Regorafenib TAS-102 or TAS-102 Regorafenib Axel Grothey Professor of Oncology Mayo Clinic Rochester

Regorafenib TAS-102 or TAS-102 Regorafenib Axel Grothey Professor of Oncology Mayo Clinic Rochester

CORRECT study design Primary Endpoint: OS mCRC after standard therapy RANDOM I ZAT I ON Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025 mCRC after standard therapy 2 : 1 Placebo + BSC 3 weeks on, 1 week off Multicenter, randomized, double-blind, placebo-controlled, phase III 2:1 randomization Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region Global trial: 16 countries, 114 active centers 1,052 patients screened, 760 patients randomized within 10 months Secondary endpoints: PFS, ORR, DCR Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers Grothey et al., Lancet 2012

Overall survival (primary endpoint) Median 6.4 mos 5.0 mos 95% CI 5.9–7.3 4.4–5.8 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052 Regorafenib Placebo 1.00 0.75 Survival distribution function 0.50 0.25 Placebo N=255 Regorafenib N=505 50 100 150 200 250 300 350 400 450 Days from randomization Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) Grothey et al. Lancet 2012

Progression-free survival (secondary endpoint) 1.00 Regorafenib Placebo Median 1.9 mos 1.7 mos 95% CI 1.9–2.1 1.7–1.7 Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: <0.000001 0.75 Survival distribution function 0.50 Placebo N=255 0.25 Regorafenib N=505 50 100 150 200 250 300 350 Days from randomization Grothey, Van Custem et al., Lancet 2012

Overall Response and Disease Control Rates (Secondary Endpoints) SD PR Regorafenib (n = 505) Placebo (n = 255) Best response, % Complete response Partial response 1.0 0.4 Stable disease 42.8 14.5 Progressive disease 49.5 80.0 Disease control rate* 41.0 14.9 *DCR = PR + SD ≥6 weeks after randomization; P<.000001. Bayer data on file. Van Cutsem E, et al. ESMO; 2012. Abstract LBA18.

PFS Benefit of Regorafenib Is Consistent Across All Subgroups Selected Subgroups N HR (95% CI) Time from first diagnosis of metastatic disease to randomization <18 months 140 0.58 (0.41-0.84) ≥18 months 620 0.48 (0.40-0.58) Prior anticancer treatment F, Ox, Iri, Bev 375 0.51 (0.41-0.65) F, Ox, Iri, Bev, anti-EGFR 385 0.50 (0.39-0.63) Prior treatment lines for metastatic disease ≤3 395 0.53 (0.43-0.67) >3 365 0.47 (0.37-0.59) KRAS mutation status (historical) 299 0.48 (0.36-0.62) Y 430 0.53 (0.43-0.65) Favors regorafenib Favors placebo 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Grothey A, et al. Lancet. 2013;381:303-312.

CONCUR Clinicaltrials.gov NCT01584830 Regorafenib 160 mg daily 3 weeks on / 1 week off (4-week cycle) n = 136 Asian patients with mCRC who progressed after standard therapies 25 centers in mainland China, Hong Kong, Taiwan, South Korea, Vietnam Failed ≥2 prior standard regimens including oxaliplatin, fluoropyrimidine, irinotecan Progression within 3 months after last standard therapy or within 6 months after adjuvant oxaliplatin Prior anti-VEGF or anti-EGFR therapy allowed, but not mandatory R 2:1 Stratification Metastases: single vs multiple organs Time from mCRC diagnosis: ≥18 vs <18 months Placebo n = 68 Primary endpoint: overall survival (OS) One-sided alpha 0.2 and assumed 33.3% OS improvement (HR=0.75 favoring regorafenib) with 154 events had 80% power Secondary endpoints: progression-free survival, response rate, disease control rate Planned subgroup analysis by prior targeted therapy (anti-VEGF, anti-EGFR) All received best supportive care Treatment until progression, unacceptable toxicity, or withdrawal Tumor assessments (CT/MRI) every 8 weeks during the treatment period Kim et al., ESMO 2014

Overall survival (OS) Primary endpoint 1.00 0.75 0.50 0.25 0.00 Regorafenib (n=136) Placebo (n=68) Events, n (%) 95 (69.9) 60 (88.2) Median, months 8.8 6.3 HR (95% CI) 0.55 (0.40 ‒ 0.77) P = 0.0002 (1-sided) OS probability 45% reduction in risk of death in the regorafenib group 100 200 300 400 500 600 Days from randomization Overall survival is defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis will be censored at their last date known to be alive; closed circles represent censored observations Comparison using a stratified log-rank test (single vs multiple organ metastases and >18 vs <18 months from mCRC diagnosis); one-sided alpha = 0.2 Cut-off date for the analysis was 29 November 2013 Kim et al., ESMO 2014

Subgroup analysis of OS by prior targeted therapy No prior targeted therapy (No prior anti-VEGF or anti-EGFR) Any prior targeted therapy (Prior anti-VEGF or anti-EGFR or both) Regorafenib (n=56) Placebo (n=26) Regorafenib (n=80) Placebo (n=42) Median, months 9.7 4.9 HR (95% CI) 0.31 (0.19 – 0.53) Median, months 7.4 6.7 HR (95% CI) 0.78 (0.51 – 1.19) 1.00 1.00 0.75 0.75 OS probability 0.50 OS probability 0.50 0.25 0.25 0.00 0.00 0 100 200 300 400 500 600 0 100 200 300 400 500 600 Days from randomization Days from randomization Closed circles represent censored observations Kim et al., ESMO 2014

(To isolate effect of subsequent chemo) Days from randomization Exploratory post hoc analysis of OS (all patients) Patients censored at the start of post-study treatment* (To isolate effect of subsequent chemo) 1.00 Regorafenib (n=136) Placebo (n=68) More censored events Events, n (%) 71 (52.2) 37 (54.4) Median, months 8.8 4.8 HR (95% CI) 0.41 (0.27 ‒ 0.62) 0.75 OS probability 0.50 same shorter 0.25 0.00 0 100 200 300 400 500 600 Days from randomization *Results should be interpreted with caution due to non-random censoring of patients who received post-study treatment Comparison using a stratified log-rank test (single vs multiple organ metastases and >18 vs <18 months from mCRC diagnosis) Cut-off date for the analysis was 29 November 2013; closed circles represent censored observations Kim et al., ESMO 2014

Days from randomization CONCUR: PFS Regorafenib (n=136) Placebo (n=68) 1.00 0.75 0.50 0.25 0.00 100 200 300 400 500 PFS probability Days from randomization Events, n (%) 120 (88.2) 65 (95.6) Median, months 3.2 1.7 HR [95% CI] 0.311 [0.222 ‒ 0.435] P< 0.0001 (1-sided) Kim et al., ESMO 2014

Grothey A, Van Cutsem E, et al. Lancet. 2013;381:303-312. Drug-Related Treatment-Emergent Adverse Events Occurring in ≥10% of Patients Adverse Event, % Regorafenib (n = 500) Placebo (n = 253) All grades Grade 3 Grade 4 Hand-foot skin reaction 46.6 16.6 7.5 0.4 Fatigue 47.4 9.2 28.1 4.7 Hypertension 27.8 7.2 5.9 0.8 Diarrhea 33.8 7.0 0.2 8.3 Rash/desquamation 26.0 5.8 4.0 Anorexia 30.4 3.2 15.4 2.8 Mucositis, oral 27.2 3.0 3.6 Thrombocytopenia 12.6 2.6 2.0 Fever 10.4 Nausea 14.4 11.1 Bleeding 11.4 Voice changes 29.4 5.5 Weight loss 13.8 2.4 *Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm Grothey A, Van Cutsem E, et al. Lancet. 2013;381:303-312.

Incidence of Grade 3 AEs Decreases Over Time 1 5 10 15 20 Frequency of AE (%) 2 3 4 6 7 8 500 417 229 193 119 91 55 43 Treatment Cycle # Patients at risk HFSR Grade 4 Fatigue Diarrhea Hypertension Rash/Desquamation Grothey A, et al. ASCO GI; 2013. Abstract #467.

Regorafenib Dose Optimization Study (ReDOS); A phase II randomized study of escalating dose regorafenib compared to standard dose regorafenib in patients with refractory mCRC Co-PIs : Tanios Bekaii-Saab (OSU), Axel Grothey (Mayo) RANDOM I ZAT I ON 1 : 1 Primary endpoint: 8-week planned continuation rate* Progression on previous standard therapy ( including EGFRi if KRAS WT) (n=120) Regorafenib dose escalation schema ( next slide) N=60 Regorafenib at 160 mg PO qday for 21 days every 28 days *% pts who complete 2 cycles of Rx and intend to initiate cycle 3 if no PD noted on the 8-week scan

Experimental Arm No SDRT* +SDRT* No SDRT* +SDRT* No SDRT* 80 mg PO qd x 1 week Wk 1 Experimental Arm No SDRT* +SDRT* 120 mg PO qd x 1 week 80 mg PO qd x 1 week Wk 2 No SDRT* +SDRT* 160 mg PO qd x 1 week 120 mg PO qd x 1 week Wk 3 No SDRT* OFF x 1 week Wk 4 *SDRT = Significant Drug Related Toxicities

EORTC QLQ-C30 Global Health Status Qin S, et al. J Clin Oncol. 2015;33(suppl 3): Abstract 697.

Mayo, MDA, and USC Experience: Chemotherapy After Regorafenib in mCRC Regorafenib treatment n = 173 [Mayo = 59, MDA = 95, USC = 19] Continue regorafenib n = 11 (6%) No further therapy n = 98 (57%) Post-regorafenib therapy n = 64 (37%) Standard Tx n = 33 Clinical trial n = 31 Kidd MT, et al. ASCO GI; January 16-18, 2014; San Francisco, CA. Abstract 678.

Efficacy of Chemotherapy After Regorafenib (n = 33) Best Response N (%) PD 11 (33%) Not evaluable 2 (6%) OR or SD 20 (61%) Reintroduction of Tx previously discontinued without definitive PD 8 (24%) Re-challenge with Tx previously discontinued due to PD 4 (12%) New Tx with no prior exposure Median OS Post-Regorafenib Discontinuation Probability of OS 6 Months 12 Months 6.5 months (CI 4.9–9.4) 52% 27% Kidd MT, et al. ASCO GI; January 16-18, 2014; San Francisco, CA. Abstract 678.

Global Randomized Phase III study RECOURSE: Refractory Colorectal Cancer Study (NCT01607957) R A N D O M I Z A T I O N TAS-102 + BSC (n = 534) 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) 35 mg/m2 b.i.d. p.o. d1-5, 8-12 q4wks Endpoints Primary: OS Secondary: PFS, Safety, Tolerability, TTF, ORR, DCR, DoR, Subgroup by KRAS (OS and PFS) 2:1 Placebo + BSC (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 Yoshino et al., WCGIC 2014

Median follow-up: 8.4 months Overall Survival TAS-102 N=534 Placebo N=266 Events # (%) 364 (68) 210 (79) HR (95% CI) 0.68 (0.58-0.81) Stratified Log-rank test p<0.0001 Median OS, months 7.1 5.3 Median follow-up: 8.4 months Alive at, % 6 months 58 44 12 months 27 18 TAS-102 534 459 294 137 64 23 7 Placebo 266 198 107 47 24 9 3 N at Risk: Months from Randomization 6 12 15 18 Survival Distribution function 10 20 30 40 50 60 70 80 90 100 Yoshino et al., WCGIC 2014

Progression-free Survival TAS-102 534 238 121 66 30 18 5 4 2 Placebo 266 51 10 1 N at Risk: Months from Randomization 6 8 12 14 16 Progression-free Distribution function 20 40 50 60 70 80 90 100 TAS-102 N=534 Placebo N=266 Events # (%) 472 (88) 251 (94) HR (95% CI) 0.48 (0.41-0.57) Stratified Log-rank test p<0.0001 Median PFS, months 2.0 1.7 Tumor assessments performed every 8 weeks Yoshino et al., WCGIC 2014

Progression-free Survival 100 90 80 70 60 Progression-free Distribution function 50 40 30 20 10 2 4 6 8 10 12 14 16 Months from Randomization

TAS-102 Toxicity Mainly Hematologic (Grade 3) Minimal Non-hematologic toxicity Grade 3 (%) Grade 4 (%) Leukopenia 19 3 Neutropenia 27 11 Anemia 18 - Thrombopenia 4.5 0.5 Van Cutsem et al., ESMO 2014

Comparison Regorafenib, TAS-102 Study CORRECT CONCUR RECOURSE Prior biologics 100% BEV 100% EGFR mAbs 60% Rego BSC N pts 505 255 136 68 534 266 mOS (mos) 6.4 5.0 8.8 6.3 7.1 5.3 HR 0.77 p=0.0052 HR 0.55 p=0.0002 HR 0.68 p<0.0001 mPFS (mos) 1.9 1.7 3.2 2.0 HR 0.49 p<0.0001 HR 0.31 p<0.0001 HR 0.48 p<0.0001 RR (%) 1.0 0.4 4.4 1.6 Main AEs HFSR Fatigue Neutropenia Diarrhea Grothey, van Cutsem et al., Lancet 2012 Li et al., WCGIC 2014 Yoshino et al., WCGIC 2014

Why Regorafenib first? Patients benefit from access to all active agents, i.e. Regorafenib AND TAS-102 Regorafenib appears to provide more benefit in less pretreated patients Regorafenib should not be used in PS2+ patients Do not let PS deteriorate before Regorafenib Side-effects can be managed Cytotoxic therapy (e.g. TAS-102) can be active after Regorafenib