utility, particularly in the refractory setting. Its activity profile is distinct from that of 5-FU, the long-standing backbone of colorectal cancer chemotherapy.

• Divergent Primary Mechanisms: The primary mechanism of 5-FU relies on the inhibition of thymidylate synthase by its metabolite, fluorodeoxyuridine monophosphate (FdUMP).[6] In contrast, the primary mechanism of TAS-102 is the direct incorporation of trifluridine into DNA.[6] This fundamental difference means that tumors that have developed resistance to 5-FU, for instance through upregulation of TS or alterations in metabolic pathways, can remain sensitive to TAS-102.
• Overcoming Resistance: TAS-102 has demonstrated consistent efficacy in patients with 5-FU-refractory cancers.[1] Its activation and metabolism are not dependent on the same enzymes as 5-FU, such as orotate phosphoribosyltransferase (OPRT), and importantly, it is not a substrate for dihydropyrimidine dehydrogenase (DPD), the key catabolic enzyme for 5-FU whose deficiency can lead to severe toxicity.[1] This lack of cross-resistance is the cornerstone of its role in the treatment continuum for gastrointestinal malignancies.[4]

B. Pharmacokinetics (ADME)

The pharmacokinetic profile of TAS-102 reflects the properties of its individual components as modulated by their interaction. The data presented are typically from studies in cancer patients receiving the combination product at the recommended dose.

Absorption

• Route of Administration: Oral.[1]
• Bioavailability: Following oral administration of the combination product, the mean bioavailability is approximately 57% for trifluridine and 27% for tipiracil.[11] This bioavailability for trifluridine is a direct result of tipiracil's inhibitory effect on its first-pass metabolism.
• Time to Peak Plasma Concentration (Tmax​): Peak plasma concentrations are reached at approximately 2 hours for trifluridine and 3 hours for tipiracil after dosing.[11]
• Food Effect: The administration of Lonsurf® with a high-fat, high-calorie meal results in a notable alteration of its pharmacokinetic profile. The peak concentration (Cmax​) of trifluridine and both the Cmax​ and area under the curve (AUC) of tipiracil are reduced by approximately 40%.[11] Despite this reduction in systemic exposure, the prescribing information universally mandates that Lonsurf® be taken with food, within one hour of finishing a meal.[24] This apparent paradox suggests a deliberate clinical decision. The pharmacokinetic data indicate that food impairs absorption, yet the clinical instruction is to take it with food. This strongly implies that the "with food" recommendation is not for the purpose of enhancing bioavailability, but rather to improve gastrointestinal tolerability. Given that nausea, vomiting, and diarrhea are prominent side effects, mitigating these toxicities to improve patient adherence and quality of life was likely prioritized over maximizing drug exposure. The efficacy demonstrated in pivotal trials was established under these "with food" conditions, validating this approach.

Distribution

• Plasma Protein Binding: The two components exhibit markedly different binding characteristics. Trifluridine is highly bound to plasma proteins, with over 96% associated primarily with serum albumin. In contrast, tipiracil shows minimal protein binding, at less than 8%.[11]
• Volume of Distribution (Vd​): The apparent volume of distribution is 21 L for trifluridine and a much larger 333 L for tipiracil, suggesting more extensive distribution of tipiracil into tissues.[11]

Metabolism

• Independence from Cytochrome P450 System: A key pharmacokinetic feature of TAS-102 is that its metabolism is independent of the cytochrome P450 (CYP) enzyme system.[11] This is a significant clinical advantage. Patients with metastatic cancer are often elderly and present with multiple comorbidities, necessitating polypharmacy. Many common medications are substrates, inhibitors, or inducers of CYP enzymes. The independence of TAS-102 from this major pathway for drug-drug interactions greatly simplifies prescribing and reduces the risk of unpredictable changes in drug exposure due to concomitant medications. This minimizes the need for dose adjustments related to interactions with common drug classes like proton pump inhibitors, antifungals, or certain antidepressants.
• Metabolic Pathways:
• Trifluridine: As previously described, the primary metabolic pathway is catabolism by thymidine phosphorylase (TP) into the inactive metabolite 5-trifluoromethyl uracil (FTY).[11]
• Tipiracil: Is metabolized to 6-hydroxymethyluracil, which is considered inactive.[11]

Excretion

• Routes of Elimination:
• Trifluridine: Following metabolism, its metabolites are primarily cleared via the kidneys, with 55% of the dose excreted in the urine. Less than 3% is excreted in feces.[11]
• Tipiracil: Is eliminated through both renal and fecal routes, with 27% recovered in urine and 50% in feces.[11]
• Terminal Half-life (t1/2​): On day 12 of the first treatment cycle, after reaching steady-state, the terminal elimination half-life is approximately 2.1 hours for trifluridine and 2.4 hours for tipiracil.[11]

Table 2: Key Pharmacokinetic Parameters of Trifluridine and Tipiracil

Parameter	Trifluridine (FTD)	Tipiracil (TPI)
Oral Bioavailability (%)	~57 11	~27 11
Time to Peak Concentration (Tmax​) (h)	~2 11	~3 11
Plasma Protein Binding (%)	>96 (to serum albumin) 11	<8 11
Volume of Distribution (Vd​) (L)	21 11	333 11
Terminal Half-life (t1/2​) (h)	~2.1 (Day 12) 11	~2.4 (Day 12) 11
Primary Route of Excretion	Renal (as metabolites) 11	Fecal and Renal 11

IV. Clinical Efficacy in Approved Indications

The clinical development program for TAS-102 has robustly established its efficacy in heavily pre-treated patient populations with metastatic colorectal and gastric cancers, leading to its approval by major regulatory agencies worldwide.

A. Metastatic Colorectal Cancer (mCRC)

The Pivotal Phase III RECOURSE Trial (NCT01607957)

The cornerstone of the approval for TAS-102 in mCRC was the RECOURSE trial, a landmark study that validated its efficacy in a global, refractory patient population.

• Study Design: RECOURSE was a large-scale, international, randomized (2:1), double-blind, placebo-controlled Phase III trial. It enrolled 800 patients with mCRC whose disease had progressed after, or who were intolerant to, all available standard therapies. This included prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic therapy (like bevacizumab), and, for patients with RAS wild-type tumors, an anti-EGFR therapy (like cetuximab or panitumumab).[23] Patients received either TAS-102 (35 mg/m² twice daily on a standard schedule) plus best supportive care (BSC), or placebo plus BSC.[36]
• Primary Endpoint: The primary objective was to demonstrate an improvement in Overall Survival (OS).[34]
• Key Efficacy Results: The trial successfully met its primary and key secondary endpoints, demonstrating both statistically significant and clinically meaningful benefits for TAS-102.
• Overall Survival (OS): Treatment with TAS-102 led to a significant prolongation of life. The median OS was 7.1 months in the TAS-102 arm compared to 5.3 months in the placebo arm. This corresponded to a Hazard Ratio (HR) for death of 0.68 (95% Confidence Interval [CI], 0.58 to 0.81; p<0.001), representing a 32% reduction in the risk of mortality.[6]
• Progression-Free Survival (PFS): TAS-102 also significantly delayed disease progression. The median PFS was 2.0 months for the TAS-102 group versus 1.7 months for the placebo group (HR 0.48; 95% CI, 0.40 to 0.55; p<0.001). This represented a 52% reduction in the risk of disease progression or death.[23]
• Disease Control Rate (DCR): The DCR, defined as the percentage of patients achieving a complete response, partial response, or stable disease, was substantially higher in the treatment arm: 44.0% for TAS-102 versus 16.3% for placebo (p<0.0001).[35]

Combination Therapy with Bevacizumab

Building on the success of monotherapy, subsequent research has established the enhanced efficacy of combining TAS-102 with the anti-angiogenic agent bevacizumab.

• Rationale: The combination of cytotoxic chemotherapy with agents targeting the vascular endothelial growth factor (VEGF) pathway is a validated and standard strategy in CRC.[38] Preclinical xenograft models had already suggested that combining TAS-102 with anti-VEGF or anti-EGFR antibodies resulted in superior tumor growth inhibition.[29]
• Clinical Evidence:
• The Phase II trial KSCC1602 provided compelling early evidence. In a population of elderly (≥70 years) patients with previously untreated mCRC, the combination of FTD/TPI plus bevacizumab yielded impressive outcomes as a first-line therapy, with a median PFS of 9.4 months and a median OS of 22.4 months. This suggested the regimen was not only effective but also well-tolerated in a more vulnerable patient population.[39]
• In the refractory setting, a meta-analysis of studies directly comparing TAS-102 monotherapy to the combination with bevacizumab demonstrated a clear survival advantage for the combination. The analysis reported a median OS of 10.41 months for the combination versus 6.95 months for monotherapy, and a median PFS of 4.35 months versus 2.53 months.[40]
• This body of evidence led to the formal approval of the TAS-102 plus bevacizumab combination by the FDA and EMA, establishing it as a new standard of care in the salvage setting for mCRC.[8]

B. Metastatic Gastric Cancer (mGC)

The efficacy of TAS-102 was also investigated and proven in patients with advanced gastric cancer, another challenging gastrointestinal malignancy.

• Pivotal Phase III TAGS Trial:
• Study Design: The TAGS trial was a randomized, double-blind, placebo-controlled study that evaluated TAS-102 in patients with heavily pretreated mGC or gastroesophageal junction (GEJ) adenocarcinoma who had received at least two prior lines of therapy.[42]
• Key Efficacy Results: Similar to the RECOURSE trial, the TAGS trial demonstrated a significant survival benefit.
• Overall Survival (OS): The median OS was 5.7 months for patients receiving TAS-102, compared to 3.6 months for those receiving placebo. This translated to a Hazard Ratio of 0.69, representing a 31% reduction in the risk of death.[42]
• Progression-Free Survival (PFS): A significant improvement in PFS was also observed, with a median of 2.0 months in the TAS-102 arm versus 1.8 months in the placebo arm (HR 0.57; p<0.0001).[42]

A notable observation across both the RECOURSE and TAGS trials is the apparent disconnect between the modest gains in median PFS and the more substantial improvements in median OS. In RECOURSE, the PFS benefit was only 0.3 months, while the OS benefit was 1.8 months.[34] Similarly, in TAGS, the PFS benefit was 0.2 months, while the OS benefit was 2.1 months.[42] This pattern suggests that the therapeutic benefit of TAS-102 may not be fully captured by traditional RECIST-based measurements of tumor progression. Several factors could contribute to this phenomenon. The drug might confer a post-progression survival benefit by slowing the rate of clinical decline even after radiological progression is declared. Furthermore, the significant delay in the time to deterioration of ECOG performance status observed in the RECOURSE trial indicates that patients on TAS-102 maintain their functional status for longer.[34] This preservation of well-being is a critical factor that can directly translate into longer overall survival, as it allows patients to better tolerate their disease and remain eligible for subsequent supportive care. This makes the OS data particularly compelling, justifying the use of a toxic therapy even when initial radiographic assessments show only modest disease stabilization.

C. Health-Related Quality of Life (HRQoL)

While the pivotal RECOURSE trial did not include a formal, direct assessment of HRQoL using validated patient-reported outcome questionnaires, it did provide an important indirect measure. The trial demonstrated a statistically significant delay in the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance status from 0 or 1 (fully ambulatory) to ≥2 (symptomatic, in bed <50% of the day). The median time to this deterioration was 5.7 months for patients on TAS-102 versus 4.0 months for those on placebo (HR 0.66, p<0.001).[34] This finding suggests a preservation of functional status and patient well-being.

To address this data gap more directly, the prospective, non-interventional Phase IV TALLISUR study was conducted in Germany. This trial employed the validated EORTC QLQ-C30 questionnaire to assess HRQoL in patients with pre-treated mCRC receiving FTD/TPI. The study found that treatment was associated with maintained HRQoL over time, while delivering survival benefits (median OS of 6.9 months) that were consistent with the results of the RECOURSE trial. This provides crucial evidence that the survival gains from TAS-102 do not come at the cost of a significant decline in patient-reported quality of life.[37]

Table 3: Summary of Pivotal Phase III Efficacy Data (RECOURSE & TAGS)

Endpoint	RECOURSE (Metastatic Colorectal Cancer)	TAGS (Metastatic Gastric Cancer)
Trial ID	NCT01607957 34	N/A (Arkenau H-T et al. 2018) 42
Patient Population	Refractory mCRC (≥2 prior lines) 34	Refractory mGC/GEJ (≥2 prior lines) 42
TAS-102 Median OS (months)	7.1 34	5.7 42
Placebo Median OS (months)	5.3 34	3.6 42
OS Hazard Ratio (95% CI)	0.68 (0.58–0.81) 34	0.69 (0.56–0.85) 42
TAS-102 Median PFS (months)	2.0 23	2.0 42
Placebo Median PFS (months)	1.7 23	1.8 42
PFS Hazard Ratio (95% CI)	0.48 (0.40–0.55) 23	0.57 (p<0.0001) 42

V. Safety, Tolerability, and Risk Management

The safety profile of TAS-102 is well-characterized and is dominated by predictable and manageable hematologic and gastrointestinal toxicities. Close monitoring and proactive management are essential for its safe administration.

A. Comprehensive Adverse Reaction Profile

• Most Common Adverse Events (Monotherapy): In patients receiving Lonsurf® as a single agent, the most frequently reported adverse reactions (occurring in ≥20% of patients) are primarily hematologic and gastrointestinal. These include anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.[9]
• Severe Myelosuppression (Grade 3-4): This is the most clinically significant and dose-limiting toxicity of TAS-102.
• Monotherapy: In the pooled safety data, severe or life-threatening (Grade 3-4) myelosuppression consisted of neutropenia (38%), anemia (17-18%), and thrombocytopenia (4-5%). Febrile neutropenia, a serious complication of severe neutropenia, occurred in approximately 3-4% of patients.[26]
• Combination with Bevacizumab: The addition of bevacizumab appears to potentiate the hematologic toxicity. In patients receiving the combination, the incidence of Grade 3-4 neutropenia increased to 52%. Grade 3-4 anemia and thrombocytopenia were reported in 5% and 4% of patients, respectively.[26]
• Fatal outcomes related to myelosuppression, including neutropenic infections, sepsis, and septic shock, have been reported, underscoring the critical need for vigilant monitoring.[11]
• Gastrointestinal Toxicity: Nausea, vomiting, and diarrhea are very common but are typically low-grade (Grade 1-2). Severe (Grade 3-4) diarrhea is infrequent, occurring in about 3% of patients on monotherapy.[23] Proactive management with standard antiemetic and antidiarrheal medications is a key component of supportive care.[47]
• Consistency Across Populations: Pharmacokinetic and safety studies have demonstrated that the tolerability profile of TAS-102 is generally consistent across different ethnic populations, including Caucasian, Japanese, and Chinese patients.[32]

B. Key Warnings and Precautions

The prescribing information for Lonsurf® highlights several critical warnings that require careful clinical attention.

• Severe Myelosuppression: As the primary toxicity, this carries the most significant warning.
• Monitoring: Complete blood counts (CBC) are mandatory before the initiation of therapy and must be repeated on Day 15 of each 28-day cycle. More frequent monitoring is indicated if clinically warranted.[8]
• Management: Treatment must be withheld, dose-reduced, or permanently discontinued in response to severe hematologic toxicity. The use of granulocyte-colony stimulating factors (G-CSF) is an appropriate supportive measure to manage neutropenia.[11]
• Embryo-Fetal Toxicity: Lonsurf® can cause fetal harm. Animal reproduction studies showed that trifluridine/tipiracil was teratogenic and caused embryo-fetal lethality at exposures similar to or lower than those achieved at the recommended human dose.[11]
• Females of Reproductive Potential: Must have a negative pregnancy test before starting treatment. They must be advised to use effective contraception during therapy and for at least 6 months after the final dose.[8]
• Males: Due to the potential for genotoxicity, males with female partners of reproductive potential must be advised to use condoms during treatment and for at least 3 months following the final dose.[24]

C. Management of Toxicities: Dose Modifications

A clear, structured approach to dose modification is essential for managing the toxicities associated with TAS-102. The following guidelines are based on the approved prescribing information.

• Initiation Criteria: A new treatment cycle should not be started unless the patient's absolute neutrophil count (ANC) is ≥1.5 × 10⁹/L and platelet count is ≥75 × 10⁹/L.[41]
• Intra-cycle Withholding Criteria: Dosing must be withheld during a cycle for any of the following:
• Absolute neutrophil count (ANC) falls below 0.5 × 10⁹/L or the patient develops febrile neutropenia.
• Platelet count falls below 50 × 10⁹/L.
• Patient experiences a Grade 3 or 4 non-hematologic adverse reaction.[26]
• Dose Reduction upon Resumption: After the toxicity has resolved to Grade 1 or baseline, Lonsurf® can be resumed at a reduced dose. The dose should be decreased by a 5 mg/m² increment from the previous dose level. A maximum of three dose reductions are permitted. The minimum tolerated dose is 20 mg/m² twice daily. If a patient cannot tolerate this dose, Lonsurf® must be permanently discontinued. Once a dose has been reduced, it should not be re-escalated in subsequent cycles.[26]

Table 4: Dose Modification Schedule for Adverse Reactions

Adverse Reaction	Interruption Criteria	Resumption Criteria	Dose Modification upon Resumption
Febrile Neutropenia or ANC < 0.5 × 10⁹/L	Withhold Lonsurf	ANC ≥ 1.5 × 10⁹/L	Reduce dose by 5 mg/m² from previous level 26
Platelets < 50 × 10⁹/L	Withhold Lonsurf	Platelets ≥ 75 × 10⁹/L	Reduce dose by 5 mg/m² from previous level 26
Grade 3 or 4 Non-hematologic Toxicity	Withhold Lonsurf	Resolution to Grade ≤1	Reduce dose by 5 mg/m² from previous level 26

D. Use in Specific Populations

• Geriatric Use (≥65 years): Elderly patients have been observed to have a higher incidence of Grade 3 or 4 hematologic toxicities compared to patients younger than 65. This includes higher rates of severe neutropenia, anemia, and thrombocytopenia, both when Lonsurf® is used as a single agent and in combination with bevacizumab. Therefore, this population requires particularly careful monitoring.[24]
• Renal Impairment:
• Mild to Moderate (Creatinine Clearance [CrCl] 30-89 mL/min): No adjustment to the starting dose is required. However, the incidence of adverse events tends to increase with advancing renal impairment, so closer monitoring is warranted.[24]
• Severe (CrCl 15-29 mL/min): A reduced starting dose of 20 mg/m² twice daily is recommended. These patients had a safety profile consistent with those with normal renal function at this reduced dose.[24]
• End-Stage Renal Disease (CrCl < 15 mL/min or requiring dialysis): Lonsurf® is not recommended as it has not been studied in this population.[47]
• Hepatic Impairment:
• Mild: No dose adjustment is necessary.
• Moderate to Severe (Total bilirubin >1.5 × ULN): Lonsurf® should not be initiated in patients with baseline moderate or severe hepatic impairment due to an observed increased risk of Grade 3 or 4 hyperbilirubinemia in this population.[24]

VI. Regulatory Status and Prescribing Information

A. Global Regulatory Approvals

TAS-102 (Lonsurf®) has secured regulatory approval in major markets around the world based on the strength of its pivotal clinical trial data.

• U.S. Food and Drug Administration (FDA):
• Metastatic Colorectal Cancer (mCRC): The initial FDA approval was granted on September 22, 2015, for Lonsurf® as a monotherapy for patients with refractory mCRC, based on the results of the RECOURSE trial.[9]
• Metastatic Gastric Cancer (mGC): The indication was expanded on February 25, 2019, to include the treatment of adult patients with previously treated advanced gastric or GEJ adenocarcinoma, following the positive results of the TAGS trial.[9]
• mCRC Combination Therapy: A significant label update occurred on August 2, 2023, with the approval of Lonsurf® for use in combination with bevacizumab for the treatment of mCRC, reflecting the superior efficacy of this regimen.[9]
• European Medicines Agency (EMA):
• Metastatic Colorectal Cancer (mCRC): Lonsurf® received its marketing authorization valid throughout the European Union on April 25, 2016.[43] The indication covers both monotherapy and use in combination with bevacizumab for patients with mCRC who have received prior therapies.[41]
• Metastatic Gastric Cancer (mGC): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in July 2019 based on the TAGS trial, the European Commission approved the indication for Lonsurf® as a monotherapy for patients with refractory mGC.[42]

This regulatory history illustrates an important evolution in the drug's clinical positioning. Initially approved as a monotherapy for salvage treatment, its proven synergy with bevacizumab led to a formal label expansion. This shift reflects its growing role not just as a last-line agent, but as a potential chemotherapeutic backbone to which other targeted therapies can be added. This progression suggests a trajectory toward integration into earlier lines of therapy in the future.

B. Dosage and Administration

The recommended dosing and administration schedule for Lonsurf® is highly specific and designed to balance efficacy with tolerability.

• Recommended Dose: The standard starting dose is 35 mg/m², calculated based on the trifluridine component. The calculated dose is then rounded to the nearest 5 mg increment. The maximum dose per administration is 80 mg (for a total of 160 mg per day).[11]
• Dosing Schedule: Lonsurf® is administered orally twice daily. The treatment cycle is 28 days long and consists of two weeks of treatment followed by two weeks of rest. Specifically, patients take the drug on Days 1 through 5 and again on Days 8 through 12 of each 28-day cycle.[23]
• Method of Administration: The tablets must be swallowed whole with a glass of water. They should be taken within one hour after finishing the morning and evening meals.[24] Patients should be instructed not to crush or chew the tablets. If a dose is missed or vomited, it should not be retaken; the patient should simply continue with the next scheduled dose.[24]

C. Drug and Food Interactions

• Food Interaction: As detailed in the pharmacology section, Lonsurf® must be taken with food.[24] This directive is in place to improve gastrointestinal tolerability, as dietary advice for managing side effects often includes eating small, bland meals.[48] This is despite pharmacokinetic data showing that a high-fat meal can reduce the absorption of the drug's components.[11]
• Drug-Drug Interactions: While Lonsurf® is not metabolized by the CYP450 system, which minimizes a major class of drug interactions, other potential interactions exist.[11] Databases list over 200 potential interactions, with approximately 49 classified as major.[53] Clinically significant interactions include:
• Competition for Thymidine Kinase (TK): Co-administration with other drugs that are substrates for human TK, such as the antiviral medication zidovudine, is not recommended. There is a potential for competitive inhibition of phosphorylation, which could decrease the efficacy of either drug. Alternative antiviral therapies should be considered.[11]
• Transporter-Mediated Interactions: Tipiracil is a substrate of the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1). Concomitant use of strong inhibitors of OCT2 or MATE1 could potentially increase plasma concentrations of tipiracil, leading to increased Lonsurf® toxicity. Patients on such combinations should be monitored closely.[11]

VII. Synthesis, Clinical Positioning, and Future Outlook

A. Expert Synthesis and Clinical Positioning

TAS-102 (Lonsurf®) has successfully carved out a critical niche in the treatment landscape for advanced gastrointestinal cancers. It is firmly established as a standard-of-care option in the third-line and beyond setting for both metastatic colorectal cancer and metastatic gastric cancer. Its primary value proposition lies in its unique, dual-component mechanism of action. By combining a DNA-damaging cytotoxic agent (trifluridine) with a pharmacokinetic enhancer (tipiracil), TAS-102 circumvents the common resistance pathways that limit the effectiveness of traditional fluoropyrimidines like 5-FU.[1] This provides a much-needed, effective option for a heavily pre-treated patient population that has exhausted standard therapies and has few remaining choices.

While the toxicity profile is significant—dominated by a high rate of severe but manageable myelosuppression—it is predictable. With vigilant hematologic monitoring, proactive supportive care (including the use of G-CSF), and strict adherence to dose modification guidelines, the drug can be administered safely to a relatively frail patient population. The approval and demonstrated superiority of the Lonsurf® plus bevacizumab combination has further solidified its clinical role, positioning it as the preferred regimen in refractory mCRC when appropriate. This evolution showcases its flexibility as a therapeutic backbone, capable of being combined with biological agents to enhance efficacy.[38]

B. Future Directions and Ongoing Research

The clinical development of TAS-102 is ongoing, with research focused on expanding its utility through new combinations and its application in earlier stages of disease.

• Novel Combination Strategies: Several clinical trials are actively investigating TAS-102 in combination with other anticancer agents to build upon the success seen with bevacizumab.
• Combination with Thalidomide: A Phase II study (NCT05266820) is exploring the combination of TAS-102 with thalidomide. The rationale is to leverage thalidomide's known anti-angiogenic and immunomodulatory effects, as well as its potential antiemetic properties, to simultaneously enhance antitumor efficacy and reduce the gastrointestinal side effects of TAS-102.[54]
• Combination with Irinotecan: Early phase studies combining TAS-102 with irinotecan have shown promising antitumor activity. However, this combination also resulted in significant overlapping hematologic toxicity, indicating that careful dose-finding and patient selection will be critical for its future development.[29]
• Combination with Anti-EGFR Antibodies: Preclinical data have shown synergistic activity when TAS-102 is combined with anti-EGFR antibodies like cetuximab or panitumumab, which increased the concentration of phosphorylated trifluridine in tumors.[29] This provides a strong rationale for clinical trials to evaluate these combinations in patients with RAS wild-type mCRC.
• Expansion into Earlier Treatment Settings: The most exciting future prospect for TAS-102 is its potential migration from the salvage setting into earlier lines of therapy.
• Adjuvant Setting / Minimal Residual Disease (MRD): A pioneering study (NCT05343013) is evaluating the ability of TAS-102 to eradicate minimal residual disease in high-risk CRC patients who are positive for circulating tumor DNA (ctDNA) after the completion of standard adjuvant chemotherapy. Success in this setting would represent a major paradigm shift, moving the drug into a potentially curative-intent role.[55]
• First-Line Therapy in Select Populations: The impressive results of the KSCC1602 trial, which tested TAS-102 plus bevacizumab as a first-line treatment for elderly patients with mCRC, have opened the door for its consideration as a less aggressive, well-tolerated alternative to intensive oxaliplatin- or irinotecan-based regimens in specific patient populations who may not be candidates for standard induction chemotherapy.[39]

In conclusion, TAS-102 represents more than just another drug for refractory cancer; it is a harbinger of a new phase in gastrointestinal cancer chemotherapy. For decades, the field has been dominated by therapies built upon the 5-FU backbone. TAS-102 is the first orally administered, mechanistically distinct fluoropyrimidine to demonstrate a clear survival benefit after the failure of 5-FU.[4] The active investigation of TAS-102 in novel combinations and earlier disease settings suggests its transformation from a last-resort drug into an integral component of the entire treatment continuum for GI cancers.[6] This success story, born from the clever rescue of a forgotten compound, not only provides a vital therapy for patients today but also illuminates a promising path for future drug development, moving the field toward a more diverse and mechanistically sophisticated armamentarium of foundational cytotoxic agents.

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