LONSURF: An antimetabolite combination agent studied in metastatic CRC and gastric cancers1,2
LONSURF:
An antimetabolite combination agent studied in metastatic CRC and gastric cancers1,2
LONSURF could be appropriate for your patients
Diagnosed with unresectable mCRC 18 months ago1,3
*Profile is fictional and is intended for discussion only. mCRC=metastatic colorectal cancer; CT=computed tomography; ECOG PS=Eastern Cooperative Oncology Group performance status; MSS=microsatellite stable.
1st–line: Treatment was initiated with FOLFOX + bevacizumab and she responded well1,6-8
2nd–line: Began therapy with FOLFIRI + bevacizumab1,6-8
*Profile is fictional and is intended for discussion only. mCRC=metastatic colorectal cancer; FOLFOX= leucovorin, fluorouracil, and oxaliplatin combination therapy; CT=computed tomography; FOLFIRI=leucovorin, fluorouracil, and irinotecan combination therapy
To treat her unresectable mCRC SHE TRANSITIONED TO LONSURF® TABLETS—FTD/TPI—BECAUSE
In the RECOURSE trial,
42% of mCRC patients in the LONSURF® tablets—FTD/TPI—arm went on to receive subsequent therapy at the end of the trial.3
In the RECOURSE trial, the mOS (95% CI) for LONSURF was 7.2 months (6.6-7.8) vs 5.2 months (4.6-5.9) for placebo (HR=0.69 [95% CI: 0.59-0.81]; P<0.0001).10†
*Profile is fictional and is intended for discussion only.
†Kaplan-Meier estimates.
CI=confidence interval; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRC=metastatic colorectal cancer; mOS=median overall survival; RECOURSE=Refractory Colorectal Cancer Study (Study 1).
Diagnosed with unresectable mCRC 18 months ago1,3
*Profile is fictional and is intended for discussion only. mCRC=metastatic colorectal cancer; CT=computed tomography; ECOG PS=Eastern Cooperative Oncology Group performance status; MSS=microsatellite stable.
1st–line: Treatment was initiated with FOLFOX + bevacizumab and she responded well1,6-8
2nd–line: Began therapy with FOLFIRI + bevacizumab1,6-8
*Profile is fictional and is intended for discussion only. mCRC=metastatic colorectal cancer; FOLFOX= leucovorin, fluorouracil, and oxaliplatin combination therapy; CT=computed tomography; FOLFIRI=leucovorin, fluorouracil, and irinotecan combination therapy
To treat her unresectable mCRC SHE TRANSITIONED TO LONSURF® TABLETS—FTD/TPI—BECAUSE
In the RECOURSE trial,
42% of mCRC patients in the LONSURF® tablets—FTD/TPI—arm went on to receive subsequent therapy at the end of the trial.3
In the RECOURSE trial, the mOS (95% CI) for LONSURF was 7.2 months (6.6-7.8) vs 5.2 months (4.6-5.9) for placebo (HR=0.69 [95% CI: 0.59-0.81]; P<0.0001).10†
*Profile is fictional and is intended for discussion only.
†Kaplan-Meier estimates.
Consider LONSURF in your treatment plan
LONSURF® (FTD/TPI) tablets was studied in the RECOURSE trial1,3
LONSURF patient considerations1,4
RECOURSE was an international, randomized, double-blind, placebo-controlled phase 3 trial.* All patients were >18 years of age, had ECOG performance status of 0 or 1, and had received at least 2 prior regimens of standard chemotherapy and were refractory to or were failing all of the following within 3 months: fluoropyrimidine, irinotecan, and oxaliplatin; an anti-VEGF biological therapy; and, if RAS wild type, an anti-EGFR therapy, which could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of this therapy. The primary efficacy endpoint was overall survival (OS).1,3,5
Patients were randomized 2:1 to receive either LONSURF 35 mg/m2 (n=534) or placebo (n=266) twice daily after meals for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest, repeated every 4 weeks plus best supportive care.1
All patients were followed for survival at scheduled 8-week intervals with computed tomography (CT) scans until 12 months after the first dose of study medication from the last patient randomized. After the end of treatment, all patients were followed for survival at scheduled 8-week time intervals until death.5
*Treatment arms were LONSURF plus best supportive care vs placebo plus best supportive care.1
LONSURF interferes with the DNA of tumor cells to inhibit proliferation1
How LONSURF® (FTD/TPI) tablets works1,3
FTD/TPI = trifluridine/tipiracil
References: 1. LONSURF [Prescribing Information]. Princeton, NJ: Taiho Oncology, Inc.; 2019. 2. Uboha N, Hochster HS. TAS-102: a novel antimetabolite for the 21st Century. Future Oncol. 2016;12(2):153-163. 3. Mayer RJ, Van Cutsem E, Falcone A, et al; for the RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. 4. Van Cutsem E, Falcone A, Garcia-Carbonero R, et al. Proxies of quality of life in metastatic colorectal cancer: analyses in the RECOURSE trial. ESMO Open. 2017;2(5):e000261. 5. Data on file. Taiho Oncology, Inc., Princeton, NJ. 6. Strickler JH, Hurwitz HI. Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist. 2012;17(4):513-524. 7. Hess KR, Varadhachary GR, Taylor SH, et al. Metastatic patterns in adenocarcinoma. Cancer. 2006;106(7):1624-1633 8. Cassidy J, Misset JL. Oxalipation-related side effects: characteristics and management. Semin Oncol. 2002;29(5 Suppl 15):11-20. 9. Clarke SJ, Yip S, Brown C, et al. Single-agent irinotecan or FOLFIRI as second-line chemotherapy for advanced colorectal cancer; results of a randomized phase II study (DaVINCI) and meta-analysis [corrected] [published correction appears in Eur J Cancer. 2012 Feb;48(3):407] Eur J Cancer. 2011;47(12):1826-1836. 10. Van Cutsem E, Mayer RJ, Laurent S, et al. The subgroups, of the phase Ill RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018;90:63–72.
INDICATIONS
LONSURF is indicated as a single agent or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine‑, oxaliplatin‑ and irinotecan‑based chemotherapy, an anti‑VEGF biological therapy, and if RAS wild‑type, an anti‑EGFR therapy.
LONSURF is indicated for the treatment of adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate,
LONSURF is indicated as a single agent or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine‑, oxaliplatin‑ and irinotecan‑based chemotherapy, an anti‑VEGF biological therapy, and if RAS wild‑type, an anti‑EGFR therapy.
LONSURF is indicated for the treatment of adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate,
Severe Myelosuppression: In the 1114 patients who received LONSURF as a single agent, LONSURF caused severe or life‑threatening myelosuppression (Grade 3‑4) consisting of neutropenia (38%), anemia (17%), thrombocytopenia (4%) and febrile neutropenia (3%). Three patients (0.3%) died due to neutropenic infection/sepsis; four other patients (0.5%) died due to septic shock. A total of 14% of patients received granulocyte‑colony stimulating factors. In the 246 patients who received LONSURF in combination with bevacizumab, LONSURF caused severe or life-threatening myelosuppression (Grade 3‑4) consisting of neutropenia (52%), anemia (5%), thrombocytopenia (4%) and febrile neutropenia (0.4%). One patient (0.4%) died due to abdominal sepsis and two other patients (0.8%) died due to septic shock. A total of 29% of patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for severe myelosuppression and resume at the next lower dosage.
Embryo‑Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the final dose.
Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LONSURF and for 1 day following the final dose.
Male Contraception: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.
Geriatric Use: Patients 65 years of age or older who received LONSURF as a single agent had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs 32%), Grade 3 anemia (20% vs 14%), and Grade 3 or 4 thrombocytopenia (6% vs 3%). Patients 65 years of age or older who received LONSURF in combination with bevacizumab had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (60% vs 46%) and Grade 3 or 4 thrombocytopenia (5% vs 4%).
Renal Impairment: No adjustment to the starting dosage of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min). Reduce the starting dose of LONSURF for patients with severe renal impairment (CLcr of 15 to 29 mL/min) to a recommended dosage of 20 mg/m2.
Hepatic Impairment: Do not initiate LONSURF in patients with baseline moderate or severe (total bilirubin > 1.5 times ULN and any AST) hepatic impairment. Patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST) were not studied. No adjustment to the starting dosage of LONSURF is recommended for patients with mild hepatic impairment.
Serious adverse reactions occurred in 25% of patients. The most frequent serious adverse reactions (≥2%) were intestinal obstruction (2.8%), and COVID-19 (2%). Fatal adverse reactions occurred in 1.2% of patients who received LONSURF in combination with bevacizumab, including rectal fistula (0.4%), bowel perforation (0.4%) and atrial fibrillation (0.4%).
The most common adverse reactions or laboratory abnormalities (≥10% in incidence) in patients treated with single‑agent LONSURF at a rate that exceeds the rate in patients receiving placebo in mCRC: anemia (77% vs 33%), neutropenia (67% vs 0.8%), asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), thrombocytopenia (42% vs 8%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 19%), and pyrexia (19% vs 14%). In metastatic gastric cancer or gastroesophageal junction (GEJ): neutropenia (66% vs 4%), anemia (63% vs 38%), nausea (37% vs 32%), thrombocytopenia (34% vs 9%), decreased appetite (34% vs 31%), vomiting (25% vs 20%), infections (23% vs 16%) and diarrhea (23% vs 14%).
Pulmonary emboli occurred more frequently in LONSURF‑treated patients compared to placebo: in mCRC (2% vs 0%) and in metastatic gastric cancer and GEJ (3% vs 2%).
Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.
The most common adverse reactions or laboratory abnormalities (≥20% in incidence) in patients treated with LONSURF in combination with bevacizumab vs LONSURF alone were neutropenia (80% vs 68%), anemia (68% vs 73%), thrombocytopenia (54% vs 29%), fatigue (45% vs 37%), nausea (37% vs 27%), increased aspartate aminotransferase (34% vs 28%), increased alanine aminotransferase (33% vs 23%), increased alkaline phosphate (31% vs 36%), decreased sodium (25% vs 20%), diarrhea (21% vs 19%), abdominal pain (20% vs 18%), and decreased appetite (20% vs 15%).
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LONSURF® (trifluridine and tipiracil) tablets consist of a thymidine‑based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase.
Following uptake into cancer cells, trifluridine, in its triphosphate form (FTD‑TP), is incorporated into the DNA, interferes with DNA function, and inhibits cell proliferation. No enzyme has been identified for the dephosphorylation of FTD‑TP, which may explain its incorporation into DNA.
Trifluridine/tipiracil demonstrated anti-tumor activity against KRAS wild type and mutant human colorectal cancer xenografts in mice.3
