Transcript A Randomized, Phase 1/2 Trial of AMG 102 or AMG 479 in

A Randomized, Phase 1/2 Trial of AMG 102 or
AMG 479 in Combination With Panitumumab vs
Panitumumab Alone in Patients With Wild-Type
KRAS Metastatic Colorectal Cancer (mCRC):
Safety and Efficacy Results
Eric Van Cutsem,1 Cathy Eng,2 Josep Tabernero,3
Elzbieta Nowara,4 Anna Świeboda-Sadlej,5
Niall C. Tebbutt,6 Edith P. Mitchell,7 Irina Davidenko,8
Lisa Chen,9 Dominic Smethurst10
1University
Hospital Gasthuisberg, Leuven, Belgium; 2The University of
Texas M.D. Anderson Cancer Center, Houston, TX; 3Vall d'Hebron University
Hospital, Barcelona, Spain; 4Instytut im. M. Sklodowskiej-Curie, Gliwice,
Poland; 5Warszawski Uniwersytet Medyczny, Warszawa, Poland; 6Austin
Health, Heidelberg, VIC, Australia; 7Thomas Jefferson University,
Philadelphia, PA; 8Krasnodar City Oncology Center, Krasnodar, Russia;
9Amgen Inc., Thousand Oaks, CA; 10Amgen Ltd., Uxbridge, UK
Disclosures
• Eric Van Cutsem: research funding from Amgen, MerckSerono, Novartis, Pfizer, Roche, Sanofi-Aventis
Introduction
• Panitumumab, a fully human monoclonal antibody against
epidermal growth factor receptor (EGFR), has demonstrated
efficacy in patients with wild-type KRAS mCRC in clinical
trials1-4
• Rilotumumab (AMG 102) and ganitumab (AMG 479) are
investigational, fully human monoclonal antibodies against
hepatocyte growth factor (HGF; ligand for c-Met receptor) and
insulin-like growth factor 1 receptor (IGF-1R), respectively
• Preclinical studies indicate that there is complex
interdependence between the HGF/c-Met and IGF-1R and
EGFR pathways5-10
• Combinations of agents that block these receptors are being
investigated for their potential to generate additive/synergistic
anticancer effects
1. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664.
2. Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.
3. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.
4. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.
5. Lesko E, et al. Front Biosci. 2008;13:1271-1280.
6. Hynes NE, et al. Nat Rev Cancer. 2005;5:341-354.
7. Jo M, et al. J Biol Chem. 2000;275:8806-8811.
8. Ahmad T, et al. J Biol Chem. 2004;279:1713-1719.
9. Roudabush FL, et al. J Biol Chem. 2000;275:22583-22589.
10. Swantek JL, et al. Endocrinology. 1999;140:3163-3169.
Rilotumumab and Ganitumab
Mechanisms of Action
IGF-1
Ganitumab (AMG 479)
Rilotumumab
( AMG 102 )
IGF-2
HGF/SF
IGF-1R
Ras
Ras
Shc
Grb2
SOS
c-Met
PI3K
Survival
Sos
AKT/PKB
PIP3
Shp2
Raf
Rac1
PAK
Cell
proliferation
PI3K
Proliferation
PIP2
Gab1
Grb2
IRS1
ERK/MAPK
Cdc42
X
Raf
X
X
Invasion
Migration
Cell Polarity
Adhesion
PTEN
MEK
AKT/PKB
ERK
Survival
mechanisms
EIk-1
This depiction is believed to be the MOA of AMG 102; this compound is investigational.
Rilotumumab (AMG 102)
targets HGF, inhibiting
downstream c-Met
signaling
Ganitumab (AMG 479)
targets IGF-1R, inhibiting
downstream signaling
through PI3K/AKT and
MAPK pathways
Study Schema
• Amgen Trial 20060447; ClinicalTrials.gov identifier NCT00788957
aPanitumumab
6 mg/kg Q2W; rilotumumab (AMG 102) 10 mg/kg Q2W with dose de-escalation to 5 mg/kg as necessary;
primary endpoint was incidence of dose-limiting toxicities
bPanitumumab 6 mg/kg Q2W; rilotumumab (AMG 102) dose based on phase 1b; ganitumab (AMG 479) 12 mg/kg Q2W;
primary endpoint was ORR
cRilotumumab 10 mg/kg Q2W; ganitumab (AMG 479) 12 mg/kg Q2W; primary endpoint was ORR
dPatients in the placebo arm of Part 2 with progressive disease or intolerance to treatment were eligible to participate in Part 3
DLT, dose-limiting toxicity; ORR, objective response rate; Q2W, every 2 weeks
• Tumor assessments were performed by the investigator using Response
Evaluation Criteria in Solid Tumors (RECIST) v1.0
Study Objectives
Primary Objectives (Part 1 and Part 2)
• Part 1: To identify a tolerable dose of rilotumumab (AMG 102) in
combination with panitumumab based on the incidence and nature
of dose-limiting toxicities (DLTs)
• Part 2: To evaluate the efficacy as measured by the objective
response rate (ORR) of rilotumumab (AMG 102) + panitumumab
and ganitumab (AMG 479) + panitumumab vs
panitumumab + placebo
Other Key Objectives (Part 2)
• Efficacy including progression-free survival (PFS) and overall
survival (OS)
• Safety
• Pharmacokinetic analysis
• Biomarker analysis
Key Eligibility Criteria
• Eastern Cooperative Oncology Group (ECOG) performance status
score of 0 or 1
• Histologically or cytologically confirmed wild-type KRAS mCRC by
local or central testing
• Progression during or following prior treatment with irinotecanand/or oxaliplatin-based chemotherapy for mCRC
• Glycosylated hemoglobin ≤ 8%
• No prior treatment with EGFR, c-Met, or IGF-1R inhibitors
Statistical Considerations for Part 2
•
Randomization was stratified by prior therapy (oxaliplatin or irinotecan vs both)
•
Bayesian analysis of response
– This method compares the posterior distribution of the ORR for the experimental arms to
that of the control arm to determine an Odds Ratio
– An ORR prior distribution for panitumumab monotherapy was derived from 4 previous
trials (patients had received both prior oxaliplatin and irinotecan)
– The ORR prior distributions for the combination arms were assumed to have the same
mean as the panitumumab alone arm
– The ORR posterior distribution for each arm combines the prior distributions with
observed ORRs from the study
•
It was prespecified that if there was ≥ 90% probability that combination therapy
was better than panitumumab alone as evaluated by objective tumor response, the
combination was considered promising
– If there was between 50% and 90% probability, the combination was considered
indeterminate
– If there was < 50% probability, the combination was considered not promising
Results
Part 1 Results (Phase 1b)
• In Part 1, no DLTs were reported for the first 6 DLTevaluable patients receiving panitumumab in combination
with rilotumumab (AMG 102) 10 mg/kg Q2W
– The 10 mg/kg Q2W dose of rilotumumab (AMG 102) was used
in Part 2
Part 2 Results (Phase 2)
• 142 patients enrolled from 37 sites in 11 countries
• The enrollment period was June 9, 2009 through
February 5, 2010
• The date for data cut-off for this analysis was July 23, 2010
• Median follow-up is 6.9 months; follow-up is ongoing
Part 2: Patient Demographics and Disease
Characteristics at Baseline
Panitumumab
+ Placebo
(n = 48)
Panitumumab
+ Rilotumumab
(AMG 102)
(n = 48)
Panitumumab
+ Ganitumab
(AMG 479)
(n = 46)
28 (58)
29 (60)
25 (54)
55.0 (19-75)
62.1 (45-78)
62.0 (33-81)
15 (31)
33 (69)
24 (50)
23 (48)a
18 (39)
28 (61)
5 (10)
27 (56)
5 (10)
32 (67)
4 (9)
29 (63)
Prior therapies for mCRC - n (%)
First-line therapy
Second-line therapy
Third-line therapy and later
46 (96)b
31 (65)
14 (29)
48 (100)
33 (69)
16 (33)
46 (100)
26 (57)
12 (26)
Prior chemotherapies for mCRC - n (%)
Oxaliplatin
Irinotecan
Oxaliplatin and irinotecan
39 (81)
30 (63)
23 (48)
42 (88)
32 (67)
26 (54)
40 (87)
26 (57)
20 (44)
Men - n (%)
Age - mean years (range)
ECOG status - n (%)
0
1
Metastatic sites - n (%)
Liver only
Liver + other sites
aOne
patient with ECOG performance score of 2 was enrolled in error; data from this patient were included in all efficacy and safety analyses
patients had not received first-line therapy for mCRC; both patients had received oxaliplatin-based chemotherapy for non-metastatic CRC in the adjuvant
setting and progressed on therapy before entering the study
bTwo
Part 2: Primary Endpoint
Overall Response Rate
Panitumumab
+ Placebo
(n = 48)
Panitumumab
+ Rilotumumab
(AMG 102)
(n = 48)
Panitumumab
+ Ganitumab
(AMG 479)
(n = 46)
10 (21)
15 (31)
10 (22)
0 (0)
0 (0)
0 (0)
Partial Response (PR)
10 (21)
15 (31)
10 (22)
Stable Disease (SD)
17 (35)
19 (40)
18 (39)
Progressive Disease (PD)
16 (33)
11 (23)
15 (33)
Unevaluable/Not done
5 (10)
3 (6)
3 (6)
56 (41-71)
71 (56-83)
61 (45-75)
3.7 (3.6-NE)
5.1 (3.7-5.6)
3.7 (3.6-5.8)
0.93
0.63
Objective Response - n (%)
Complete Response (CR)
Disease control ratea - % (95% CI)
Duration of response - median months
(95% CI)
Posterior probability of Odds Ratio > 1b
aDisease
control rate = CR + PR + SD
is calculated based on ORR; an OR > 1 favors the combination arm over panitumumab alone
NE, not estimable
bOR
• Responses were required to be confirmed at least 4 weeks after response criteria were first met
Part 2: Progression-Free Survival
Panitumumab ± Rilotumumab (AMG 102)
(AMG 102)
(AMG 102)
Panitumumab ± Ganitumab (AMG 479)
(AMG 479)
(AMG 479)
Adverse Events in Part 2
(Any Grade in ≥ 20% or Grade 3/4 in ≥ 2 Patients)
Panitumumab
+ Placebo
(n = 48)
AE (Preferred term) - %
Any AE
Rash
Acneiform dermatitis
Pruritus
Skin fissures
Paronychia
Dry skin
Acne
Skin toxicity
Constipation
Decreased appetite
Abdominal pain
Diarrhea
Hypomagnesemia
Fatigue
Anemia
Asthenia
Any Grade
94
52
33
25
17
15
15
0
0
25
17
15
10
21
21
17
15
Grade 3/4
52
8
10
0
0
2
0
0
0
6
2
6
0
2
2
8
0
Panitumumab
+ Rilotumumab
(AMG 102)
(n = 48)
Any Grade
Grade 3/4
98
71
58
29
35
15
21
0
15
2
31
4
23
2
8
4
2
2
10
0
21
2
10
4
15
4
29
4
10
4
4
0
8
0
Panitumumab
+ Ganitumab
(AMG 479)
(n = 46)
Any Grade
Grade 3/4
100
63
48
13
26
11
28
2
26
0
20
2
22
0
11
0
4
4
13
0
20
2
9
7
26
2
41
15
17
2
2
0
13
4
AE, adverse event
•
There were 9 grade 5 AEs; 1 occurred in the panitumumab alone arm and 4 occurred each in the combination arms
― All except 1 were due to disease progression; 1 fatal AE was due to staphylococcal sepsis (panitumumab +
ganitumab [AMG 479] arm)
― None were reported to be related to investigational product
Conclusions
• This is the first study to show promising evidence of efficacy by an
HGF (c-Met pathway) inhibitor (rilotumumab [AMG 102]) when
combined with panitumumab in patients with mCRC
• The activity as assessed by ORR for patients receiving rilotumumab
(AMG 102) plus panitumumab is promising (per prospectively
specified Bayesian criterion)
• Efficacy of ganitumab (AMG 479) plus panitumumab combination
therapy as determined by ORR was indeterminate
• The safety profiles of the drug combinations were generally similar
to that of panitumumab alone with some exceptions, including a
higher rate of grade 3/4 rash with rilotumumab and of
hypomagnesemia with ganitumab
• Analyses of biomarkers of response in serum and tissue samples
are underway