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.

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 5.3 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 2016. Abstract 3547. 2. Mayer RJ, et al. N Engl J Med. 2015;372:1909-1919. Slide credit: clinicaloptions.com

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-102 35 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;372:1909-1919.

RECOURSE: Subanalysis Kidney function classified according to calculated CrCl Normal: CrCl ≥ 90 mL/min Mild impairment: CrCl 60-89 mL/min Moderate impairment: CrCl 30-59 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 2016. Abstract 3547.

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: 60-89 mL/min Moderate impairment: 30-59 mL/min eGFR category values: Normal: ≥ 90 mL/min/1.73 m2 Mild impairment: 60-89 mL/min/1.73 m2 Moderate impairment: 30-59 mL/min/1.73 m2 *See slidenotes for category values. Slide credit: clinicaloptions.com Mayer RJ, et al. ASCO 2016. Abstract 3547.

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: 60-89 mL/min Moderate impairment: 30-59 mL/min eGFR category values: Normal: ≥ 90 mL/min/1.73 m2 Mild impairment: 60-89 mL/min/1.73 m2 Moderate impairment: 30-59 mL/min/1.73 m2 *See slidenotes for category values. Slide credit: clinicaloptions.com Mayer RJ, et al. ASCO 2016. Abstract 3547.

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 (0.51-0.81) .0002 0.71 (0.53-0.96) .0247 0.85 (0.47-1.56) .6049 Median PFS, mos 1.9 1.7 2.0 3.2 1.8 0.51 (0.41-0.63) 0.47 (0.35-0.62) 0.38 (0.21-0.67) < .0007 DCR, disease control rate. CR/PR rates not significantly different regardless of renal function Slide credit: clinicaloptions.com Mayer RJ, et al. ASCO 2016. Abstract 3547.

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 (0.50-0.80) .0001 0.71 (0.53-0.95) .0222 0.44 (0.21-0.92) .0243 Median PFS, mos 2.9 1.8 1.9 1.7 1.2 0.44 (0.35-0.54) 0.58 (0.43-0.77) .0002 0.31 (0.15-0.63) .0007 DCR, disease control rate. CR/PR rates not significantly different regardless of hepatic function Slide credit: clinicaloptions.com Mayer RJ, et al. ASCO 2016. Abstract 3547.

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 2016. Abstract 3547.

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 2016. Abstract 3547.

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 2016. Abstract 3547.

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