DALLA CAPECITABINA AL TAS 102

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1 DALLA CAPECITABINA AL TAS 102 Milano 29 settembre 2016 LE PROSPETTIVE NELLA RICERCA Armando Santoro Humanitas Cancer Center

2 THE 1,2.AND 3 LINE CHEMOTHERAPY IN CRC M BEVACIZUMAB AFLIBERCET RAS wt RAS mu FOLFOX FOLFIRI FOLFOXIRI XELOX XELIRI RAS wt CETUXIMAB PANITUMUMAB..and after

3 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Mayer RJ et al., N Engl J Med14;372: , 2015

4 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer TAS-102 combines Trifluridine, a nucleoside analogue which is incorporated into DNA and disrupts DNA synthesis and inhibits thymidylate synthetase and the Thymidine Phosphorylase inhibitor, Tipiracil that prevents the degradation of Trifluridine TAS-102 improved OS and PFS in patients whose disease had progressed after treatment with fluorouracil-based combinations Mayer RJ et al., N Engl J Med14;372: , 2015

5 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Primary site, % KRAS mutational status, % Baseline Characteristics of the ITT Population Colon Rectum Wild-type Mutant Time since diagnosis <18 months of metastasis, % 18 months Number of prior 2 regimens % 3 4 All prior systemic cancer therapeutic agents, % Fluoropyrimidine Irinotecan Oxaliplatin Bevacizumab Anti-EGFR mantibody Regorafenib TAS-102 N= Placebo N= > Mayer RJ et al., N Engl J Med14;372: , 2015

6 Progression-free survival Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer 90 RECOURSE TAS -102 n = 534 Placebo n = Median PFS, months HR (95% CI) 0.48 ( ) Stratified log-rank test: < Months from randomisation Mayer RJ et al., N Engl J Med14;372: , 2015

7 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Mayer RJ et al., N Engl J Med14;372: , 2015

8 % with ECOG performance status <2 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer RECOURSE TAS -102 n = 534 Placebo n = Events # (%) 383 (72) 216 (81) Median, months HR (95% CI) 0.66 ( ) Stratified log-rank test: < Time to ECOG Performance Status of 2 or Higher Months from randomisation 18 Mayer RJ et al., N Engl J Med14;372: , 2015

9 Overall Survival % Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer RECOURSE TAS -102 n = 534 Placebo n = 266 Median OS, months HR (95% CI) 0.68 ( P value.001 TAS-102 Placebo Mayer RJ et al., N Engl J Med14;372: , 2015

10 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Mayer RJ et al., N Engl J Med14;372: , 2015

11 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Frequency of Adverse Events Event TAS-102 (N=533) Placebo (N=265) Any Gr. Gr. 3 Any Gr. Gr. 3 Any event, % Any serious event, % Most common events a, % Nausea Vomiting <1 Decreased appetite Fatigue Diarrhea <1 Abdominal pain Fever <1 Asthenia AEs primary reason for discontinuation in 3.6% TAS-102 and 1.5% placebo treated patients Dose reductions due to AEs occurred in 14% of patients in the TAS-102 arm Mayer RJ et al., N Engl J Med14;372: , 2015

12 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Adverse Events of Special Interest Events TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Febrile neutropenia Stomatitis Hand-foot syndrome Alopecia Proteinurea Cardiac ischaemia events, % Thromboembolic events, % Pulmonary embolism Mayer RJ et al., N Engl J Med14;372: , 2015

13 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Adverse Events of Special Interest Event TAS-102 (N=533) Placebo (N=265) Any Gr. Gr. 3 Any Gr. Gr. 3 Laboratory abnormalities a, % Neutropenia <1 0 Leukopenia Anemia Thrombocytopenia <1 Increase in alanine aminotransferase Increase in aspartate aminotransferase Increase in total bilirubin Increase in alkaline phosphatase Increase in creatinine 13 <1 12 <1 Bone marrow toxicities higher in TAS-102 group as expected 9% of patients in the TAS-102 group received granulocyte colony-stimulating factor Mayer RJ et al., N Engl J Med14;372: , 2015

14 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer TAS-102 vs placebo was significantly better in: OS PFS Conclusions across essentially all stratification factors and predefined subgroups A statistically significant prolongation of time to ECOG PS 2 was observed TAS-102 has an acceptable toxicity profile The most frequently observed toxicities were gastrointestinal and hematologic; rate of febrile neutropenia was 3.8% Mayer RJ et al., N Engl J Med14;372: , 2015

15 Overall Survival % Overall Survival % REGORAFENIB: PHASE 3 TRIALS CORRECT 1 23% reduction in the risk of death 1,0 CONCUR 2 45% reduction in the risk of death 75 0,8 50 0,6 0, Regorafenib 160 mg + BSC Placebo + BSC ,2 0 0 Regorafenib 160 mg + BSC Placebo + BSC Days Since Randomization CORRECT Regorafenib n = 505 Placebo n = 255 Median OS, months 6,4 5,0 HR (95% CI) 0.77 ( ) P value.0052 CONCUR Regorafenib n = 136 Placebo n = 68 Median OS, months 8,8 6,3 HR (95% CI) 0.55 ( ) P value.0002 (1-sidded) 1 Grothey A, et al. Lancet, 26;381:303-12, 2013; 2 Li J, et al. Lancet Oncol, 16:619-29, 2015

16 PFS Probability PFS probability REGORAFENIB: PHASE 3 TRIALS 1,00 CORRECT 1 51% reduction in risk of progression or death 1,00 CONCUR 2 69% reduction in risk of progression or death 0,75 0,50 Regorafenib 160 mg + BSC Placebo + BSC 0,75 0,50 Regorafenib 160 mg + BSC Placebo + BSC 0,25 0, Time from Randomization, months 0, CORRECT Regorafenib n = 505 Placebo n = 255 CONCUR Regorafenib n = 136 Placebo n = 68 Median PFS, months 1,9 1,7 HR (95% CI) 0.49 ( ) Median PFS, months 3,2 1,7 HR (95% CI) 0.31 ( ) P value <.0001 P value <.0001 (1-sided) 1 Grothey A, et al. Lancet, 26;381:303-12, 2013; 2 Li J, et al. Lancet Oncol, 16:619-29, 2015

17 NEW DRUGS IN CHEMORESISTANT MCRC Trial Therapy RR PFS (mo) OS (mo) Yoshino Lancet Onc 2012 phase II Pl + BSC TAS-102+BSC n=169 0% vs 1% 1.0 vs 2.0 HR 0.41 (central assessment) 6.6 vs 9.0 HR 0.56 Van Cutsem RECOURSE, ESMO 2014 Pl + BSC TAS-102+BSC n= % vs 1.6% 1.7 vs 2.0 HR 0.48; 5.3 vs 7.1 HR 0.68 Grothey, CORRECT Lancet 2013 BSC Regorafenib n=753 0% vs 1% 1.7 vs 1.9 HR vs 6.4 HR 0.77 Li, CONCUR ESMO-GI 2014 BSC Regorafenib n=204 0% vs 4.4% 1.7 vs 3.2 HR vs 8.8 HR 0.55

18 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Pro e contro di lonsurf vs regorafenib TAS-1022

19 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Patient selection is crucial Trial Therapy RR Mayer, N Eng J Med 2015 BSC vs TAS % vs 1.6% Grothey, Lancet 2013 BSC vs Regorafenib 0% vs 1% Li, Lancet Oncol, 2015 BSC vs Regorafenib 0% vs 4.4% Patients with poor performance status and rapidly progressive disease are less likely to benefit from both drugs

20 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Patient selection is crucial Significant improvements in OS in pts 65y receveing TAS-102 vs placebo (7.0 vs 4.6 m, P=0.0002). PFS HR was 0.41 for pts 65y, favoring TAS-102 (P<0.0001). I In pts 65y, DCR was 48.7% with TAS-102 vs 15.5%. An age-related difference in overall incidence of AEs wasn t observed in either treatment arm Van Cutsem E. et al J Clin Oncol 34, 2016 (suppl 4S; abstr 638)

21 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Patient selection according to AE

22 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Patient selection according to AE Cardiotoxicity of capecitabine, 5-Fuoruracile, TAS 102 and S1 TAS-102 is not catabolized by DPD, with consequently reduced formation of FBAL and other cardiotoxic 5FU catabolites (F-citrate) TAS- 102, may represent a drug of choice for patients with known cardiac disease. [Petrelli et al., BMC Cancer, 2016]

23 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Patient selection according to prior therapy RECOURSE trial TAS-102 N=534 Placebo N=266 All prior systemic cancer therapeutic agents, % Fluoropyrimidine Irinotecan Oxaliplatin Bevacizumab Anti-EGFR mantibody Regorafenib > During patient accrual into the RECOURSE study, regorafenib became available: the clinical benefit associated with TAS-102 was maintained regardless of prior treatment with regorafenib Although both agents have an OS benefit, in clinical practice oncologists often fail to incorporate them into treatment in favor of recycling prior lines of chemotherapy or other unproven approaches.

24 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Perspectives and challenges The favorable toxicity profile of TAS 102 makes it an ideal partner for combination with: Irinotecan [Doi T, et al. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients. Invest New Drugs. 2015] Oxaliplatin [Nukatsuka M, et al. Efficacy of combination chemotherapy using, TAS-102, with oxaliplatin on human colorectal and gastric cancer xenografts. Anticancer Res. 2015] Targeted agents [Kuboki Y, et al. An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE). J Clin Oncol. 2015] Indeed, a number of trials are ongoing, evaluating the role of TAS-102 in earlier lines of therapy, and in the maintenance and/or second line settings

25 ONGOING CLINICAL TRIALS OF TAS-102 IN mcrc Phase I Study of TAS-102 and Radioembolization With 90Y Resin Microspheres for Chemo- Refractory Colorectal Liver Metastases Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With RAS Wild-Type Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (APOLLON An Open-Label, Multi-Center, Phase 2 Study of Switch Maintenance With TAS-102 Plus Bevacizumab Following Oxaliplatin or Irinotecan-Based Fluoropyrimidine-Containing Induction Chemotherapy in Patients With Metastatic Colorectal Cancer (ALEXANDRIA) Randomized, Double-Blind, Phase III Study of TAS-102 Versus Placebo in Asian Patients With Metastatic Colorectal Cancer refractory or Intolerable to Standard Chemotherapies (TERRA) A Phase I Study of SGI-110 Combined With Irinotecan Followed by Randomized Phase II Study of SGI-110 Combined With Irinotecan Versus Regorafenib or TAS-102 in Previously Treated Metastatic Colorectal Cancer Patients A Multicenter Phase 1/2 Trial of TAS-102 With Bevacizumab for Metastatic Colorectal Cancer Refractory to Standard Therapies (C-TASK FORCE Multicenter Phase 1b/2 Trial of Nintedanib With TAS-102 in Patients With Metastatic Colorectal Cancer (mcrc) Who Had Progression on or Were Intolerant to Standard Therapies (N-TASK FORCE) Randomized Phase II Study of Regorafenib Followed by Cetuximab versus Reverse Sequence for Wild-Type KRAS Metastatic Colorectal Cancer Previously Treated with Fluoropyrimidine, Oxaliplatin, and Irinotecan (REVERECE A Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With Wild-Type Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (APOLLON Trial Identifier NCT NCT NCT NCT NCT UMIN UMIN UMIN UMIN

26 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? Perspectives.and challenges PREDICTIVE BIOMARKERS TO MAKE AN INFORMED DECISION REGARDING HOW TO SEQUENCE REGORAFENIB AND TRIFLURIDINE/TIPIRACIL. [SALEM ME, ET AL. J CLIN ONCOL 2016; CLINICALTRIALS.GOV/CT2/SHOW/NCT ] DIFFERENT SUBGROUPS OF PATIENTS MIGHT HAVE DIFFERENTIAL RESPONSES TO REGORAFENIB AND TAS 102 TREATMENT. REGORAFENIB MAY INCREASE OS IN PATIENTS WITH HIGH LEVEL OF TIE1 (AN ANGIOPOIETIN RECEPTOR) [TABERNERO J, ET AL. LANCET ONCOL. 2015] GIVEN THEIR LACK OF OVERLAPPING TOXICITY, FUTURE STUDIES MAY FOCUS ON USING TAS-102 PLUS REGORAFENIB COMBINATION THERAPY

27 New dilemma in CRC treatment: how to use and sequence TAS-102 and regorafenib? PERSPECTIVES.AND CHALLENGES AN HEAD-TO-HEAD COMPARISONS OF THE 2 DRUGS IN TERMS OF EFFICACY OR SAFETY HAVE NOT BEEN PERFORMED YET: ARE SUCH STUDIES LIKELY TO OCCUR?

28 THE PHYLOSOPHY OF RESEARCH DRUG- ORIENTED research PATIENT-ORIENTED research Short-term results Tumor shrinkage Short-term safety Selected subgroups Registration Survival benefit Quality of life Beyond short-term tox Reproducibility Affordability

29 THE PROPOSAL IN PRETREATED MCRC. BEYOND THE COMPANIES VS

30 BACK-UP SLIDES

31 Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Study Overview: Baseline Characteristics of the ITT Population TAS 102 (N=534) Placebo (N=266 ) TAS 102 (N=534) Placebo (N=266 ) Mayer RJ et al., N Engl J Med14;372: , 2015

32 Grothey A, et al. Lancet, 26;381:303-12, 2013; Li J, et al. Lancet Oncol, 16:619-29, 2015; Tougeron D, et al. Ann Oncol, 25: , 2014; Van Cutsem E, et al. Ann Oncol, 26:118, 2015, Regorafenib: from clinical trials to the real world Efficacy outcomes Adverse Events

33 WHICH STUDIES WITH TAS-102? CRC M+ TAS-102 VS REGORAFENIB (Phase 3 or 2) GASTRIC CANCER PHASE 2 STUDY WITH TAS 102 BILIARY CANCER PHASE 2 STUDY WITH TAS 102 PANCREATIC CANCER PHASE 2 STUDY WITH TAS 102 BREAST CANCER PHASE 2 STUDY WITH TAS 102