INDICATION: LONSURF is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan‑based chemotherapy, an anti‑VEGF biological therapy, and if RAS wild type, an anti‑EGFR therapy.
Category 2A

Trifluridine and tipiracil (LONSURF) is recommended by the National Comprehensive Cancer Network® (NCCN®) as an option for 3rd‑line or subsequent-line treatment of mCRC1

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Important Safety Information Prescribing Information Patient Information
INDICATION: LONSURF is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan‑based chemotherapy, an anti‑VEGF biological therapy, and if RAS wild type, an anti‑EGFR therapy.

Efficacy & Safety

LONSURF:
  • Extended overall survival2
  • Maintained or improved ECOG performance status3
  • Demonstrated safety profile4

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Dosage
Why LONSURF?

Efficacy

Help extend survival with LONSURF

In the initial RECOURSE survival analysis, LONSURF — studied under TAS-102 — provided a statistically significant reduction in risk of mortality (32%)2

  • mOS (95% CI): 7.1 months (6.5-7.8) vs 5.3 months (4.6-6.0) (HR=0.68 [95% CI: 0.58-0.81]; P<0.001)*
  • Number (%) of deaths was 364 (68) for LONSURF and 210 (79) for placebo†

In the follow-up survival analysis, LONSURF maintained a 2-month benefit in median OS vs placebo3

  • The follow-up survival analysis was conducted 9 months after the initial RECOURSE analysis
*Kaplan-Meier estimates.
†Prespecified study endpoint.

Follow-up survival analysis: OS in patients with refractory mCRC3

Reduction in risk of refractory metastatic colorectal cancer mortality with LONSURF
*Kaplan-Meier estimates.

Percent of patients surviving at 6 and 12 months4*

LONSURF Effectiveness percent of patients surviving at 6 and 12 months
*Kaplan-Meier estimates.

89% of the planned dose was received by patients in the LONSURF group vs 94% in the placebo group. The planned dose reflects the total targeted dose while patients were receiving treatment.4

Significantly prolonged progression‑free survival2,4,5

Reduction in risk of refractory metastatic colorectal cancer progression with LONSURF
*Kaplan-Meier estimates.
†Prespecified study endpoint.

Give patients the potential to maintain performance status with LONSURF

69% n=496
of patients taking LONSURF maintained or improved their ECOG performance status in the RECOURSE trial6
  • 180 patients with ECOG performance status of 0 maintained their performance status
  • 152 patients with ECOG performance status of 1 maintained their performance status
  • 8 patients with ECOG performance status of 1 improved their performance status to 0

Results were based on the ECOG performance status scale. Grade 0 is defined as fully active and able to carry on all predisease performance without restriction. Grade 1 is defined as restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light housework, office work.7

42% of patients in the LONSURF arm went on to receive subsequent therapy at the end of the trial4

– Approximately 16% of these patients received a regimen containing regorafenib5

Adverse Events

WARNINGS AND PRECAUTIONS

Severe Myelosuppression: In Study 1, LONSURF caused severe and life‑threatening myelosuppression (Grade 3‑4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF‑treated 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 febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose as clinically indicated.

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 with LONSURF.

LONSURF has a demonstrated safety profile4

Hematologic laboratory test abnormalities4
LONSURF
(n=533*), %
Placebo
(n=265*), %
All Gr
Gr 3‑4
All Gr
Gr 3‑4
Anemia†
77
18
33
3
Neutropenia
67
38
<1
0
Thrombocytopenia
42
5
8
<1
  • *Percentage based on number of patients with post-baseline samples, which may be less than 533 (LONSURF) or 265 (placebo).
  • †No Grade 4 definition for anemia in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
Adverse events (≥5%) reported in patients treated with LONSURF and reported more commonly (>2%) than in patients taking placebo4
LONSURF
(n=533), %
Placebo
(n=265), %
All Gr
Gr 3‑4*
All Gr
Gr 3‑4*
Gastrointestinal disorders
Nausea
48
2
24
1
Diarrhea
32
3
12
<1
Vomiting
28
2
14
<1
Abdominal pain
21
2
18
4
Stomatitis
8
<1
6
0
General disorders and administration site conditions
Asthenia
18
3
11
3
Fatigue
35
4
23
6
Fever
19
1
14
<1
Metabolism and nutrition disorders
Decreased
appetite
39
4
29
5
Skin and subcutaneous tissue disorders
Alopecia
7
n/a
1
n/a
  • *No Grade 4 definition for nausea, abdominal pain, or fatigue in NCI CTCAE for Adverse Events, version 4.03.
Other AEs of clinical importance4
LONSURF
(n=533), %
Placebo
(n=265), %
All Gr
Gr 3‑4
All Gr
Gr 3‑4
Hand‑foot
syndrome
2
0
2
0
Febrile
neutropenia
4
4
0
0
  • Standard safety monitoring and grading were performed using NCI CTCAE for Adverse Events, version 4.03.
  • In the RECOURSE study, 3.6% of patients discontinued LONSURF due to an AE and 13.7% required a dose reduction2
    • -The most common AEs leading to a dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea
  • In the RECOURSE study, 9.4% of patients in the LONSURF group received granulocyte‑colony stimulating factor (G‑CSF)2

Study Design

RECOURSE: Refractory Colorectal Cancer Study (Study 1)2,5
An international, double‑blind, randomized, placebo‑controlled phase 3 clinical trial

Inclusion criteria:

  • ≥18 years of age4
  • Confirmed adenocarcinoma of the colon or rectum4
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 12
  • Received at least 2 prior regimens of standard chemotherapy and were refractory to or were failing all of the following within 3 months2,4:
    - Fluoropyrimidine, irinotecan and oxaliplatin
    - Anti‑VEGF biological therapy
    - Anti‑EGFR therapy (if RAS wild type)
  • Disease progression based on imaging during or within 3 months of the last administration of each of the standard chemotherapies5
LONSURF Refractory Metastatic Colorectal Cancer Study Design LONSURF Refractory Metastatic Colorectal Cancer Study Design 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

Patient Demographics4

LONSURF Patient Demographics
  • *Race was self-reported.
  • †Eastern Cooperative Oncology Group (ECOG) performance status is scored on a scale of 0 to 5, with 0 indicating no symptoms, 1 indicating mild symptoms, and higher numbers indicating increasing degrees of disability.

All patients received prior treatment with fluoropyrimidine‑, oxaliplatin‑, and irinotecan‑based chemotherapy. All but one patient received bevacizumab, and all but two patients with KRAS wild‑type tumors received panitumumab or cetuximab.2

Clinical Guidelines

Trifluridine and tipiracil (LONSURF) is recommended as a 3rd-line or subsequent-line treatment option for mCRC1
Category 2A

The National Comprehensive Cancer Network® (NCCN®) recommends trifluridine and tipiracil (LONSURF) as a potential 3rd‑line or subsequent-line treatment option in both KRAS‑mutant and wild‑type mCRC patients. See below for potential treatment algorithms.1

Kras Mutant Patients

Example Treatment Algorithm

1st-LINE

FOLFOX
+
bevacizumab

2nd-LINE

FOLFIRI
+
bevacizumab

3rd-LINE

Trifluridine
and
tipiracil

4th-LINE

Other
treatment
options

Kras Wild-Type Patients

Example Treatment Algorithm

1st-LINE

FOLFIRI
+
cetuximab

2nd-LINE

FOLFOX
+
bevacizumab

3rd-LINE

Trifluridine
and
tipiracil

4th-LINE

Other
treatment
options

1st-LINE

FOLFIRI
+
bevacizumab

2nd-LINE

FOLFOX
+
bevacizumab

3rd-LINE

Irinotecan
+
cetuximab

4th-LINE

Trifluridine
and
tipiracil

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2018. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form or any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

For additional mCRC treatment algorithms please view the following NCCN Guidelines.

Download PDF

In the RECOURSE international clinical trial:

42%
of patients in the LONSURF arm went on to receive subsequent therapy at the end
of the trial4
98%
of patients were refractory to or failing on fluoropyrimidine-based therapy in a prior
treatment regimen4
To view the RECOURSE study design, click here.

Category 2A = based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2018 and the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.1.2018. © National Comprehensive Cancer Network, Inc 2018. All rights reserved. Accessed April 27, 2018. To view the most recent and complete version of the guidelines, go online to NCCN.org. 2. LONSURF [Prescribing Information]. Princeton, NJ: Taiho Oncology, Inc.; 03/2017 3. Van Cutsem E, Mayer RJ, Laurent S, et al; for the RECOURSE Study Group. The subgroups of the phase III 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. 4. 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. 5. Data on file. Taiho Oncology, Inc., Princeton, NJ. 6. 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. 7. Oken MM, Creech RH, Tormey DC, et al.; Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

Important Safety Information +

WARNINGS AND PRECAUTIONS

Severe Myelosuppression: In Study 1, LONSURF caused severe and life‑threatening myelosuppression (Grade 3‑4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%), and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF‑treated 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 febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery, resume LONSURF at a reduced dose as clinically indicated.

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 with LONSURF.

USE IN SPECIFIC POPULATIONS

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 breast‑fed infant or the effects on milk production. Because of the potential for serious adverse reactions in breast‑fed infants, 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 over who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 anemia (26% vs 12%), and Grade 3 or 4 thrombocytopenia (9% vs 2%).

Hepatic Impairment: Patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST) were not studied. No adjustment to the starting dose of LONSURF is recommended for patients with mild hepatic impairment. Do not initiate LONSURF in patients with baseline moderate or severe (total bilirubin greater than 1.5 times ULN and any AST) hepatic impairment.

Renal Impairment: In Study 1, patients with moderate renal impairment (CLcr=30 to 59 mL/min, n=47) had a higher incidence (difference of at least 5%) of ≥Grade 3 adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr ≥90 mL/min, n=306) or patients with mild renal impairment (CLcr=60 to 89 mL/min, n=178).

Patients with moderate renal impairment may require dose modifications for increased toxicity. Patients with severe renal impairment were not studied.

ADVERSE REACTIONS

Most Common Adverse Drug Reactions in Patients Treated With LONSURF (≥5%): The most common adverse drug reactions in LONSURF‑treated patients vs placebo‑treated patients with refractory mCRC, respectively, were asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%).

Additional Important Adverse Drug Reactions: The following occurred more frequently in LONSURF‑treated patients compared to placebo: infections (27% vs 15%) and pulmonary emboli (2% vs 0%).

The most commonly reported infections which occurred more frequently in LONSURF‑treated patients were nasopharyngitis (4% vs 2%) and urinary tract infections (4% vs 2%).

Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.

Laboratory Test Abnormalities in Patients Treated With LONSURF: Laboratory test abnormalities in LONSURF‑treated patients vs placebo-treated patients with refractory mCRC, respectively, were anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%).

Please see full Prescribing Information.