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

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

3. 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

4. Overall survival (primary endpoint)
Median mos mos
95% CI – –5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value:
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< at approximately 74% of events required for final analysis)
Grothey et al. Lancet 2012

5. Progression-free survival (secondary endpoint)
1.00
Regorafenib Placebo
Median mos mos
95% CI – –1.7
Hazard ratio: 0.49 (95% CI: 0.42–0.58)
1-sided p-value: <
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

6. 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<
Bayer data on file. Van Cutsem E, et al. ESMO; Abstract LBA18.

7. 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 ( )
≥18 months
620
0.48 ( )
Prior anticancer treatment
F, Ox, Iri, Bev
375
0.51 ( )
F, Ox, Iri, Bev, anti-EGFR
385
0.50 ( )
Prior treatment lines for metastatic disease ≤3
395
0.53 ( )
>3
365
0.47 ( )
KRAS mutation status (historical)
299
0.48 ( ) Y
430
0.53 ( )
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:

8. CONCUR
Clinicaltrials.gov NCT
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

9. 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 = (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

10. 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
Days from randomization
Days from randomization
Closed circles represent censored observations
Kim et al., ESMO 2014

11. (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
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

12. 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< (1-sided)
Kim et al., ESMO 2014

13. 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:

14. Incidence of Grade 3 AEs Decreases Over Time1 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; Abstract #467.

15. 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

16. 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

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

18. 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.

19. 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.

20. 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

21. 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 ( )
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

22. 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 ( )
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

23. 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

24. 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

25. 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

26. 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