a randomized, placebo-controlled, phase 2 study of tivantinib (arq 197) in combination with...
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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.
Study ARQ197-A-U252; Presented by C. Eng, MD
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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.
Study ARQ197-A-U252; Presented by C. Eng, MD
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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.
Study ARQ197-A-U252; Presented by C. Eng, MD
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)
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a Other includes clinical progression, investigator discretion, patient decision, patient relocation.
Study ARQ197-A-U252; Presented by C. Eng, MD
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)
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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)
Study ARQ197-A-U252; Presented by C. Eng, MD
Study ARQ197-A-U252; Presented by C. Eng, MD
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)
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Events Median, mo 95% CI
T 44 8.3 5.6 - 10.8
P 37 7.3 5.3 - 9.0
Study ARQ197-A-U252; Presented by C. Eng, MD12
Overall SurvivalFull Analysis Set (median follow-up: 21.5 mo)
Overa
ll S
urv
ival,
%
0 4 8 16 2412 20 28 32
Time Since Randomization, mo
100
50
75
25
0
Tivantinib (n = 60)
Placebo (n = 57)
HR = 0.70 (95% CI, 0.42 - 1.17)Stratified log-rank P = 0.25
Events Median, mo 95% CI
T 31 19.8 13.4 - 27.0
P 31 16.9 12.2 - 20.4
Study ARQ197-A-U252; Presented by C. Eng, MD13
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]
Study ARQ197-A-U252; Presented by C. Eng, MD14
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)
Study ARQ197-A-U252; Presented by C. Eng, MD
Study ARQ197-A-U252; Presented by C. Eng, MD
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.
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Outcomes in Patients Treated With Prior Oxaliplatin
Study ARQ197-A-U252; Presented by C. Eng, MD
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
HR = 0.66 (95% CI, 0.41 - 1.09)Stratified log-rank P = 0.10
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
Time Since Randomization, mo
1.0
0.6
0.8
0.4
0.2
0.0
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Tivantinib PlaceboORR 42.6% 27.1%
Tivantinib (n = 47; 33 events)Placebo (n = 48; 33 events)
Tivantinib (23 events)
Placebo (28 events)
Study ARQ197-A-U252; Presented by C. Eng, MD
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
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Study ARQ197-A-U252; Presented by C. Eng, MD19
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,
%
Time Since Randomization, mo
100
50
75
25
0
Overa
ll S
urv
ival,
%
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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
Tivantinib(n = 11)Placebo(n = 12)
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%
Study ARQ197-A-U252; Presented by C. Eng, MD20
PFS and OS by Serum HGF LevelHGF-High
Pro
gre
ssio
n-F
ree S
urv
ival,
%
0
100
50
75
25
0
Tivantinib(n = 29)Placebo(n = 28)
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
Tivantinib(n = 30)Placebo(n = 28)
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%
Study ARQ197-A-U252; Presented by C. Eng, MD21
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)
Events Median, mo 95% CI
High 17 11.6 7.4, 19.2
Low 13 20.4 14.1, 26.0
80
Study ARQ197-A-U252; Presented by C. Eng, MD
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
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Study ARQ197-A-U252; Presented by C. Eng, MD
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
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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
Study ARQ197-A-U252; Presented by C. Eng, MD
We thank the patients and their families and all the investigators
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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