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Treatment after anti-EGFR and
anti-VEGF
Alain J. Gelibter
Regina Elena National Cancer Institute
Rome
Main Signaling and pathway
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
Raf
MEKK-1
MEK
mTOR
MKK-7
ERK
JNK
Apoptosis
Resistance
Proliferation
Angiogenesis
Metastasis
Selumetinib is a potent inhibitor of MEK Pathway in Cancer
Growth
Factors
•
Constitutive activation of the pathway has been
implicated in driving many cancers and in
resistance to cancer
•
Mutant Ras & Raf proteins are key activators of the
Ras-Raf-MEK-ERK pathway
– B-Raf Mutations
Extracellular
GDP
GTP
RAS
RAS*
Raf
MEK1
MEK2
AZD6244
MEK Pathway
ERK1
ERK2
Cytoplasm
• Malignant melanomas (66%)
• Papillary thyroid cancers (40%)
• Colorectal cancer (8-10%)
– Ras Mutations
• Colon (40%)
• Pancreatic cancers (90%)
• NSCLC (20%)
Therapies for KRAS Mutated Colorectal Cancer That Is
Resistant to EGFR Monoclonal Antibody Therapy
Cancer Res 2011
AS703026 and AZD6244
inhibit tumor growth of
cetuximab-resistant
tumor attributed by K-ras
mutation
Cancer Res 2011
The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus
irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm)
metastatic colorectal cancer (CRC).
Patients
• KRASm or BRAFm
Metastatic colorectal
cancer
• Progression during or
after 1st-line
bevacizumab/
oxaliplatin/
fluoropyrimidine
• Measurable or
nonmeasurable disease
Howard S. Hochster, ASCO GI 2013:
Treatment
Patients (Pts) were
treated with IRI 180
mg/m2 iv q2w and SEL 50
or 75 mg po bid. Dose
escalation was traditional
3+3 (50 mg bid SEL, then
75 mg bid).
In Part B/phase II, primary
endpoint was PIdetermined response rate
(RR)
The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus
irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm)
metastatic colorectal cancer (CRC).
Patients
IRI + AZD6244
(n = 31)
Male/Female
Median age (range)
18/13
54 (27-75)
Caucasian/other race
Patients
IRI + AZD6244
(n = 31)
Partial response (PR)
3 (10%)
Stable disease
16 (52%)
24/7
SEL 50 mg BID
3
Median numbr of cycles
3.5
SEL 75 mg BID
28
Median PFS (mts)
3.4
6 pts were on study for more than 6 (up to 22) months
Grade 3 AEs included (N):
diarrhea 3, fatigue 2,
neutropenia 2, and 1 each
thrombocytopenia, enteritis,
GI bleed, rash
MET Pathway and MET-Inhibiting
Anticancer Agents
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
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
IGF-2
( AMG 102)
HGF/SF
IGF-1R
Ras
Ras
Shc
Grb2
SOS
c-Met
PI3K
Survival
Sos
Gab1
Grb2
Proliferation
PIP2
AKT/PKB
PIP3
Shp2
Raf
Rac1
PAK
ERK/MAPK
Cdc42
X
X
X
Invasion
Migration
Cell Polarity
Adhesion
Raf
IRS1
Cell
proliferation
PI3K
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 IGF1R, 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 irinotecan- and/or oxaliplatin-based
chemotherapy for mCRC
• No prior treatment with EGFR, c-Met, or IGF-1R inhibitors
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)
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
ONARTUZUMAB
• Onartuzumab is a monoclonal antibody designed to bind to MET and inhibit HGF/SF binding.
Traditional bivalent antibodies to MET potentially activate, rather than inhibit, MET signaling
by inducing MET dimerization. In contrast, the monovalent design of onartuzumab inhibits
HGF/SF binding without inducing MET dimerization.
Onartuzumab binds to the
Sema domain of MET, an
extracellular region
essential for binding its
ligand, HGF/SF
Inhibits HGF/SF from binding to
MET, thereby blocking ligandinduced MET dimerization and
activation of the intracellular
kinase domain
Blockade of MET
activation inhibits its
downstream pathways,
preventing cancer cell
growth, survival, and
metastasis
PD and efficacy analysis of the B-RAF inhibitor
dabrafenib (GSK436) in combination with the MEK
inhibnitor TRAMETINIB (GSK 212) in pts with BRAF
V600E mutant CRC
ASCO 2013
Overview of BRAF-mutant CRC
• BRAF V600 mutations occur in 5-10% of CRC
– Occur in K-ras wild type population
– Worse prognosis than KRAS mutant or KRAS-BRAF wild type
– May predict lack of response to anti-EGFR treatment
• Distinct undrlying biology of BRAF-mutant CRC
• Novel therapeutic strategies for BRAF-mutant CRC are
critically needed.
1. Van Cutsem E, et al. ASCO 2010. Abstract 3570. 2. Tol J, et al. NEJM. 2009;361:98-99. 3. Di Nicolantonio F, et al. J Clin Oncol.
2008;26:5705-5712. 4. Laurent-Puig P, et al. J Clin Oncol. 2009;27:5924-5930. 5. Loupakis F, et al. Br J Cancer. 2009;101:715-721. 6.
Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 7. Bokemeyer C, et al. ASCO 2010. Abstract 3506.
BRAF Mutations in First-Line Setting
• CRYSTAL and OPUS combined analysis
– Patients with wild-type KRAS/mutated BRAF
• Worse outcomes vs wild-type KRAS/wild-type BRAF
• Still experienced non-significant improvements (small N)
Outcome
Wild-type KRAS/
Mutated BRAF
Wild-type KRAS/
Wild-type BRAF
Cetuximab +
CT
CT Only
P Value
Cetuximab +
CT
CT Only
P Value
Median PFS, mos
7.1
3.7
.267
10.9
7.7
< .001
Median OS, mos
14.1
9.9
.079
24.8
21.1
.041
Median ORR, %
21.9
13.2
.4606
60.7
40.9
< .0001
Bokemeyer C, et al. ASCO 2010. Abstract 3506.
B-RAF mutation: Melanoma vs CRC
B-RAF mutant melanoma
Response rate 60-80%
B-RAF mutant CRC
Response rate less than 10%
Same target, same drug, different disease…….different response!!!
Flaherty et al NEJM 2010 Kopetz et al ASCO 2010
PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in
combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts
with BRAF V600E mutant CRC
• Dabrafenib (150mg BID)
• Trametinib (2mg QD)
PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in
combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts with
BRAF V600E mutant CRC
Patients
(n = 40)
Patients
Gender:Female
32 (80%)
Number of lines of prior systemic
anticancer therapy
ECOG 1
18 (45%)
0
2 (5%)
B-RAF V600E Mutation
40 (100%)
1
5 (13%)
2
12 (30%)
Disease sites at
screening n (%)
(n = 40)
<3 sites
18 (45%)
>3
21 (53%)
> 3 sites
19 (48%)
Prior EGFR inhibitor
18 (45%)
PD and efficacy analysis of the B-RAF inhibitor dabrafenib (GSK436) in
combination with the MEK inhibnitor TRAMETINIB (GSK 212) in pts
with BRAF V600E mutant CRC
• 1 (3%) achieved a complete response (confirmed, on study >12m),
• 3 (9%) achieved a partial response and 18 (53%) had stable disease
(SD).
Efficacy
Median PFS was 3.5 mo (95% CI: 1.8-4.9);
7 pts (24%) remained on study for ≥6 cycles
with 9 pts still on study.
Toxicity
Any grade
(n = 40)
AE any grade
Grade3-4
Pyrexia
10%
67%
Nausea
5%
56%
Fatigue
8%
53%
Chills
3%
47%
Vomiting
5%
39%
Headache
0
31%
Anemia
20%
28%
Diarrhea
3%
25%
2 pts discontinued due to AEs.
pERK reduction
• Decreased pERK staining vs pre-dose samples was seen in
all post-dose samples leading to absolute (49% ±29%) and
relative (69% ±28%, normalized to total ERK) reduction in
pERK.
Study conclusions
• Treatment with D and T combine safetely in B-RAF mutant
CRC patients
• Clinical activity is seen in a subset of patients
• About 1/3 of PTS with at least a minor response
• 25% of PTS with PFS > 6 mts
• Biomarker analyses
• Reduction in pERK observed in all patients.
• PIK3CA mutations do not preclude clinical activity
• MSI and low EGFR may be associated with better outcomes
Next step for BRAF/MEK Inhibition?
BRAF/MEK/EGFR Inhibitor Combination Study in
Colorectal Cancer
An open-label, three-part Phase 1/2 study to investigate the safety,
pharmacokinetics, pharmacodynamics and clinical activity of
trametinib (GSK1120212) and dabrafenib (GSK2118436) when
administered in combination with the anti-EGFR antibody
panitumumab in subjects with BRAF-mutation V600E or V600K
positive colorectal cancer (CRC).
The phosphatidylinositol 3-kinase
(PI3K) signaling cascade
Activation
Inhibition
Inhibition of PI3K signaling can diminish
cell proliferation, and in some
circumstances, promote cell death
Activation of PI3K signaling in Cancer
• PI3K signaling is activated in human cancers via several
different mechanisms.
• Increased PI3K signaling is often due to direct mutational
activation or amplification of genes encoding key
components of the PI3K pathway such as PIK3CA and AKT1,
or loss of PTEN
Philip AJ Cancer Research
Genetic alterations of the PI3K Signaling
Pathway in Cancer
PI3K inhibitors in Clinical trials.
mTOR inhibitors
A Phase II Trial of Bevacizumab plus Everolimus for Patients with
Refractory Metastatic Colorectal Cancer
Altomare The Oncologist 2011
A Phase II Trial of Bevacizumab plus Everolimus for Patients with
Refractory Metastatic Colorectal Cancer
8 patients had minor responses (16%) and an
additional 15patients (30%) had stable disease
(SD). No CR, not PR.
PFS was 2.3 months;
Altomare The Oncologist 2011
A Phase II Trial of Bevacizumab plus Everolimus for Patients with
Refractory Metastatic Colorectal Cancer
Conclusions
• Bevacizumab plus everolimus is generally tolerable but
may have risks related to mucosal damage and/or wound
healing.
• Bevacizumab plus everolimus appears to have modest
activity in refractory mCRC in patients.
Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus
(RAD001) for Patients With Refractory, Metastatic Colorectal Cancer
Methods
• The phase Ib study followed a 3+3 dose-escalation design
with three dose levels.
• The primary objective in the follow-on phase II study was
improvement in 2-month progression-free survival (PFS)
from 30% (historical benchmark) to 50% in patients with
refractory, metastatic colorectal cancer.
Wolpin BM The Oncologist 2013
Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus
(RAD001) for Patients With Refractory, Metastatic Colorectal Cancer
Wolpin BM The Oncologist 2013
Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus
(RAD001) for Patients With Refractory, Metastatic Colorectal Cancer
• By independent radiologic review, 50% of 40 patients with refractory
metastatic colorectal cancer had stable disease as their best response.
• Nearly 20% of patients remained on study treatment for 6 months.
• The disease control rate (DCR) of 50% and median PFS of 3.0 months compare
favorably to trials in similar patient populations with refractory colorectal
cancer, Including a 99-patient phase II trial of everolimus alone (DCR: 25.3%;
median PFS: 1.7 months), a 50-patient phase II trial of bevacizumab and
everolimus (DCR: 46%; median PFS: 2.3 months).
Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus
(RAD001) for Patients With Refractory, Metastatic Colorectal Cancer
• The phase II study met its primary endpoint, with 50% of patients achieving PFS
at 2 months.
• Outcomes did not appear to differ by tumor KRAS mutation status.
• In contrast, better outcomes in patients who developed grade 1 hypertension
while receiving tivozanib and everolimus. (predictive biomarker for
antiangiogenenic agents in colorectal cancer?).
• Thus, modest efficacy was suggested for this drug combination in a patient
population that greatly needs novel treatment programs.
PI3K pathway: Conclusions
• It remains unclear whether single-agent PI3K pathway inhibitors will promote
dramatic responses (comparable to gefitinib in EGFR-mutant lung Cancers even
in sensitive cancers.
• Most models of cancers that are sensitive to single-agent PI3K pathway
inhibitors have demonstrated tumor stasis in vivo rather than frank tumor
regressions.
• Data suggest that cancers with KRAS mutations may be fairly resistant to PI3K
pathway inhibitors.
• Consequently, necessary to combine PI3K pathway inhibitors with other agents
Conclusions and Future directions
• Predictive biomarkers have the potential to improve
selection of the right drug for the right patient, but, aside
from K-RAS (n-RAS), there has been little progress in
incorporating these into clinical practice in CRC.
• Identification of Biomarkers strongly needed
• Multitarget treatment are needed after preclinical and
pharmacodynamic studies