Transcript Best of ASCO 2006: Colorectal Cancer

Managing Multi-Organ
Toxicities from the Use of
Angiogenesis Inhibitors in
Colorectal Cancer
Axel Grothey
Professor of Oncology
Mayo Clinic College of Medicine
Rochester, MN
Disclosures
• Honorarium: Roche
• Research support: Genentech, Bayer,
Amgen, Sanofi-Aventis, BMS
The Complex Process of Tumor
Angiogenesis
Growth factors/
cytokines
Growth factors receptors
FAK
Src
Ras
Pericytes
PI-3K
MEK
Growth factors
and receptor
HIF-1
Akt
Transcription
Factors
Angiogenic/
survival factors
VEGF
IL-8
B-FGF
Ang-1, -2
Surface
peptides
Erk
VEGF, Ang-1, -2
α
Integrins
VEGF
TUMOR CELL
β
Akt-P
Erk
BCL-2 and
family members
RBC’s
ENDOTHELIAL CELL
Lumen
Rationale for Targeting VEGF
Pathway
• VEGF is the key mediator of angiogenesis
• VEGF is overexpressed in a wide variety of
•
•
tumors; eg,
• Breast cancer
• Colorectal cancer
• Non–small cell lung cancer
• Pancreatic cancer
• Renal cell carcinoma
Level of VEGF expression correlates with
• Tumor growth and metastasis
VEGF inhibition suppresses tumor growth in
animal models
Dvorak. J Clin Oncol. 2002;20:4368; Fan et al. Oncogene. 2005;24:2647; Ferrara. J Mol Med. 1999; 77:527; Hicklin et al. J
Clin Oncol.2005;23:1011; Shaheen et al. Cancer Res. 1999;59:5412; Takahashi et al. Cancer Res. 1995;55:3964;
Warren et al. J Clin Invest. 1995;95:1789.
FDA Approved Anti-angiogenesis
Agents
• Bevacizumab
• VEGF(-A)
• Only Anti-angiogenesis drug approved in
colorectal cancer – focus of this presentation
• Sorafenib
• VEGFR-2/-3, PDGFR, RAF, c-KIT
• Sunitinib
• VEGFR-2, PDGFR, c-KIT
Anti-VEGF Approaches and
Agents: Summary
Bevacizumab
VEGF-Trap
VEGFR-1
IMC-1121b
VEGFR-2
IMC-18F1
Sunitinib
Vatalanib
Sorafenib
Vandetanib
Motesanib
Axitinib
Cediranib
Pazopanib
Sunitinib
Vatalanib
Motesanib
Axitinib
Cediranib
Pazopanib
VEGFR-3
Sunitinib
Sorafenib
Vandetanib
Motesanib
Axitinib
Cediranib
Pazopanib
Src
PI3-K
PKC
Akt
Akt/PKB
MEK
EPC Recruitment
Migration
Invasion
eNOS
Lymphangiogenesis
Vasculogenesis
MAPK
Migration Permeability
Proliferation Survival
Modified from: Kowanetz and Ferrara. Clin Cancer Res. 2006;12:5018-5022.
Comparison Between
Anti-VEGF MoAbs and TKIs
MoAbs
TKIs
IV
Oral
Long (days)
Short (hours)
Target specificity
High
Non-specific
Off-target toxicity
None
Present
Routes of
administration
Half-life
Side-Effects of Anti-VEGF
Therapies
Pertinent Side-Effects of
Anti-VEGF Therapy
• Hypertension
• Arterial thrombotic/ thromboembolic
events (ATEs)
•
•
•
•
Gastrointestinal perforation (GIP)
Bleeding
Delayed wound healing
(Proteinuria)
How Do We Obtain Information on
Safety of Novel Agents?
• Randomized and non-randomized clinical trials
• Do study-patients reflect characteristics of
patients seen in clinical practice?
• Pooled data or meta-analyses of clinical trials
• Rare events detectable, but methodologic
limitations of meta-analyses
• Observational cohort studies
• Less restrictive eligibility criteria compared
with clinical trials, larger sample size, but
uncontrolled study
• Case reports
Phase III Trial of IFL ± Bevacizumab in
FirstLine mCRC (AVF2107g):
Grade 3/4 Adverse Events
IFL + Placebo
(n=397)
IFL + Bevacizumab
(n=393)
Any
74
85†
Events lead to
hospitalization
40
45
Hypertension
2
11†
Bleeding
3
3
0.8
0.8
GI perforation
0
2
Diarrhea
25
32
Adverse Events (% Pts)
Proteinuria
†P<0.01.
Hurwitz et al. N Engl J Med.2004;350:2335.
E4499 Carboplatin Paclitaxel +/- BEV
Phase III First-Line Trial in NSCLC: G3+ AEs
Adverse Events (% Pts)
Any
Hypertension
Bleeding events
• CNS hemorrhage
• Epistaxis
• Hematemesis
• Hemoptysis
• Melena or GI bleeding
Venous thrombus/embolism
Proteinuria
Neutropenia
Thrombocytopenia
Hyponatremia
Febrile neutropenia
*P<0.05.
CP
(n=441)
CP + Bevacizumab
(n=427)
65
1
1
0
0.2
0
0.2
0.4
3
0
17
0.2
1
2
78
7*
4*
0.7
0.7
0.5
1.9
0.9
5
3*
26*
2*
4*
5*
CNS = central nervous system; GI = gastrointestinal.
Sandler et al. N Engl J Med, 2006;355:2542
E2100 Paclitaxel +/- BEV
Phase III First-Line in mBC: G3+ AEs
% of Patients
Hypertension*
Thromboembolic
Bleeding
Proteinuria†
Neuropathy††
Fatigue
Neutropenia
 LVEF
Paclitaxel
(n=330)
0
1
0
0
14
3
3
Paclitaxel + BEV
(n=342)
13
1
0.9
2
21
5
5
0
0.3
*P<0.0001; †P=0.0004;††P=0.01. Miller et al. NEJM 2007
AVF2119 Capecitabine +/- BEV
Phase III 2nd line mBC: G3+ AEs
Capecitabine
(n=215)
Capecitabine + BEV
(n=229)
0.5
18
Proteinuria*
0
1
Thrombosis
4
6
Hand-foot syndrome
24
28
Bleeding*
0.5
0.4
CHF/cardiomyopathy
1
3
Diarrhea*
11
12
Adverse Events (% Pts)
Hypertension*
*No grade 4.
Miller et al. J Clin Oncol. 2005;23:792.
BRiTE: Bevacizumab Regimens: Investigation of
Treatment Effects and Safety
• Initiated at time of FDA approval of BEV (Feb 2004), major
objective to describe BEV-related safety in large, community
based patient population (1st line mCRC)
• 1o Objective: Safety
– Including GIP, ATE, G3/4 bleeding, post-op bleeding/ wound
healing complications, HTN, and other BEV-related SAEs
• 2o Objective: Effectiveness
– Progression-free survival, response rate, and overall
survival
• 1953 pts enrolled 3/04-6/05 from 248 sites in 49 states in US
Selected BEV-Associated AEs
Comparison: Registry vs Phase III Trial
Adverse Event (% pts)
AVF2107 IFL + BEV
(N=402)
BRiTE registry
(N=1953)
Hypertension requiring
medication
11.0
16.4
G3/4 bleeding
3.1
2.2
GI perforation
1.5
1.7
ATE
2.1
1.5
Post-op bleeding or
wound-healing compl.
2.1
1.4
Other
N/A
3.5
Grothey et al. ASCO, Chicago, June 1-5, 2007
Hurwitz et al., NEJM 2004
Hypertension
Generalized Adverse Event Associated With
Anti-VEGF Therapy: Severe Hypertension
Tumor
(% Pts)
Bevacizumab
Sorafenib Sunitinib
RCT
BRiTE/First-BEAT
mCRC1-3
12 / 9 / 4
16 / 5.3
─
─
NSCLC4
7
─
─
─
MBC5-6
13/ 18
─
─
─
RCC7-8
─
─
~3
8
Severe hypertension defined as either NCI-CTC grade 3/4 or grade 4/5 hypertension
1. AVF2107g; 2. E3200; 3. NO16966; 4. E4599; 5. E2100; 6. AVF2119; 7.TARGET.
8. Sunitinib first-line; RCT = randomized controlled trial
Avastin (bevacizumab) PI; Miller et al. J Clin Oncol. 2005;23:792; Nexavar (sorafenib) PI.
Motzer et al. NEJM 2007; Sandler et al. NEJM, 2006;355:2542.
BRiTE: Patients Requiring New or Changed
Medication by Hypertension Status at
Baseline
No HTN before BEV
(N=1131)
Pre-existing HTN
(N=829)
16.3%
16.5%
Kozloff et al. Gastrointestinal Cancers Symposium, Orlando, Jan 19-21, 2007
% Pts with anti-HTN medication
Classes of Anti-HTN Medication Used in Patients
With Pre-existing HTN
Kozloff et al. Gastrointestinal Cancers Symposium, Orlando, Jan 19-21, 2007
Arterial Thrombotic/
Thromboembolic Events
(ATEs)
Arterial Thromboembolic Events (ATE) in
Trials of Bevacizumab + Chemotherapy
% of Patients
(Total n=1745)
ATEs (overall)*
Cerebrovascular
Cardiovascular
Fatal
Chemotherapy Alone
(n=782)
1.9
0.5
1.0
0.4
Bevacizumab + Chemotherapy
(n=963)
4.4
1.9
2.1
0.7
• ATEs included cerebral or myocardial infarction, TIAs, angina
• Risk factors for developing ATE in multivariate analysis
• Age ≥65 y (P=0.01)
For pts >65 yrs and Hx of ATE,
• Prior history of ATE (P<0.01) incidence on BEV = 18% vs 2%
*Pooled analysis of 5 randomized trials (3 mCRC, 1 NSCLC, 1 tMBC)
Scappaticci et al., JNCI 2007
Pooled Analysis: Incidence of
ATEs by Risk Group
No. of Patients/n (%)
Baseline Risk
Factor
Chemotherapy
+ BEV
PFS
OS
13/782 (1.7)
37/963 (3.8)
0.54
0.66
None
5/490 (1.0)
11/602 (1.8)
0.53
0.73
Age ≥65 y
7/279 (2.5)
24/339 (7.1)
0.57
0.61
History of ATEs
2/59 (3.4)
14/89 (15.7)
0.61
0.38
Age ≥65 y and
history of ATEs
1/46 (2.2)
12/67 (17.9)
0.55
0.59
All patients
Chemotherapy +
Placebo
Hazard Ratio
in AVF2107
Skillings et al. ASCO, 2005. Abstract 3019. Updated from poster presentation.
Incidence of ATEs in BRiTE
Patient characteristics
% Pts with ATE
All patients (N=1953)
1.8
<65 y (n=1057)
1.4
>65 (n=896)
2.2
0 (n=837)
1.0
>1 (n=981)
2.4
Hx of arterial
disease
Yes (n=352)
3.7
No (n=1601)
1.4
Hx of HTN
Yes (n=827)
2.7
No (n=1126)
1.2
Yes (n=441)
0.9
No (n=1496)
2.1
Yes (n=188)
3.2
No (n=1765)
1.6
Age
PS
Anti-coag. Tx
Aspirin use
Sugrue et al. ASCO, Chicago, June 1-5, 2007
Types of Severe ATEs Reported in
BRiTE
Sugrue et al. ASCO, Chicago, June 1-5, 2007
Number of events
ATE Incidence From Start of BEV
Treatment
Months from start of BEV
Sugrue et al. ASCO, Chicago, June 1-5, 2007
GI Perforation
BRiTE: Incidence of GIP in Patients With
Specific Medical Characteristics
Characteristics
% Incidence of GIP (n/N)
All
1.7 (33/1960)
YES
NO
3.3 (10/304)*
1.4 (23/1656)
Endoscopy within 1
month of BEV
2.6 (7/217)
1.5 (26/1688)
Adj. radiation
2.3 (6/264)
1.6 (27/1696)
Aspirin/NSAID
0 (0/33)
1.7 (33/1927)
Hx peptic ulcer
1.8 (1/56)
1.7 (32/1904)
Diverticulosis
1.8 (2/114)
1.7 (31)
Intact primary TU
*P<0.05
Sugrue et al, ASCO, Atlanta, June 2-6, 2006
Clinical/Pathologic Findings in
Patients With GIP
Clinical/pathologic findings
Patients (N=33)
At least 1 associated finding
22
• Tumor at site of perforation
11
• GI obstruction
6
• Peritoneal carcinomatoisis
3
• Intra-abdominal abscess
3
• Acute diverticulitis
2
None
11
Sugrue et al., ASCO, Atlanta, June 2-6, 2006.
Number of events
Incidence of GIP in BRiTE and in BEV
Treatment Arms of Phase III Studies in mCRC
Months from start of BEV
Sugrue et al, ASCO, Atlanta, June 2-6, 2006.
Study
% GIP
BRiTE
(N=1960)
1.7
AVF2107
IFL+BEV
(N=393)
1.5
E3200
FOLFOX+BEV
(N=293)
1.7
E3200
BEV mono
(N=234)
1.7
Bleeding
BRiTE Registry: Incidence of Serious
Bleeding Events (sBEs)
Characteristic
Factors
associated
with higher
sBE rates
N Patients
G 3/4 (%)
All patients
1953
2.6
Rectal cancer
399
4.0
Antiplatelet therapy
(including aspirin)
219
4.6
Any AC therapy
442
4.1
FDAC
133
6.0
Prophylactic AC
309
3.2
AC = anticoagulation; FDAC = full-dose anticoagulation.
Flynn et al. Gastrointestinal Ca Symp 2008, Jan 25-27, 2008. Abstract 346.
Delayed Wound Healing
Anti-VEGF Therapy and Effect on
Wound Healing
• VEGF plays an essential role in wound healing
• Bevacizumab-containing regimens may interfere
with wound healing
• In Hurwitz trial 13% WHC for major surgery on
BEV (compared with 3.4% on placebo)
• BEV has half-life of ~3 weeks
• Recommendation
• Wait for ~6 weeks after the last dose of
bevacizumab before performing elective
hepatic resection
Ellis et al. J Clin Oncol 2005;23:4853 Scappaticci et al. J Surg Oncol 2005; 91:173-180
BRiTE Registry: Serious Wound Healing
Complications after Surgery
Characteristic
# of Pts Undergoing
On-Study Surgery
sWHCa (%)
Overall
622
3.7
399
223
345
277
295
272
55
140
480
57
556
487
134
4.0
3.1
5.2
1.8
3.1
4.0
5.5
3.6
3.8
7.0
3.2
3.1
6.0
Age
Gender
ECOG PS
<65 yrs
≥65 yrs
Male
Female
0
≥1
Unknown
AC therapy at
baseline
Aspirin
Primary tumor
site
a
Yes
No
Yes
No
Colon
Rectum
sWHC= Serious wound healing complications. These occurred most frequently within the first week following surgical
procedures. Due to the small number of events, a multivariate analysis could not be performed. AP= antiplatelet therapy.
Sugrue et al. Gastrointestinal Ca Symp 2008, Jan 25-27, 2008. .Abstract 450.
Other Adverse Events
Associated With Bevacizumab
• Reversible posterior leukoencephalopathy
syndrome (RPLS), incidence <0.1%
• Nasal septum perforation
Avastin (bevacizumab) PI., Fakih Oncologist 2006
Elderly Patients
Patient Baseline Characteristics,
by Age Subgroup in BRiTE
All
<65 y
(N = 1953) (n = 1057)
65–74 y
(n = 533)
≥75 y
(n = 363)
≥80 y
(n = 161)
Median age, years
63.6
55.3
69.5
79.2
82.5
Male, %
55.7
54.2
57.4
57.3
52.2
ECOG PS ≥1, %
49.2
42.6
54.4
60.6
60.9
Hx arterial disease, %
18.0
8.9
24.8
34.7
27.3
Median albumin, g/dL
3.8
3.9
3.7
3.7
3.6
Median alkaline
phosphatase, U/L
101.0
104.0
100.0
98.5
97.0
Colon primary, %
79.4
77.9
80.9
81.8
81.4
Kozloff et al. GI Cancers Symposium 2008. Abstract 454.
First-Line Chemotherapy Regimens
by Age Subgroup
FOLFOX
Bolus 5-FU/LV
FOLFIRI
XELOX
IFL/Saltz
Infusional 5-FU
Patients, %
Other
Overall
<65
65–74
Age, years
5-FU, 5-fluorouracil; IFL, irinotecan + 5-FU + LV; LV, leucovorin.
Kozloff et al. GI Cancers Symposium 2008. Abstract 454.
≥75
≥80
2nd Line Therapy Received by Patients,
by Age Subgroup
• A greater proportion of elderly patients received no treatment post–
first progression compared with patients <65 years.
• Older patients were less likely to be treated with bevacizumabcontaining therapy after PD
≥75 yrs
(n = 249)
≥80 yrs
(n = 109)
18.4
20.5
25.7
35.6
36.3
38.5
39.4
51.5
45.3
41.0
34.9
All
(N = 1484)
<65 y
(n = 833)
No treatment, %
15.6
12.9
Chemotherapy, %
36.3
Chemotherapy +
Bevacizumab, %
48.1
Kozloff et al. GI Cancers Symposium 2008. Abstract 454.
65–74 y
(n = 402)
Safety and Effectiveness Outcomes, by Age
Subgroup in BRiTE
All
(N = 1953)
<65 y
(n = 1057)
65–74 y
(n = 533)
≥75 y
(n = 363)
≥80 y
(n = 161)
GI perforation
2.0
2.6
1.5
1.1
0.6
Post-op bleeding or
WHCs
5.1
5.5
4.5
4.5
3.8
ATE
1.9
1.6
1.3
3.9
3.7
Grade 3/4 bleeding
2.6
2.2
3.4
2.5
1.2
New/worsening HTN
20.7
20.5
20.6
21.2
21.1
Median PFS, months
9.9
10.2
9.7
9.8
9.2
1-yr survival rate, %
74.4
77.1
72.5
69.4
65.8
Median OS, months
23.5
27.3
21.3
19.5
16.2
Safety, %
Survival
Kozloff et al. GI Cancers Symposium 2008. Abstract 454.
PFS by Age Subgroup in BRiTE
• The median PFS with bevacizumab-based therapy
was generally similar across all subgroups.
Kozloff et al. GI Cancers Symposium 2008. Abstract 454.
Bevacizumab: Safety
Management
Bevacizumab: Precautions
Associated With Use
• Infusion reactions with first dose of bevacizumab: <3%
• Severe reactions: 0.2% of patients
• Interrupt therapy and administer appropriate
medical therapy
• Monitor blood pressure during treatment (every 2-3
weeks)
• Permanently discontinue bevacizumab in patients
with hypertensive crisis
• Temporarily suspend bevacizumab in patients with
severe hypertension that is not controlled with
medical management
Bevacizumab: Precautions
Associated With Use (Cont'd)
• Monitor for proteinuria with serial urinalyses (??)
• Interrupt bevacizumab treatment when proteinuria
•
•
≥ 2 grams/24 hrs
• Resume bevacizumab therapy when proteinuria
< 2 grams/24 hrs
Nursing mothers should discontinue nursing during
and for a prolonged period following treatment
Safety and effectiveness of bevacizumab in pediatric
patients has not been studied
Bevacizumab: Dose
Modifications
• No recommended dose reductions
• Permanent discontinuation
• GI perforation
• Wound dehiscence requiring medical intervention
• Severe ATE
• Serious bleeding
• Nephrotic syndrome
• Hypertensive crisis or encephalopathy
• RPLS (discontinue and treat hypertension)
Bevacizumab: Dose
Modifications (Cont'd)
• Temporary suspension
• Moderate to severe proteinuria
• Severe hypertension that is not controlled with
medical management
• Suspension for elective surgery (half-life ~ 3 weeks)
• Should be suspended at least 6 weeks prior and
should not be resumed until surgical incision is
fully healed (4 weeks)
Selected AEs Associated with Different
Anti-VEGF Therapies: Summary
• Bevacizumab:
•
•
numerous clinical and two large observational
studies → extensive safety data
• Hypertension / ATEs / GI perforation / wound
healing / bleeding
Sorafenib
• Hypertension / hand-foot syndrome / fatigue
Sunitinib
• Hypertension / fatigue / hand-foot syndrome /
diarrhea / congestive heart failure
Conclusions
Bevacizumab in CRC
• BEV has become part of standard of care in the
therapy of advanced CRC, it is widely used
• No serious side-effects in majority of patients
• Patients cannot distinguish between BEV or
placebo
• Minority of patients (<10%) with rare, but definitely
serious events
• ATE, GI perforation, bleeding
• Appropriate patient selection pertinent!
• In doubt start without BEV…