1. Advanced Colorectal Cancer: Which biologic agent and for whom?
Axel Grothey
Professor of Oncology
Mayo Clinic Rochester

2. A high number of agents is currently available for the treatment of mCRC
5-FU
Capecitabine
Irinotecan
Oxaliplatin
Bevacizumab
Cetuximab
Regorafenib
Aflibercept
Panitumumab

3. ESMO Guidelines 2012
Schmoll et al., Ann Oncol 2012

4. Landscape in mCRC before ASCO 2013
Bevacizumab and EGFR mAbs competing for first-line patients in KRAS wt CRC
Bevacizumab and Aflibercept competing for second-line patients with each other, and with EGFR mAbs in KRAS wt CRC
Best sequence of therapies (VEGFi vs EGFRi) still to be established
Regorafenib as salvage therapy option

5. Questions How can biologics be used to their full potential?
Duration of therapy
Predictive markers
Can a patient population be identified which would benefit most from one specific treatment strategy?

6. Anti-VEGF Agents

7. XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design
Recruitment June 2003 – May 2004
Recruitment Feb 2004 – Feb 2005
XELOX N=317
XELOX + placebo
N=350
XELOX + bevacizumab
N=350
FOLFOX4
N=317
FOLFOX4 + placebo N=351
FOLFOX4 + bevacizumab
N=350
Initial 2-arm open-label study (N=634)
Protocol amended to 2x2 placebo- controled design after bevacizumab phase III data1 became available (N=1401)
Cassidy & Saltz, JCO 2008
1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

8. NO16966 PFS Subgroup Analyses: On-Treatment Population
XELOX Group
FOLFOX Group
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Survival
Survival
7.0 m
9.5 m
8.4 m
10.6 m
Study day
Study day
HR = 0.61 [97.5% CI 0.48–0.78]
P ≤ .0001
HR = 0.65 [97.5% CI 0.50–0.84]
P = .0002
XELOX + placebo
XELOX + Bev
FOLFOX4 +
placebo
FOLFOX-4 +
Bev VS VS
Saltz et al., ASCO GI 2007

9. AVEX - PFS HR=0.53 (95% CI: 0.41–0.69) P<0.001 Cape + BEV (n=140)
Cape (n=140)
1.0
0.8
0.6
0.4
0.2
0.0
HR=0.53 (95% CI: 0.41–0.69)
P<0.001
PFS estimate
5.1 mo
9.1 mo 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Time (months)
Number at risk
Cape + BEV
140
121 99 80 68 55 41 28 23 16 13 9 8 3 2 1
Cape
140
109 82 56 38 25 13 9 6 4 2 1
Cunningham et al, ASCO GI 2013

10. CAIRO-3 R N=558 MT CFI PFS1 PFS2 TT2PD XELOXx6 CTX-BEV PFS2 11.5 10.5
Mos MT
CFI
HR P
PFS1
8.5
4.1
0.44 <
PFS2
11.5
10.5
0.81
0.028
TT2PD
19.8
15.0
0.67 < OS
21.7
18.2 MT R
PD1
PD2
CFI
XELOXx6
CTX-BEV
N=558
PFS1
MT:
LD-Cape (625 mg/m2 BID daily) + BEV (7.5 mg/KG every 3 wks)
PFS2
TT2PD
PFS2: time from R until PD upon re-introduction of XELOX-B
TT2PD: time from R until PD upon any treatment after PFS1
Koopman, M et al. ASCO 2013

11. CAIRO-3 R PFS from start 1st line: N=558 4 + 11.5 mos = 15.5 mos
XELOXx6
CTX-BEV
Mos MT
CFI
HR P
PFS2
11.5
10.5
0.81
0.028 MT R
PD2
CFI
XELOXx6
CTX-BEV
PFS from start 1st line:
mos = 15.5 mos
First-line PFS
ΔOS 3.5 months!
N=558
PFS2
PFS2: time from R until PD upon re-introduction of XELOX-B
Koopman, M et al. ASCO 2013

12. ML18147 study design (phase III)
Standard 2nd-line CT (oxaliplatin or irinotecan-based) until PD
BEV + standard first-line CT (either oxaliplatin or irinotecan-based) (n=820) PD
Randomize 1:1
BEV (2.5 mg/kg/wk) + standard 2nd-line CT (oxali or irino-based) until PD
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
Primary endpoint
Overall survival (OS) from randomization
Secondary endpoints included
Progression-free survival (PFS)
Best overall response rate
Safety
Stratification factors
First-line CT (oxaliplatin-based, irinotecan-based)
First-line PFS (≤9 months, >9 months)
Time from last BEV dose (≤42 days, >42 days)
ECOG PS at baseline (0/1, 2)
Bennouna et al., Lancet Oncol 2012

13. Bennouna et al., Lancet Oncol 2012
OS: ITT population
CT (n=410)
BEV + CT (n=409)
1.0
0.8
0.6
0.4
0.2
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p= (log-rank test)
OS estimate
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
p= (log-rank test)
9.8 mo
11.2 mo
No. at risk CT
BEV + CT
Time (months)
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
Bennouna et al., Lancet Oncol 2012

14. Bennouna et al., Lancet Oncol 2012
PFS: ITT population
CT (n=410)
BEV + CT (n=409)
1.0
0.8
0.6
0.4
0.2
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p< (log-rank test)
PFS estimate
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
p< (log-rank test)
4.1 mo
5.7 mo
Time (months)
No. at risk CT
BEV + CT
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
Bennouna et al., Lancet Oncol 2012

15. Large molecule VEGF inhibitors
VEGF-A
VEGF-R1
(Flt-1)
Migration
Invasion
Survival
VEGF-R3
(Flt-4)
Lymphangio-
genesis
VEGF-R2
(KDR/Flk-1)
Proliferation
Permeability
PlGF
VEGF-B
VEGF-C,
VEGF-D
Functions Y
Bevacizumab Y
Ramucirumab
Aflibercept
(VEGF Trap)

16. 16
EFC10262: VELOUR Phase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept)
Aflibercept 4 mg/kg IV + FOLFIRI q 2 weeks
600 pts
mCRC after failure of an oxaliplatin based regimen R
1:1
SPEAKER NOTES
The large, phase III randomized trial, VELOUR, has enrolled 1226 patients with previously treated metastatic CRC whose disease progressed on an oxaliplatin-based regimen. Patients are randomized to receive either aflibercept plus FOLFIRI or FOLFIRI alone.
An important stratification in this trial is patients who have received prior bevacizumab-containing therapy in the front-line setting. In the United States, the majority of patients receive bevacizumab-containing therapy as treatment for their newly diagnosed mCRC.
VELOUR has completed accrual of patients.
The primary endpoint in this trial is median OS.
An interim analysis of the data from VELOUR determined that the trial should continue to final analysis of OS.
Final results are expected in late 2011.
More details on this trial are available at clinicaltrials.gov (NCT ).
Placebo + FOLFIRI q 2 weeks
Stratification factors:
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
600 pts
30% of patients had prior BEV
PIs: Allegra, Van Cutsem 16

17. VELOUR Study OS
PFS
HR 0.82
HR 0.76
Van Cutsem et al., JCO 2012 17

18. Progression-Free Survival
Aflibercept: VELOUR Phase III: OS and PFS Stratified by Prior Bevacizumab
Overall Survival
Strata (as per UVRS) N
HR (95.34% CI) HR
Interaction P
All patients
1,226
0.82 ( )
Prior BEV No
Yes
0.79 ( )
0.86 ( )
.5668 1 2 3
Favors aflibercept
Favors placebo
Progression-Free Survival
Strata (as per UVRS) N
HR (95% CI) HR
Interaction P
All patients
1,226
0.76 ( )
Prior BEV No
Yes
853
373
0.80 ( )
0.66 ( )
.1958 1 2 3
Favors aflibercept
Favors placebo
Adapted from Van Cutsem E, et al. J Clin Oncol Sep 4. [Epub ahead of print].

19. VELOUR Response Rates
Van Cutsem E, et al. J Clin Oncol. 2012;30(28):

20. Safety – Most frequent AEs, with ≥5% difference in incidence between treatment arms, excluding anti-VEGF class events
Safety Population, % of patients
Placebo, N = 605
Aflibercept N = 611
All Grades
Grade 3-4
Diarrhea
56.5
7.8
69.2
19.3
Neutropenia**
Complicated neutropenia
56.3
29.5
2.8
67.8
36.7
5.7
Asthenic conditions (HLT)
50.2
10.6
60.4
16.9
Stomatitis & ulceration (HLT)
34.9
5.0
54.8
13.7
Thrombocytopenia**
33.8
1.7
47.4
3.3
Infections (SOC)
32.7
6.9
46.2
12.3
Decrease appetite
23.8
1.8
31.9
3.4
Weight decreased
14.4
0.8
2.6
Palmar plantar erythrodysaesthesia
4.3
0.5
11.0
Skin hyperpigmentation
8.2
Dehydration
3.0
1.3
9.0
AEs leading to treatment discontinuation:
AFL: 26.6%
PL: 12.1%
Van Cutsem E, et al. J Clin Oncol. 2012;30(28):

21. Conclusion anti-VEGF Therapy
Duration of VEGF-inhibition matters
Treatment to progression
Maintenance strategies
Treatment beyond progression
Clinical synergism between FP + bevacizumab
Positive distinguishing factors for aflibercept vs BEV in 2nd line Tx not clear
Head-to-head comparison warranted (Efficacy? Toxicity?)
BEV combinable with FOLFOXIRI (TRIBE)

22. EGFR Monoclonal antibodies

23. mAbs Target Tumor Cell-Bound EGFR
Ligand
Extracellular
EGF-R
Ras
PI3K
PTEN
Raf
Intracellular
Akt
MEK
MAPK
Cell survival
DNA
Cell Motility
Proliferation
Angiogenesis
Metastasis

24. mAbs Target Tumor Cell-Bound EGFR
Ligand
Extracellular
EGF-R
Ras
PI3K
PTEN
Raf
Intracellular
Akt
MEK
MAPK
Cell survival
DNA
Cell Motility
Proliferation
Angiogenesis
Metastasis

25. NCIC CTG CO.17: Randomized Phase III Trial in mCRC Cetuximab vs BSC (no cross-over)
KRAS mut
KRAS wild-type
All patients
BSC
n=83
Cetux
n=81
n=113
n=117
n=285
n=287 RR 0%
1.2%
12.8%
6.6%
PFS (mos)
1.8
1.9
3.8
OS (mos)
4.6
4.5
4.8
9.5
6.1
<0.0001
<0.0001
<0.0001
0.0046
Karapetis et al. NEJM 2008

26. CRYSTAL: FOLFIRI ± Cetuximab: PFS Non-KRAS adjusted
1.0
Subgroup effect
No benefit
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
HR = 0.851
P =
8.0 vs 8.9 mos
PFS estimate
N=1217
The design of this trial is similar to the Hurwitz trial: 5-FU/LV/irino +/- a targeted agent, but the PFS curves look very different, in particular, when the KRAS mut CRC are included.
FOLFIRI
FOLFIRI + Cetuximab 2 4 6 8 10 12 14 16 18 20
PFS (mos)
Van Cutsem et al, 2009

27. CRYSTAL: FOLFIRI +/- Cetuximab PFS in patients with KRAS wt tumors
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
FOLFIRI
(n=350)
FOLFIRI + cetuximab
(n=316)
No of events
189
146
Median PFS
8.4 months
9.9 months
[95% CI]
[7.4‒9.2]
[9.0‒11.3]
HR [95% Cl]
p-value
0.70 [0.558‒0.867]
0.0012
Probability of PFS
FOLFIRI + cetuximab
FOLFIRI 12 4 8 16 20
Time (months)
Number of patients
FOLFIRI
350
237
111 22 4
FOLFIRI + cetuximab
316
227
128 40 8 1
van Cutsem et al., J Clin Oncol 2011

28. PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status
“Final Analysis”
WT KRAS
MT KRAS
Median (mos) (95% CI)
Panitumumab + FOLFOX4
10.0 (9.3 – 11.4)
FOLFOX4
8.6 (7.5 – 9.5)
Median (mos) (95% CI)
Panitumumab + FOLFOX4
7.4 (6.9 – 8.1)
FOLFOX4
9.2 (8.1 – 9.9)
HR = 0.80 (95% CI: 0.67 – 0.95)
Log-rank p-value = 0.01
HR = 1.27 (95% CI: 1.04 – 1.55)
Log-rank p-value = 0.02
Douillard et al., JCO 2011

29. PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS WT mCRC
0.7
Cetuximab
Panitumumab
0.6
0.5
0.4
0.3
1‒HR
0.2
NORDIC VII3
0.1
COIN4
CRYSTAL6
PICCOLO7
PRIME5
Amado9
CO.1710
1818
–0.1
If we look at the PFS/DFS data from studies of EGFR inhibitors, we can see that they improve with later lines of therapy; offering their greatest efficacy values in 3L
It therefore makes sense to use these in 3L if possible
N01471
–0.2
PETACC-82*
–0.3
Adjuvant 1L 2L
3L (single agent)
1. Alberts, et al. JAMA 2012; 2. Salazar, et al. ESMO 2012; 3. Tveit, et al. JCO 2012; 4. Maughan, et al. Lancet Douillard, et al. JCO 2010; 6. Van Cutsem, et al. JCO 2011; 7. Seymour, et al. ASCO Peeters, et al. JCO 2010; 9. Amado, et al. JCO 2008; 10. Karapetis, et al. NEJM 2008
*KRAS mutant CRC

30. Updated Analysis of PRIME study
KRAS exon 2 codon 12/13
40%
KRAS exon 3 codon 61 4%
KRAS exon 4 codon 117/146 6%
NRAS exon 2 codon 12/13 3%
NRAS exon 3 codon 61
BRAF exon 15 codon 600 8%
17%
Oliner et al., ASCO 2013

31. OS HR 0.83 (KRAS wt cod 12/13) Detriment! HR 0.78 (all RAS wt)
Oliner et al., ASCO 2013

32. Satore-Bianchi et al., PLoS 2009
Outcome to EGFR mAb therapy based on KRAS, BRAF, PIK3CA and PTEN (n=132)
Satore-Bianchi et al., PLoS 2009

33. FIRE-3 Phase III study design 1st-line therapy KRAS wild-type
FOLFIRI
+ Cetuximab
Cetuximab:
400 mg/m2
i.v. 120min
initial dose
250 mg/m2
i.v. 60min
q 1w
mCRC
1st-line therapy KRAS wild-type
N= 592 C e t u x i m a b : 4 m g / m 2 i . v . 1 2 m i n i n i t i a l d o s e 2 5 m g / m 2 i . v . 6 m in q 1 w
Randomize 1:1
FOLFIRI + Bevacizumab
Bevacizumab: 5 mg/kg i.v min q 2w B e v a c i z u m a b : 5 m g / k g i . v . 3 - 9 m i n q 2 w
FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2
irinotecan: 180 mg/m2 5-FU: 2,400 mg/m2 (i.v. 46h)
Primary objective: Overall response rate (ORR) (inv assessed)
Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%)
284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5%
Heinemann et al., ASCO 2013

34. Assessable for response
FIRE-3 ORR
Primary Endpoint
FOLFIRI + Cetuximab
FOLFIRI + Bevacizumab
Odds ratio p
ORR %
95%-CI
ITT
population
62.0
56.2 – 67.5
58.0
52.1 – 63.7
(N= 592)
1.18
0.183
Assessable for response
(N= 526)
1.52
72.2
66.2 – 77.6
63.1
57.1 – 68.9
0.017
p = Fisher´s exact test (one-sided)
Heinemann et al., ASCO 2013

35. FIRE-3 PFS 10.0 10.3 Events Median (months) 95% CI n/N (%)
1.0
n/N (%)
― FOLFIRI + Cetuximab
250/297
8.8 – 10.8
(84.2%)
0.75
― FOLFIRI + Bevacizumab
242/295
10.3
9.8 – 11.3
Probability of survival
(82.0%)
HR 1.06 (95% CI 0.88 – 1.26)
Log-rank p= 0.547
0.50
0.25
0.0 12 24 36 48 60 72
months since start of treatment
numbers
297
100 99 19 15 10 6 5 4 3
at risk 295
Heinemann et al., ASCO 2013

36. FIRE-3 Overall survival
Events n/N (%)
Median (months)
28.7
95% CI
1.0
― FOLFIRI + Cetuximab
158/297
24.0 – 36.6
(53.2%)
0.75
― FOLFIRI + Bevacizumab
185/295
25.0
22.7 – 27.6
Probability of survival
(62.7%)
HR 0.77 (95% CI: 0.62 – 0.96)
Log-rank p= 0.017
0.50
0.25
0.0 12 24 36 48 60 72
months since start of treatment
numbers
297
218
214
111 60 47 29 18 9 2
Heinemann et al., ASCO 2013
at risk 295

37. FIRE-3 Overall survival
Events n/N (%)
Median (months)
28.7
95% CI
1.0
PFS
― FOLFIRI + Cetuximab
158/297
24.0 – 36.6
(53.2%)
0.75
― FOLFIRI + Bevacizumab
185/295
25.0
22.7 – 27.6
Probability of survival
(62.7%)
HR 0.77 (95% CI: 0.62 – 0.96)
Log-rank p= 0.017
0.50
Split of curves
0.25
0.0 12 24 36 48 60 72
months since start of treatment
numbers
297
218
214
111 60 47 29 18 9 2
Heinemann et al., ASCO 2013
at risk 295

38. Potential reasons for OS difference with same PFS
Imbalance in post-progression therapy
First-line therapy affects sensitivity of cancer cells to subsequent treatments
Early clonal selection
Is there an optimal sequence of treatment options?
First-line therapy is highly effective in a subpopulation of CRC with long-lasting treatment benefit

39. FIRE-3 Overall survival
Who are these pts?
Analysis of RAS, PIK3CA, BRAF,
PTEN, EGFR ligands
1.0
― FOLFIRI + Cetuximab
0.75
― FOLFIRI + Bevacizumab
Probability of survival
0.50
0.25
0.0 12 24 36 48 60 72
months since start of treatment
numbers
297
218
214
111 60 47 29 18 9 2
Heinemann et al., ASCO 2013
at risk 295

40. Conclusions EGFR mAbs (1)
Efficacy in KRAS wt CRC well established
Cetuximab and panitumumab likely interchangeable
Further molecular refinement of patient population beyond KRAS codon 12/13 essential
To avoid detrimental effect of therapy
To enrich patient population with better benefit/side-effect margin
More data on H2H cetuximab vs BEV will come from (RAS wt analysis!)

41. Conclusions EGFR mAbs (2)
All-RAS wild-type CRC = 40-45% of CRC
Further molecular refinements in future (PTEN, EGFR ligands, PIK3CA…) could cut the patient population suitable for EGFR mAbs down to 30-35%
This refined patient population could sustain a marked benefit from use of first-line EGFR mAbs!
EGFR mAbs could turn into the trastuzumab of CRC after all

42. regorafenib

43. Confidential • Advisory Board • 30 Sept 2012
Regorafenib (BAY ), an Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways
Biochemical
Activity
Regorafenib IC50
mean ± SD nmol/l (n)
VEGFR1
13 ± 0.4 (2)
Murine VEGFR2
4.2 ± 1.6 (10)
Murine VEGFR3
46 ± 10 (4)
TIE2
311 ± 46 (4)
PDGFR-β
22 ± 3 (2)
FGFR1
202 ± 18 (6)
KIT
7 ± 2 (4)
RET
1.5 ± 0.7 (2)
RAF-1
2.5 ± 0.6 (4)
B-RAF
28 ± 10 (6)
B-RAFV600E
19 ± 6 (6) F Cl O N H
Regorafenib
Questions and Probes for Facilitator:
How would you interpret regorafenib’s multi-kinase inhibitor properties in its ability to prolong OS in patients with mCRC?
How should regorafenib be positioned given its multi-kinase inhibitor properties?
Inhibition of proliferation
Inhibition of tumor microenvironment signaling
Inhibition of
neoangiogenesis
KIT
PDGFR
RET
PDGFR-β
FGFR
VEGFR1-3
TIE2
Wilhelm SM, et al. Int J Cancer. 2011;129(1):
Mross K, et al. Clin Cancer Res. 2012;18(9):
Strumberg D, et al. Expert Opin Invest Drugs. 2012;21(6):

44. CORRECT study design PS 0-1 Life expectancy 3 months!
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: time from diagnosis of mCRC, geographical region
Global trial: 16 countries, 114 active centers
1,052 patients screened, 760 patients randomized within 10 months
PS 0-1
Life expectancy 3 months!
Grothey, Van Custem et al., Lancet 2012

45. 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, Van Custem et al., Lancet 2012

46. Progression-free survival (secondary endpoint)
Pts beyond the “point of return”?
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

47. Summary and Conclusions
Biologics play an important role in the treatment of mCRC to optimize outcome
Identification of patient population benefitting from one specific sequence of intervention is emerging
All-RAS wild-type (+ other factors?) could favor EGFR mAbs in first-line mCRC
At this point however, at least until results are available, BEV first-line is an appropriate option in KRAS wt mCRC
Duration of therapy and access to all available treatment options essential
Even in recent studies (CAIRO/FIRE) only a minority of pts received all agents

48. Advances in the Treatment of Stage IV CRC
1980
1985
1990
1995
2000
2005
2010
2015
median overall survival
BSC
5-FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab
Aflibercept
Regorafenib
BBP