the role of angiogenesis inhibition in breast cancer today...
TRANSCRIPT
The Role of Angiogenesis
Inhibition in Breast Cancer
Today: Lessons Learned
Hope S. Rugo, MD Professor of Medicine
Director, Breast Oncology and Clinical
Trials Education
UCSF Helen Diller Family Comprehensive Cancer Center
VEGF Binding Induces Multiple Downstream
Signaling Pathways
Selected Agents Targeting the
VEGF Pathway
Class Examples Targets Stage of Development Company
Agents targeting the VEGF ligand
Antibodies Bevacizumab
Ramucirumab
VEGF
VEGFR2
Phase III
Phase III
Genentech
ImClone
Soluble receptors
VEGF-TRAP (aflibercept)
VEGF and PlGF Phase III Regeneron/Sanofi Aventis
Agents targeting the VEGF Receptors
Small molecule inhibitors
Sunitinib
Axitinib
SU014813
Pazopanib
Sorafenib
VEGFR-2, PDGFR, c-Kit
VEGFR-2
VEGFR1,2; c-Kit
VEGFR1,2; (PDGFR, c-Kit)
Raf, VEGFR1,2; c-Kit
Phase III*
Phase II/III
Phase II
Phase II/III
Phase III**
Pfizer
Pfizer
Pfizer
GSK
Bayer/Onyx
Vatalanib
AEE788
VEGFR-1/2 PDGFR, c-Kit
VEGFR1,2; ErbB1,2
Phase II/III
Phase I/II
Novartis
Novartis
Vandetinib
Cediranib
Motesanib
ABT 869
Brivanib
TKI258
VEGFR-2/EGFR
VEGFR, c-Kit
VEGFR1,2; PDGFR, c-Kit
VEGFR1,2
VEGFR2, FGFR
VEGFR, FGFR, PDGFR
Phase II/III
Phase II/III
Phase II/III
Phase I/II
Phase II
Phase II
Astra Zeneca
Astra Zeneca
Amgen
Abbott
BMS
Novartis
Phase III Trial with Bevacizumab Therapy in
Metastatic Breast Cancer
Capecitabine
alone Capecitabine + bevacizumab
P Value
Overall response rate (%) 9.1 19.8 0.001
Progression-free survival (mo) 4.17 4.86 0.518
Overall survival (mo) 14.52 15.05 0.627
Capecitabine (n=230)
Capecitabine + bevacizumab
(15 mg/kg q3w) (n=232)
PD
PD
Miller et al. JCO 23:792-799, 2005.
R
A
N
D
O
M
I
Z
A
T
I
O
N
Previously treated
MBC
MBC not previously treated with
chemotherapy
(N = 722)
Stratification
- Disease-free interval
- Adjuvant therapy
- ER+, ER–, unknown
- Number of metastatic sites
Paclitaxel: 90 mg/m2 IV infusion over 1 hr weekly x 3 wk followed by 1 wk of rest
Bevacizumab: 10 mg/kg following paclitaxel Rx on wk 1 and 3 per cycle
R
Paclitaxel: 90 mg/m2 IV infusion over 1 hr weekly x 3 wk followed by 1 wk of rest
E2100:
Supported Accelerated Approval in 2008
Miller K, et al. NEJM, 2007.
0.8
0.6
0.4
0.2
0.0
1.0
36 30 24 12 6 0
Pro
po
rtio
n w
ith
ou
t even
t
HR = 0.483 (0.385, 0.607)
Log-rank test, p ≤ 0.0001
Paclitaxel (n = 354)
Paclitaxel + Bevacizumab (n = 368)
18
Time, mo
E2100 PFS by IRF (Kaplan-Meier)
Miller K, et al. NEJM 2007, JCO 2008
©2009 by American Society of Clinical Oncology
Patient Disposition, IRF Review of E2100
• 89.9% had at least one image
• 82% had both baseline/post baseline radiographic data
– 34 +255 censored (40% overall, 35% after day 1)
• 86.6% had PFS determined
• 472 (65%) had measurable disease at baseline
Gray R et al. JCO 2009;27:4966-4972.
3 Randomized Phase III Trials in Previously
Untreated MBC
Previously
untreated
MBC
Chemo +
No Bev
Chemo +
Bev
Optional
second-line
Chemo +
Bev
(AVADO and
RIBBON-1
only)*
E2100
Paclitaxel
AVADO
Docetaxel
RIBBON-1
Capecitabine,
Taxane, or
Anthracycline
Treat
until
PD
R
A
N
D
O
M
I
Z
E
*~ 50% of patients received bevacizumab at crossover
N=2,447 patients from 3 trials
Control (n=1,008); BV + chemo (n=1,439)
PFS primary endpoint HR for PFS relatively similar across trials
Bevacizumab And Chemotherapy in the
First-Line Setting: PFS
1.0
0.8
0.6
0.4
0.2
0
PFS
est
imat
e
0 6 12 18 24 30
Time (months)
9.2 8.0
AVADO
HR=0.67* (0.54–0.83) p=0.0002§
1.0
0.8
0.6
0.4
0.2
0
PFS
est
imat
e
0 6 12 18 24 30 36
Time (months)
8.1 10.0
Placebo + docetaxel (n=241) Bevacizumab 15mg/kg q3w + docetaxel (n=247)
Placebo + docetaxel (n=207) Bevacizumab + taxane/ anthracycline (n=415)
1.0
0.8
0.6
0.4
0.2
0 0 6 12 18 24 30
Time (months)
HR=0.64* (0.52–0.80) p<0.0001
HR=0.69* (0.56–0.84) p=0.0002
Placebo + capecitabine (n=206) Bevacizumab + capecitabine (n=409)
8.6 5.7
RIBBON-1‡: taxane/anthracycline cohort
HR=0.48* (0.39–0.61) p<0.0001
PFS
est
imat
e
1.0
0.8
0.6
0.4
0.2
0
PFS
est
imat
e
0 6 12 18 24 30 36
Time (months)
Paclitaxel (n=354) Bevacizumab + paclitaxel (n=368)
5.8 11.3
E2100 (IRF assessment)
RIBBON-1‡: capecitabine cohort
E21001 AVADO2
RIBBON-1§3
Capecitabine T/anthr
Pac
Bev
+ pac
Placebo
+ doc
Bev*
+ doc
Placebo
+ cap
Bev
+ cap
Placebo
+ T/a
Bev
+ T/a
Median OS,
months 24.8 26.5 31.9 30.2 21.2 29.0 23.8 25.2
HR
0.87
p=0.14
1.03
p=0.85
0.85
p=0.27
1.03
p=0.83
1-year OS
rate, %‡ 74 81 76 84 74 81 83 81
p=0.017 p=0.02 p=0.076 p=0.44
Secondary Endpoint: Overall Survival (OS)
*15mg/kg q3w; ‡Exploratory p values §
O’Shaughnessy et al. ASCO 2010. Abstract 1005.
Pooled Safety Analysis of Bevacizumab +
Chemotherapy vs Chemotherapy Alone
Select Grade ≥ 3 Adverse Event,* %
Chemotherapy +
Bevacizumab
(n = 1679)
Chemotherapy
Alone
(n = 982)
Neutropenia 10.0 7.1
Sensory neuropathy 9.5 8.5
Hypertension 9.0 1.2
Febrile neutropenia 6.5 3.5
Venous thromboembolic event 2.8 3.8
Proteinuria 2.3 0
Total deaths 51.3 55.8
MBC 47.4 51.5
Treatment-related 2.1 1.8
Other 1.5 1.4
*Occurring in ≥ 2% of pts in either arm
Caveats: Interpretation of OS: Chemotherapy,
Cross-Over and Subsequent Therapy • Is effect on absolute improvement in PFS drug or schedule
related? – Only ECOG 2100 used weekly paclitaxel
– AVADO discontinued chemo at a set time
• 51% of patients in the non-bev arm received bevacizumab post-progression compared to 40% who continued bev after first-line
• 42% vs 35% (non bev vs bev) received 3 or more subsequent lines of therapy following progression
• Was this trial powered to detect a survival benefit in an unselected first line population? (Broglio and Berry, JNCI, 2009)
• 11.11 FDA: “….women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, …., that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”
Summary of Efficacy with Bevacizumab and
Paclitaxel in Breast Cancer:
PFS in First-Line Studies
Study Chemotherapy N PFS with bevacizumab
(mo)
E2100 Weekly paclitaxel 722 11.3
RIBBON I (2:1) Weekly paclitaxel/ anthracycline
622 9.2 (10.7 IRC)
Weekly taxane (exploratory)
307 9.2
CALGB 40502 Weekly paclitaxel
283 (paclitaxel arm only)
10.6
TURANDOT Weekly paclitaxel
564 11
Rugo et al, ASCO 2012, Zielinski et al, ESMO 2012, abstract 3170
All Patients GEPARquinto NSABP B-40
No Bev (969) Bev (956) No Bev (595) Bev (584)
pCR (inv) in breast (%) 20.6 24.6 28.2 34.5
0.04 P=0.02
pCR (inv) breast/node 18.3 21.7 23 27.6
0.07 P=.08
pCR (inv/noninv) breast/node
14.9 18.4
0.04 (HR1.29; 1.02-1.65)
TN Disease TN HR+
pCR (inv) in breast (%) 31 39.8 47 52 15.1 23.2
P=.022 P=.34 P=.007
pCR breast/node 32.7 40.1 41 44 11.1 16.8
Inv only in NSABP P=.059 P=.458 P=.03
pCR (inv/noninv) breast/node
27.9 39.3 Both trials: significant increase in pCR in tumors with high grade histology P=.003
von Minckwitz et al, NEJM 2012; Bear et al, NEJM 2012 Test for homogeneity NS
What Could Explain These Seemingly
Conflicting Results?
• Most straightforward
– Differences in study design
• German trial more locally advanced, non-responders withdrawn
• Different sequencing of drugs
– Local testing results are clearly variable, and may not be validated
with central testing
– Conclusions may therefore be biased in an
unknown direction
• Importance of central confirmation of IHC results
– Pathology reports reviewed centrally
• Subtype specificity
– Are we defining real biologic subtypes using IHC criteria?
• Host biology
– Conflicting results across disease types
• Clearly, we need a marker!
Subsets and Biomarkers:
Can clinical and biologic
markers predict response?
16
Hypoxic Signatures and Basal-like Tumors
VEGF 13-gene VEGF-signature
exp
ress
ion
Hypoxia related features are common in basal-like tumors; 13 gene hypoxia
signature correlates with poor outcome, includes VEGF and HIF-1a related genes.
Higher intratumoral VEGF levels in TNBC Linderholm et al. Ann Oncol 2009.
Hu et al., BMC Medicine 2009
No. at risk:
BEV + CT 112 65 26 8 4
Placebo + CT 47 11 4 2
TNBC population: PFS
PFS
BEV + CT
(n=112)
PLA + CT
(n=47)
Events, n (%) 94 (84) 42 (89)
Median, months 6.0 2.7
HRa (95% CI)
Log-rank test
0.494 (0.33–0.74)
p=0.0006
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20 25
Time (months)
2.7 6.0
aStratified analysis (CT regimen, interval from
LR/MBC diagnosis to 1st progression)
Estimated
probability
BEATRICE: Phase III Trial of Adjuvant Bevacizumab
in Triple-Negative Breast Cancer
Cameron et al., SABCS 2012; abstract S6-5
• BEATRICE study design
Eligibility criteria: • Resected triple-negative (centrally confirmed) invasive early breast cancer
4-8 cycles of standard chemotherapy (investigator’s choice)
RANDOMI ZE
(N=2591)
4-8 cycles of standard chemotherapy (investigator’s choice) + bevacizumab 5 mg/kg/wk equivalent for 1 year duration
Chemotherapy options: •Taxane-based (≥4 cycles) •Anthracycline-based (≥4 cycles) •Anthracycline + taxane (3-4 cycles each)
Primary endpoint: DFS Secondary endpoints: OS, breast cancer-free interval, DFS, distant DFS, safety, biomarkers
BEATRICE: Phase III Trial of Adjuvant Bevacizumab
in Triple-Negative Breast Cancer
Cameron et al., SABCS 2012; abstract S6-5
• Efficacy results
– None of the subgroups examined (age, baseline ECOG performance status, region, race, menopausal status, tumor size, # of positive LNs, adjuvant chemotherapy, HR status, and surgery) showed a significant effect on invasive DFS
• Safety results
Outcome
Chemo alone (n=1290)
Chemo + bevacizumab (n=1301)
HR (95%CI)
P-value
3-yr invasive DFS 82.7% 83.7% 0.87 (0.72-1.07) .18
OS -- -- 0.84 (0.64-1.12) .23
Adverse events, % of patients
Chemo alone (n=1271)
Chemo + bevacizumab (n=1288)
Any AE Grade ≥3 AE Grade 5 AE
99% 57% 0.2%
99% 72% 0.3%
AE leading to chemo and/or bev discontinuation AE leading to bev discontinuation
2%
--
20%
18%
BEATRICE Trial: Biomarker Results
Baseline Plasma Concentration HR* P-Value
Median VEGF-A
High 0.81 .7415
Low 0.89
3rd Quartile VEGF-A
High 0.64 .3551
Low 0.92
Median VEGFR-2
High .61 .0291
Low 1.24
•Biomarker analysis performed to investigate potential predictive markers of benefit from adjuvant bevacizumab • Sub-study included 45% of total patient population • Evaluated correlation of biomarkers with invasive disease-free survival
* HR <1.0 indicates CT plus Bev better than CT alone
Carmeliet et al., SABCS 2012; abstract P3-06-34
Paclitaxel 90mg/m2 weekly
x 3 q4 weeks /
Placebo 10 mg/kg q2w
Paclitaxel 90 mg/m2 weekly x 3 q4 weeks /
Bevacizumab 10 mg/kg q2w
Confirmatory Study Schema: MERiDiAN
Co-Primary Endpoints: PFS (All Patients) , PFS (VEGF high subset)
Secondary Endpoints: OS; ORR; Symptoms/QoL; Safety
MBC, HER2-Negative Chemo-naïve
N=480
Stratification
• VEGF-A (low/high) • Adjuvant therapy (yes/no) • Hormonal status (ER +/-) R
A N
D O
M I Z
E D
LEA: Effect of Adding Bevacizumab to First-Line
Endocrine Therapy in Advanced Breast Cancer
• Design
– 380 patients, first line therapy, post-menopausal women
• Results:
– Baseline characteristics were well-balanced:
• Approximately 80% had metastatic disease
• Approximately 50% had received previous adjuvant hormonal therapy
• Approximately 90% of patients received letrozole; the remainder received fulvestrant
– Adverse events increased on the bevacizumab-containing arm included leukopenia and thrombocytopenia (P < .01); also fatigue, hypertension, hemorrhage, elevated liver enzymes, and proteinuria (P < .001).
Martin et al., SABCS 2012; abstract S1-7
Outcome
Endocrine therapy
Endocrine therapy + bevacizumab
HR (95% CI)
P-value
Median PFS 13.8 months 18.4 months 0.83 (0.65-1.06) .14
Median OS 42 months 41 months 1.18 (0.77-1.81) .47
Endocrine Therapy: Tamoxifen or Aromatase Inhibitor (letrozole) Double-blind, placebo-controlled Primary Endpoint: Progression-free Survival Circulating tumor and endothelial cells measured during treatment PI: Dickler
CALGB 40503: First-line Endocrine Rx +/- Bevacizumab
ER or PR+
MBC
1st line Rx
+/- Measurable
Post-Menopausal or
Ovarian suppression Endocrine therapy + Placebo
Endocrine therapy + Bevacizumab
(15mg/kg IV q3wks)
Endpoint
Capecitabine/
Sorafenib
(n = 115)
Capecitabine/
Placebo
(n = 114) HR P Value
Median PFS 6.4 months 4.1 months 0.576 .0006
First-line 7.5 months 4.1 months 0.498 .0022
Second-line 5.7 months 4.1 months 0.652 .0339
Overall Response Rate 38% 31% NR .1229
CR 2% <1% NR NR
PR 36.5% 30% NR NR
Baselga et al. J Clin Oncol: May, 2012.
Phase II Trial: Capecitabine/Sorafenib vs.
Capecitabine/Placebo as First- or Second-Line Therapy
for Locally Advanced or Metastatic BC: Results
• Efficacy was seen across all prespecified and exploratory subgroups, including those with prior
taxane and anthracycline exposure.
Safety:
– Sorafenib assoicated with • An increase in grade 3 HFSR with the sorafenib regimen (44% vs 13%)
• Increase in all grade rash, diarrhea, stomatitis, neutropenia, and hypertension
– Overall treatment discontinuation was less frequent with sorafenib (65% vs. 79%)
Phase III Resilience trial is in progress, using a reduced dose of sorafenib
Phase III trial of Docetaxel +/- Ramicirumab (IMC
1121B) as First-Line Therapy in HER2-Negative,
Unresectable LABC or MBC (closed to accrual)
Endpoints
• Primary: Progression-free survival
• Secondary: Time to treatment failure, overall survival
(n = 1113)
PI: John Mackey www.clinicaltrials.gov
VEGFR-2 directed recombinant human monoclonal antibody (IgG1)
Eligibility criteria:
• HER2– disease
• First-line treatment
• Locally recurrent or
metastatic breast
cancer
Docetaxel (75 mg/m2)
Placebo
q3w
Docetaxel (75 mg/m2)
Ramucirumab (10 mg/kg)
q3w
Angiopoietins (Ang)/Tie2 signaling pathway and its functions on vascular remodeling.
Cascone T , Heymach J V JCO 2012;30:441-444
©2012 by American Society of Clinical Oncology
2012 Ongoing Trials in NCI Database for
Breast Cancer (Selected)
• Therapeutic trials
– Bevacizumab (N=89)
– Sorafenib (n=10)
– Ramucirumab (n=3)
– Others (pazopanib, vascular disrupting
agents, angiopoeitin inhibitors)
• Bevacizumab – trials to look for
– Phase III adjuvant
• E5103: HER2 negative
• CALGB 40603: neoadjuvant TNBC
• BETH: HER2+
– Phase III metastatic
• CALGB 40503 (ER+)
• TANIA (Bev or not post progression)
• MERiDiAN
– Randomized phase II in TNBC
• Paclitaxel +/- MetMAB +/- bevacizumab
– GWAS and miRNA for biomarker evaluation
• Sorafenib
– Phase III - Resiliance
• Capecitabine +/-sorafenib
– Phase II
• With chemotherapy or hormone therapy
• Ramucirumab
– Phase III
• Paclitaxel +/- ramucirumab
– Randomized phase II
• Eribulin +/- ramucirumab
• Capecitabine +/- ramucirumab
• Vascular disrupting agents, angiopoeitin inhibitors
• Bevacizumab for lymphedema (phase I)
Paraphrasing William Osler:
• Antiangiogenic therapy still holds promise for the treatment of breast
cancer
We need to change our approach:
• Design better prospective trials we need a more accurate understanding
of biologic subtype and markers to predict response…..
– GEPARquinto and NSABP B-40: central IHC, subtyping and molecular
profiling
– Focus on biomarker development
– New targeted agents
• Countering resistance
– Immune modulation?
– Combination therapy?
The benefit of experience is not in treating
everyone, but in treating wisely.