Lansurf 20 mg/8.19 mg film-coated tablets 20 mg + 8.19 mg blister No. 20

Instructions Lansurf 20 mg/8.19 mg film-coated tablets 20 mg + 8.19 mg blister No. 20

Composition

active ingredients: trifluridine/tipiracil;

Lansurf 15 mg/6.14 mg: 1 tablet contains 15 mg of trifluridine and 6.14 mg of tipiracil (as 7.065 mg of tipiracil hydrochloride);

Lansurf 20 mg/8.19 mg: 1 tablet contains 20 mg of trifluridine and 8.19 mg of tipiracil (as 9.420 mg of tipiracil hydrochloride);

excipients: lactose monohydrate, pregelatinized starch (corn), stearic acid;

film coating for 15 mg/6.14 mg tablets: hypromellose, macrogol (8000), titanium dioxide (E 171), magnesium stearate;

film coating for 20 mg/8.19 mg tablets: hypromellose, macrogol (8000), titanium dioxide (E 171), red iron oxide (E 172), magnesium stearate;

gray ink for marking: shellac, red iron oxide (E 172), yellow iron oxide (E 172), titanium dioxide (E 171), indigo carmine aluminum lake (E 132), carnauba wax, talc.

Dosage form

Film-coated tablets.

Main physicochemical properties:

Lansurf 15 mg/6.14 mg: round, biconvex, film-coated tablet of white color, marked "15" on one side and "102" and "15 mg" on the other side, applied in gray ink;

Lansurf 20 mg/8.19 mg: round, biconvex, pale red film-coated tablet, marked "20" on one side and "102" and "20 mg" on the other side in gray ink.

Pharmacotherapeutic group

Antineoplastic agents. Antimetabolites. Structural pyrimidine analogues; trifluridine, combinations. ATX code L01B C59.

Pharmacological properties

Pharmacodynamics.

Mechanism of action. Lansurf contains the antineoplastic thymidine nucleoside analogue trifluridine and the thymidine phosphorylase (TPase) inhibitor tipiracil hydrochloride in a molar ratio of 1:0.5 (mass ratio 1:0.471). After entering cancer cells, trifluridine is phosphorylated by thymidine kinase, then metabolized in cells to a substrate of deoxyribonucleic acid (DNA) and incorporated directly into DNA, thereby disrupting DNA function and preventing cell proliferation. However, after oral administration, trifluridine is rapidly degraded by thymidine phosphorylase and is rapidly metabolized. For this reason, the thymidine phosphorylase inhibitor tipiracil hydrochloride was included in the composition of the drug.

In preclinical studies, the trifluridine/tipiracil hydrochloride combination demonstrated antitumor activity against colorectal cancer cell lines, both sensitive and resistant to 5-fluorouracil (5-FU).

The cytotoxic activity of trifluridine/tipiracil hydrochloride against several human tumor xenografts was highly correlated with the amount of trifluridine incorporated into DNA, suggesting a primary mechanism of action.

Pharmacodynamic effects: In an open-label study in patients with advanced solid tumors, there was no clinically significant effect of Lansurf on QT/QTc interval prolongation compared to placebo.

Clinical efficacy and safety

Metastatic colorectal cancer

Randomized Phase III Study of Lansurf as Monotherapy vs. Placebo

The clinical efficacy and safety profile of Lansurf were evaluated in an international, randomized, double-blind, placebo-controlled phase III study (RECOURSE) in 800 patients with metastatic colorectal cancer who had previously received treatment for this disease. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), overall response rate, and disease control rate. Patients continued treatment until disease progression or unacceptable toxicity (see section 4.2). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at baseline. The primary site of disease was colon (62%) or rectum (38%). At study entry, KRAS status was either wild-type (49%) or mutant (51%). The median number of prior lines of therapy for metastatic disease was 3. All patients had received prior fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. All but 1 patient received bevacizumab, and all but 2 patients with KRAS wild-type tumors received panitumumab or cetuximab. The two treatment groups were comparable with respect to demographic and baseline disease characteristics.

Table 1. Efficacy assessment based on the results of a phase III clinical trial (RECOURSE) in patients with metastatic colorectal cancer

a Kaplan-Meier estimation.

b Brookmeyer and Crowley methodology.

c Stratified log-rank test (groups: KRAS gene status, time from diagnosis of first metastasis, region).

The results of the updated OS analysis, conducted on 89% (712 patients) of cases, confirmed a clinically meaningful and statistically significant advantage of Lansurf in combination with OPT in terms of patient survival compared to placebo in combination with OPT (relative risk 0.69; 95% CI [0.59 to 0.81]; p < 0.0001) and the median OS was 7.2 months compared to 5.2 months, respectively, and the 1-year survival rates were 27.1% and 16.6%, respectively. Data analysis demonstrated a benefit for Lansurf in terms of OS and PFS in all prespecified subgroups, including race, geographic region, age (< 65; ≥ 65), gender, ECOG performance status, KRAS status, time since diagnosis of first metastasis, number of metastatic sites, and primary tumor site. The survival benefit for Lansurf was maintained when data were analyzed for all important prognostic factors, namely: time since diagnosis of first metastasis, ECOG performance status, and number of metastatic sites (relative risk 0.69; 95% CI [0.58 to 0.81]). 61% (485 participants) of all randomized patients received a fluoropyrimidine as the basis of their prior therapy before randomization, and 455 of these (94%) were refractory to a fluoropyrimidine at the time. The benefit of Lansurf in terms of OS was maintained in these patients (relative risk 0.75, 95% CI [0.59 to 0.94]). 18% (144 participants) of all randomized patients received regorafenib before randomization. Lansurf also demonstrated an advantage in terms of OS in this group of patients (relative risk 0.69, 95% CI [0.45 to 1.05]). This effect was also observed in the group of patients who had not previously received regorafenib (relative risk 0.69, 95% CI [0.57 to 0.83]). The disease control rate (complete response, partial response or stable disease) was significantly higher in patients who received Lansurf (44% vs. 16%, p < 0.0001). Treatment with Lansurf in combination with OPT resulted in a statistically significant prolongation of the performance status (PS) score < 2 compared with the group receiving placebo in combination with OPT. The median time to achieve PS ≥ 2 in the Lansurf and placebo groups was 5.7 months and 4.0 months, respectively, with a relative risk of 0.66 (95% CI: [0.56, 0.78]), p < 0.0001).

The clinical efficacy and safety of Lansurf in combination with bevacizumab compared with Lansurf alone were evaluated in an international, randomized, open-label phase III study (SUNLIGHT) in patients with metastatic colorectal cancer who had received up to two prior systemic therapies for advanced disease, including fluoropyrimidine-based therapies, irinotecan, oxaliplatin, anti-VEGF and/or anti-EGFR monoclonal antibodies in patients with wild-type RAS tumors. The primary endpoint was OS and the secondary endpoint was PFS. A total of 492 patients were randomized (1:1) to receive Lansurf with bevacizumab (N = 246) or Lansurf alone (N = 246). Patients received Lansurf (starting dose 35 mg/m2) orally twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle as monotherapy or in combination with bevacizumab (5 mg/kg) administered intravenously. Patients continued therapy until disease progression or unacceptable toxicity (see Dosage and Administration). Bevacizumab monotherapy was not permitted. Baseline characteristics were generally comparable between the two groups. The median age was 63 years (range: 20-90), 44% were >65 years and 12% were >75 years, 52% were male and 95% were Caucasian, 46% had ECOG PS 0 and 54% had ECOG PS 1. The primary site of disease was colon (73%) or rectum (27%). Overall, 71% of patients had a RAS mutant tumor. The median duration of treatment was 5 months in the Lansurf-bevacizumab group and 2 months in the Lansurf group. Overall, 92% of patients had received a maximum of two prior systemic therapies for advanced disease, 5% had received one regimen, and 3% had received more than two. All patients had previously received fluoropyrimidine, irinotecan, and oxaliplatin-based therapy, 72% had previously received anti-VEGF monoclonal antibodies, and 94% of patients with wild-type RAS tumors had previously received anti-EGFR monoclonal antibodies.

Lansurf in combination with bevacizumab resulted in a statistically significant improvement in OS and PFS compared with Lansurf monotherapy (see Table 2).

Table 2. Efficacy assessment based on the results of the phase III clinical study (SUNLIGHT) in patients with metastatic colorectal cancer

a Kaplan-Meier estimation.

b Brookmeyer and Crowley methodology.

c Stratified log-rank test (groups: region, time since diagnosis of first metastasis, RAS status).

The advantage in terms of OS and PFS was consistently observed across all randomized groups and pre-specified subgroups, including gender, age (< 65; > 65), primary disease location (right-sided, left-sided), ECOG performance status (0, > 1), prior surgical resection, number of metastatic sites (1–2, > 3), neutrophil/lymphocyte ratio (NLR < 3, NLR > 3), number of prior anticancer drug regimens (1, > 2), BRAF status, MSI (microsatellite instability) status, prior bevacizumab therapy, and subsequent regorafenib therapy.

Metastatic gastric cancer

The median age of the 507 patients randomized was 63 years, 73% were male, 70% were Caucasian, 16% were Asian, and <1% were Black/African American, and all patients had a baseline ECOG performance status (PS) of 0 or 1. The primary cancer was gastric cancer (71.0%) or gastroesophageal junction cancer (28.6%), or both (0.4%). The median number of prior therapies for metastatic disease was 3. Almost all (99.8%) patients had received prior fluoropyrimidine therapy, 100% had received prior platinum therapy, and 90.5% had received prior taxane therapy. Approximately half (55.4%) of the patients had received prior irinotecan, 33.3% had received ramucirumab, and 16.6% had received HER2-targeted therapy. The two treatment groups were comparable in terms of demographic and baseline disease characteristics. The results of the OS analysis, performed on 76% (384 patients) of the cases, demonstrated that Lansurf in combination with OPT resulted in a statistically significant improvement in OS compared with placebo in combination with OPT with a hazard ratio (HR) of 0.69 (95% CI: 0.56, 0.85; 1- and 2-sided p-values were 0.0003 and 0.0006, respectively), corresponding to a 31% reduction in the risk of death in the Lansurf group. The median OS was 5.7 months (95% CI: 4.8, 6.2) in the Lansurf group compared with 3.6 months (95% CI: 3.1, 4.1) in the placebo group; and the 1-year survival rates were 21.2% and 13.0%, respectively. Patients receiving Lansurf and OPT had significantly better PFS (hazard ratio (HR): 0.57; 95% CI [0.47 to 0.70]; p < 0.0001) (see Table 3).

Table 3. Efficacy assessment based on the results of a phase III clinical study (TAGS) in patients with metastatic gastric cancer

a Kaplan–Meier estimate.

b Brookmeyer and Crowley methodology.

c Stratified log-rank test (groups: region, baseline ECOG performance status, prior ramucirumab therapy).

Data analysis demonstrated the superiority of Lansurf in terms of OS and PFS in all randomization groups and in most pre-specified subgroups, including gender, age (< 65; ≥ 65 years), ethnicity, ECOG performance status, prior ramucirumab therapy, prior irinotecan therapy, number of prior regimens (2; 3; ≥ 4), prior gastrectomy, primary tumor location (gastric; gastroesophageal junction), and HER2 status. The overall response rate (complete response + partial response) was not significantly higher in patients receiving Lansurf (4.5% vs. 2.1%, p-value = 0.2833), but the disease control rate (complete response or partial response, or stable disease) was significantly higher in patients receiving Lansurf (44.1% vs. 14.5%, p < 0.0001). The median time to deterioration in ECOG performance status to ≥ 2 was 4.3 months for the Lansurf group compared to 2.3 months for the placebo group with a hazard ratio (HR) of 0.69 (95% CI: 0.562, 0.854), p-value = 0.0005.

Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Lansurf in all subsets of the paediatric population in refractory metastatic colorectal cancer and refractory metastatic gastric cancer.

Elderly patients: Data on patients aged 75 years and older who received Lansurf are limited (87 patients (10%) in the pooled RECOURSE and TAGS studies, of which 2 patients were aged 85 years and older). The effect of Lansurf on CV outcomes was similar in patients aged < 65 years and ≥ 65 years.

Absorption. When Lansurf was administered orally with [14C]-trifluridine, at least 57% of the administered trifluridine was absorbed and only 3% of the administered dose was excreted in the feces. When Lansurf was administered orally with [14C]-tipiracil hydrochloride, at least 27% of the administered tipiracil hydrochloride was absorbed and 50% of the total radioactive dose was recovered in the feces, suggesting that tipiracil hydrochloride absorption from the gastrointestinal tract is moderate. After single (35 mg/m2) and multiple (35 mg/m2/dose twice daily) administration of Lansurf in patients with advanced solid tumors, the mean times to peak plasma concentrations (tmax) of trifluridine and tipiracil hydrochloride were approximately 2 and 3 hours, respectively. In a pharmacokinetic (PK) analysis of multiple doses of Lansurf (35 mg/m2/dose twice daily for 5 days per week with a 2-day break for 2 weeks followed by a 14-day break, repeated every 4 weeks), the area under the concentration-time curve from time 0 to the last measured concentration (AUC0-last) of trifluridine was approximately 3-fold higher and the maximum concentration (Cmax) was approximately 2-fold higher after multiple dosing (Day 12 of Cycle 1) of Lansurf than after a single dose (Day 1 of Cycle 1).

However, there was no accumulation of tipiracil hydrochloride and subsequent accumulation of trifluridine during consecutive cycles (day 12 of cycles 2 and 3) of Lansurf. Contribution of tipiracil hydrochloride. Administration of a single dose of Lansurf (35 mg/m2/dose) increased the mean AUC0-last of trifluridine by 37-fold and Cmax by 22-fold with reduced variability compared to trifluridine monotherapy (35 mg/m2/dose).

Food effects: When Lansurf was administered as a single dose of 35 mg/m2 to 14 patients with solid tumors after a standard high-calorie, high-fat meal, the area under the concentration-time curve (AUC) of trifluridine was unchanged, and the Cmax of trifluridine, Cmax and AUC of tipiracil hydrochloride were decreased by approximately 40% compared to those obtained in the fasted state. In clinical studies, Lansurf was administered 1 hour after the morning and evening meals (see section 4.2).

Distribution: The binding of trifluridine to human plasma proteins was greater than 96%, with trifluridine bound primarily to human serum albumin. The binding of tipiracil hydrochloride to plasma proteins was less than 8%. After a single dose of Lansurf (35 mg/m2) in patients with advanced solid tumors, the apparent volume of distribution (Vd/F) of trifluridine and tipiracil hydrochloride was 21 L and 333 L, respectively.

Biotransformation. During metabolism, trifluridine was primarily eliminated by thymidine phosphorylase to form the inactive metabolite 5-[trifluoromethyl]uracil. Absorbed trifluridine was metabolized and excreted in the urine as the isomers 5-[trifluoromethyl]uracil and trifluridine glucuronide. Other minor metabolites, 5-carboxyuracil and 5-carboxy-2'-deoxyuridine, were also detected, but their levels in plasma and urine were very low or residual. Tipiracil hydrochloride was not metabolized in human liver S9 fraction or in cryopreserved human hepatocytes. Tipiracil hydrochloride was the major component and 6-hydroxymethyluracil was the major metabolite in human plasma, urine and feces.

Elimination. After multiple administration of Lansurf at the recommended dose and regimen, the mean elimination half-life (t1/2) of trifluridine on day 1 of course 1 and day 12 of course 1 was 1.4 and 2.1 hours, respectively. The mean t1/2 for tipiracil hydrochloride on day 1 of course 1 and day 12 of course 1 was 2.1 and 2.4 hours, respectively. After a single oral administration of Lansurf (35 mg/m2) in patients with advanced solid tumors, the clearance (CL/F) of trifluridine and tipiracil hydrochloride was 10.5 and 109 L/h, respectively. After a single oral administration of Lansurf with [14C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. Most of the radioactivity was excreted in the urine (55% of the dose) within 24 hours, while excretion in the faeces and exhaled air was less than 3% in both cases. After a single oral dose of Lansurf with [14C]-tipiracil hydrochloride, the amount of radioactivity excreted was 77% of the administered dose, of which 27% was excreted in the urine and 50% in the faeces.

Linearity/non-linearity: In a dose-ranging study (15 to 35 mg/m2 twice daily), there was a trend for the area under the time-concentration curve (AUC0-10) for trifluridine to increase more than expected with increasing dose; however, the oral clearance (CL/F) and volume of distribution (Vd/F) of trifluridine were largely unchanged over the 20 to 35 mg/m2 dose range. Other concentrations of trifluridine and tipiracil hydrochloride were dose proportional.

Age, gender, and race: Population PK analysis revealed no clinically significant effect of patient age, gender, or race on the pharmacokinetics of trifluridine or tipiracil hydrochloride.

Renal impairment. Population PK analysis showed that Lansurf exposure in patients with mild renal impairment (CrCl = 60–89 mL/min) was similar to that in patients with normal renal function (CrCl ≥ 90 mL/min). Lansurf exposure was higher in patients with moderate renal impairment (CrCl = 30–59 mL/min). Theoretically calculated (CrCl) had high covariance for oral clearance CL/F in both final models of trifluridine and tipiracil hydrochloride. The mean AUC ratios in patients with mild renal impairment (38 subjects) and moderate renal impairment (16 subjects) compared to those in patients with normal renal function (84 subjects) were 1.31 and 1.43 for trifluridine and 1.34 and 1.65 for tipiracil hydrochloride, respectively. In a dedicated study, the pharmacokinetics of trifluridine and tipiracil hydrochloride were evaluated in cancer patients with normal renal function (CrCl ≥90 mL/min, N = 12), mild (CrCl 60–89 mL/min, N = 12), moderate (CrCl 30–59 mL/min, N = 11), or severe (CrCl 15–29 mL/min, N = 8) renal impairment. Patients with severe renal impairment received an adjusted starting dose of 20 mg/m2 twice daily (reduced to 15 mg/m2 twice daily based on individual safety and tolerability). Renal impairment following repeated dosing resulted in a 1.6- and 1.4-fold increase in total trifluridine concentrations in patients with moderate and severe renal impairment, respectively, compared to patients with normal renal function; Cmax remained similar. Total tipiracil hydrochloride concentrations in patients with moderate and severe renal impairment following repeated dosing were 2.3- and 4.1-fold higher, respectively, compared to patients with normal renal function; this is due to a decrease in clearance with increasing severity of renal impairment. The pharmacokinetics of trifluridine and tipiracil hydrochloride have not been studied in patients with end-stage renal failure (CrCl < 15 mL/min or requiring dialysis) (see sections 4.2 and 4.4).

Hepatic impairment. In patients with mild hepatic impairment, no initial dose adjustment is required (see section 4.2). Lansurf is not recommended for use in patients with moderate or severe pre-existing hepatic impairment due to the high incidence of grade 3 or 4 hyperbilirubinemia in patients with moderate pre-existing hepatic impairment (see section 4.4).

Gastrectomy. It was not possible to study the effect of gastrectomy on PK parameters based on a population PK analysis, as only a few patients had undergone gastrectomy (1% of the total).

Pharmacokinetic-pharmacodynamic relationship. The efficacy and safety profile of Lansurf in metastatic colorectal cancer were compared in high (> median) and low (≤ median) concentration groups based on mean AUC values of trifluridine. The OS rate was better in the higher AUC group compared to the lower AUC group (mean OS rates were 9.3 and 8.1 months, respectively). Over the entire follow-up period, all AUC groups showed better results than placebo. Grade ≥ 3 neutropenia occurred more frequently in the higher AUC group (47.8%) compared to the lower AUC group (30.4%).

Indication

Colorectal cancer

Lansurf is indicated in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have previously received two anticancer therapy regimens including fluoropyrimidine-based chemotherapy, oxaliplatin and irinotecan, anti-VEGF and/or anti-EGFR agents.

Lansurf is indicated as monotherapy for adult patients with metastatic colorectal cancer who have been previously treated or for whom available therapies are contraindicated, including fluoropyrimidine-based chemotherapy, oxaliplatin, and irinotecan, as well as anti-VEGF and anti-EGFR agents.

Stomach cancer

Lansurf is indicated as monotherapy for adult patients with metastatic gastric cancer, including patients with gastroesophageal junction adenocarcinoma, who have previously received at least two regimens of systemic therapy, with disease progression.

Contraindication

Hypersensitivity to the active substances or to any excipient of the drug.

Interaction with other medicinal products and other types of interactions

In vitro studies have shown that trifluridine, tipiracil hydrochloride and 5-[trifluoromethyl]uracil (FTY) did not inhibit the activity of human cytochrome P450 isoforms (CYP). In vitro studies have shown that trifluridine, tipiracil hydrochloride and FTY did not induce human cytochrome P450 isoforms (see section "Pharmacokinetics"). In vitro studies have shown that trifluridine is a substrate of the nucleoside transporters CNT1, ENT1 and ENT2. Therefore, caution should be exercised when using drugs that interact with these transporters. Tipiracil hydrochloride is a substrate for the transporters OCT2 and MATE1, so its concentration may increase when Lansurf is used simultaneously with inhibitors of the transporters OCT2 and MATE1.

Caution should be exercised when using medicinal products that are substrates of human thymidine kinase, such as zidovudine. Such medicinal products, when used concomitantly with Lansurf, may compete with the effector, trifluridine, for activation by thymidine kinase. Therefore, when using antiviral medicinal products that are substrates of human thymidine kinase, monitoring for possible reduction in antiviral efficacy should be performed and consideration should be given to switching to an alternative antiviral agent that is not a substrate of human thymidine kinase, such as lamivudine, didanosine and abacavir (see section 5.1).

It is not known whether Lansurf may reduce the effectiveness of hormonal contraceptives. Therefore, women using hormonal contraceptives should also use barrier methods of contraception.

Application features

Bone marrow depression. Lansurf has been associated with an increased incidence of myelosuppression, including anemia, neutropenia, leukopenia, and thrombocytopenia. Complete blood counts should be performed prior to initiation of treatment and as needed to monitor toxicity, but at least prior to the start of each course of treatment. Treatment should not be initiated if the absolute neutrophil count is < 1.5 × 109/L, the platelet count is < 75 × 109/L, or if the patient has persistent Grade 3 or 4 non-hematological clinically significant toxicity after previous courses of treatment. Serious infections have been reported following treatment with Lansurf (see section 4.8). Since most of these events occurred in the setting of bone marrow depression, patients should be closely monitored and appropriate measures should be taken as clinically indicated, such as antimicrobials and granulocyte colony-stimulating factor (G-CSF). In RECOURSE and TAGS, 9.4% and 17.3% of patients in the Lansurf treatment group, respectively, used G-CSF primarily for therapeutic purposes.

Renal impairment: Use in patients with end-stage renal disease (creatinine clearance (CrCl) < 15 mL/min or requiring dialysis) is not recommended as Lansurf has not been studied in this patient population (see section 5.2). The overall incidence of adverse reactions is similar in subgroups of patients with normal renal function (CrCl ≥ 90 mL/min), mild (CrCl 60–89 mL/min) or moderate (CrCl 30–59 mL/min) renal impairment. However, the incidence of serious adverse reactions, severe reactions and reactions leading to dose modification tends to increase with increasing severity of renal impairment. In addition, blood concentrations of trifluridine and tipiracil hydrochloride were higher in patients with moderate renal impairment than in patients with normal or mild renal impairment (see section 5.2). Patients with severe renal impairment (CrCl 15-29 mL/min) and an adjusted starting dose of 20 mg/m2 twice daily had a safety profile consistent with that of Lansurf in patients with normal or mild renal impairment. Their sensitivity to trifluridine was similar to that of patients with normal renal function, and their sensitivity to tipiracil hydrochloride was increased compared to patients with normal renal function, mild, and moderate renal impairment (see sections 5.2 and 5.1).