What’s New in Non-Colorectal Gastrointestinal Malignancies ...hopehealthreseda.com/Articles/Friday...

What’s New in Non-Colorectal

Gastrointestinal Malignancies in

2014?

Andrew H. Ko, MD

Division of Hematology/Oncology

University of California, San Francisco

Abstr # Title Presenting

author

4000 A randomized double-blind phase 2 study of ruxolitinib

or placebo with capecitabine as second-line therapy in

patients with metastatic pancreatic cancer

H. Hurwitz

4005 RAINBOW: A global, phase III, randomized, double-blind

study of ramucirumab plus paclitaxel versus placebo

plus PTX for metastatic GEJ and gastric adenocarcinoma

following disease progression on first-line platinum- and

fluoropyrimidine-containing combination therapy --

Efficacy analysis in Japanese and Western patients

S. Hironaka

4003 Phase III study of apatinib in advanced gastric cancer: A

randomized, double-blind, placebo-controlled trial

S. Qin

4008 Phase III trial to compare capecitabine/cisplatin (XP)

versus XP plus concurrent capecitabine-radiotherapy in

gastric cancer: The final report on the ARTIST trial

J. Lee

4006 STORM: A phase III randomized, double-blind, placebo-

controlled trial of adjuvant sorafenib after resection or

ablation to prevent recurrence of hepatocellular

carcinoma

J. Bruix

50th Anniversary-Themed Education Session: The Past, Present,

and Future of Noncolorectal Gastrointestinal Cancers: Have We

Moved the Bar?

(A. Lowy, R. Mayer, P.

Kunz)

ABSTRACT 4000:

A RANDOMIZED DOUBLE-BLIND PHASE 2 STUDY OF

RUXOLITINIB OR PLACEBO WITH

CAPECITABINE AS SECOND-LINE THERAPY IN

PATIENTS WITH METASTATIC PANCREATIC CANCER

Hurwitz H,1 Uppal N,2 Wagner SA,3 Bendell JC,4 Beck JT,5

Wade S,6 Nemunaitis JJ,7 Stella PJ,8 Pipas JM,9 Wainberg ZA,10 Manges R,11

Garrett WM,12 Hunter DS,12 Clark J,12 Leopold L,12

Levy RS,12 and Sandor V,12 on behalf of the RECAP investigators

1Duke University Medical Center, Durham, NC, 2NYU Langone Arena Oncology, Lake Success, NY; 3Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; 4Sarah Cannon Research Institute, Nashville, TN; 5Highlands Oncology Group, Fayetteville, AR; 6Virginia Cancer Institute, Richmond, VA; 7Mary Crowley Medical Research Center, Dallas TX; 8St. Joseph Mercy Health System - Alexander Cancer Care Center, Ann Arbor, MI; 9Dartmouth Hitchcock Medical Center - Section of Hematology and Oncology, Lebanon, NH; 10UCLA Division of Hematology-Oncology,

Los Angeles, CA; 11Investigative Clinical Research of Indiana, LLC; 12Incyte Corporation, Wilmington, DE

• Although we have an expanding array of

therapeutic options for advanced pancreatic

cancer, currently there is NO established

standard of care for patients who have

progressed on first-line treatment, and NO

validated biomarkers that help guide us in

therapeutic decision-making.

Current approach in treatment sequencing

for advanced pancreatic cancer

FOLFIRINOX

(PS 0-1): Gemcitabine/nab-pacitaxel

(PS 2 or less): Gemcitabine monotherapy; BSC

??

Gemcitabine-based

(e.g. gemcitabine, gem/erlotinib, gem/nab-paclitaxel)

(PS 0-1): FOLFOX, CapOx, maybe FOLFIRINOX

(PS 2 or less): Capecitabine; BSC

(PS 0-1): Irinotecan-based regimen if no prior exposure 3

rd l

ine

2

nd l

ine

1

st li

ne

Regimen for refractory advanced pancreatic cancer

Sample size

Median PFS/TTP (months)

Median OS (months)

OFF (oxaliplatin, 5-FU, folinic acid)1 76 3.0 6.1

FOLFOX2 46 3.7 5.8

CapOx3 41 2.3 5.4

FOLFIRI4 63 3.0 6.6

Irinotecan5 56 2.9 5.3

Capecitabine6 39 2.3 7.6

MM-398 (nanoliposomal CPT11)7 40 2.4 5.2

Erlotinib8 50 1.6 4.1

Capecitabine/erlotinib9 30 3.4 6.5

Sunitinib10 77 1.3 3.7

Selumetinib/erlotinib11 46 1.9 7.5

1. Pelzer, J Clin Oncol 2008 (abstract); 2. Berk, Hepatogastroent 2012; 3. Xiong, Cancer 2008; 4. Neuzillet, World J

Gastroent 2012; 5.Takahara, Cancer Chemother Pharmacol 2013; 6. Boeck, Oncology 2007; 7. Ko, Br J Cancer 2013;

8. Tang, J Clin Oncol 2009 (abstract); 9. Kulke, J Clin Oncol 2007; 10. O’Reilly, Oncologist 2010; 11. Ko, J Clin Oncol 2013

(abstract).

Enter ruxolitinib, an inhibitor of

JAK-STAT signaling

• Janus kinases (JAKs): mediate cytokine signaling by activating STAT transcription factors

• Persistent activation of Stat3 is oncogenic and prevalent in many solid tumors1

• In mouse models of pancreatic cancer, JAK-STAT signaling is required for cancer progression2 and contributes to cancer-related cachexia3

• Pancreatic cancer: clinical hallmarks of weight loss, cachexia, anorexia all reflect systemic inflammation

• Ruxolitinib reduced levels of inflammatory cytokines and improved symptoms and overall survival in myelofibrosis4-5

1) Hedvat, Cancer Cell 2009. 2) Lesina Cancer Cell. 2011;

3) Gilabert, J Cell Physiol 2014; 4) Verstovsek S, N Engl J Med 2012;

5) Harrison C, et al. N Engl J Med 2012.

Inflammatory

Cytokines

JAK1 JAK2, JAK3,TYK2

P

STAT

P

7

RECAP study design

Endpoints

• Primary: OVERALL SURVIVAL

• Secondary: Clinical benefit response, ORR (RECIST), PFS, QoL, safety

• Prospectively defined subgroup analyses, including C-reactive protein, albumin, and performance status, were conducted to explore an inflammation hypothesis

1) Burris HA, et al. J Clin Oncol 1997;15:2403-13.

Patient Eligibility

• Histologically confirmed

metastatic PDAC

• Karnofsky PS ≥60

• Failed gemcitabine

R

A

N

D

O

M

I

Z

E

D

Ruxolitinib

(15 mg BID, days 1–21)

Capecitabine

(1000 mg/m2 BID, days 1–

14)

Placebo

(BID, days 1–21)

Capecitabine

(1000 mg/m2 BID, days 1–

14)

n=64

n=63

1:1

8

Med OS 136.5 v 129.5 days 6-mo surv 42% v 35% HR 0.79 (p=0.25)

Med OS 83 v 55 days 6-mo surv 42% vs 11% HR 0.47 (p=0.01)

Entire study population (n=127)

CRP > 13 mg/L (n=60)

Is C-reactive protein a reasonable predictive biomarker?

Dancey, Clin Cancer Res 2010.

• C-reactive protein Well-characterized and sensitive marker of systemic

inflammation and tissue damage

• First acute-phase protein to be described (originally identified in serum of

patients with Strep pneumoniae – precipitates the somatic C-polysaccharide of

bacteria)

• NOT necessarily specific for JAK signaling (…but does that matter?)

• Definition of predictive biomarker (per NCI Investigational Drug Steering

Committee): “a characteristic that is objectively measured and evaluated… that

provides evidence about the probability of benefit or toxicity from a specific

intervention”

• Classic examples in cancer therapy: HER2 trastuzumab; KRAS

cetuximab; BRAF vemurafenib

• Advantage of CRP: Separate companion diagnostic test would not need

to be developed!

Objective response rate (ORR) and clincial

benefit response (CBR)

Ruxolitinib

+ Cape

Placebo

+ Cape

ITT, n (%)

Overall response (CR + PR)

CR

PR

Stable disease (SD)

Disease control (CR + PR + SD)

Clinical benefit response*

64

5 (7.8)

1 (1.6)

4 (6.3)

21 (32.8)

26 (40.6)

8 (12.5)

63

1 (1.6)

0

1 (1.6)

22 (34.9)

23 (36.5)

1 (1.6)

CRP > 13 mg/L, n (%)

Overall response (CR + PR)

CR

PR

Stable disease (SD)

Disease control (CR + PR + SD)

Clinical benefit response*

31

2 (6.5)

0

2 (6.5)

9 (29.0)

11 (35.5)

6 (19.4)

29

1 (3.4)

0

1(3.4)

5 (17.2)

6 (20.7)

1 (3.4)

11 * Composite of pain, weight, and performance status

Complete Response (CR)Partial Response (PR)Stable Disease (SD)Progressive Disease (PD)

Ch

an

ge F

rom

Baseli

ne f

or

Su

m o

f T

arg

et

Lesio

ns,

%

–100

–80

–60

–40

–20

0

20

40

60

80

100

120

140

160

180

200

Ruxolitinib Placebo

Change from baseline in

target lesions* (ITT)

*Investigator assessed.

12

Grade 3 or 4 Adverse Events

Adverse event, n (%) Ruxolitinib

+ Cape (n = 59)

Placebo

+ Cape (n = 60)

Mean exposure, days 99.6 67.4

Anemia 9 (15.3) 1 (1.7)

Thrombocytopenia 1 (1.7) 2 (3.3)

Neutropenia 0 1 (1.7)

Patients with any grade ≥ 3 AE 44 (74.6) 49 (81.7)

13

Recapping RECAP

• Smart trial design and drug development strategy!

Start with enrollment of broader, unselected patient population, but

with pre-planned analysis of subgroup(s) of interest

Striking results in select subgroup can then inform an enriched

patient selection strategy in subsequent phase III trial (JANUS)

Will capecitabine-alone reference arm be deterrent to study enrollment?

• Survival benefit of ruxolitinib may relate to alleviating

cachexia and inanition, as much as reducing tumor burden

• Our options for refractory pancreatic cancer may be

expanding significantly in the future!

MM-398 (nanoliposomal irinotecan)

CRS-207 (mesothelin-expressing attenuated Listeria vaccine)

ABSTRACT 4005: RAINBOW: A GLOBAL, PHASE III, RANDOMIZED, DOUBLE-BLIND STUDY OF (RAMUCIRUMAB PLUS PACLITAXEL) VS. (PLACEBO PLUS PACLITAXEL) FOR METASTATIC GE JUNCTION AND GASTRIC ADENOCARCINOMA FOLLOWING PROGRESSION ON FIRST-LINE PLATINUM- PLUS FLUOROPYRIMIDINE-BASED THERAPY -- EFFICACY ANALYSIS IN JAPANESE AND WESTERN PATIENTS

Shuichi Hironaka1, Yasuhiro Shimada2, Naotoshi Sugimoto3, Yoshito Komatsu4,

Tomohiro Nishina5, Kensei Yamaguchi6, Yoshihiko Segawa7,Yasushi Omuro8, Takao

Tamura9, Toshihiko Doi10, Seigo Yukisawa11, Hirofumi Yasui12, Fumio Nagashima13,

Masahiro Gotoh14, Taito Esaki15, Michael Emig16, K a Chandrawansa17, Kei Muro18,

Hansjochen Wilke19, Atsushi Ohtsu20

1Chiba Cancer Center, Chiba, Japan; 2National Cancer Center Hospital, Tokyo, Japan; 3Osaka Medical Center for Cancer and Cardiovascular Diseases,

Osaka, Japan; 4Hokkaido University Hospital, Sapporo, Japan; 5 Shikoku Cancer Center, Matsuyama, Japan; 6Saitama Cancer Center, Kita-adachi-gun,

Japan; 7Saitama Medical University International Medical Center, Hidaka, Japan; 8Tokyo Metropolitan Cancer and Infectious Diseases Center

Komagome Hospital, Tokyo, Japan; 9Kinki University Faculty of Medicine Hospital, Ikoma, Japan; 10National Cancer Center Hospital East, Kashiwa,

Japan; 11Tochigi Cancer Center, Utsunomiya, Japan; 12Shizuoka Cancer Center, Shizuoka, Japan; 13Kyorin University Hospital, Tokyo, Japan; 14Osaka

Medical College Hospital, Osaka, Japan; 15National Kyushu Cancer Center, Fukuoka, Japan; 16Eli Lilly and Company, Heidelberg, Germany; 17Eli Lilly

and Company, Bridgewater, NJ; 18Aichi Cancer Center, Nagoya, Japan; 19Kliniken Essen Mitte Center of Palliative Care, Essen, Germany; 20National

Cancer Center Hospital East, Kashiwa, Japan

Current treatment of metastatic

gastric cancer

• Typical first-line regimen consists of a fluoropyrimidine plus platinum analog, +/- an anthracycline – e.g. FOLFOX, EOX Efficacy results from phase II and phase III trials: RR 30-60%; survival 8-12

months1

• Only prior targeted therapy with demonstrated efficacy = trastuzumab (Herceptin) ToGA phase III trial (n=594): addition of trastuzumab to cisplatin/

fluoropyrimidine median OS from 11.1 to 13.5 months (HR 0.74, p=0.0048)2

Applicable only for the 22% of patients with HER2-positive disease (defined as IHC 3+ and/or FISH+)

• Second-line efficacy demonstrated for both taxanes and irinotecan (improved survival compared to best supportive care)3,4

1. Cunningham, N Eng J Med 2008; 2. Van Cutsem, Lancet 2010;

3. Bang, J Clin Oncol 2012; 4. Ford, Lancet Oncol 2014.

Is there a role for anti-angiogenesis agents

in gastric cancer?

• Tumoral expression of VEGF is independent prognostic indicator of worse outcome on stage-for-stage basis; also correlates with MVD, LN involvement, and hepatic metastases (Lieto, Ann Surg Oncol 2008; Maeda, Cancer 1996; Song, World J Gastroent 2002)

• Serum/plasma VEGF levels correlate with disease stage and presence of M1 disease; independent prognostic factor for survival (Karayiannakis, Ann Surg 2002; Yoshikawa, Cancer Letter 2000)

• Inhibition of VEGF activity by a neutralizing antibody inhibited primary tumor growth and macroscopic liver metastases in gastric cancer xenograft model (Kanai, Int J Caner 1998;77:933-6)

Phase III AVAGAST trial Ohtsu et al, J Clin Oncol 2011; 29:3968-76.

Stratification factors: 1. Geographic region 2. Fluoropyrimidine backbone 3. Disease status

Capecitabine/cisplatin (XP) + Placebo q3w

Capecitabine*/cisplatin (XP) + Bevacizumab q3w

Locally advanced or metastatic gastric cancer

(n=774)

R

PFS 5.3 months OS 10.1 months

PFS 6.7 months (HR 0.80, p=00037) OS 12.1 months (HR 0.87, p=0.1002)

AVAGAST: regional differences in efficacy

Region

Chemo + Placebo Median (months)

Chemo + Bevacizumab

Median (months)

Delta (months)

Hazard Ratio

OS Asia 12.1 13.9 1.8 0.97

Europe 8.6 11.1 2.5 0.85

America 6.8 11.5 4.7 0.63

Ohtsu et al, J Clin Oncol 2011; 29:3968-76.

This highlights differences in gastric cancer

between Asian and Western patients

• Asian patients, compared to Western patients, have: – Younger age at diagnosis – More localized disease at presentation (53% in Japan vs

27% in U.S.) – Tumors more commonly located in distal (lower) portion

of stomach, and greater proportion of signet ring histology

– Better stage-stratified survival – Different responsiveness to systemic therapy

Ohtsu, Gastrointest Cancer Res 2007; Gill, J Clin Oncol 2003; Theuer et al, Cancer 2000; Hironaka J Clin Oncol 2013;

Thuss-Patience, Eur J Cancer 2011; Ford, Lancet Oncol 2014.

Different therapeutic approaches to

anti-angiogenesis

Medscape.org

DIFFERENT PHARMACOLOGIC APPROACHES TO BLOCKING VEGF SIGNALING

(sunitinib, apatinib)

(ramucirumab)

Ramucirumab

• Fully human IgG1 monoclonal antibody

• Binds with high affinity (approximately 50 pM) and specificity to extracellular VEGF-binding domain of VEGFR-2 – Fewer off-target toxicities

than VEGFR TKIs – Blocks binding of all VEGFs to

VEGFR2 (more complete target inhibition than bevacizumab – VEGF-A ligand only)

Spratlin, J Clin Oncol 2010; Mackey, Clin

Breast Cancer 2009; Zhu, Clin Cancer Rex

2013; Clin Lung Cancer 2012; Garcia,

Cancer 2014.

Median OS 5.2 vs. 3.6 months (HR 0.78) Median PFS 2.1 vs. 1.3 months (HR 0.483)

April 2014: FDA approves ramucirumab as monotherapy

for second-line treatment of metastatic gastric cancer

(REGARD trial)

Fuchs, Lancet 2014; 383:31-9.

Positive phase III RAINBOW trial Wilke H, et al. J Clin Oncol 2014 (LBA7)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ove

rall

Su

rviv

al P

rob

ab

ility

Months

RAM+PTX

PL*+PTX

RAM + PTX

n = 330

Placebo + PTX

n = 335

HR

P - value

Median OS

(mos) 9.63 7.36

0.807

P = 0.0169

Median PFS

(mos) 4.40 2.86

0.635

P <0.0001

ORR

(95% CI)

28%

23.3%, 33.0%

16%

12.6%, 20.4%

P = 0.0001

Japan

(N = 140)

West

(N = 398)

n % n %

Age (years) Median (range) 64.0 (29 – 76) 60.0 (24 – 84)

≥65 68 48.6 149 37.4

ECOG PS 0

1

80

60

57.1

42.9

143

255

35.9

64.1

1st-line therapy Doublet*

Triplet**

140

0

100

0

247

148

62.1

37.2

Primary tumor Gastric

GEJ

130

10

92.9

7.1

276

122

69.3

30.7

Histologic subtype

(Lauren

classification)

Intestinal

Diffuse

53

75

37.9

53.6

178

134

44.7

33.7

Notable differences in baseline patient characteristics

*Doublet: platinum / fluoropyrimidine

**Triplet: platinum / fluoropyrimidine with anthracycline

Differences in ORR and PFS, Japanese vs

Western patients

Japan West

RAM + PTX

N = 68

PL + PTX

N = 72

RAM + PTX

N = 198

PL + PTX

N = 200

ORR, % 41 19 27 13

p-value 0.0035 0.0004

DCR, % 94 75 77 57

p-value 0.0021 <0.0001

Median PFS (mos) 5.6 mos 2.8 mos 4.2 mos 2.8 mos

p-value 0.0002 (HR 0.503) <0.0001 (HR 0.631)

Overall survival

Time Since Randomization (Months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ove

ra

ll S

urviv

al

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ram+Pac

Censored

Plc+Pac

Censored

RAM +

PTX PL + PTX

Pts / Events 68/53 72/56

Median (mos) 11.4 11.5

6-mos (%) 94.1 71.4

12-mos (%) 47.1 48.6

HR (95% CI) 0.880 (0.603 - 1.284)

P-value (log-

rank) 0.5113 (stratified)

Time Since Randomization (Months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ove

ra

ll S

urviv

al

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ram+Pac

Censored

Plc+Pac

Censored

Japan (N = 140) RAM +

PTX PL + PTX

Pts / Events 198/155 200/161

Median (mos) 8.6 5.9

6-mos (%) 66.0 49.0

12-mos (%) 34.8 21.7

HR (95% CI) 0.726 (0.580 - 0.909)

P-value (log-

rank) 0.0050 (stratified)

West (N = 398)

Post Discontinuation Treatment (PDT)

Japan West

RAM + PTX

N = 68

PL + PTX

N = 72

RAM + PTX

N = 198

PL + PTX

N = 200

n % n % n % n %

Treatment discontinued 67 98.5 69 95.8 188 94.9 193 96.5

Disease progression 60 88.2 61 84.7 138 69.7 143 71.5

Adverse event 5 7.4 6 8.3 27 13.6 27 13.5

Patients with any PDT 51 75.0 54 75.0 76 38.4 72 36.0

3rd line 50 73.5 53 73.6 74 37.4 69 34.5

≥4th line 17 25.0 25 34.7 27 13.6 14 7.0

Japan West

RAM + PTX

n = 68

PL + PTX

n = 71

RAM + PTX

n = 196

PL + PTX

n = 197

Preferred Term†

Any Gr

%

Gr ≥3

%

Any Gr

%

Gr ≥3

%

Any Gr

%

Gr ≥3

%

Any Gr

%

Gr ≥3

%

Neutropenia† 85.3 66.2 52.1 25.4 42.9 32.1 24.4 14.7

Febrile Neutropenia 4.4 4.4 4.2 4.2 2.6 2.6 1.5 1.5

Neuropathy 70.6 4.4 54.9 5.6 38.3 11.2 29.9 5.6

Decreased appetite 54.4 2.9 46.5 5.6 35.7 2.6 27.4 2.5

Fatigue 48.5 1.5 39.4 2.8 65.3 16.8 48.2 6.6

Diarrhea 42.6 4.4 33.8 2.8 28.1 2.6 18.8 1.0

Vomiting 30.9 1.5 19.7 1.4 25.5 2.6 19.8 4.1

Hypertension 23.5 4.4 1.4 0 28.6 18.9 7.1 2.5

Hemorrhage 67.6 4.4 26.8 1.4 36.7 4.6 14.2 1.5

Epistaxis 54.4 0 14.1 0 27.0 0 6.6 0

GI hemorrhage 11.8 2.9 5.6 1.4 10.2 4.6 6.1 1.5

Proteinuria 29.4 4.4 7.0 0 11.7 0 5.6 0

Hypertension 23.5 4.4 1.4 0 28.6 18.9 7.1 2.5

Difference in Adverse Events, Japanese vs. Western pts

Take-home messages

• Ramucirumab can be used in the salvage setting in

advanced/metastatic gastric cancer, both as

monotherapy (REGARD) and in combination with

paclitaxel (RAINBOW).

• It is worth noting ethnic differences in efficacy and

toxicity profiles to ramucirumab (and other drugs?).

– However, successive generations of Asian patients born in the

U.S. are likely to result in gradually shifting biology and

outcomes for these individuals that approximate those of

Western patients.

ABSTRACT 4003:

PHASE III STUDY OF APATINIB IN

METASTATIC GASTRIC CANCER: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Shukui Qin*, Jin Li*, Jianming Xu, Jianping Xiong, Changping Wu, Yuxian

Bai, Wei Liu, Jiandong Tong, Yunpeng Liu, Ruihua Xu, Zhehai Wang, Qiong

Wang, Xuenong Ouyang, Yan Yang, Yi Ba, Jun Liang, Xiaoyan Lin, Deyun

Luo, Rongsheng Zheng, Kaichun Wu, Guoping Sun, Liwei Wang, Leizhen

Zheng, Hong Guo, Jingbo Wu, Nong Xu, Jianwei Yang, Honggang Zhang,

Ying Cheng, Ningju Wang, Lei Chen, Zhining Fan, Hao Yu

Shukui Qin*, PLA Cancer Center, Bayi Hospital, Nanjing, China

Jin Li*, Fudan University Shanghai Cancer Center, Shanghai, China

Apatinib

Small molecule tyrosine kinase inhibitor that highly and selectively inhibits VEGFR2

Phase I / IIa study (N=65)1

– CR: 1.54% , PR: 12.31%, SD: 66.15% ,

– MTD: 850 mg PO daily

Li J, et al. J Clin Oncol 2013; 31:3219-3225.

CN

N

NH

O

N

NH .CH3SO3H

Phase III study design

• Primary endpoint = overall survival

• Stratification factor: number of metastatic sites (≤ 2 vs. >2)

Advanced gastric cancer

s/p 2 prior lines of

systemic therapy R

Apatinib 850mg po. QD 28days as

1 cycle

(N=181)

Placebo po. QD 28days as 1 cycle

(N=92)

Crossover

(N=14)

2:1

Patient demographics and baseline

characteristics

Parameters Apatinib (n=176) Placebo (n=91) P value

Age(mean±SD) , years

55.01±9.92 56.08±9.74 0.5905

ECOG,% 0 1

27.27 72.73

16.48 83.52

0.1422

Lines of therapy,% ≤3 >3

65.91 34.09

63.74 36.26

0.7867

Chemotherapy drug, n(%) fluorouracil platinum taxane doxorubicin irinotecan Targeted

VEGF/VEGFR+ EGFR/HER-2+

168(95.5) 154(87.5) 121(68.8) 25(14.2) 23(13.1)

6(3.4) 8(4.5)

87(95.6) 82(90.1) 59(64.8) 12(13.2) 18(19.8)

6(6.6) 8(8.8)

Efficacy results

Apatinib (n=176)

Placebo (n=91)

Overall survival 6.5 months 4.7 months HR 0.709 (p=0.0149)

Progression-free survival

2.6 months 1.8 months HR 0.444 (p<0.001)

ORR (central review)

1.7% 0% P=0.002

Disease control rate (central review)

31.8% 11.0%

Kaplan-Meier curve for overall survival

Overall survival of FAS population

6.5m

4.7m

+ Censored

Logrank P=0.0149

—— Apatinib -- -- Placebo

Adverse event Apatinib (n=176) Placebo (n=91) P value

Proteinuria 47.73% 16.48% <0.0001

Neutropenia 37.50% 9.89% <0.0001

Hypertension 35.23% 5.49% <0.0001

Hand-foot syndrome 27.84% 2.20% <0.0001

Elevation of transaminase

27.84% 21.98% 0.3763

Thrombocytopenia 25.00% 6.59% 0.0002

Hyperbilirubinemia 24.43% 14.29% 0.0582

Fatigue 20.45% 14.29% 0.2459

Safety : Non-hematological AEs (incidence ≥20% of all grade)

Take-home messages

. First-line Second-line Third-line (and

beyond)

Combination regimens

EOX/ECF, DCF, FOLFOX, FOLFIRI, carboplatin/paclitaxel

Single agents (chemotherapy)

Docetaxel/paclitaxel, irinotecan, capecitabine/5-FU

Targeted agents

Trastuzumab

Ramucirumab

Apatinib (N/A in U.S.)

?

?

ABSTRACT 4008:

PHASE III TRIAL TO COMPARE ADJUVANT

CAPECITABINE/CISPLATIN (XP) VERSUS XP PLUS

CONCURRENT CAPECITABINE-RADIOTHERAPY (XRT) IN

GASTRIC CANCER (GC): THE FINAL REPORT OF THE ARTIST TRIAL

Jeeyun Lee, Do Hoon Lim, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Seung

Tae Kim, Kyoung-Mee Kim, Min Gew Choi, Jae Moon Bae, Sung Kim, Tae Sung

Sohn, and Won Ki Kang

Gastric Cancer Center

Sungkyunkwan University School of Medicine

Samsung Medical Center, Seoul, Korea

Macdonald, J. S. et al. N Engl J Med 2001;345:725-730

INT 0116: efficacy results

Relapse-free survival

19 vs. 30 months

(p < 0.001)

Overall survival

36 vs. 27 mos.

(p < 0.001)

Surgery was NOT standardized: suboptimal LN dissection in many patients!

10% D2

36% D1

54% D0 (!!)

Other positive phase III results have evaluated

chemotherapy only – not radiation

n Treatment arm Results

MAGIC trial

(Cunningham et

al, N Eng J Med

2006)

503 ECF x 3 cycles surgery

ECF x 3 cycles

5-y r OS

36 vs 23%

(HR 0.75)

Japanese trial

(Sakuramoto et al,

N Eng J Med

2007)

529 Surgery (D2)

S-1 x 1 year

3-year OS

80 vs 70%

(HR 0.68)

CLASSIC trial

(Bang et al,

Lancet 2012)

1,058 Surgery (D2)

CapOx x 8 cycles

3-year DFS

74 vs 59%

(HR 0.56)

So… (1) Which of these different perioperative options is

preferable in resectable gastric cancer? and (2) How

important is radiation?

Postoperative

chemotherapy +

radiation

Pre- and

postoperative

chemotherapy

Postoperative

chemotherapy

alone

Intergroup 0116

(5-FU/LV

5-FU/RT

5-FU/LV)

MAGIC trial

(ECF = epirubicin,

cisplatin, 5-FU)

Japanese phase

III trial

(S-1)

CLASSIC trial

(CapOx)

Adjuvant ChemoRadiotherapy Trial In

Stomach Tumors (ARTIST)

Lee et al, J Clin Oncol 2011

• D2 resected gastric adenocarcinoma

• pStage Ib to IV(M0) • Stratified by (1)

stage, (2) type of surgery (STG v TG)

XP

R A N D O M I Z A T I O N

XP

X: capecitabine 2,000 mg/m2/d D1-D14 P: cisplatin 60 mg/m2 D1 XRT: capecitabine 1,650 mg/m2/d daily

concurrently with RT 45 Gy for 5 weeks

XP

XP

XP XP XP XP

XP XP XRT

XP arm (6 cycles of XP)

XPRT arm (2XP/XRT/2XP)

Primary endpoint: 3-y DFS

Overall Survival

0 6 12 18 24 30 36 42 48 54 60 0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bilit

y

XPRT

XP

Months

Pt

at

risk

XPR

T

230 220 201 184 178 171

XP 228 217 204 191 179 166

130 death events occurred Hazard ratio 1.130 (95% CI, 0.775-1.647) P=0.5272

Disease-Free Survival

XPRT

XP

0 6 12 18 24 30 36 42 48 54 60 0.0

0.2

0.4

0.6

0.8

1.0

Months

Pro

ba

bilit

y

Pt

at

risk

XPR

T

230 208 184 177 173 170

XP 228 210 185 169 158 153

141 recurrence events occurred Hazard ratio 0.740 (95% CI, 0.520-1.050) P=0.9222

Lee J, J Clin Oncol 2011 (2014 update)

Disease-Free Survival:

by Lymph Node Status


0 12 24 36 48 60 72 840.0

0.2

0.4

0.6

0.8

1.0

Months

0 12 24 36 48 60 72 840.0

0.2

0.4

0.6

0.8

1.0

Months

• In 396 patients with LN+ disease, 3-yr DFS was 76% v 72% (P=0.04)

XPRT

XP

XPRT

XP

LN- Disease LN+ Disease

Disease-Free Survival:

by Lauren Classification

0 12 24 36 48 60 72 840.0

0.2

0.4

0.6

0.8

1.0

Months

0 12 24 36 48 60 72 840.0

0.2

0.4

0.6

0.8

1.0

Months

XPRT

XP

XPRT

XP

Diffuse Intestinal

• In 163 patients with intestinal type, 3-yr DFS was 94% v 83% (P=0.01)

Pattern of recurrence


XP arm

(n=228)

XPRT arm

(n=230) P

Locoregional recurrence* 29 (13%) 15 (7%) 0.033

Distant metastases† 62 (27%) 56 (24%) 0.5568

* Recurrence at anastomosis site,

duodenal stump, tumor bed, remnant

stomach, or at regional LNs within

RT field † LN recurrence outside RT field,

peritoneal seeding, liver metastasis,

or metastases to extra-abdominal

sites; second malignancy in

5 patients

Remnant

stomach

Tumor bed

Duodenal

stump A-site

Remnant

stomach

Tumor bed

Duodenal

stump A-site

XP arm (6%) XPRT arm (3%)

Unresolved clinical question: So to which patients

should we be offering post-op radiation?

• Based on this study, postoperative radiation:

– Decreases locoregional recurrence

– Confers a small but significant DFS (not OS) benefit in

LN (+) disease and intestinal-type tumors

• ARTIST-II trial will be limited to LN(+) patients only

• Other ongoing studies (CRITICS, TOPGEAR trial

are similarly addressing +/- chemoRT question in

the perioperative setting

• Lessons learned from CALGB 80101? – Postoperative ECF 5FU/RT ECF NO BETTER than 5FU

5FU/RT 5FU (Fuchs et al, J Clin Oncol 2011, abstr 4003)

Presented by:

ABSTRACT 4006:

STORM: A PHASE III, RANDOMIZED,

DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF

ADJUVANT SORAFENIB AFTER RESECTION OR

ABLATION TO PREVENT RECURRENCE OF

HEPATOCELLULAR CARCINOMA

Jordi Bruix, Tadatoshi Takayama, Vincenzo Mazzaferro, Gar-Yang Chau, Jiamei Yang,

Masatoshi Kudo, Jianqiang Cai, Ronnie T Poon, Kwang-Hyub Han, Won Young Tak,

Han Chu Lee, Tianqiang Song, Sasan Roayaie, Luigi Bolondi, Kwan Sik Lee,

Masatoshi Makuuchi, Fabricio Souza, Marie-Aude Le Berre, Gerold Meinhardt,

Josep M Llovet, on behalf of the STORM Investigators

Surgical resection and other locoregional

therapies for HCC

– Orthotopic liver transplant • Carefully selected patients (Mazzaferro vs Yao criteria)

– Partial resection • Only 20-25% of patients are potential candidates due to

decompensated liver disease / vascular invasion / multi-focal tumors

– Ablation • Percutaneous ethanol

• Radiofrequency waves

• Cryotherapy

• High-intensity focused ultrasound

– Embolization • Chemoembolization, drug-eluting beads

• Radioembolization (Y-90-labeled beads)

– Conformal radiation (SBRT)

Clinical context

• Patients with HCC who undergo resection or local

ablation have high rates of recurrence

– Post-hepatectomy recurrence in 50-65% range in many

series (reviewed in Merchant et al, Int J Hepatol 2011)

– Meta-analyses suggest ablative approaches (e.g. RFA)

are associated with even higher rates of recurrence than

hepatectomy (Zhou et al, BMC Gastroent 2010)

• There is no evidence to date that supports the role of

adjuvant therapy to reduce this risk of relapse

RAS

Endothelial cell or Pericyte

Angiogenesis:

PDGF-b

VEGF

VEGFR-2 PDGFR-b

Paracrine

stimulation

Mitochondria

Apoptosis

Tumor cell

PDGF

VEGF

EGF/HGF

Proliferation

Survival

Mitochondria

EGF/HGF

HIF-2

Autocrine loop

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

Wilhelm S et al. Cancer Res. 2004;64:7099-7109.

RAF

Differentiation

Proliferation

Migration

Tubule formation

Sorafenib

Sorafenib

Nucleus

Sorafenib targets both cell proliferation and

angiogenesis

Phase III SHARP trial (n=602) Llovet et al, N Eng J Med 2008

Median survival 10.7

vs. 7.9 mos (p<0.001)

Phase III Asia-Pacific trial (n=226) Cheng et al, Lancet Oncol 2009

Median survival, 6.5 vs 4.2 months

(HR 0.68, p=0.014)

STORM trial design

Sorafenib

400 mg BID

(n=556)

Placebo

(n=558)

Surgical

resection

4 weeks

(+/− 1 week)

4 weeks

(3-7 weeks) Treatment for 4 years or until

recurrence or withdrawal

Endpoints

• Primary: RFS (recurrence-free survival)

• Secondary: TTR (time to recurrence), OS (overall

survival)

• Other: patient-reported outcomes, pharmacokinetics,

biomarkers

Stratification

• Region: Americas, Europe, Asia-Pacific

• Resection vs local ablation

• Child-Pugh A vs B7

• Intermediate vs high recurrence risk

No

residual

HCC confirmed by

independent

radiologic

review

R 1:1

≤4 months

HCC

diagnosis

Presented by: Jordi Bruix on behalf of the STORM Investigators

Local

ablation (RFA or PEI)

Risk of recurrence Intermediate High

Surgical resectiona

All of the following:

• Single tumor ≥2 cm

• Well / moderately differentiated

• Without microvascular invasion or

satellite tumors

Single tumor any size and any of the following:

• Microvascular invasion

• Satellite tumors

• Poorly differentiated

or

2-3 tumors each ≤3 cma

Ablationb Single tumor 2-3 cm Single tumor >3-5 cm or 2-3 tumors each ≤3 cm

Key inclusion criteria

• No extrahepatic spread or macrovascular invasion

• No residual disease present 3 to 7 weeks after resection or complete local ablation (RFA

or PEI) confirmed by independent radiologic review

• No prior anti-cancer therapy for HCC

• Child-Pugh status A (5, 6) or B7 (no ascites)

• ECOG PS 0

• HCC with an intermediate or high recurrence risk


Baseline characteristics

Stratification factors, n (%) Sorafenib

(n=556)

Placebo

(n=558)

Region

Americas (North, South)

Asia-Pacific (inc. Australia, New

Zealand)

Europe

60 (10.8)

330 (59.4)

166 (29.9)

60 (10.8)

330 (59.1)

168 (30.1)

Curative treatment

Local ablation

Surgical resection

106 (19.1)

450 (80.9)

108 (19.4)

450 (80.6)

Risk of recurrence

Intermediate

High

298 (53.6)

258 (46.4)

308 (55.2)

250 (44.8)

Child-Pugh score

A

B

541 (97.3)

15 (2.7)

538 (96.4)

16 (2.9)

Number of lesions, n (%)

1

2

≥3

506 (91.0)

44 (7.9)

6 (1.1)

521 (93.4)

33 (5.9)

4 (0.7)


Relapse-free survival (independent review)

Sorafenib

(n=556)

Placebo

(n=558)

Events, n (%) 194 (34.9) 270 (48.4)

Median RFS

(95% CI)

33.4 months

(27.6-44.0)

33.8 months

(27.6-39.0)


CI, confidence interval

558

556

442

349

387

298

322

244

295

221

266

192

250

172

229

153

213

135

166

102

121

70

88

50

21

6

15

4

1

1 Placebo

Sorafenib

RF

S p

roba

bili

ty (

%)

Months Number at risk

100

75

50

25

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

HR = 0.940 (sorafenib / placebo)

95% CI 0.780-1.134

p=0.26 (1-sided)

~6% reduction in risk of recurrence or death

Subgroup analysis of RFS (independent review)


N HR (95% CI)

All patients (ITT) 1114 0.940 (0.780-1.134)

<65 years 744 0.942 (0.752-1.179)

≥65 years 370 1.007 (0.722-1.405)

Male 912 0.951 (0.777-1.165)

Female 202 0.887 (0.564-1.396)

Americas 120 0.931 (0.513-1.691)

Asia-Pacific 660 1.006 (0.792-1.277)

Europe 334 0.871 (0.617-1.230)

Intermediate risk 606 0.926 (0.710-1.209)

High risk 508 0.933 (0.721-1.207)

Child-Pugh A 1079 0.954 (0.791-1.152)

Child-Pugh B 35 0.760 (0.270-2.141)

Local ablation 214 0.970 (0.656-1.434)

Surgical resection 900 0.937 (0.759-1.156)

Hepatitis B 561 0.900 (0.695-1.166)

Hepatitis C 297 0.849 (0.601-1.199)

Alcohol use 109 1.183 (0.614-2.280)

1.4 0.2 0.6 1.0 2.0 2.4

Favors sorafenib Favors placebo

Hazard ratio (95% CI)

ITT, intention to treat

Overall survival

aFirst planned OS interim analysis alpha = 0.000449 (1-sided)


Sorafenib

(n=556)

Placebo

(n=558)

Events, n (%) 102 (18.3) 115 (20.6)

Median OS Not reached Not reached

64

100

75

50

25

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

558

556

540

503

520

482

504

460

477

445

450

419

433

395

403

367

381

340

298

251

134

110

78

62

29

21

5

5

212

176

420

383

HR = 0.995 (sorafenib / placebo)

95% CI 0.761-1.300

p=0.48 (1-sided)a

OS

pro

babili

ty (

%)

Months

Placebo

Sorafenib

Number at risk

Adverse events occurring in ≥10% of patients

NCI CTCAE (v3.0)

Patients, %

Sorafenib

(n=559)

Placebo

(n=548)

All

grade

s

Grade

3

Grade

4

Grade

5

All

grade

s

Grade

3

Grade

4

Grade

5

HFSR 72.5 28.1 --- --- 5.5 0.7 --- ---

Alopecia 33.6 --- --- --- 3.5 --- --- ---

Rash / desquamation 23.1 3.2 0.2 0 13.0 0.2 0 0

Diarrhea 43.6 6.4 0 0 11.7 0.9 0 0

Hypertension 26.5 6.3 0.4 0 12.4 1.8 0 0

Fatigue 19.7 2.3 0.2 --- 15.0 0.5 0 ---

Hepatobiliary (other) 16.6 8.4 4.3 0 25.5 15.0 6.2 0.2

Abdominal pain (not otherwise specified)

14.3 1.3 0 --- 10.8 0 0 ---

Platelets 13.6 5.7 0.2 0 7.1 1.8 0 0

Weight loss 10.7 1.4 --- --- 2.6 0 --- ---

ALT 10.0 5.4 0.2 --- 7.1 3.8 0 ---


ALT, alanine aminotransferase; HFSR, hand-foot skin reaction

Clinical implications of this study

• Reinforces the principle that more is not

always better in cancer treatment!

– At this point, adjuvant sorafenib following

resection/ablation of HCC should NOT be

recommended

– Neither have data from randomized phase II/III

studies to date demonstrated a clear overall or

progression-free survival benefit for sorafenib

following chemoembolization (SPACE trial;

ECOG 1208 [ongoing])

CONCLUSION:

The past, present, and future of non-

colorectal gastrointestinal cancers:

have we moved the bar?

R. Mayer, A. Lowy, P. Kunz

From 5FU to FOLFIRINOX (Mayer)

1960 2000 2002 2004 2006 2008 2010 2012 2014

5FU

(1960s)

Cisplatin

(1978)

Oxaliplatin

(2002)

Gemcitabine

(1996)

Gem /

Nab-paclitaxel

(2013)

Trastuzumab

(2010)

Sorafenib

(2007)

Irinotecan

(1996)

Capecitabine

(2001)

Ramucirumab

(2014)

Erlotinib

(2005)

Everolimus

(2011)

Sunitinib

(2011)

FOLFIRINOX

(2011)

IMPORTANT OBSERVATIONS AND ADVANCES IN

PANCREATIC CANCER BETWEEN 1964 AND 2014

• Development of a transgenic mouse model that recapitulates

the human disease

• Increased incidence in families with a history of Peutz-

Jegher syndrome, hereditary non-polyposis colon cancer,

and BRCA syndromes

• Introduction of ERCP allowing the placement of stents to

nonsurgically relieve tumor-related obstructive jaundice

• Improved surgical technique leading to decreased operative

morbidity and mortality

• Successful use of gemcitabine as adjuvant therapy and

FOLFIRINOX and gemcitabine/nab-paclitaxel to treat

metastatic disease

IMPORTANT ADVANCES IN HEPATOCELLULAR

CARCINOMA BETWEEN 1964 AND 2014

• Chronic infection with hepatitis B or hepatitis C virus is the most common causative factor; the incidence of hepatocellular carcinoma can be markedly reduced by vaccination against hepatitis B

• Curative potential of orthotopic liver transplantation in highly selected patients

• Palliative benefit of transhepatic chemoembolization

• Sorafenib prolongs survival in patients with advanced disease and preserved liver function but is not effective in the adjuvant setting

IMPORTANT ADVANCES IN GASTRIC CANCER

BETWEEN 1964 AND 2014

• Incidence and mortality rates in the U.S. continue to decrease

• Two subtypes of gastric cancer:

– intestinal (ulcerated lesions in the antrum following long standing atrophic gastritis)

– diffuse (submucosal infiltration causing lack of distensibility)

• Association with Helicobacter pylori infection

• A germ line mutation in the CDH1 gene which regulates E-cadherin is associated with familial gastric cancer

• The small survival benefit achieved with extended (D2 and D3) surgical resections may be offset by increased perioperative morbidity and mortality

• Adjuvant chemoradiation therapy prolongs survival

• Application of targeted therapies vs HER2 and VEGFR2

IMPORTANT ADVANCES IN ESOPHAGEAL

CANCER BETWEEN 1964 AND 2014

Marked increased in adenocarcinomas in the United

States

Linkage of the development of adenocarcinomas to

obesity, chronic gastric reflux, and Barrett’s

esophagus

Pre-operative chemoradiation therapy extends

survival

PET scans provide more accurate staging and offer

rapid early assessment of responsiveness to

treatment

Non-colorectal GI cancers

Changing 5-Year Survival Expectations in the United

States for GI Cancers: 1975-1977 vs 2005-2008

1975-1977 2005-2008

Probability of 5-year

survival

Esophagus 5% 19%

Gastric 15% 28%

Hepatocellular 3% 16%

Pancreatic 2% 6%

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