Abstract: 3508

A Randomized, Placebo-Controlled, Phase 2 Study of Tivantinib (ARQ 197) in Combination With Cetuximab and

Irinotecan as Second-Line Therapy in Patients With KRAS Wild‑Type Metastatic Colorectal Cancer

Cathy Eng,1 Lowell L. Hart,2 Aleksey Severtsev,3 Oleg Gladkov,4

Lothar Muller,5 Mikhail V. Kopp,6 Vladimir Vladimirov,7 Robert Langdon,8 Bogdan Kotiv,9 Sandro Barni,10 Ching Hsu,11 Ellen Bolotin,11

Reinhard von Roemeling,11 Brian Schwartz,12 Johanna C. Bendell13

1The University of Texas M.D. Anderson Cancer Center, Houston, TX; 2Florida Cancer Specialists/Sarah Cannon

Research Institute, Fort Myers, FL; 3The Central Clinical Hospital #1, Moscow, Russia; 4Chelyabinsk Regional Clinical Oncological Dispensary, Chelyabinsk, Russia; 5Onkologische Schwerpunktpraxis Leer-Emden, Leer,

Germany; 6Samara Regional Clinical Oncology Dispensary, Samara, Russia; 7Pyatigorsk Oncological Dispensary, Pyatigorsk, Russia; 8Nebraska Methodist Hospital Cancer Center, Omaha, NE; 9Military Medical Academy, St. Petersburg, Russia; 10Azienda Ospedaliera di Treviglio Ospedale, Treviglio, Italy; 11Daiichi Sankyo, Inc.,

Edison, NJ; 12ArQule, Inc., Woburn, MA; 13Sarah Cannon Research Institute, Nashville, TN

Abstract: 3508

2

Disclosures

• The trial was funded by Daiichi Sankyo, Inc., a member of

the Daiichi Sankyo Group, and ArQule, Inc.

• I have received research funding from Daiichi Sankyo

for this trial

Study ARQ197-A-U252; Presented by C. Eng, MD

3

CRC Background• Colorectal cancer (CRC) is the fourth most common cancer

and second leading cause of cancer death in the US (for men and women combined)1

• Approximately 40% of patients develop metastatic disease2

• Current standard treatments are administered as single agents or in combination and may include3

– Chemotherapy (fluoropyrimidines, oxaliplatin, irinotecan/CPT-11)– Monoclonal antibodies (bevacizumab, cetuximab, panitumumab)– Small molecules (regorafenib)

1. American Cancer Society Cancer. Colorectal Cancer Facts and Figures 2013. http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013.

2. Fedorowicz Z, et al. Cochrane Database Syst Rev. 2008;(2):CD006039. DOI: 10.1002/14651858.CD006039.pub4.3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. V.3.2013. www.nccn.org.


http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013

4

MET in CRC• MET overexpression may occur in 30% to 70% of CRC

tumors, and is associated with poor prognosis and resistance to radiation1

• MET plays an important role in CRC progression and metastasis2

• Resistance to cetuximab has been associated with activation of alternative RTK pathways, including MET3

• We hypothesized that adding tivantinib to cetuximab plus irinotecan may decrease resistance to cetuximab and improve patient outcomes

1. Takeuchi H, et al. Clin Cancer Res. 2003;9(4):1480-1488.2. Zeng ZS, et al. Cancer Lett. 2008;265(2):258-269.3. Walther A, et al. Nat Rev Cancer. 2009;9(7):489-499.


5

Tivantinib (ARQ 197)• A selective oral MET inhibitor with a novel

ATP-independent binding mechanism1

• Broad-spectrum antitumor activity was demonstrated in preclinical studies including MET-high CRC cell lines2,3 when provided as a single-agent and when combined with chemotherapy

• Promising phase 1b data in CRC showed safety of the combination at full dose and included 4 objective responses in 9 patients4

Reprinted from Eathiraj et al.

1. Eathiraj S, et al. J Biol Chem. 2011;286(23):20666-20676. 2. Munshi N, et al. Mol Cancer Ther. 2010;9(6):1544-1553. 3. Lu S, et al. Z Gastroenterol. 2012;50:P5_31. DOI: 10.1055/s-0031-1295987. 4. Eng C, et al. Ann Oncol. 2012;23(suppl 4). Abstract PD-0018.


Phase 2 Study Design

Eligibility• Age ≥ 18 years• Inoperable, locally advanced

or metastatic disease• KRAS WT• 1 line of prior systemic Tx• ECOG PS 0-1• No prior anti-EGFR therapy

RANDOMIZE

N = 1501:1

DOUBLE

BLIND

Tivantinib(ARQ 197)360 mg PO BID

Cetuximab 500 mg/m2 IV q14 days

+

PlaceboPO BID

Irinotecan 180 mg/m2 IV q14 days

Cetuximab 500 mg/m2 IV q14 days

+Irinotecan

180 mg/m2 IV q14 days

Primary Endpoint:PFSSecondary Endpoints:OS, ORR, safety

Stratification Factors:1) ECOG PS (0 vs 1)2) Best response to 1st-

line therapy (CR/PR/SD vs PD)

6 Study ARQ197-A-U252; Presented by C. Eng, MD

Accrual and Statistics• Accrual: Jul 2010 to Feb 2012 in US, Russia, France, Italy, Germany

• Recruitment was discontinued early before the pre-specified goal of 150 patients was reached. The number of PFS events for analysis was decreased from 110 to 80, providing 70% power to detect a 50% improvement in median PFS at P = 0.10 (1-sided)

Total Patients Randomized 122

Full Analysis Set: pts with postbaseline scan eligible for efficacy analysis 117

Safety Data Set: pts who received study drug 121

7 Study ARQ197-A-U252; Presented by C. Eng, MD

Patient DispositionTivantinib Placebo

Randomized, n 62 60

Full analysis set, n 60 57

Treatment discontinuation, n (%) 53 (85.5) 47 (78.3)

Progressive disease 34 (54.8) 28 (46.7)

Adverse event 12 (19.4) 6 (10.0)

Patient withdrew consent 1 (1.6) 3 (5.0)

Lost to follow-up 1 (1.6) 0

Death 0 1 (1.7)

Othera 5 (8.1) 9 (15.0)

Treatment ongoing, n (%) 9 (14.5) 13 (21.7)

8

a Other includes clinical progression, investigator discretion, patient decision, patient relocation.


Study ARQ197-A-U252; Presented by C. Eng, MD9

Patient CharacteristicsFull Analysis Set

Tivantinib (n = 60)

Placebo (n = 57)

Prior radiation, n (%) 9 (15.0) 10 (17.5)

Prior surgery, n (%) 53 (88.3) 48 (84.2)

Time from diagnosis to treatment, d ± SD 684 ± 587 691 ± 614

Prior systemic cancer therapy, n (%)

Fluoropyrimidine 60 (100) 55 (97)

Oxaliplatin 47 (78) 48 (84)

Bevacizumab 33 (55) 25 (44)

Irinotecan 10 (17) 11 (19)

Other 6 (10) 8 (14)

Best response to prior therapy, n (%)

CR, PR, SD 44 (73.3) 35 (61.4)

PD 16 (26.7) 22 (38.6)

10

Patient DemographicsFull Analysis Set

Tivantinib (n = 60) Placebo (n = 57)

Mean age, y ± SD(min - max)

57.1 ± 12.6 (29 - 79)

56.7 ± 12.6 (27 - 79)

Gender, n (%)Male 26 (43.3) 32 (56.1)Female 34 (56.7) 25 (43.9)

Race, n (%)Caucasian 57 (95.0) 54 (94.7)Black 2 (3.3) 1 (1.8)Asian 1 (1.7) 2 (3.5)

ECOG score, n (%)

0 36 (60.0) 28 (49.1)

1 24 (40.0) 29 (50.9)



Progression-Free SurvivalFull Analysis Set (median follow-up: 15.9 mo)

HR = 0.85 (95% CI, 0.55 - 1.33)Stratified log-rank P = 0.38

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0 3 9 156 12 18 21

Time Since Randomization, mo

100

75

50

25

0Placebo (n = 57)Tivantinib (n = 60)

11

Events Median, mo 95% CI

T 44 8.3 5.6 - 10.8

P 37 7.3 5.3 - 9.0


Overall SurvivalFull Analysis Set (median follow-up: 21.5 mo)

Overa

ll S

urv

ival,

%

0 4 8 16 2412 20 28 32


100

50

75

25

0

Tivantinib (n = 60)

Placebo (n = 57)



T 31 19.8 13.4 - 27.0

P 31 16.9 12.2 - 20.4


Best Overall ResponseFull Analysis Set

Best Response, n (%)Tivantinib

(n = 60)Placebo(n = 57)

Complete response 0 0

Partial response 27 (45.0) 19 (33.3)

Stable disease 22 (36.7) 22 (38.6)

Progressive disease 9 (15.0) 13 (22.8)

Not evaluable 2 (3.3) 3 (5.3)

Objective response rate (CR + PR) [95% CI]

27 (45.0)[33.1 - 57.5]

19 (33.3)[22.5 - 46.3]

Stable disease or better [95% CI]

49 (81.7)[70.1 - 89.4]

41 (71.9)[59.2 - 81.9]


Tumor ResponseInvestigator Assessed

TivantinibPlacebo

-120-110-100

-90-80-70-60-50-40-30-20-10

0102030405060708090

100110120

Ch

an

ge

Fro

m B

as

eli

ne

, %

15

Adverse Events (> 15% Frequency)Safety Population

Preferred Term, n (%)

Tivantinib(n = 62)

Placebo (n = 59)

All Grades Grade ≥ 3 All Grades Grade ≥ 3

Rash 36 (58) 5 (8) 34 (58) 5 (9)

Diarrhea 33 (53) 8 (13) 30 (51) 5 (9)

Nausea 27 (44) 6 (10) 27 (46) 4 (7)

Fatigue 24 (39) 3 (5) 20 (34) 2 (3)

Vomiting 20 (32) 3 (5) 18 (31) 3 (5)

Neutropenia 18 (29) 12 (19) 12 (20) 6 (10)

Abdominal pain 12 (19) 0 15 (25) 4 (7)

Decreased appetite 11 (18) 1 (2) 7 (12) 1 (2)

Dry skin 11 (18) 0 10 (17) 0

Constipation 10 (16) 0 11 (19) 0

Dermatitis acneform 8 (13) 1 (1) 9 (15) 1 (2)

Anemia 7 (11) 0 18 (31) 1 (2)



Outcomes in Key SubgroupsGroup

Tivantinib,n (%)

Placebo,n (%)

PFS HR (95% CI)a

OS HR (95% CI)a

All 60 57 0.85 (0.54 - 1.31) 0.68 (0.41 - 1.13)

Male 26 (43) 32 (56) 1.28 (0.69 - 2.38) 1.09 (0.53 - 2.25)

Female 34 (57) 25 (44) 0.52 (0.27 - 0.98) 0.45 (0.22 - 0.94)

ECOG 0 36 (60) 28 (49) 1.10 (0.60 - 2.01) 0.75 (0.36 - 1.54)

ECOG 1 24 (40) 29 (51) 0.69 (0.34 - 1.39) 0.63 (0.30 - 1.36)

Age ≤ 65 y 45 (75) 41 (72) 0.81 (0.49 - 1.37) 0.60 (0.33 - 1.08)

Age > 65 y 15 (25) 16 (28) 0.88 (0.37 - 2.10) 0.99 (0.37 - 2.65)

Prior systemic therapy

Oxaliplatin 47 (78) 48 (84) 0.66 (0.41 - 1.09) 0.58 (0.33 - 1.02)

Fluoropyrimidine 60 (100) 55 (96) 0.80 (0.51 - 1.24) 0.66 (0.40 - 1.10)

Irinotecan 10 (17) 11 (19) 3.36 (1.11 - 10.18) 1.00 (0.30 - 3.30)

Bevacizumab 33 (55) 25 (44) 0.61 (0.32 - 1.15) 0.73 (0.37 - 1.42)

a HR/OR < 1.0 favors tivantinib; HR/OR > 1.0 favors placebo.

16

Outcomes in Patients Treated With Prior Oxaliplatin


OSPFSHR = 0.58 (95% CI, 0.33 - 1.02)Stratified log-rank P = 0.06

Median 95% CI

T 22.3 mo 13.2 - 30.1

P 14.1 mo 10.6 - 19.4


Median 95% CI

T 8.3 mo 6.0 - 11.7

P 7.2 mo 3.7 - 8.0

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0 4 8 1612 20 24Time Since Randomization, mo

1.0

0.6

0.8

0.4

0.2

0.0O

vera

ll S

urv

ival,

%

0 4 8 1612 24 2820 32


1.0

0.6

0.8

0.4

0.2

0.0

17

Tivantinib PlaceboORR 42.6% 27.1%

Tivantinib (n = 47; 33 events)Placebo (n = 48; 33 events)

Tivantinib (23 events)

Placebo (28 events)


Biomarkers• MET IHC

– Available archival tissue tested centrally for total MET expression using the anti-MET (SP44) antibody (Spring Biosciences)

– High: ≥ 50% of tumor cells with immunostainingintensity of 2+ or 3+

– N = 67 (59 primary tumors; 8 metastatic lesions)

• HGF serum concentration

– N=115– High: > mean baseline concentration for the

subgroup– Low: ≤ mean baseline concentration

18


PFS and OS by MET ExpressionMET-High MET-Low

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0 3 6 9 12 15 18

100

50

75

25

0

Tivantinib(n = 24)Placebo(n = 20)

Overa

ll S

urv

ival,

%

0 4 8 12 16 20 24 28 32Time Since Randomization, mo

100

50

75

25

0

0 3 6 9 12 15 2118

100

50

75

25

0

Pro

gre

ssio

n-F

ree S

urv

ival,

%


100

50

75

25

0

Overa

ll S

urv

ival,

%

21

HR = 0.78 (95% CI, 0.24 - 2.47)Log-rank P = 0.67

HR = 0.22 (95% CI, 0.06 - 0.80)Log-rank P = 0.01

HR = 0.74 (95% CI, 0.36 - 1.52)Log-rank P = 0.41

HR = 0.58 (95% CI, 0.25 - 1.36)Log-rank P = 0.20


PFS

OS

0 4 8 12 16 20 24 28 32

ORR: T = 54.2%; P = 30.0% ORR: T = 27.3%; P = 41.7%


PFS and OS by Serum HGF LevelHGF-High

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0

100

50

75

25

0


HR = 0.70 (95% CI, 0.37 - 1.32)Log-rank P = 0.27

PFS

4 8 12 16 20 24

Time Since Randomization, mo Time Since Randomization, mo

HGF-Low

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0

100

50

75

25

0


HR = 0.94 (95% CI, 0.50 - 1.80)Log-rank P = 0.86

4 8 12 16 20 24

Overa

ll S

urv

ival,

%

0

100

50

75

25

0

HR = 0.61 (95% CI, 0.30 - 1.23)Log-rank P = 0.16

OS

4 8 12 16 20 24

Overa

ll S

urv

ival,

%

0

100

50

75

25

0

HR = 0.70 (95% CI, 0.31 - 1.57)Log-rank P = 0.38

28 32 4 8 12 16 20 24 28 32

ORR: T = 44.8%; P = 25.0% ORR: T = 46.7%; P = 39.3%


Overall Survival by Baseline Serum HGF Level in Placebo Patients

HR = 2.14 (95% CI: 1.01, 4.53)

Overa

ll s

urv

ival,

%

0 5 1510 20 25Time Since Randomization, mo

100

60

40

20

0

Low (n = 28)High (n = 28)


High 17 11.6 7.4, 19.2

Low 13 20.4 14.1, 26.0

80


Conclusions• Tivantinib in combination with cetuximab and irinotecan had a

similar safety profile to cetuximab and irinotecan alone, except for a higher incidence of neutropenia

• PFS, ORR, and OS all trended in favor of tivantinib, particularly among patients who received prior oxaliplatin

• Efficacy signals in the small MET-high (by IHC) subgroup were inconclusive; require further validation with a larger sample size

• HGF serum concentration appears to be a prognostic indicator of OS and warrants further analysis

• While results are encouraging, they highlight the need for uniform tissue and blood collection prior to enrollment to allow more robust correlative outcome assessments in the MET pathway

22


Next Steps for Tivantinib• These encouraging findings will be informed by additional data from

ongoing studies:

– Phase 1 study of tivantinib in combination with FOLFOX in the US(ASCO 2013, abstract 2544)

– Phase 2 study of tivantinib in combination with cetuximab in patients who failed cetuximab, currently enrolling in Italy

– Phase 3 study of tivantinib vs placebo in MET-high HCC (2nd-line) (ASCO 2013, poster TPS4519)

• Additional work is needed to better characterize changes in MET expression from diagnosis through treatment and following progression of disease, particularly in oxaliplatin-pretreated patients

– Prior studies suggest that MET overexpression is a late event, thus MET analysis as predictive biomarker may be best obtained from metastatic lesions

• Based on these results the most promising path forward will be determined

23

Acknowledgments

Principle investigatorsFrancis Arena, Lake Success, NY, USAAlberto Bessudo, San Diego, CA, USACorrado Boni, Reggio Emilia, ItalyRoger Brito, Boynton Beach, FL, USABrian Choi, Riverside, CA, USAChristophe Desauw, Lille, France Irfan Firdaus, Cincinnati, OH, USANashat Gabrail, Canton, OH, USAGeorge Geils, Jr., Charleston, SC, USAPhilip Gold, Seattle, WA, USAJayne Gurtler, Metairie, LA, USAJames Hays, Centralia, IL, USADavid Hoffman, Beverly Hills, CA, USARalf-Dieter Hofheinz, Mannheim, GermanyHaresh Jhangiani, Fountain Valley, CA, USDinesh Kapur, Norwich, CT, USAOmar Kayaleh, Orlando, FL, USAIgor Kiselev, Kursk, Russia


We thank the patients and their families and all the investigators

24

This study was sponsored by Daiichi Sankyo, Inc., a member of the Daiichi Sankyo Group, and ArQule, Inc.

Fred Kudrik, Columbia, SC, USAPallavi Kumar, Baltimore, MD, USAWen Wee Ma, Buffalo, NY, USARobert Marschke, Fort Collins, CO, USAMichael McCormack, Hagerstown, MD, USAShubham Pant, Oklahoma City, OK, USAHervé Perrier, Marseille, FranceMaciej Rotarski, Bayonne, FranceArmando Santoro, Rozzano, Milan, ItalyHans-Joachim Schmoll, Halle (Saale), GermanyJens Siveke, Munchen, Germany

DMC members: John Lindsay Marshall, Jean Grem, Mithat Gonen, Vanessa BeddoArQule, Inc: Yinpu Chen, Julia Kazakin, Matt McLeodDaiichi Sankyo: Abdel-Baset Halim, Taina Lopez, Dale Shuster, Koichi Tazaki, Hamim Zahir Editorial support provided by Accuverus

Abstract: 3508

Documents

Transcript of Abstract: 3508