1. Trifluridine/Tipiracil (TAS-102) Improves Survival in Patients With Metastatic CRC and Mild Renal/Hepatic Impairment: Subgroup Analysis of RECOURSE
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
CRC, colorectal cancer.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. TAS-102 in Metastatic CRC
TAS-102 an oral combination of trifluridine (FTD) and tipiracil hydrochloride (TPI) approved in 9/2015 for metastatic CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy[1]
FTD: thymidine-based nucleoside analogue that causes DNA dysfunction
TPI: thymidine phosphorylase inhibitor that improves FTD bioavailability
RECOURSE: randomized phase III trial demonstrated OS benefit with TAS-102 in pts with metastatic, refractory CRC vs placebo (2.1 vs mos; HR: 0.68; P < .001)[2]
Current study: subgroup analysis of RECOURSE evaluating efficacy and safety of TAS-102 in pts with renal and hepatic impairment[1]
CRC, colorectal cancer.
1. Mayer RJ, et al. ASCO Abstract Mayer RJ, et al. N Engl J Med. 2015;372:
Slide credit: clinicaloptions.com

3. TAS-102 in Metastatic CRC: Phase III RECOURSE Study Design
Randomized 2:1; stratified by tumor status (WT vs mutant KRAS), time between first dx of metastases and randomization (< 18 vs ≥ 18 mos), geographic region (Japan vs US, Europe, Australia
TAS mg/m2 BID + BSC
Days 1-5, 8-12 of 28-day cycle
(n = 534)
Placebo + BSC
(n = 266)
Previously treated metastatic CRC ≥ 2 lines (including fluoropyrimidines,
irinotecan, oxaliplatin,
and bevacizumab;
cetuximab or panitumumab
in pts with
KRAS wild-type tumors)
ECOG PS 0-1
(N = 800)
Until disease progression, death, unacceptable toxicity, or patient withdrawal of consent
BSC, best supportive care; CRC, colorectal cancer; DCR, disease control rate; dx, diagnosis; ECOG, Eastern Cooperative Oncology Group; PS, performance status; WT, wild type.
Primary endpoint: OS
Secondary endpoint: PFS, ORR, DCR, safety
Slide credit: clinicaloptions.com
Mayer RJ, et al. N Engl J Med. 2015;372:

4. RECOURSE: Subanalysis
Kidney function classified according to calculated CrCl
Normal: CrCl ≥ 90 mL/min
Mild impairment: CrCl mL/min
Moderate impairment: CrCl mL/min
Liver function classified according to NCI criteria
Mild G1 impairment: total bilirubin ≤ ULN, AST > ULN
Mild G2 impairment: total bilirubin > 1 to 1.5 x ULN, any AST
AST, aspartate aminotransferase; CrCl, creatinine clearance; NCI, National Cancer Institute; ULN, upper limit of normal; .
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

5. RECOURSE: Pt Population (Renal Subgroup)
Characteristic
Normal
Mild Impairment
Moderate Impairment
TAS-102
(n = 307)
Placebo
(n = 145)
(n = 178)
(n = 91)
(n = 47)
(n = 27)
Mean age, yrs (SD)
57.4 (9.56)
56.8 (10.54)
66.1 (8.54)
65.9 (6.81)
70.6 (6.18)
71.5 (5.43)
Male, %
67.1
66.2
55.1
61.5
44.7
37.0
ECOG PS 1, %
41.7
42.8
43.3
42.9
55.3
59.3
KRAS wild type, %
50.8
49.0
47.8
53.8
42.6
40.7
Time since diagnosis of metastasis ≥ 18 mos, %
79.5
80.7
78.1
75.8
83.0
81.5
Baseline renal function (CrCl), %*
Mild impairment
Moderate impairment
100
Baseline eGFR, %*
82.1
16.6
83.4
14.5
44.9
46.1
5.6
41.8
52.7
4.4
6.4
48.9
3.7
44.4
CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; PS, performance status; SD, standard deviation.
Renal function (CrCl) category values:
Normal: ≥ 90 mL/min
Mild impairment: mL/min
Moderate impairment: mL/min
eGFR category values:
Normal: ≥ 90 mL/min/1.73 m2
Mild impairment: mL/min/1.73 m2
Moderate impairment: mL/min/1.73 m2
*See slidenotes for category values.
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

6. RECOURSE: Pt Population (Hepatic Subgroup)
Characteristic
Normal
Mild G1
Mild G2
TAS-102
(n = 325)
Placebo
(n = 157)
(n = 169)
(n = 83)
(n = 34)
(n = 17)
Mean age, yrs (SD)
61.4 (10.54)
61.4 (10.64)
61.3 (9.72)
60.9 (10.73)
62.3 (9.80)
63.2 (10.41)
Male, %
62.5
62.4
58.6
59.0
64.7
ECOG PS 1, %
40.6
43.3
46.7
41.0
50.0
82.4
KRAS wild type, %
46.5
47.8
52.1
51.8
58.8
Time since diagnosis of metastasis ≥ 18 mos, %
82.2
82.8
75.1
72.3
76.5
Baseline renal function (CrCl), %*
Mild impairment
Moderate impairment
58.2
32.0
90.8
49.7
37.6
12.1
56.2
37.3
6.5
62.7
31.3
6.0
29.4
11.8
17.6
Baseline eGFR, %*
56.1
33.1
8.3
69.8
24.9
4.7
67.5
26.5
2.4
20.6
23.5
CRC, colorectal cancer; CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate; PS, performance status; SD, standard deviation.
Renal function (CrCl) category values:
Normal: ≥ 90 mL/min
Mild impairment: mL/min
Moderate impairment: mL/min
eGFR category values:
Normal: ≥ 90 mL/min/1.73 m2
Mild impairment: mL/min/1.73 m2
Moderate impairment: mL/min/1.73 m2
*See slidenotes for category values.
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

7. RECOURSE: Efficacy (Renal Subgroup)
Characteristic
Normal
Mild Impairment
Moderate Impairment
TAS-102
(n = 289)
Placebo
(n = 140)
(n = 166)
(n = 89)
(n = 45)
(n = 26)
DCR, %
42.2
19.3
45.2
12.4
53.3
15.4
P value
< .0001
.0022
Survival
(n = 307)
(n = 145)
(n = 178)
(n = 91)
(n = 47)
(n = 27)
Median OS, mos
7.4
5.3
6.7
4.7
6.9
HR (95% CI) P value
0.64 ( ) .0002
0.71 ( ) .0247
0.85 ( ) .6049
Median PFS, mos
1.9
1.7
2.0
3.2
1.8
0.51 ( )
0.47 ( )
0.38 ( )
< .0007
DCR, disease control rate.
CR/PR rates not significantly different regardless of renal function
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

8. RECOURSE: Efficacy (Hepatic Subgroup)
Characteristic
Normal
Mild G1
Mild G2
TAS-102
(n = 306)
Placebo
(n = 150)
(n = 158)
(n = 83)
(n = 33)
(n = 17)
DCR, %
52.6
18.0
31.0
13.3
33.3
11.8
P value
< .0001
.0027
.1729
Survival
(n = 325)
(n = 157)
(n = 169)
(n = 34)
Median OS, mos
9.9
6.9
5.2
3.5
2.4
HR (95% CI) P value
0.63 ( ) .0001
0.71 ( ) .0222
0.44 ( ) .0243
Median PFS, mos
2.9
1.8
1.9
1.7
1.2
0.44 ( )
0.58 ( )
.0002
0.31 ( )
.0007
DCR, disease control rate.
CR/PR rates not significantly different regardless of hepatic function
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

9. RECOURSE: Safety (Renal Subgroup)
Anemia and neutropenia most frequent grade ≥ 3 laboratory abnormality with TAS-102 across subgroups
AEs, %
Normal
Mild Impairment
Moderate Impairment
TAS-102
(n = 306)
Placebo
(n = 145)
(n = 178)
(n = 91)
(n = 47)
(n = 26)
Overall AEs
97.7
91.7
99.4
95.6
97.9
92.3
Nausea
52.3
28.3
44.4
20.9
36.2
7.7
Vomiting
27.1
16.6
29.2
15.4
25.5
Diarrhea
30.4
13.1
33.1
14.3
38.3
3.8
Fatigue
35.6
32.0
16.5
42.6
Asthenia
19.3
57.2
62.9
48.4
70.2
42.3
Grade ≥ 3
66.7
51.7
70.8
51.6
85.1
53.8
Serious AE
27.5
30.3
39.6
30.8
Treatment-related AEs
84.3
56.6
88.2
45.1
11.7
52.8
61.7
9.2
0.7
9.0
12.8
AE, adverse event.
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

10. RECOURSE: Safety (Hepatic Subgroup)
Anemia and neutropenia most frequent grade ≥ 3 laboratory abnormality with TAS-102 across subgroups
AEs, %
Normal
Mild G1
Mild G2
TAS-102
(n = 325)
Placebo
(n = 157)
(n = 169)
(n = 83)
(n = 34)
(n = 17)
Overall AEs
98.2
91.1
98.8
96.4
97.1
94.1
Nausea
49.5
22.9
45.0
26.5
50.0
17.6
Vomiting
29.5
15.3
24.9
13.3
23.5
Diarrhea
35.1
11.5
28.4
14.5
20.6
Fatigue
32.3
19.1
43.2
30.1
Asthenia
22.5
12.1
11.2
8.4
11.8
Grade ≥ 3
67.7
43.9
71.0
61.4
79.4
82.4
Serious AE
26.2
26.8
34.3
41.0
41.2
76.5
Treatment-related AEs
88.0
52.2
82.2
57.8
52.9
52.6
8.9
42.0
12.0
5.9
7.7
1.2
14.7
AE, adverse event.
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

11. RECOURSE: Subanalysis Conclusions
OS and PFS benefits observed with TAS-102 vs placebo in normal and mild renal/hepatic impairment subgroups of metastatic CRC
PFS and DCR benefits also observed in moderate renal impairment subgroup but with more grade ≥ 3 treatment-related toxicity
Authors suggest small sample size and/or comorbidities may have influenced lack of OS benefit
Higher exposure to trifluridine may have contributed to AEs
CRC, colorectal cancer; DCR, disease control rate
Slide credit: clinicaloptions.com
Mayer RJ, et al. ASCO Abstract 3547.

12. Go Online for More CCO Coverage of ASCO 2016!
Short slideset summaries of all the key data
Additional CME-certified analyses with expert faculty commentary on all the key studies in:
Breast, genitourinary, and lung cancers
Hematologic malignancies
Immunotherapy
clinicaloptions.com/oncology