Metastatic Colorectal Cancer

Trifluridine and tipiracil (LONSURF) is

recommended by the National
Comprehensive Cancer
Network® (NCCN®)

as a 3rd-line or subsequent-line
treatment option for mCRC1,2

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Metastatic GEJ/Gastric Cancer
Why LONSURF?

Efficacy

For patients with previously treated mCRC, help extend survival with LONSURF3,4

LONSURF® (FTD/TPI) tablets was studied in the RECOURSE trial4,5,6

LONSURF was studied in 800 patients with previously treated mCRC in the RECOURSE (Refractory Colorectal Cancer Study) trial, an international, randomized, double-blind, placebo-controlled phase 3 trial.4,5,6

Patients had received at least 2 prior regimens of standard chemotherapy and were refractory to or were failing all of the following within 3 months5,6

  • Fluoropyrimidine, irinotecan and oxaliplatin
  • Anti-VEGF biological therapy
  • Anti-EGFR therapy (if RAS wild type)

In the final survival analysis, LONSURF maintained a 2-month benefit in mOS vs placebo3

The final survival analysis was conducted 9 months after the initial RECOURSE analysis3

Final survival analysis: OS in patients with previously treated mCRC3,4

Reduction in risk of Previously Treated metastatic colorectal cancer mortality with LONSURF

OS was defined as the time (in months) from randomization until death.

mOS=median OS.

aKaplan-Meier estimates.

Help prolong progression-free survival4,5,6

Secondary endpoint: Reduction in risk of progression or death in patients with previously treated mCRC4,5,6

Reduction in risk of progression or death in patients with previously treated metastatic colorectal cancer with LONSURF

PFS was defined as the time (in months) from randomization to the first radiologic confirmation of disease progression or death from any cause.

mPFS=median PFS.

aKaplan-Meier estimates.

bPrespecified study endpoint.

Give patients the potential to maintain performance status4,5

LONSURF delayed the time to worsening of ECOG performance status to 2 or higher5

Median time to deterioration of ECOG PS to ≥2, based on a post-hoc analysis5

Reduction in risk of deterioration of ECOG in patients with previously treated metastatic colorectal cancer with LONSURF

PS=performance status.

Time to worsening of PS was prespecified in the statistical analysis plan before the data were unblinded.

ECOG Performance Status7

Results were based on the ECOG performance status scale.

  • Grade 0 = fully active and able to carry on all pre-disease performance without restriction
  • Grade 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light housework, office work
  • Grade 2 = ambulatory and capable of all self care, but unable to carry out any work activities; up and about >50% of waking hours
  • Grade 3 = capable of only limited self care and confined to a bed or chair >50% of waking hours
  • Grade 4 = completely disabled and cannot carry on any self care and totally confined to a bed or chair
Overall Survival

In the final survival analysis, LONSURF maintained a 2-month benefit in mOS vs placebo3

The final survival analysis was conducted 9 months after the initial RECOURSE analysis3

Final survival analysis: OS in patients with previously treated mCRC3,4

Reduction in risk of Previously Treated metastatic colorectal cancer mortality with LONSURF

OS was defined as the time (in months) from randomization until death.

mOS=median OS.

aKaplan-Meier estimates.

Progression-free Survival

Help prolong progression-free survival4,5,6

Secondary endpoint: Reduction in risk of progression or death in patients with previously treated mCRC4,5,6

Reduction in risk of progression or death in patients with previously treated metastatic colorectal cancer with LONSURF

PFS was defined as the time (in months) from randomization to the first radiologic confirmation of disease progression or death from any cause.

mPFS=median PFS.

aKaplan-Meier estimates.

bPrespecified study endpoint.

ECOG Performance Status

Give patients the potential to maintain performance status4,5

LONSURF delayed the time to worsening of ECOG performance status to 2 or higher5

Median time to deterioration of ECOG PS to ≥2, based on a post-hoc analysis5

Reduction in risk of deterioration of ECOG in patients with previously treated metastatic colorectal cancer with LONSURF

PS=performance status.

Time to worsening of PS was prespecified in the statistical analysis plan before the data were unblinded.

ECOG Performance Status7

Results were based on the ECOG performance status scale.

  • Grade 0 = fully active and able to carry on all pre-disease performance without restriction
  • Grade 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light housework, office work
  • Grade 2 = ambulatory and capable of all self care, but unable to carry out any work activities; up and about >50% of waking hours
  • Grade 3 = capable of only limited self care and confined to a bed or chair >50% of waking hours
  • Grade 4 = completely disabled and cannot carry on any self care and totally confined to a bed or chair

Preserve the potential for more active treatment

  • 42% of patients in the LONSURF arm went on to receive subsequent therapy at the end of the trial5
  • Approximately 16% of these patients received a regimen containing regorafenib4

Safety

Consider an option with a consistent safety profile6

Hematologic abnormalities5,6

LONSURF + BSC
(n=533),%
Placebo + BSC
(n=265),%
All Gra Gr 3-4 All Gra Gr 3-4
Anemiab 77 18 33 3
Neutropenia 67 38 1 0
Thrombocytopenia 42 5 8 <1
Febrile neutropenia 4 4 0 0
  • aWorst Grade ≥1 grade higher than baseline, with percentages based on number of patients with post-baseline samples, which may be <533 (LONSURF) OR 265 (placebo).
  • bOne Grade 4 anemia adverse reaction based on clinical criteria was reported.

What else was discovered in the RECOURSE trial?

  • Hand-foot syndrome was reported in 2% of patients in the LONSURF group, and 2% of patients in the placebo group. No Grade 3/4 was reported5
  • 69% of patients who developed neutropenia (any grade) during the trial developed it during cycle 14
  • 9.4% of patients in the LONSURF group received granulocyte-colony stimulating factor (G-CSF)5

In RECOURSE, 3.6% of patients discontinued LONSURF for an adverse reaction and 14% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reductions were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea6

AEs* in ≥5% of patients treated with LONSURF and occurring more
commonly (>2%) than in patients taking placebo6

LONSURF + BSC
(n=533),%
Placebo + BSC
(n=265),%
All Gr Gr 3-4a All Gr Gr 3-4a
General
Asthenia/fatigue 52 7 35 9
Pyrexia 19 1 14 <1
Gastrointestinal
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
Metabolism and nutrition
Decreased appetite 39 4 29 5
Infectionsb 27 6 16 5
Nervous system
Dysgeusia 7 0 2 0
Skin and subcutaneous tissue
Alopecia 7 0 1 0
  • aNo Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology.
  • bIncidence reflects 64 preferred terms in the Infections and Infestations system organ class.
  • *Treatment arms were LONSURF plus BSC vs placebo plus BSC.

What else was discovered in the RECOURSE trial?

  • Hand-foot syndrome was reported in 2% of patients in the LONSURF group, and 2% of patients in the placebo group. No Grade 3/4 was reported5
  • 69% of patients who developed neutropenia (any grade) during the trial developed it during cycle 14
  • 9.4% of patients in the LONSURF group received granulocyte-colony stimulating factor (G-CSF)5

In RECOURSE, 3.6% of patients discontinued LONSURF for an adverse reaction and 14% of patients required a dose reduction. The most common adverse reactions or laboratory abnormalities leading to dose reductions were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea6

Study Design

LONSURF® (FTD/TPI) tablets was studied in the RECOURSE trial4,5,6

RECOURSE was an international, randomized, double-blind, placebo-controlled phase 3 clinical trial4,6

Inclusion criteria4,5,6:

  • Age ≥18 years
  • Confirmed adenocarcinoma of the colon or rectum
  • ECOG performance status of 0 or 1
  • 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
  • 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 chemotherapies

2:1 Randomization6

LONSURF + BEST SUPPORTIVE CARE (n=534)

35 mg/m2 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

Placebo + BEST SUPPORTIVE CARE (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

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.4

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®)

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

NCCN recommends trifluridine and tipiracil (LONSURF) as a potential 3rd line or subsequent-line treatment option in both RAS-mutant and wild-type mCRC patients. See below for potential treatment algorithms.1,2

NCCN Guidelines for Metastatic Colon Cancer Treatment NCCN Guidelines for Metastatic Colon Cancer Treatment

These example patients are BRAF WT, pMMR/MSS, NTRK gene fusion negative, and HER2 WT.

*These treatment algorithms are examples only; other treatment options are recommended in the NCCN Guidelines®.

Trifluridine and tipiracil is a treatment option for patients who have progressed through all available regimens.

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

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.

In the RECOURSE international clinical trial:

42%
of patients in the LONSURF arm went on to receive subsequent therapy at the end
of the trial2
98%
of patients in the LONSURF arm were refractory to or were failing on fluoropyrimidine-based therapy in a prior treatment regimen5
To view the RECOURSE study design, click here.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.2.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed June 9, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed June 9, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. 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. Data on file. Taiho Oncology, Inc., Princeton, NJ. 5. 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. 6. LONSURF [Prescribing Information]. Princeton, NJ: Taiho Oncology, Inc.; 2019. 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.

INDICATIONS

INDICATIONS

LONSURF is indicated 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, HER2/neu‑targeted therapy.

Indications and Important Safety Information +

INDICATIONS

LONSURF is indicated 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, HER2/neu‑targeted therapy.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Severe Myelosuppression: LONSURF caused severe and life‑threatening myelosuppression (Grade 3‑4) consisting of neutropenia (38%), anemia (18%), thrombocytopenia (5%), and febrile neutropenia (3%). Two patients (0.2%) died due to neutropenic infection. A total of 12% 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, absolute neutrophil count less than 500/mm3, 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 and for at least 6 months after the final dose.

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 (46% vs 32%), Grade 3 anemia (22% vs 16%), and Grade 3 or 4 thrombocytopenia (7% vs 4%).

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. 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.

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). Patients with severe renal impairment (CLcr < 30 mL/min) 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 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%), infections (27% vs 16%), abdominal pain (21% vs 18%), pyrexia (19% vs 14%), stomatitis (8% vs 6%), dysgeusia (7% vs 2%), and alopecia (7% vs 1%). In metastatic gastric cancer or gastroesophageal junction (GEJ), the most common adverse drug reactions, respectively were, nausea (37% vs 32%), 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: (2% vs 0%) in mCRC and (3% vs 2%) in metastatic gastric cancer and GEJ.

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 mCRC, respectively, were anemia (77% vs 33%), neutropenia (67% vs 1%), and thrombocytopenia (42% vs 8%). In metastatic gastric cancer or GEJ, the test abnormalities, respectively, were neutropenia (66% vs 4%), anemia (63% vs 38%), and thrombocytopenia (34% vs 9%).

Please see full Prescribing Information.