Results of a multicenter, randomized, doubleblind, phase III study of TAS-102 plus best
supportive care (BSC) versus placebo plus BSC
in patients with metastatic colorectal cancer
(mCRC) refractory to standard therapies
(RECOURSE)
Takayuki Yoshino, M. D.
National Cancer Center Hospital East
Chiba, Japan
Robert Mayer, Alfredo Falcone, Atsushi Ohtsu, Rocio Garcia-Carbonero,
Nobuyuki Mizunuma, Kentaro Yamazaki, Yasuhiro Shimada, Josep Tabernero,
Yoshito Komatsu, Alberto Sobrero, Eveline Boucher, Marc Peeters, Ben Tran,
Heinz-Josef Lenz, Alberto Zaniboni, Howard Hochster, Fabio Benedetti,
Manuel Aivado, Lukas Makris, Masanobu Ito, Eric Van Cutsem, and
the RECOURSE study Group
Conflict of Interest Disclosure
• The presenter has no conflicts of interest
associated with this trial
TAS-102; Mechanism of Action
TPase
F3dThd (FTD)
Inhibition of
tumor growth
FTY
(inactive form)
TPI
F3dTMP
F3dTDP
TAS-102
DNA dysfunction
(Oral Combination Drug)
FTD
TPI
F3dTTP
FTD incorporation
into DNA
Molar ratio = 1 : 0.5
FTD：Trifluridine
TPI：Tipiracil-HCl
Differentiation between 5-FU and TAS-102
5-FU
TAS-102
5-FU
FTD
FdUMP
F3dTMP
F3dTDP
Phosphorylation
F3dTTP
Inhibit
Incorporation into DNA
TS
dUMP
DNA
duplication
dTMP
dTTP
Inhibit DNA duplication
DNA damage
FTD
T
T
Thymidine（T）
Preclinical Results with TAS-102
• In pre-clinical studies, TAS-102 was effective against cell lines
with acquired resistance to 5-FU 1
• In an animal study, co-administration with TPI increased the
plasma AUC of FTD by 100-fold 2
• In Xenograft Models, the anti-tumor effect of TAS-102 appeared
to occur through FTD incorporation into DNA 3 ; incorporation of
FTD into DNA was 700-fold greater than that of 2’-deoxy-5fluorouridine (FdUrd) 4
• 5-FU, capecitabine, S-1, and UFT work primarily by inhibiting
thymidylate synthase whereas TAS-102, while structurally
similar, acts as an antimetabolite (i.e., incorporated into DNA)
1. Emura T, et al., Int J Mol. Med. 2004:545-49
2. Emura T, et al., Int J Oncol. 2005;27:449-55
3. Tanaka N, et al., AACR 2012 (Abstr 1783)
4. Data on file
Clinical Rationale for TAS-102 in mCRC:
Phase I and Phase II Experiences
• Japanese Randomized Phase II trial for Patients with mCRC 1:
– Total 172 patients, who received all of prior fluoropyrimidine, irinotecan
and oxaliplatin, were randomized
– The median OS was 9.0 vs. 6.6 months (HR=0.56 p=0.0011)
– The most common grade 3 or 4 toxicity was hematological toxicity
The recommended dose (RD)
was determined to be 35
mg/m2/dose orally twice
daily 2,3
1. Yoshino T, Ohtsu A, et al., Lancet Oncol. 2012;13(10):993-1001
2. Doi T, Ohtsu A, Yoshino T, et al., Br J Cancer 2012;107(3):429-34
3. Patel M, Bendell J, Mayer RJ, et al., J Clin Oncol 2012; 30 (suppl; abstr 3631)
Global Randomized Phase III study
RECOURSE: Refractory Colorectal Cancer Study
(NCT01607957)
Metastatic colorectal cancer (mCRC)
• 2 or more prior regimens
• Refractory / Intolerable
– fluoropyrimidine
– irinotecan
– oxaliplatin
– bevacizumab
– anti-EGFR if wild-type KRAS
• ECOG PS 0-1
• Age ≥ 18
(target sample size: 800)
R
A
N
D
O
M
I
Z
A
T
I
O
N
TAS-102 + BSC
(n = 534)
35 mg/m2 b.i.d. p.o.
d1-5, 8-12 q4wks
2:1
Placebo + BSC
Endpoints Primary: OS
Secondary: PFS, Safety,
Tolerability, TTF, ORR, DCR,
DoR, Subgroup by KRAS (OS
and PFS)
(n = 266)
d1-5, 8-12 q4wks
•
•
Treatment continuation until progression, intolerant toxicity or patient refusal
Multicenter, randomized, double-blind, placebo-controlled, phase III
– Stratification: KRAS status, time from diagnosis of metastatic disease,
geographical region
•
•
Sites: 13 countries, 114 sites
Enrollment: June 2012 to October 2013
RECOURSE: Endpoints
Primary Endpoint: Overall Survival (OS)
– OS comparison between the two treatment arms are based
on the intent-to-treat (ITT) population
– Designed to detect an OS hazard ratio of 0.75 (25% risk
reduction), with a 1-sided type I error of 0.025, 90% power
– A target of 571 events was required
– Planned sample size was 800
Key Secondary Endpoints
–
–
–
–
Progression Free Survival (PFS)
Overall Response Rate (ORR)
Disease Control Rate (DCR)
Safety
RECOURSE: Key Eligibility
• Histologically or cytologically confirmed adenocarcinoma of
the colon or rectum
• Received at least 2 prior regimens of standard
chemotherapies for mCRC and is refractory to or failing those
chemotherapies
– Patients who have progressed based on imaging during or
within 3 months of the last administration of each
standard chemotherapy, including fluoropyrimidines,
irinotecan, oxaliplatin, bevacizumab, and
cetuximab/panitumumab for wild-type KRAS patients
– Patients who discontinued a treatment due to intolerance
to that therapy were also eligible
• ECOG performance status 0-1
Patient Demographics and Characteristics
(Intent-to-treat population)
TAS-102
N=534
Placebo
N=266
63.0 (27-82)
63.0 (27-82)
Male
61.0
62.0
Female
39.0
38.0
White
57.3
58.3
Asian
34.5
35.3
Black
0.7
1.9
Japan
33.3
33.1
Western
66.7
66.9
Europe
50.7
49.6
US
12.0
13.2
3.9
4.1
0
56.4
55.3
1
43.6
44.7
Age, median (range)
Gender, %
Race, %
Geographic Region, %
Australia
ECOG PS, %
Patient Disease Characteristics
(Intent-to-treat population)
TAS-102
N=534
Placebo
N=266
Colon
63.3
60.5
Rectum
36.7
39.5
Wild-type
49.1
49.2
Mutant
50.9
50.8
Time since diagnosis of
metastasis, %
< 18 months
20.8
20.7
> 18 months
79.2
79.3
Number of prior regimens for
metastatic, %
1-2
25.8
25.6
3
28.8
25.6
>4
45.3
48.9
Fluoropyrimidine
100
100
Irinotecan
100
100
Oxaliplatin
100
100
Bevacizumab
100
99.6
Anti-EGFR (if wild KRAS*)
99.6
99.3
Regorafenib
17.0
19.9
Primary site, %
KRAS mutational status, %
All prior systemic cancer
therapeutic agents, %
*Based on historical patient record
Patient Disease Characteristics (cont’d)
(Intent-to-treat population)
TAS-102
N=534
Placebo
N=266
100
100
Refractory to Fluoropyrimidine at any time it was given
97.6
99.6
Refractory to Fluoropyrimidine last time it was given
92.7
89.8
Patients receiving 5-FU as last Regimen Prior to
Randomization, %
61.4
58.6
Patient receiving prior 5-FU, %
Refractory to Fluoropyrimidine
91.8
89.7
Overall Survival
Events # (%)
100
TAS-102
N=534
Placebo
N=266
364 (68)
210 (79)
HR (95% CI)
90
0.68 (0.58-0.81)
Stratified Log-rank test p<0.0001
Survival Distribution function
80
Median OS, months
7.1
5.3
Median follow-up: 8.4 months
70
Alive at, %
60
50
6 months
58
44
12 months
27
18
40
30
20
10
0
N at Risk:
TAS-102
Placebo
0
3
6
534
266
459
198
294
107
9
12
Months from Randomization
137
47
64
24
15
18
23
9
7
3
Progression-free Survival
100
Progression-free Distribution function
90
Events # (%)
80
TAS-102
N=534
Placebo
N=266
472 (88)
251 (94)
HR (95% CI)
0.48 (0.41-0.57)
Stratified Log-rank test p<0.0001
70
Median PFS, months
60
2.0
1.7
Tumor assessments performed every 8 weeks
50
40
30
20
10
0
0
N at Risk:
TAS-102
Placebo
2
4
6
8
10
12
14
16
5
1
4
1
2
0
Months from Randomization
534
266
238
51
121
10
66
2
30
2
18
2
Overall Response
(tumor response evaluable population, investigator assessment)
Best response, %
Complete response or Partial response*
Stable disease
Disease control rate**
Progressive disease
Per RECIST version 1.1
*Not significant
**CR, PR or SD, p<0.0001
TAS-102
N=502
Placebo
N=258
1.6
0.4
42.4
15.9
44.0
16.3
51.8
75.6
Key Subgroup Analysis of OS
Subgroup
Favors Placebo
Favors TAS-102
Events/N
HR
[95% CI]
Median (mos)
TAS-102 : PBO
574 / 800
0.68 [0.58, 0.81]
7.1 : 5.3
Wild Type
Mutant Type
280 / 393
294 / 407
0.58 [0.45, 0.74]
0.80 [0.63, 1.02]
8.0 : 5.7
6.5 : 4.9
Geographic Region
Japan
West (AU/EU/US)
227 / 266
347 / 534
0.75 [0.57, 1.00]
0.64 [0.52, 0.80]
7.8 : 6.7
6.5 : 4.8
317 / 441
0.75 [0.59, 0.96]
6.8 : 4.9
All Subjects
KRAS Status
Refractory to 5-FU when
given as last therapy prior
to randomization*
0
0.5
1
1.5
2
Hazard Ratio: TAS-102 versus Placebo (95% CI)
*Not prespecified subgroup
Non-Hematologic Adverse Events Occurring in >10% of Patients
(as-treated population)
Non-Hema Adverse events, %
TAS-102 (N=533)
Placebo (N=265)
All Gr.
Gr. 3
Gr. 4
All Gr.
Gr. 3
Gr. 4
Nausea
48.4
1.9
0
23.8
1.1
0
Decreased appetite
39.0
3.6
0
29.4
4.9
0
Fatigue
35.3
3.9
0
23.4
5.7
0
Diarrhea
31.9
2.8
0.2
12.5
0.4
0
Vomiting
27.8
2.1
0
14.3
0.4
0
Pyrexia
18.4
0.9
0.2
14.0
0.4
0
Asthenia
18.2
3.4
0
11.3
3.0
0
Constipation
15.2
0.2
0
15.1
1.1
0
Abdominal pain
14.8
2.1
0
13.6
3.4
0
Cough
10.7
0.4
0
11.3
0.8
0
Dyspnoea
10.5
2.1
0.4
12.8
2.3
0
Oedema peripheral
9.9
0.2
0
10.2
0.8
0
Weight decreased
7.7
0
0
10.2
0
0
One treatment-related death was observed in TAS-102
Hematologic Laboratory Abnormalities Occurring in >10% of Patients
(as-treated population)
Lab abnormalities, %
TAS-102 (N=533)
Placebo (N=265)
All Gr.
Gr. 3
Gr. 4
All Gr.
Gr. 3
Gr. 4
Leukopenia
77.1
18.6
2.8
4.6
0
0
Anemia
76.5
18.2
0*
33.1
3.0
0
Neutropenia
66.9
26.5
11.4
0.8
0
0
Lymphocytopenia
64.6
18.2
3.3
39.7
9.2
0.8
Thrombocytopenia
42.2
4.5
0.6
8.0
0
0.4
Hematology
*One case of grade 4 was reported in AE
Occurring in < 10% of Patients but Clinically Important Adverse Events
(as-treated population)
Adverse events, %
TAS-102 (N=533)
Placebo (N=265)
All Gr.
Gr. 3
Gr. 4
All Gr.
Gr. 3
Gr. 4
Febrile neutropenia
3.8
2.8
0.9
0
0
0
Stomatitis
7.9
0.4
0
6.0
0
0
Hand-foot syndrome
2.3
0
0
2.3
0
0
Cardiac ischaemia events, %
0.4
0.2
0
0.4
0
0.4
Acute myocardial infarction
0.2
0.2
0
0
0
0
Angina pectoris
0.2
0
0
0
0
0
Myocardial ischaemia
0
0
0
0.4
0
0.4
Conclusions
• TAS-102 demonstrated a clinically relevant
improvement in OS and PFS compared with placebo in
mCRC pts refractory / intolerant to standard therapies
– TAS-102 prolonged overall survival across all major
prespecified subgroups including KRAS and region, and
across the subgroup with patients refractory to 5-FU
• TAS-102 was well tolerated
– The most frequently observed toxicities were gastrointestinal
and hematologic, the rate of febrile neutropenia was 3.8%
• The RECOURSE results support TAS-102 as a new
treatment option for patients with refractory mCRC
Thanks to the Patients, Their Families and
Study Team/Participants
Austria:
Australia:
Belgium:
Czech Republic:
France:
Germany:
Ireland:
Italy:
Japan:
Spain:
Kathrin Strasser-Weippl, Andreas Petzer, Werner Scheithauer, Josef Thaler
Ben Tran, Timothy Price, Nick Pavlakis, Niall Tebbutt, Guy van Hazel
Jean-Luc Canon, Yves Humblet, Stephanie Laurent, Jean Luc Van Laethem, Eric Van Cutsem, Marc Peeters
Eugen Kubala, Jan Vydra
Antoine Adenis, Thierry Andre, Denis Smith, Fabienne Portales, Eveline Boucher, Christophe Borg
Andreas Block, Dirk Buschmann, Volker Heinemann, Elke Jaeger, Goetz von Wichert, Markus Moehler, Ingo
Schwaner, Hans-Joachim Schmoll, Heinz-Dieter Hofheinz, Meinolf Karthaus, Claus-Henning Koehne, Gunnar
Folprecht, Thomas Zander
Ray McDermott, David Fennelly, Brian Bird
Alessandro Bertolini, Corrado Boni, Fortunato Ciardiello, Maria di Bartolomeo, Alfredo Falcone, Emiliano
Tamburini, Alberto Sobrero, Marco Tampellini, Alberto Zaniboni, Giacomo Carteni', Salvatore Siena
Yoshito Komatsu, Yasushi Tsuji, Hirofumi Fujii, Toshikazu Moriwaki, Kensei Yamaguchi, Takayuki Yoshino,
Tadamichi Denda, Nobuyuki Mizunuma, Yasuo Hamamoto, Yasuhiro Shimada, Norisuke Nakayama, Kentaro
Yamazaki, Kei Muro, Masahiro Goto, Naotoshi Sugimoto, Akihito Tsuji, Tetsuji Takayama, Tomohiro Nishina,
Taito Esaki, Hideo baba
Jesus Garcia Foncillas, Laura Lema, Carles Pericay, Maria Jose Safont, Josep Tabernero, Rocio GarciaCarbonero, Andres Cervantes Ruiperez, Alberto Carmona Bayonas, Jose Manzano, Manuel Benavides,
Federico Longo, Antonieta Salud
Sweden:
Jan-Erik Frodin, Bengt Glimelius
UK:
USA:
Stephen Falk, Leslie Samuel, David Cunningham, John Bridgewater, Daniel Swinson, David Cunningham
Jerilyn Hart, Philip Stella, Ari Baron, Ronald Yanagihara, Christopher Vaughn, Derrick Spell, Heinz-Josef Lenz,
James Knost, Robert Mayer, Nashat Gabrail, Howard Hochster, Ali Khojasteh, Timothy Kasunic, David Ryan,
Omar Kayaleh, Pei Hua Lu, Brian DiCarlo, Steven Hager, Devinder Singh, Jyotsna Fuloria, J. Marc Pipas,
Heinz Lenz, Patrick Loehrer, Timothy O'Brien
RECOURSE was supported by Taiho Oncology Inc./Taiho Pharmaceutical Co. Ltd.