Reviewing the Role of VEGF Targeting

Agents in the Treatment of GI Cancers

This activity is supported by an educational grant from Bayer Healthcare

Pharmaceuticals.
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Faculty
Jordi Bruix, MD John L. Marshall, MD
Professor of Medicine Chief, Division of Hematology/Oncology
University of Barcelona Department of Medicine
Head, Barcelona Clinic-Liver Cancer Georgetown University Hospital
Group Washington, DC
Liver Unit
Hospital Clinico of Barcelona Neeta Somaiah, MD
Barcelona, Spain Assistant Professor
Department of Sarcoma Medical
Yelena Y. Janjigian, MD Oncology
Assistant Professor of Medicine University of Texas M. D. Anderson
Weill Cornell Medical College Cancer Center
Assistant Attending Physician Houston, Texas
Gastrointestinal Oncology Service
Memorial Sloan Kettering Cancer Center
New York, New York
VEGF Inhibition: Mechanism of Action
 VEGF Inhibition: Mechanism of Action
Demcizumab
Bevacizumab
MEDI0639
VEGFA VEGFA Enoticumab
Ziv-aflibercept VEGFB VEGFC VEGFC Ang2
PIGF VEGFD VEGFD PF-03446962
PDGF FGF DII4
TRC105 TGF Ang1
Ramucirumab
CD105 Notch

NP1 VEGFR1 VEGFR2 VEGFR3 Galunisertib ALK1 Tie2 PDGFR FGFR

TGFRII
Endothelial cell Regorafenib
Sunitinib
Sorafenib
Lenvatinib
Pazopanib
Migration Proliferation Survival Permeability

Clarke JM, et al. J Gastrointest Oncol. 2013:4:253-263. Angiogenesis

Adapted with permission from AME Publishing Company. Slide credit: clinicaloptions.com
VEGF Inhibitors
PlGF VEGF-C,
VEGF-A
VEGF-B VEGF-D
Bevacizumab

Ramucirumab

Ziv-aflibercept
(VEGF trap)

Sunitinib Sorafenib

Lenvatinib Regorafenib
Functions

VEGF-R1 VEGF-R2 VEGF-R3

(Flt-1) (KDR/Flk-1) (Flt-4)
Migration Proliferation Lymphangiogenesis
Invasion Survival
Survival Permeability Slide credit: clinicaloptions.com
VEGF-Targeted Agents Used in Each GI Tumor
Type
CRC HCC Gastric/GEJ GIST
Bevacizumab
Pazopanib
Ramucirumab
Regorafenib
Sorafenib
Sunitinib
Ziv-aflibercept

Slide credit: clinicaloptions.com

VEGF Targeting in Colorectal Cancer
 Median OS by First-line Regimen for mCRC[1]
Best Supportive Care 4-6 mos

5-FU/LV 12-14 mos

IFL or FOLFIRI 15-16 mos

FOLFOX4 or CapeOx 19-20 mos

IFL + Bevacizumab 20.3 mos

FOLFOX6 21.5 mos

FOLFIRI + Bevacizumab[1,2] 24.0-25.8 mos

FOLFIRI + Bevacizumab[2] 29.8 mos

0 6 12 18 24 30

1. Gallagher DJ, et al. Oncology. 2010;78:237-248.

Median OS (Mos)
2. Cremolini C, et al. Lancet Oncol. 2015;16:1306-1315. Slide credit: clinicaloptions.com
 First-line Chemotherapy + Bevacizumab
Regimens in mCRC: Phase III Efficacy
Comparative Regimens Median PFS, Mos Median OS, Mos
IFL/bev vs IFL[1] 10.6 vs 6.2* 20.3 vs 15.6*
FOLFOX4 or XELOX + bev vs
9.4 vs 8.0 21.3 vs 19.9*
FOLFOX4 or XELOX[2]
FOLFOX/bev vs FOLFIRI/bev[3] 10.3 vs 10.2 23.7 vs 25.5*
FOLFOXIRI/bev vs FOLFIRI/bev[4] 12.3 vs 9.7* 29.8 vs 25.8*
Wild-type RAS and BRAF 37.1
Mutant RAS 25.6
Mutant BRAF 13.4
*Statistically significant difference.
Bev-associated toxicities include hypertension, arterial thromboembolic events,
gastrointestinal perforation, and wound healing complications[5]
1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019.
3. Bendell JC, et al. Oncologist. 2012;17:1486-1495. 4. Cremolini C, et al. Lancet Oncol. 2015;16:1306-1315. Slide credit: clinicaloptions.com
5. Bevacizumab [package insert]. 2011.
 TRIBE: FOLFOXIRI/Bev vs FOLFIRI/Bev
in First-line mCRC
100 RAS and BRAF wild-type FOLFOXIRI + bev
90 RAS and BRAF wild-type FOLFIRI + bev
80
RAS-mutant FOLFOXIRI + bev
RAS-mutant FOLFIRI + bev
70 BRAF-mutant FOLFOXIRI + bev
60 BRAF-mutant FOLFIRI + bev
OS (%) 50
40
30
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Follow-up (Mos)
Pts at Risk, n
RAS and BRAF wild-type FOLFOXIRI + bev 48 46 43 40 32 29 26 17 8 5 3 0 0 0
RAS and BRAF wild-type FOLFIRI + bev 45 42 38 35 29 26 20 14 10 5 1 0 0 0
RAS-mutant FOLFOXIRI + bev 117 111 99 85 67 54 36 20 13 8 3 2 0 0
RAS-mutant FOLFIRI + bev 119 111 106 85 58 47 40 27 13 7 1 0 0 0
BRAF-mutant FOLFOXIRI + bev 16 14 10 8 7 4 3 3 0 0 0 0 0 0
BRAF-mutant FOLFIRI + bev 12 8 5 4 3 2 1 0 0 0 0 0 0 0

Cremolini C, et al. Lancet Oncol. 2015;16:1306-1315. Slide credit: clinicaloptions.com

 Head-to-Head Trials of Bevacizumab vs
Cetuximab in First-line KRAS Wild-Type mCRC
FIRE-3[1] FOLFIRI +
Untreated pts with Bevacizumab 5 mg/kg Q2W
mCRC with KRAS (n = 295)
wild-type tumors
(N = 592) FOLFIRI +
Cetuximab 400 mg/m2 loading then 250 mg/m2 Q1W
(n = 297)

CALGB/SWOG 80405[2] FOLFOX or FOLFIRI Q2W +

Bevacizumab 5 mg/kg Q2W
Untreated advanced
or pts with mCRC (n = 559)
with KRAS wild-type ~ 70% FOLFOX; 30% FOLFIRI
tumors FOLFOX or FOLFIRI Q2W +
(N = 1137) Cetuximab 400 mg/m2 loading then 250 mg/m2 Q1W
(n = 578)
1. Heinemann V, et al. Lancet Oncol. 2014;15:1065-1075. 2. Venook AP, et al. ASCO 2014. Abstract LBA3. Slide credit: clinicaloptions.com
 FIRE-3: OS in Pts With Wild-Type KRAS Exon 2
100 Events, Median
n/N (%) OS, Mos 95% CI
FOLFIRI + 158/297 28.7 24.0-36.6
75 cetux (53.2)
FOLFIRI + 185/295 25.0 22.7-27.6
OS (%)

bev (62.7)
50 (HR: 0.77; 95% CI: 0.62-0.96; log-rank P = .017)

25

0
0 12 24 36 48 60 72
Pts at Risk, n Mos Since Start of Treatment
FOLFIRI + cetux 297 218 111 60 29 9 0
FOLFIRI + bev 295 214 111 47 18 2 0
Heinemann V, et al. Lancet Oncol. 2014;15:1065-1075. Slide credit: clinicaloptions.com
 FIRE-3: OS in Pts With All-RAS Wild Type
100 Events Median OS,
n/N (%) Mos 95% CI
FOLFIRI + 91/171 33.1 24.5-39.4
75 cetux (53.2)
FOLFIRI + 110/171 25.6 22.7-28.6
OS (%)

bev (64.3)
50 (HR: 0.70; 95% CI: 0.53-0.92; log-rank P = .011)

25 Median = 7.5 mos

0
0 12 24 36 48 60 72
Pts at Risk, n Mos Since Start of Treatment
FOLFIRI + cetux 171 128 71 39 20 6
FOLFIRI + bev 171 127 68 26 9 1
Heinemann V, et al. Lancet Oncol. 2014;15:1065-1075. Slide credit: clinicaloptions.com
 CALGB/SWOG 80405: No Difference in PFS, OS in
Pts With All-RAS Wild Type
100
PFS OS
100

80 CT + bev 80 CT + bev
CT + cetux CT + cetux
PFS (%)

OS (%)
60 60

40 40

20 20

0 0
0 12 24 36 48 60 72 0 12 24 36 48 60 72 84 96
Mos From Study Entry Mos From Study Entry
Pts at CT + bev 256 112 49 23 13 6 CT + bev 256 199 147 77 35 16 5 2
Risk, n CT + cetux 270 126 49 18 5 2 1 CT + cetux 270 205 164 88 41 24 7 1 1
Arm Median PFS, HR (95% CI) Arm Median OS, HR (95% CI)
Mos (Range) P Value Mos (Range) P Value
11.3 1.1 31.2 0.9
CT + bev CT + bev
(10.3-12.6) (0.9-1.3) (26.9-34.3) (0.7-1.1)
11.4 32.0
CT + cetux CT + cetux
(9.6-12.9) P = .31 (27.6-38.5) P = .40

Lenz H, et al. ESMO 2014. Abstract 501O. Slide credit: clinicaloptions.com

 Optimizing First-line Therapy in KRAS Wild-Type
mCRC: EGFR- vs VEGF-Targeted mAbs
Trial Comparative Regimens Median PFS, Median OS,
Mos Mos
PEAK[1] mFOLFOX6/Pmab vs
10.9 vs 10.1 34.2 vs 24.3*
(N = 285) mFOLFOX6/bev
FIRE-3[2] FOLFIRI/cetux vs
10.0 vs 10.3 28.7 vs 25.0*
(N = 592) FOLFIRI/bev
mFOLFOX or
CALGB/SWOG
FOLFIRI/cetux vs 10.4 vs 10.8 29.9 vs 29.0
80405[3]
mFOLFOX or (NS) (NS)
(N = 1137)
FOLFIRI/Bev
*Statistically significant difference.
Primary endpoint of ORR was not significantly different between treatment arms in
the FIRE-3 study (62% vs 58%; P = .18)[2]
1. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240-2247. 2. Heinemann V, et al. Lancet Oncol. Slide credit: clinicaloptions.com
2014;15:1065-1075. 3. Venook AP, et al. ASCO 2014. Abstract LBA3.
 CAIRO3: Maintenance With Capecitabine +
Bevacizumab vs Observation
Upon first
progression
(PFS1)
Capecitabine +
Untreated pts Bevacizumab
with mCRC pts (n = 279)
with SD or better Until second
CAPOX-B
after 6 cycles progression
induction
CAPOX-B (PFS2)
induction Observation
(N = 558) (n = 279)

Simkens LH, et al. Lancet. 2015;385:1843-1852. Slide credit: clinicaloptions.com

 CAIRO3: PFS1
100 Median PFS1, Mos (95% CI)
Observation 4.1 (3.9-4.2)
80
Maintenance 8.5 (6.5-10.3)
Stratified HR 0.43 (0.36-0.52)
PFS (%)

60
P Value < .0001
40 (Adjusted HR: 0.40; P < .0001)
Maintenance
20

Observation
0
0 12 24 36 48 60
Pts at Risk, n Mos
Observation 279 18 7 5 2 1
Maintenance 278 96 36 10 4 3
Simkens LH, et al. Lancet. 2015;385:1843-1852. Slide credit: clinicaloptions.com
 TML (ML18147) Trial: Bevacizumab After
Progression
Stratified by: ECOG PS, first-line PFS; time since last
bevacizumab dose; first-line chemo (irinotecan vs oxaliplatin)
Bevacizumab 2.5 mg/kg/wk +
Pts with mCRC who Second-line chemotherapy
Until PD,
failed first-line (n = 409)
unacceptable
chemotherapy (irinotecan
or oxaliplatin based) + toxicity, or
bevacizumab* Second-line chemotherapy withdrawal
(N = 820) (n = 410)
Switch from first-line regimen; 58% irinotecan
*Pts excluded if PFS < 3 mos, received
oxaliplatin; 42% oxaliplatin irinotecan.
< 3 mos of first-line bevacizumab, or
progressed > 3 mos after last
bevacizumab dose.

Primary endpoint: OS
Secondary endpoints: safety, PFS, response
Bennouna J, et al. Lancet Oncol. 2013;14:29-37. Slide credit: clinicaloptions.com
 TML (ML18147) Trial: OS in ITT Population
1.0
CT (n = 410)
Bev + CT (n = 409)
0.8
Probability of OS (Unstratified HR: 0.81; 95% CI: 0.69-0.94;
log-rank P = .0062)
0.6
(Stratified HR: 0.83; 95% CI: 0.71-0.97;
0.4 log-rank P = .0211)

0.2

9.8 mos 11.2 mos

0
0 6 12 18 24 30 36 42 48
Mos
Pts at Risk, n
CT 410 293 162 51 24 7 3 2 0
Bev + CT 409 328 188 64 29 13 4 1 0
Bennouna J, et al. Lancet Oncol. 2013;14:29-37. Slide credit: clinicaloptions.com
 TML (ML18147) Trial: Adverse Events
Chemotherapy Chemotherapy +
(n = 409) Bevacizumab
Adverse Event, % (n = 401)
All Grade Grade 3-5 All Grade Grade 3-5
Hypertension 7 1 12 2
Proteinuria 1 -- 5 <1
Bleeding/hemorrhage 9 <1 26 2
Abscess and fistulae -- -- 1 <1
GI perforation <1 <1 3 2
CHF <1 <1 <1 --
VTE/ATE 4/1 3/< 1 6/< 1 5/< 1
Wound healing complications <1 <1 1 <1
Bennouna J, et al. Lancet Oncol. 2013;14:29-37. Slide credit: clinicaloptions.com
 RAISE: Ramucirumab + FOLFIRI After
Progression
Stratified by ECOG PS, first-line PFS, time since last
bevacizumab dose, first-line chemo (irinotecan vs oxaliplatin)

FOLFIRI +
Pts with mCRC who Ramucirumab 8 mg/kg
progressed on first- (n = 536) Until PD,
line FOLFOX +
unacceptable
bevacizumab*
(N = 1072) toxicity, or
FOLFIRI + withdrawal
Placebo
*Pts excluded if PFS < 3 mos, received
< 3 mos first-line bevacizumab, or
(n = 536)
progressed > 3 mos after last
bevacizumab dose.

Primary endpoint: OS
Secondary endpoints: safety, PFS, response
Tabernero J, et al. Lancet Oncol. 2015;16:499-508. Slide credit: clinicaloptions.com
 RAISE: OS
Ramucirumab + FOLFIRI
100 Placebo + FOLFIRI
90
Median OS, Mos (95% CI)
80
OS Estimate (%) Ramucirumab: 13.3 (12.4-14.5)
70
Placebo: 11.7 (10.8-12.7)
60
50 (HR: 0.844; 95% CI: 0.730-0.976;
40 log-rank P = .0219)
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Pts at Risk, n
Ramucirumab + FOLFIRI 536 497 421 345 269 195 114 78 53 34 22 12 4 0 0
Placebo + FOLFIRI 536 486 400 329 228 166 108 66 44 22 10 2 2 1 0
Tabernero J, et al. Lancet Oncol. 2015;16:499-508. Slide credit: clinicaloptions.com
 Second-line Therapy in mCRC: Comparison of
Phase III Trials
Median OS, Median PFS, Response
Trial First Line Second Line
Mos Mos Rate, %
TML[1] CT +
CT/bev vs CT 11.2 vs 9.8 5.7 vs 4.1 5.4 vs 3.9
(N = 819) bev
HR: 0.81; HR: 0.68;
P = .0062 P <.0001
Oxaliplatin-based
VELOUR[2] FOLFIRI/ziv-aflibercept vs
CT 13.5 vs 12.1 6.9 vs 4.7 19.8 vs 11.1
(N = 1226) FOLFIRI/placebo
bev
HR: 0.82; HR: 0.76;
P = .0001
P = .0032 P < .0001
Oxaliplatin-based
RAISE[3] FOLFIRI/ramucirumab vs
chemo + 13.3 vs 11.7 5.7 vs 4.5 13.4 vs 12.5
(N = 1072) FOLFIRI/placebo
bev
HR: 0.84; HR: 0.79;
P = .022 P = .0005
1. Bennouna J, et al. Lancet Oncol. 2013;14:29-37. 2. Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.
3. Tabernero J, et al. Lancet Oncol. 2015;16:499-508. Slide credit: clinicaloptions.com
 CORRECT Trial: Regorafenib vs Placebo + BSC
After Progression
Randomized 2:1
Stratified by previous VEGF-targeting
agents, time from diagnosis of
metastatic disease, geographic region
Regorafenib 160 mg PO QD
Wks 1-3 of 4-wk cycle + BSC
Pts with mCRC who (n = 505)
progressed on or No crossover
within 3 mos of Placebo QD allowed
previous therapy Wks 1-3 of 4-wk cycle + BSC
(N = 760) (n = 255)

Primary endpoint: OS
Grothey A, et al. Lancet. 2013;381:303-312. Slide credit: clinicaloptions.com
 CORRECT: PFS and OS
1.00 Placebo (n = 255)
Regorafenib (n = 505)
0.75
PFS Median PFS: 1.9 vs 1.7 mos
0.50
Survival Distribution Function
(HR: 0.49; 95% CI: 0.42-0.58;
0.25 P < .0001)

0
0 50 100 150 200 250 300 350
1.00 Days From Randomization

0.75 Median OS: 6.4 vs 5.0 mos

OS (HR: 0.77; 95% CI: 0.64-0.94;
0.50 P = .0052)

0.25

0
0 2 4 6 8 10 12 14 16 18
Grothey A, et al. Lancet. 2013;381:303-312. Days From Randomization Slide credit: clinicaloptions.com
 CORRECT: AEs in 10% of Pts
Regorafenib Placebo
AEs, % (n = 500) (n = 253)
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Fatigue 47 9 <1 28 5 <1
HFSR 47 17 0 8 <1 0
Diarrhea 34 7 <1 8 1 0
Anorexia 30 3 0 15 3 0
Voice changes 29 <1 0 6 0 0
Hypertension 28 7 0 6 1 0
Oral mucositis 27 3 0 4 0 0
Rash/desquamation 26 6 0 4 0 0
Nausea 14 <1 0 11 0 0
Weight loss 14 0 0 2 0 0
Fever 10 1 0 3 0 0
AEs leading to permanent tx
8.2 1.2
discontinuation

Grothey A, et al. Lancet. 2013;381:303-312. Slide credit: clinicaloptions.com

VEGF Targeting in Hepatocellular Carcinoma
 BCLC Staging and Treatment Strategy
HCC

Very early stage (0)
Single 2 cm
Child-Pugh A, PS 0
Potential candidate
for liver transplantation
Prognosis
Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal stage (D)
Single, or 3 nodules 3 cm Multinodular Portal invasion Child-Pugh C,
Child-Pugh A-B, PS 0 Child-Pugh A-B*, PS 0 Extrahepatic spread PS 3/4
Child-Pugh A-B,* PS 1/2
Single 3 nodules
3 cm

Portal
pressure
No Yes bilirubin

Normal Increased Associated

diseases

No Yes
Treatment

Ablation Resection Transplant Ablation TACE Sorafenib

BSC
Effective treatments with survival benefit
*Note that Child-Pugh classification is not sensitive enough to accurately identify those pts with advanced liver failure who would deserve liver transplant consideration.
Pts with end-stage cirrhosis due to heavily impaired liver function (Child-Pugh C or earlier stages with predictors of poor prognosis, high MELD score)

should be considered for liver transplantation. In these pts, HCC may become a contraindication if exceeding the enlistment criteria.
Reprinted from Gastroenterology, Vol 150, Bruix J, et al. Evidence-based diagnosis, staging, and treatment of patients with Slide credit: clinicaloptions.com
hepatocellular carcinoma, p. 835-853, 2016, with permission from Elsevier.
 TTP and OS According to Occurrence of
Dermatologic AEs in First 60 Days
TTP OS
1.0 1.0
Probability of Progression

Probability of Survival
0.8 0.8

0.6 0.6

0.4 P = .016 0.4 P = .009

0.2 0.2

0.0 0.0
0 10 20 30 40 50 60 0 10 20 30 40 50 60
TTP (Mos) Survival (Mos)
Yes: 8.1 mos (95% CI: 1.6-14.5) Yes: 18.2 mos (95% CI: 11.9-24.4)
vs vs
No: 3.9 mos (95% CI: 2.08-5.7) No: 10.1 mos (95% CI: 10.1-13.0)
Reig M, et al. J Hepatol. 2014;61:318-324. Slide credit: clinicaloptions.com
 RESORCE: Phase III Trial of Regorafenib vs
Placebo in Second-line HCC
152 centers in 21 countries in North/South America, Europe, Australia, Asia
Randomized 2:1
Stratified by geography (Asia vs other), macrovascular invasion, extrahepatic
disease, ECOG PS (0 vs 1), AFP (< 400 ng/mL vs 400 ng/mL)

Regorafenib 160 mg PO QD
Pts with HCC with Days 1-21 of 28-day cycle
documented + BSC
radiologic (n = 379)
Until PD, unacceptable
progression on
sorafenib toxicity, or withdrawal
Placebo
(N = 573)
Days 1-21 of 28-day cycle
+ BSC
(n = 194)

Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com

 RESORCE: Key Inclusion Criteria
HCC confirmed by histological or cytological analysis or diagnosed by
noninvasive assessment per AASLD criteria in a pt with confirmed cirrhosis
BCLC stage B or C pts who could not benefit from resection, local ablation,
or chemoembolization
Documented radiological progression while receiving sorafenib
Randomization within 10 wks after the last sorafenib dose
Tolerability of previous sorafenib, defined as receiving sorafenib 400
mg/day for at least 20 of the last 28 days of treatment
ECOG PS 0/1
Child-Pugh A liver function
Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com
 RESORCE: Study Endpoints
Primary endpoint: OS[1]
90% power to detect 43% increase in median OS at 370 events;
1-sided alpha 0.025 (estimated median OS for placebo: 8 mos)
Secondary[1] (by modified RECIST for HCC[2] and RECIST 1.1[3])
TTP
PFS
Response rate
Disease control rate
Other: duration of response, duration of stable disease, health-related
quality of life, pharmacokinetic and biomarker analyses[1]
1. Bruix J, et al. Lancet. 2017;389:56-66. 2. Lencioni R, Llovet JM. Semin Liver Dis. 2010;30:52-60.
Slide credit: clinicaloptions.com
3. Eisenhauer EA, et al. Eur J Cancer. 2009;45:228-247.
 RESORCE: Baseline Characteristics I
Regorafenib Placebo Characteristic, Regorafenib Placebo
Characteristic
(n = 379) (n = 194) % (n = 379) (n = 194)
Male, % 88 88 ECOG PS 0/1 65/35 67/33
Median age, 62 Etiology of
64 (54-71)
yrs (range) (55-68) HCC*
Race, % Alcohol use 24 28
White Hepatitis B 38 38
36 35 Hepatitis C 21 21
Asian
41 40 NASH 7 7
Black
2 1 Other 7 5
Other/not
21 24 Unknown 17 16
reported
*Pts may have > 1.
Geographic
38 38
region: Asia, %
Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com
 RESORCE: Baseline Characteristics II

Regorafenib Placebo
Characteristic, %
(n = 379) (n = 194)
BCLC stage A/B/C < 1/14/86 0/11/89
Child-Pugh class A/B 98/1* 97/3
MVI 29 28
EHD 70 76
MVI and/or EHD 80 84
AFP 400 ng/mL 43 45
Cirrhosis present (investigator assessed) 75 74
*Child-Pugh class missing on 1 pt.

Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com

 RESORCE: OS
Regorafenib Placebo
100 (n = 379) (n = 194)

Probability of Survival (%)

90 Events, n (%) 233 (61) 140 (72)
80 Censored, n (%) 147 (39) 54 (28)
70 Median OS, mos 10.6 (9.1-12.1) 7.8 (6.3-8.8)
60 (95% CI)
50 Regorafenib (HR 0.63; 95% CI: 0.50-0.79; 1-sided P < .0001)
40
30
20 Placebo
10
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos From Randomization
Pts at Risk, n
Regorafenib 379 316 224 170 122 78 54 34 21 10 4 0
Placebo 194 149 95 62 37 26 16 8 5 3 1 0
Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com
 RESORCE: PFS
100 Regorafenib Placebo
90 (n = 379) (n = 194)

Probability of PFS (%) 80 Events, n (%) 293 (77) 181 (93)

70 Censored, n (%) 86 (23) 13 (7)
60 Median PFS, 3.1 1.5
50 mos (95% CI) (2.8-4.2) (1.4-1.6)
40 (HR 0.46; 95% CI: 0.37-0.56; 1-sided P < .0001)
30 Regorafenib
20
10 Placebo
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos From Randomization
Pts at Risk, n
Regorafenib 379 166 76 43 27 14 8 7 4 0 0 0
Placebo 194 37 15 6 3 2 1 1 0 0 0 0
Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com
 RESORCE: Time to Progression

Probability of Progression (%)

100 Placebo Regorafenib Placebo
90 (n = 379) (n = 194)
80 Events, n (%) 274 (72) 173 (89)
70 Censored, n (%) 105 (28) 21 (11)
60 Median TTP, mos 3.2 1.5
50 Regorafenib (95% CI) (2.9-4.2) (1.4-1.6)
40 (HR 0.44; 95% CI: 0.36-0.55; 1-sided P < .0001)
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos From Randomization
Pts at Risk, n
Regorafenib 379 164 75 41 27 14 8 7 4 0 0 0
Placebo 194 36 15 6 3 2 1 1 0 0 0 0
Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com
 RESORCE: Best Overall Tumor Response
Modified RECIST[1] RECIST 1.1[2]
Outcome, % Regorafenib Placebo Regorafenib Placebo
(n = 379) (n = 194) (n = 379) (n = 194)
Response rate 11 4 6.6 2.6
P = .009 P = .04
DCR 65 36 65.7 34.5
P < .001 P < .001
Response
CR 1 0 0 0
PR 10 4 6.6 2.6
SD 54 32 58.8 32.0
Non-CR/non-PD <1 0 0.3 0
PD 23 56 22.4 57.2
Not evaluable 5 4 5.0 4.6
Not assessed 7 4 6.9 3.6
Clinical progression* 23 21 22.7 20.6

1. Bruix J, et al. Lancet. 2017;389:56-66. 2. Bruix J, et al. ESMO GI 2016. Abstract LBA03. Slide credit: clinicaloptions.com
 RESORCE: TEAEs
TEAE Drug-Related TEAE
AEs, % Regorafenib Placebo Regorafenib Placebo
(n = 379) (n = 194) (n = 379) (n = 194)
Any grade 100 93 93 52
Grade 3 56 32 46 16
Grade 4 11 7 4 1
Grade 5 (death) 13 20 2* 1
Serious 44 47 10 3
Leading to dose modification 68 31 54 10
Leading to permanent d/c 25 19 10 4
*Drug-related grade 5 events in the regorafenib group (n = 7): meningorrhagia, hemorrhagic shock, myocardial infarction, duodenal
perforation, death not otherwise specified, general physical health deterioration, hepatic encephalopathy.
Drug-related grade 5 events in the placebo group (n = 2) were due to hepatic failure.

Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com

 RESORCE: TEAEs in > 5% of Either Arm
TEAE Drug-Related TEAE

Regorafenib Placebo Regorafenib Placebo

AEs, % (n = 379) (n = 194) (n = 379) (n = 194)
Gr Gr Gr Gr Gr Gr Gr
Any Any Any Gr 3 Any
3 4 3 4 4 3 4
HFSR 53 13 N/A 8 1 N/A 52 13 N/A 7 1 N/A
Fatigue 40 9 N/A 32 5 N/A 29 6 N/A 19 2 N/A
Hypertension 31 15 <1 6 5 0 23 13 <1 5 3 0
Bilirubin increased 29 10 1 18 8 3 19 6 <1 4 2 0
AST increased 25 10 1 20 10 2 13 4 1 8 5 1
Ascites 16 4 0 16 6 0 2 1 0 1 1 0
Anemia 16 4 1 11 5 1 6 1 <1 1 1 0
Hypophosphatemia 10 8 1 2 2 0 6 4 1 1 1 0
Lipase increased 7 5 2 3 2 0 5 4 <1 2 1 0

Bruix J, et al. Lancet. 2017;389:56-66. Slide credit: clinicaloptions.com

Treatment Approach for HCC: Sequential
Concept
Resection/transplantation/ablation Liver-only disease
Limited tumor burden

Chemoembolization Liver-only disease

No vascular invasion
Preserved liver function
ECOG PS 0
Selective approach

Sorafenib No tumor burden limit

Preserved liver function
ECOG PS 0-2

Regorafenib No tumor burden limit

Preserved liver function
ECOG PS 0-2
Slide credit: clinicaloptions.com
Angiography After Second TACE:
Disseminated Disease

Slide credit: clinicaloptions.com

HandFoot Skin Reaction on Sorafenib

Slide credit: clinicaloptions.com

 REACH: OS
Ramucirumab Placebo
100 (n = 283) (n = 282)
90 Median OS, mos 9.2 7.6
80 (HR: 0.87; 95% CI: 0.72-1.05; P = .14)
70
6-mo survival, % 65.5 56.1
60
OS (%)

12-mo survival, % 39.7 33.9

50
40
30
20 Ramucirumab
10 Placebo
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Mos Since Randomization

Zhu AX, et al. Lancet Oncol. 2015;16:859-870. Slide credit: clinicaloptions.com

 REACH: OS by AFP Level
100
AFP 400 ng/mL
80 Ramucirumab
Censored Ramucirumab Placebo

OS (%)
60 Placebo (n = 119) (n = 131)
Censored
Median, mos 7.8 4.2
40
(HR: 0.67; 95% CI: 0.51-0.90; P = .006)
20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
100
AFP < 400 ng/mL Ramucirumab Placebo
80 (n = 160) (n = 150)
Median, mos 10.1 11.8
OS (%)

60
(HR: 1.09; 95% CI: 0.84-1.43; P = .51)
40

20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Zhu AX, et al. Lancet Oncol. 2015;16:859-870. Mos Since Randomization Slide credit: clinicaloptions.com
VEGF Targeting in Gastric Cancer
 Chemotherapy for Metastatic Esophagogastric
Cancer
First-line fluoropyrimidine with platinum in most pts[1-7]
Addition of docetaxel may be beneficial in select pts[2]
Epirubicin should be avoided due to increased toxicity with
minimal benefit[6]
Chemotherapy-refractory EG cancer is a uniformly fatal illness
and an unmet therapeutic need

1. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 2. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-
4997. 3. Webb A, et al. J Clin Oncol. 1997;15:261-267. 4. Kang YK, et al. Ann Oncol. 2009;20:666-673. 5. Al-
Batran S-E, et al. J Clin Oncol. 2008;26:1435-1442. 6. Guimbaud R, et al. J Clin Oncol. 2014;32:3520-3526.
7. Koizumi W, et al. Lancet Oncol. 2008;9:215-221. Slide credit: clinicaloptions.com
 Genomic Spectrum of Esophagogastric Cancer
(ESCC)
CCND1 amplification
TP63/SOX2 amplification
KDM6A amplification
Gastroesophageal Adenocarcinomas With CIN
Upper esophagus ERBB2 amplification
50%
VEGF-A amplification
TP53 amplification
Gastric Adenocarcinomas With EBV Infection
Mid esophagus EBV-CIMP
PIK3CA mutation
9%
PD-L1/2 overexpression

Lower esophagus Gastric Adenocarcinomas With MSI

Hypermutation
GEJ Gastric-CIMP 22%
Proximal stomach MLH1 silencing
Gastric Adenocarcinomas With GS
Body/fundus
Diffuse histology
CDH1, RHOA mutations 20%
Antrum/pylorus
CLDN18-ARHGAP fusions
Janjigian YY, et al. ESMO 2016. Abstract 3244.
Kim J, et al. Nature. 2017;[Epub ahead of print]. Slide credit: clinicaloptions.com
 VEGFR-2 Inhibitors: Second and Later Lines of
Therapy
Modest clinical benefit as second- and third-line treatment[1-4]
Ramucirumab + paclitaxel (RAINBOW): 2.2-mo median OS benefit, 28% ORR[1]
Regorafenib (INTEGRATE): 1.7-mo median PFS benefit[3]
Apatinib: 1.8-mo median OS benefit, additional studies under way[4]
No proven OS benefit in first-line setting (AVAGAST negative, RAINFALL
ongoing)[5,6]
No clear biomarker for response
Elevated serum VEGF-A and low tissue neuropilin levels have questionable
predictive value[7]
1. Wilke H, et al. Lancet Oncol. 2014;15:1224-1235. 2. Fuchs CS, et al. Lancet. 2014;383:31-39. 3. Pavlakis
N, et al. J Clin Oncol. 2016;34:2728-2735. 4. Li J, et al. J Clin Oncol. 2016;34:1448-1454. 5. Ohtsu A, et al.
J Clin Oncol. 2011;29:3968-3976. 6. ClinicalTrials.gov. NCT02314117. 7. Van Cutsem E, et al. J Clin Oncol.
2012;30:2119-2127. Slide credit: clinicaloptions.com
 Randomized Second-line Gastric Cancer Studies
(2009-2016): Median OS
Median OS by Study Arm, Mos
Regorafenib vs BSC[1] 5.8
(N = 147) 4.5

Ramucirumab vs BSC[2] 5.2

(N = 355) 3.8 Active treatment
BSC/ASC
Docetaxel vs ASC[3] 5.2
(N = 168) 3.6

CT (docetaxel or irinotecan) vs BSC[4] 5.3

(N = 202) 3.8

Irinotecan vs BSC[5] 4.0

(N = 40) 2.4

0 1 2 3 4 5 6 7 8
1. Pavlakis N, et al. J Clin Oncol. 2016;34:2728-2735. 2. Fuchs CS, et al. Lancet. 2014;383:31-39. 3. Ford HE,
et al. Lancet Oncol. 2014;15:78-86. 4. Kang JH, et al. J Clin Oncol. 2012;30:1513-1518. 5. Thuss-Patience PC, Slide credit: clinicaloptions.com
et al. Eur J Cancer. 2011;47:2306-2314.
 BSC Ramucirumab in Metastatic Gastric or GEJ
Cancer (REGARD): OS
Ramucirumab Placebo
1.0 Ramucirumab Pts/events 238/179 117/99
Proportion Remaining Alive

Placebo Median, mos 5.2 (4.4-5.7) 3.8 (2.8-4.7)

0.8 Censored (95% CI)
6-mo OS, % 42 32
0.6 12-mo OS, % 18 11

0.4 (HR: 0.776; 95% CI: 0.603-0.998; P = .0473)

0.2

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28
Pts at Risk, n Mos
Ramucirumab 238 154 92 49 17 7 3 0 0
Placebo 117 66 34 20 7 4 2 1 0

Fuchs CS, et al. Lancet. 2014;383:31-39. Slide credit: clinicaloptions.com

 REGARD: PFS, Response
1.0 Ramucirumab Ramucirumab Placebo
Proportion Without Progression

Placebo Pts/events 238/199 117/108

0.8 Censored Median, mos 2.1 (1.5-2.7) 1.3 (1.3-1.4)
(95% CI)
0.6
12-wk PFS, % 40 16
ORR, % 3 3
0.4 DCR, % 49 23

0.2 (HR: 0.483; 95% CI: 0.376-0.620; P < .0001)

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Mos
Pts at Risk, n
Ramucirumab 238 213 113 65 61 45 30 18 18 11 5 4 2 1 1 1 1 0
Placebo 117 92 27 11 7 4 2 2 2 2 2 1 1 0 0 0 0 0

Fuchs CS, et al. Lancet. 2014;383:31-39. Slide credit: clinicaloptions.com

 REGARD: AEs of Interest
AE, % Ramucirumab (n = 236) Placebo (n = 115)
Any Grade Grade 3 Any Grade Grade 3
Hypertension* 16 8 8 3
Bleeding/hemorrhage 13 3 11 3
Arteriothromboembolic 2 1 0 0
Venous thromboembolic 4 1 7 4
Proteinuria 3 <1 <3 <0
GI perforation <1 <1 <1 <1
Fistula (GI and non-GI) <1 <1 <1 <1
Infusion-related reaction <1 0 2 0
Cardiac failure <1 0 0 0
*Includes increased blood pressure.
No grade 4 hypertension observed among ramucirumab-treated pts.

Fuchs CS, et al. Lancet. 2014;383:31-39. Slide credit: clinicaloptions.com

 Second-line Ramucirumab in Advanced Gastric
Cancer (RAINBOW): OS
RAINBOW[1] REGARD[2]
1.0 Ram/Pac Placebo/Pac Ram
Pts/events, n 330/256 335/260 238/199
0.8 Median, mos 9.63 7.38 5.2
(95% CI) (8.48-10.81) (6.31-8.38) (4.4-5.7)
Probability of OS

0.6 6-mo OS, % 72 57 42

12-mo OS, % 40 30 18

0.4 (HR: 0.807; 95% CI: 0.678-0.962; P = .0169)

Median OS: 2.3 mos

0.2
Ram + pac
Placebo + pac
Censored
0
0 4 8 12 16 20 24 28
Mos
1. Wilke H, et al. Lancet Oncol. 2014;15:1224-1235. 2. Fuchs CS, et al. Lancet. 2014;383:31-39. Slide credit: clinicaloptions.com
 RAINBOW: PFS, Responses
1.0 RAINBOW[1] REGARD[2]
0.9 Ram/Pac Placebo/Pac Ram
Pts/events, n 330/279 335/296 238/199
0.8 Median, mos 4.40 (4.24-5.32) 2.86 (2.79-3.02) 2.1 (1.5-2.7)
(95% CI)
Probability of PFS

0.7
6-mo PFS, % 36 17
0.6 12-mo PFS, % 22 10
ORR, % 28 16 (P = .0001) 3
0.5 DCR, % 80 64 (P < .0001) 49
0.4 (HR: 0.635; 95% CI: 0.536-0.752; P < .0001)
0.3

0.2
Ram + pac
0.1 Placebo + pac
Censored
0
0 2 6 10 14 18 22
Mos
1. Wilke H, et al. Lancet Oncol. 2014;15:1224-1235. 2. Fuchs CS, et al. Lancet. 2014;383:31-39.
 RAINFALL: Capecitabine/5-FU + Cisplatin
Ramucirumab in Metastatic Gastric Cancer
Randomized, double-blind phase III trial

Pts with Ramucirumab 8 mg/kg IV Days 1, 8

metastatic Capecitabine* 1000 mg/m2 PO Days 1-14
gastric/GEJ Cisplatin 80 mg/m2 IV Day 1
21-day
cancer with no cycles
prior first-line Placebo IV Days 1, 8
therapy Capecitabine* 1000 mg/m2 PO Days 1-14
(N = 616, Cisplatin 80 mg/m2 IV Day 1
planned) *Pts unable to take capecitabine receive 5-FU 800 mg/m2/day Days 1-5.

Primary endpoint: PFS

Secondary endpoints: OS, PFS2, ORR, DCR, TTP, DoR, QoL, PK
ClinicalTrials.gov. NCT02314117.
 Phase II INTEGRATE: Second-line Regorafenib
for Metastatic or Recurrent Gastric Cancer
Double-blind, randomized, placebo-controlled phase II trial
Randomized 2:1; stratified by previous lines of 28-day cycles
therapy (1 vs 2), and geographic region
Regorafenib
Pts with locally recurrent 160 mg PO Days 1-21
or metastatic (n = 97) All pts treated until
gastric/GEJ cancer with PD or prohibitive
1 or 2 previous lines of Placebo toxicity
therapy; ECOG PS 1 PO Days 1-21
(N = 147) (n = 50)

Primary endpoint: PFS

Secondary endpoints: ORR, clinical benefit at 2 mos, OS, safety, QoL
Pavlakis N, et al. J Clin Oncol. 2016;34:2728-2735.
 Phase II INTEGRATE: Second-line Regorafenib
for Metastatic or Recurrent Gastric Cancer: PFS
1.0 Median PFS:
2.6 vs 0.9 mos
Proportion Alive and

Placebo
0.8
Progression Free

Regorafenib
0.6 (HR 0.40; 95% CI: 0.28-0.59; Effect consistent
stratified log-rank P < .001) across multiple
0.4 variables,
0.2 including primary
site, number of
0
0 1 2 3 4 5 6 7 8
lines of treatment,
Mos From Random Assignment
and plasma
Pts at Risk, n VEGF-A
Placebo 50 16 9 4 3 1 1 1 0
Regorafenib 97 63 48 34 27 17 13 9 8
Pavlakis N, et al. J Clin Oncol. 2016;34:2728-2735. Slide credit: clinicaloptions.com
 Phase II INTEGRATE: Second-line Regorafenib
for Metastatic or Recurrent Gastric Cancer: OS
1.0 Median OS:
Placebo 5.8 vs 4.5 mos
Proportion Alive

0.8
Regorafenib
0.6

0.4

0.2 (HR 0.74; 95% CI: 0.51 to 1.08;

stratified log-rank P = .147)
0
0 1 2 3 4 5 6 7 8
Mos From Random Assignment
Pts at Risk, n
Placebo 50 44 37 31 27 19 14 12 10
Regorafenib 97 93 83 67 58 48 39 34 32
Pavlakis N, et al. J Clin Oncol. 2016;34:2728-2735. Slide credit: clinicaloptions.com
 Phase II INTEGRATE: Second-line Regorafenib
for Metastatic or Recurrent Gastric Cancer: AEs
AEs Grade 3 Occurring in > 5% of Pts Regorafenib Placebo Safety
in Regorafenib Arm, n (%) (n = 97) (n = 50) profile
Anorexia 6 (6) 3 (6) similar to
AST level increased 9 (9) 0 (0) previously
Abdominal pain 5 (5) 1 (2) reported
Hypertension 10 (10) 1 (2) with
GGT level increased 6 (6) 4 (8) regorafenib
ALT level increased 8 (8) 3 (6)
Skin and subcutaneous tissues disorders 6 (6) 0 (0)
Pain 5 (5) 2 (4)
Hypophosphatemia 5 (5) 0 (0)
At least 1 grade 3-5 AE 65 (67) 26 (52)
Pavlakis N, et al. J Clin Oncol. 2016;34:2728-2735. Slide credit: clinicaloptions.com
 VEGF Targeting in
Gastrointestinal Stromal Tumors
 GIST Timeline

1983 1995 1998 2002 2006 2013

First described CD34 identified 2 major Accelerated FDA approval FDA approval
by Mazur and as relatively discoveries[3]: FDA approval of sunitinib as of regorafenib
Clark[1] specific KIT staining of imatinib[4] second-line as third-line
marker[2]; 94% of GIST therapy therapy
similarities Activating
between GIST mutations in
cells and KIT gene (5
interstitial cells of out of 6)
Cajal

1. Mazur MT, et al. Am J Surg Pathol. 1983;7:507-519. 2. Miettinen M, et al. Am J Surg Pathol. 1995;19:207-
216. 3. Hirota S, et al. Science. 1998;279:577-580. 4. Dagher R, et al. Clin Cancer Res. 2002;8:3034-3038. Slide credit: clinicaloptions.com
 Molecular Classification of GIST
KIT PDGFRA Wild Type
(~ 85% GISTs) (~ 5% to 7%) (10% to 15 %)
BRAF mutation
(V600E exon 15)
IGF-1R
Succinate
Dehydrogenase
Alternate mutations
Exon 9 (18.1%) (AKT/PTEN/TRK)
Membrane
Exon 11 (66.9%) Exon 12 (0.8%)
Exon 13 (1.6%)
Cytoplasm
Exon 17 (1.6%) Exon 18 (3.9%)

Heinrich MC, et al. J Clin Oncol. 2003;21:4342-4349. Hirota S, et al. Science. 1998;279:577-580. Slide credit: clinicaloptions.com
 Improved Prognosis With Targeted Therapies
Chemotherapy and radiotherapy have limited value[1,2]
~ 20% of pts have unresectable/metastatic disease; > 40% of resected tumors
recur and metastasize
Pre-imatinib[1,2]
Localized disease: 5-yr OS < 50%
Metastatic GIST median OS: 5-12 mos
With targeted therapy (post-2001)[3]
Localized disease 5-yr OS: > 80%
Metastatic GIST median OS: 60 mos[4,5] (pre-sunitinib/regorafenib < 60 mos)[3]
1. Nilsson B, et al. Cancer. 2005;103:821-829. 2. Gold JS, et al. Ann Surg Oncol. 2007;14:134-142.
3. Joensuu H, et al. Lancet Oncol. 2012;13:265-274. 4. Demetri GD, et al. Lancet. 2006. 368:1329-1338.
5. Demetri GD, et al. Lancet. 2013;381:295-302. Slide credit: clinicaloptions.com
 Imatinib Resistance
Nearly one half of pts develop resistance to initial imatinib/targeted therapy
within 2 yrs
Primary resistance (within 6 mos, 10% to 15%)
KIT exon 17, PDGFR exon 18 mutations, BRAF, KRAS
Diffuse progression
Secondary resistance
Acquired secondary mutations: usually in tumors with exon 11 primary mutation
Activation of alternate drivers/pathways: PI3K/AKT/mTOR, IGFR1
Focal progression or diffuse progression
Kee D, et al. Ther Adv Med Oncol. 2012;4:255-270.
Li J, et al. Med Oncol. 2015;32:111. Slide credit: clinicaloptions.com
 Phase III Trial of Sunitinib in Imatinib-Refractory
GIST
Randomized 2:1
Stratified by progression within
< 6 mos vs > 6 mos or intolerance;
MPQ score (0 vs 1)

Sunitinib 50 mg/day x 4 wks Until PD; off-study

followed by 2 wks off with option to
(n = 207) continue sunitinib
Pts with imatinib
refractory/intolerant
GIST
(N = 312) Placebo Until PD; crossover
(n = 105) permitted

Primary endpoint: time to tumor progression (RECIST criteria)

Secondary endpoints: PFS, OS, ORR, time to response, DoR, duration of
performance status maintenance, safety
Demetri GD, et al. Lancet. 2006. 368:1329-1338. Slide credit: clinicaloptions.com
 Sunitinib in Imatinib-Refractory GIST: Responses

Sunitinib Placebo
Response, %
(n = 207) (n = 105)
PR 7 0
SD 58 48
< 6 mos 47 49
6 mos 19 1

Demetri GD, et al. Lancet. 2006. 368:1329-1338. Slide credit: clinicaloptions.com

 Sunitinib in Imatinib-Refractory GIST: Improved
Time to Progression, OS
100 100
Sunitinib (n = 207)
Time to Tumor Progression

90 median 27.3 wks 90

80 Placebo (n = 105) 80
70 median 6.4 wks 70
66 66 Sunitinib

OS (%)
(%)

50 (HR: 0.33; 95% CI: 50 (n = 207)

40 0.23-0.47; P < .0001) 40
30 30 Placebo (n = 105)
20 20
(HR: 0.49; 95% CI: 0.29-0.83;
10 10 P = .007)
0 0
0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 60
Wks Wks
Pts at Risk, n Pts at Risk, n
Sunitinib 207 106 67 53 34 18 5 1 0 Sunitinib 207 167 117 97 71 50 31 11 3 1 0
Placebo 105 36 9 2 1 0 0 0 0 Placebo 105 85 57 43 31 22 13 3 1 0 0

Demetri GD, et al. Lancet. 2006. 368:1329-1338. Slide credit: clinicaloptions.com

 Sunitinib in Imatinib-Refractory GIST: Reduced
Risk of Tumor Progression in All Subgroups
Risk Reduction
n HR (95% CI) In favor of sunitinib In favor of
Baseline Factor placebo
Age < 65 yrs 219 0.37 (0.25-0.55)
Age 65 yrs 93 0.24 (0.13-0.46)
Weight < 50 kg 14 0.13 (0.03-0.55)
Weight 50 kg 297 0.34 (0.24-0.48)
Male 196 0.32 (0.21-0.48)
Female 116 0.34 (0.19-0.62)
White 275 0.34 (0.24-0.49)
Not white 27 0.18 (0.06-0.57)
Initial diagnosis < 6 mos 3 N/A
Initial diagnosis 6 mos 308 0.32 (0.22-0.45)
ECOG PS 0 140 0.28 (0.17-0.46)
ECOG PS 1 168 0.37 (0.23-0.58)
MPQ 0 137 0.37 (0.22-0.62)
MPQ 1 171 0.28 (0.18-0.43)
Imatinib treatment 6 mos 53 0.43 (0.21-0.92)
Imatinib treatment > 6 mos 246 0.31 (0.21-0.46)
Max imatinib dose 400 mg 57 0.27 (0.12-0.59)
Mas imatinib dose > 400 mg 253 0.33 (0.23-0.48)

Study Location
US and Canada (North America) 143 0.38 (0.23-0.60)
Rest of world 169 0.29 (0.18-0.49)
0 0.50 1.00 1.50
Demetri GD, et al. Lancet. 2006. 368:1329-1338. HR (95% CI) Slide credit: clinicaloptions.com
 GRID: Phase III Trial of Regorafenib in Advanced
GIST
Randomized 2:1
Stratified by prior lines of
treatment, geographic region

Regorafenib 160 mg/day x 3 Until PD; off-study

wks of 4 wk cycle with option to
(n = 133) continue regorafenib
Pts with
metastatic/unresectable
GIST progressing after
imatinib and sunitinib Placebo Until PD; crossover
(N = 199) (n = 66) permitted

Primary endpoint: PFS (modified RECIST)

Secondary endpoints: OS, TTP, ORR, DCR, safety, tolerability
Demetri GD, et al. Lancet. 2013;381:295-302. Slide credit: clinicaloptions.com
 GRID: Responses

Regorafenib Placebo
Response, %
(n = 133) (n = 66)
DCR (CR + PR + durable
52.6 9.1
SD 12 wks)
ORR 4.5 1.5
CR 0 0
PR 4.5 1.5
SD (at any time) 71.4 33.3
PD 21.1 63.6

Demetri GD, et al. Lancet. 2013;381:295-302. Slide credit: clinicaloptions.com

 GRID: Survival
PFS OS
Regorafenib
100 Placebo

(HR: 0.27; 95% CI: 0.19-0.39; P < .0001)

75
Survival (%)

50 (HR: 0.77; 95% CI: 0.42-1.41; P = .199

25

0
0 2 4 6 8 10 0 2 4 6 8 10 12
Mos Since Randomization Mos Since Randomization
Pts at Risk, n
Regorafenib 82 72 27 9 126 119 94 39 10 1
Placebo 12 5 0 0 61 57 41 16 3 1

Demetri GD, et al. Lancet. 2013;381:295-302. Slide credit: clinicaloptions.com

 GRID: PFS by Subgroup
HR
n (95% CI)
All pts 199 0.27 (0.19-0.39)
Anticancer line of therapy Third 113 0.23 (0.14-0.37)
Fourth or more 86 0.31 (0.18-0.54)
Region Asia 47 0.30 (0.15-0.62)
Rest of world 152 0.24 (0.16-0.37)
North America 36 0.42 (0.19-0.92)
Not North America 163 0.22 (0.15-0.34)
Sex Male 127 0.31 (0.20-0.48)
Female 72 0.18 (0.09-0.34)
Age < 65 yrs 136 0.30 (0.19-0.46)
65 yrs 63 0.15 (0.08-0.30)
BMI < 25 112 0.29 (0.18-0.46)
25 to < 30 56 0.24 (0.12-0.48)
30 22 0.19 (0.06-0.61)
ECOG PS 0 110 0.22 (0.14-0.37)
1 89 0.30 (0.18-0.51)
Duration of imatinib treatment < 6 mos 22 0.50 (0.17-1.73)
6 to < 18 mos 33 0.19 (0.07-0.55)
18 mos 144 0.24 (0.15-0.36)
Mutation biomarkers KIT exon 11 mutation 51 0.21 (0.10-0.46)
KIT exon 9 mutation 15 0.24 (0.07-0.88)
0 0.5 1.0 1.5 2.0

Favors regorafenib Favors placebo

Demetri GD, et al. Lancet. 2013;381:295-302. Slide credit: clinicaloptions.com
 Common Drug-Related AEs With Sunitinib and
Regorafenib
Sunitinib[1] Regorafenib[2]
AE, n (%) (n = 202) (n = 132)
Grade 3/4 Any Grade Grade 3/4 Any Grade
Any event NR 168 (83) 79 (60) 130 (98)
Handfoot skin reaction 9 (4) 28 (13) 26 (20) 74 (56)
Hypertension 6 (3) 21 (11) 31 (23) 64 (49)
Diarrhea 7 (3) 59 (29) 7 (5) 53 (40)
Fatigue 10 (5) 68 (34) 3 (2) 51 (39)
Oral mucositis 1 (1) 31 (16) 2 (2) 50 (38)
Anorexia 0 (0) 38 (19) 0 (0) 27 (21)
Rash 2 (1) 26 (13) 3 (2) 24 (18)
Nausea 1 (1) 48 (24) 1 (1) 21 (16)
Myalgia/asthenia 6 (3) 24 (12) 1 (1) 18 (14)

1. Demetri GD, et al. Lancet. 2006;368:1329-1338. 2. Demetri GD, et al. Lancet. 2013;381:295-302. Slide credit: clinicaloptions.com
 Notable Lower Incidence Toxicities
Anemia/leukopenia/neutropenia/lymphopenia and
thrombocytopenia (5% to10% grade 3/4 with sunitinib)
Hypothyroidism (4% with sunitinib)
Proteinuria
Thromboembolic events

Demetri GD, et al. Lancet. 2006;368:1329-1338. Slide credit: clinicaloptions.com

Available TKIs

KIT+PDGFR+VEGFR+ KIT+/PDGFR+
Sorafenib Nilotinib
Cediranib Dasatinib
Cabozantinib Ponatinib
Pazopanib Masitinib
Vandetanib DCC2618
Motesanib Crenolanib
Dovitinib BLU-285
Famitinib

Slide credit: clinicaloptions.com

 GIST Treatment Algorithm
No
Localized GIST
-Assess if reducing tumor
bulk improves chance of
organ preservation or R0
resection AND no resistant
mutation?
Yes
Newly Diagnosed GIST
-Staging (CT/MRI or PET/CT)
-Molecular testing for
mutations
Advanced/Metastatic
-Imatinib 400 mg/day
-Increase to 800 mg/day if
exon 9 KIT mutation
Surgery Adjuvant Imatinib
-Assess risk for recurrence -400 mg/day for at least 3
(size/mitotic rate/location/rupture) yrs in high-risk pts
Neoadjuvant Imatinib
Surgery
(400 mg/day) -Adjuvant imatinib for high-risk
-Continue till maximum reduction in size pts (based on pre-imatinib risk
or when R0 surgery becomes feasible assessment)
Consider Surgery
-If all visible residual tumor
can be removed or for focal
progression
-Continue TKI
Responding to Imatinib/TKI
(Continue long-term)
Consider Localized
Liver-Directed
Therapy
-Embolization/RFA
-Continue TKI
Options
-Imatinib 800 mg/day
-Sunitinib
Progression on Imatinib/TKI -Regorafenib
-Primary or secondary resistance -Clinical trials (consider
early for PDGFR D842V
mutation)
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