Role of Trifluridine & Tipiracil in the

Treatment of Metastatic CRC and Gastric

Cancer

Dr Indranil Ghosh
Senior consultant and Hony Prof (AHERF)
Department of Medical Oncology,
Apollo Cancer Center
Kolkata, India
 Mechanism of Action

Onco Targets Ther. 2020; 13: 7459–7465 2

• Trifluridine is incorporated
in DNA after
phosphorylation and
induces DNA dysfunction
• Tipiracil is a thymidine
phosphorylase inhibitor
that increases the
bioavailability of
trifluridine

Drugs Ther Perspect (2017) 33:110–118. 3

Clin Colorectal Cancer. 2017 Jun; 16(2): 85–92. 4
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Patients with mCRC (RECOURSE Study)

• Objective: To evaluate the efficacy and safety of trifluridine/tipiracil in patients

with mCRC with or without exposure to biologic therapy

• Study type: Phase III, randomized, double-blind, placebo-controlled

• Line of therapy: 3rd

• Primary End point: OS

• Secondary End point: ORR, PFS and Safety

5
N Engl J Med 2015; 372:1909-1919
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Patients with mCRC (RECOURSE Study)

Inclusion Criteria
• Age ≥ 18 years
• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
• Known KRAS status (mutant or wild-type)
• Refractory or intolerant to 2 or more prior chemotherapy regimens
• With or without prior anti-VEGF and anti-EGFR therapy
• ECOG status: 0 or 1

• Adequate renal, hepatic and bone marrow function

6
N Engl J Med 2015; 372:1909-1919
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Patients with mCRC (RECOURSE Study)
Study Design

Total patients:
800

Median follow-up period: 11.8 months

TT: 534 Placebo: 266

mDoT: 6.7 weeks mDoT: 5.7 weeks

7
N Engl J Med 2015; 372:1909-1919
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Patients with mCRC (RECOURSE Study)

Results

Efficacy Parameter Trifluridine + Tipiracil Placebo P value

DCR (CR+PR+SD ≥6 weeks) 44% 16% <0.001

mOS 7.1 months 5.3 months <0.001

Time to deterioration of
5.7 months 4 months <0.001
ECOG PS ≥ 2

Confidential, not to be reproduced 11

N Engl J Med 2015; 372:1909-1919
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in Patients
with mCRC (RECOURSE Study)

Key Takeaways
Risk of disease progression is 52% lower with Trifluridine + Tipiracil compared to
placebo

Risk of mortality is 32% lower with Trifluridine + Tipiracil compared to placebo

Risk of deterioration of ECOG PS to ≥2 is 34% lower with Trifluridine + Tipiracil

compared to placebo

12
N Engl J Med 2015; 372:1909-1919
 Pivotal Clinical Studies

S.No. Name of the Study Indication

1 TERRA (Asian Population) mCRC
2 Switcher Analysis mCRC
3 PRECONNECT mCRC
Metastatic Gastric or GEJ
4 TAGS adenocarcinoma

13
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Asian Patients with mCRC (TERRA Study)

• Objective: To evaluate the efficacy and safety of trifluridine/tipiracil in Asian

patients with mCRC with or without exposure to biologic therapy

• Study type: Phase III, randomized, double-blind, placebo-controlled

• Line of therapy: 3rd

• Primary End point: OS

• Secondary End point: ORR, PFS and Safety

14
J Clin Oncol. 2018;36(4):350-358.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Asian Patients with mCRC (TERRA Study)

Inclusion Criteria
• Age ≥ 18 years
• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
• Known KRAS status (mutant or wild-type)
• Refractory or intolerant to 2 or more prior chemotherapy regimens
• With or without prior anti-VEGF and anti-EGFR therapy
• ECOG status: 0 or 1
• Measurable or non-measurable metastatic lesions

15
J Clin Oncol. 2018;36(4):350-358.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Asian Patients with mCRC (TERRA Study)
Study Design

Total patients:
406

Median follow-up period: 13.8 months

TT: 271 Placebo: 135

mDoT: 3.5 cycles mDoT: 2.2 cycles

16
J Clin Oncol. 2018;36(4):350-358.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Asian Patients with mCRC (TERRA Study)

Tolerability Parameter TT Placebo

Dose reduction 8.5% 0.7%

Dose delay for ≥ 8 days 14.2% 1.8%

Treatment discontinuation due to an adverse event 10% 9.6%

Grade 3 or 4 adverse events 46% 10%

Confidential, not to be reproduced 17

J Clin Oncol. 2018;36(4):350-358.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Asian Patients with mCRC (TERRA Study)

Results

Efficacy Parameter Trifluridine + Tipiracil Placebo P value

DCR 44.1% 14.6% <0.001

mOS 7.8 months 7.1 months 0.035

Time to deterioration of
7 months 5.9 months 0.071
ECOG PS ≥ 2

Confidential, not to be reproduced 18

J Clin Oncol. 2018;36(4):350-358.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in Asian
Patients with mCRC (TERRA Study)

Key Takeaways
Risk of disease progression is 57% lower with Trifluridine + Tipiracil compared to
placebo

Risk of mortality is 21% lower with Trifluridine + Tipiracil compared to placebo

Trifluridine + Tipiracil is effective and well-tolerated in Asian patients with mCRC

irrespective of KRAS mutation status and exposure to biologic therapy

19
J Clin Oncol. 2018;36(4):350-358.
 FTD + TPI to REG vs REG to FTD + TPI (Switcher
Analysis):
Real-World Adherence in mCRC

• Objective: To evaluate the treatment adherence of Tipa to Rego vs Rego to Tipa in

patients with mCRC

• Study type: Retrospective

• Line of therapy: 3rd

• Study outcomes: Medication Possession Ratio (MPR) and Proportion of Days

Covered (PDC)

20
Oncologist. 2020;25(1): e75–e84.
 FTD + TPI to REG vs REG to FTD + TPI (Switcher
Analysis):
Real-World Adherence in mCRC

For both MPR and PDC, patients with a value >0.80 were considered adherent to their therapy
21
Oncologist. 2020;25(1): e75–e84.
 FTD + TPI to REG vs REG to FTD + TPI (Switcher
Analysis):
Real-World Adherence in mCRC
Study Design

Total patients: 179

Tipa to Rego: 96 Rego to Tipa: 83

22
Oncologist. 2020;25(1): e75–e84.
 FTD + TPI to REG vs REG to FTD + TPI (Switcher
Analysis):
Real-World Adherence in mCRC
Results

Outcome FTD + TPI to REG REG to FTD + TPI P value

Proportion of adherent patients

79.2% 57.8% 0.004
 MPR ≥0.80
 PDC ≥0.80 at 3 months 81.1% 49.4% <0.001
 PDC ≥0.80 at 6 months 44.2% 22.7% 0.011
Time to first treatment discontinuation
 No Gap of ≥45 days 107 days 81 days <0.001
 No Gap of ≥60 days 110 days 84 days <0.001

23
Oncologist. 2020;25(1): e75–e84.
 FTD + TPI to REG vs REG to FTD + TPI (Switcher Analysis):
Real-World Adherence in mCRC

Key Takeaways
FTD + TPI to REG switchers are twice more likely to have an MPR ≥0.80 and over four
times more likely to have a PDC ≥0.80 compared with REG to FTD + TPI switchers

Risk of first treatment discontinuation is 34% lower with FTD + TPI to REG switchers
compared with REG to FTD + TPI switchers

Patients who switched from FTD + TPI to REG showed higher adherence and longer time
to discontinuation of their first treatment compared with those who switched from REG
to FTD + TPI

24
Oncologist. 2020;25(1): e75–e84.
 Third-line Therapy in Refractory mCRC
(PRECONNECT study)

• Objective: To evaluate the efficacy and safety of TT in patients with refractory

mCRC

• Study type: Phase III, Multicentre, Open-label, Single-arm

• Line of therapy: 3rd line

• Primary End point: Safety

• Secondary End points: PFS, QoL

ESMO Open. 2020; 5(3): e000698.

25
 Third-line Therapy in Refractory mCRC
(PRECONNECT study)
Inclusion Criteria
• Age ≥ 18 years

• Histologically confirmed adenocarcinoma of the colon or rectum

• Known KRAS status (mutant or wild-type)

• Refractory or intolerant to 2 or more prior chemotherapy regimens

• With or without prior anti-VEGF and anti-EGFR therapy

• ECOG status: 0 or 1

• Adequate renal, hepatic, cardiac and bone marrow function

ESMO Open. 2020; 5(3): e000698.

26
 Third-line Therapy in Refractory mCRC
(PRECONNECT study)

Study Design
• No. of patients: 793

• mDOT: 2.8 months

• Median number of cycles: 3

ESMO Open. 2020; 5(3): e000698.

27
 Third-line Therapy in Refractory mCRC
(PRECONNECT study)
Results Efficacy Parameter Result

DCR 34.4%

mPFS 2.8 months

Median time to ECOG deterioration (PS≥2) 8.9 months

73.9% of patients, with the most
common being neutropaenia (39.1% of
Grade ≥3 AEs
patients), anaemia (9.8%) and
asthenia/fatigue (5.0%).

ESMO Open. 2020; 5(3): e000698.

Confidential, not to be reproduced 28
 Third-line Therapy in Refractory mCRC
(PRECONNECT study)

Key Takeaways
Safety and efficacy are consistent with that observed in the phase III RECOURSE
trial

QoL is maintained during treatment with no clinically meaningful deterioration

At the end of treatment, 79.8% of patients maintained an ECOG PS of 0 or 1,

allowing subsequent treatment

ESMO Open. 2020; 5(3): e000698.

29
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Metastatic Gastric Cancer (TAGS Study)

• Objective: To evaluate the efficacy and safety of trifluridine/tipiracil in patients

with heavily pretreated metastatic gastric cancer

• Study type: Phase III, randomized, double-blind, placebo-controlled

• Line of therapy: 3rd

• Primary End point: OS

• Secondary End point: ORR, PFS and Safety

30
Lancet Oncol. 2018;19(11):1437-1448.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Metastatic Gastric Cancer (TAGS Study)

Inclusion Criteria Exclusion Criteria

• Age ≥ 18 years • Any other active malignancy
• Histologically confirmed, unresectable, • CNS metastasis
metastatic gastric adenocarcinoma (including • Active infection
adenocarcinoma of the gastroesophageal
• Serious organ dysfunction
junction)
• Autoimmune disorders
• Two or more lines of prior therapy
• History of organ transplantation requiring
• Previous regimens: fluoropyrimidine, platinum immunosuppressive therapy
agent, taxane or irinotecan, or both
• ECOG status: 0 or 1
• Measurable or non-measurable metastatic
lesions
31
Lancet Oncol. 2018;19(11):1437-1448.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Metastatic Gastric Cancer (TAGS Study)
Study Design

Total patients:
507
• Median follow-up period: 10.7 months
• 16% in TT arm received granulocyte

TT: 337 Placebo: 170 colony-stimulating factor

mDoT: 6.7 weeks mDoT: 5.7 weeks

32
Lancet Oncol. 2018;19(11):1437-1448.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Metastatic Gastric Cancer (TAGS Study)

Tolerability Parameter TT Placebo

Dosing modification (dosing delay or dose
reduction) 58% 22%

Treatment discontinuation due to an adverse event 13% 17%

Grade 3 or 4 treatment-related adverse events 53% 14%

Confidential, not to be reproduced 33

Lancet Oncol. 2018;19(11):1437-1448.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Metastatic Gastric Cancer (TAGS Study)

Results

Efficacy Parameter Trifluridine + Tipiracil Placebo P value

DCR 44% 14% <0.0001

mOS 5.7 months 3.6 months 0.0005

Time to deterioration of
4.3 months 2.3 months 0.0005
ECOG PS ≥ 2

Confidential, not to be reproduced 34

Lancet Oncol. 2018;19(11):1437-1448.
 Trifluridine + Tipiracil vs Placebo: Third-line Therapy in
Metastatic Gastric Cancer (TAGS Study)

Key Takeaways
Risk of disease progression is 43% lower with Trifluridine + Tipiracil compared to
placebo

Risk of mortality is 31% lower with Trifluridine + Tipiracil compared to placebo

Risk of deterioration of ECOG PS to ≥2 is 41% lower with Trifluridine + Tipiracil

compared to placebo

35
Lancet Oncol. 2018;19(11):1437-1448.
Approved Indications & Dosage
Indication Line of therapy Dosage
Metastatic colorectal cancer who have been
previously treated with 35 mg/m2 twice daily on Days 1 to
fluoropyrimidine-, oxaliplatin-and irinotecan-based 3rd 5 and Days 8 to 12 of each 28-day
chemotherapy, an anti-VEGF biological therapy, and cycle
if RAS wild-type, an anti-EGFR therapy

Metastatic gastric or gastroesophageal junction

adenocarcinoma previously treated with at least 2 35 mg/m2 twice daily on Days 1 to
prior lines of chemotherapy that included a 5 and Days 8 to 12 of each 28-day
3rd
fluoropyrimidine, a platinum, either a taxane or cycle
irinotecan, and if appropriate, HER2-targeted
therapy

Dosing is based on the Trifluridine component

Maximum dose is 80 mg per dose
Dose is rounded up to the nearest 5 mg increment

36
Recommended Dosage According to Body Surface Area (BSA)

Confidential, not to be reproduced 37

Dose Modification for Adverse Reactions

Recommended Dose Level 1 Dose Reduction Level 2 Dose Reduction Level 3 Dose Reduction

35 mg/m2 30 mg/m2 25 mg/m2 20 mg/m2

Dose escalation is not permitted after it has been reduced.

38
Dosage in Hepatic Impairment

Degree of impairment Dose adjustment

Mild (Child-Pugh A) No

Moderate (Child-Pugh B) Not recommended

Severe (Child-Pugh C) Not recommended

39
Dosage in Renal Impairment
Creatinine Clearance (mL/min) Dose adjustment

60 to 89 No

30 to 59 No
20 mg/m2
15 to 29 One dose reduction to 15 mg/m2
is permitted

40
Administration
• Should be taken with food until disease progression or unacceptable toxicity

• Tablets should be swallowed whole. Not to be crushed

• Tipanat is a cytotoxic drug. Should be handled with care

41
Thank You