The Role of Angiogenesis Inhibition in Breast Cancer Today: Lessons Learned

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1 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

2 VEGF Binding Induces Multiple Downstream Signaling Pathways

3 Selected Agents Targeting the VEGF Pathway Class Examples Targets Agents targeting the VEGF ligand Antibodies Bevacizumab Ramucirumab VEGF VEGFR2 Stage of Development Phase III Phase III Company Genentech ImClone Soluble receptors VEGF-TRAP (aflibercept) Agents targeting the VEGF Receptors Small molecule inhibitors Sunitinib Axitinib SU Pazopanib Sorafenib Vatalanib AEE788 Vandetinib Cediranib Motesanib ABT 869 Brivanib TKI258 VEGF and PlGF Phase III Regeneron/Sanofi Aventis VEGFR-2, PDGFR, c-kit VEGFR-2 VEGFR1,2; c-kit VEGFR1,2; (PDGFR, c-kit) Raf, VEGFR1,2; c-kit VEGFR-1/2 PDGFR, c-kit VEGFR1,2; ErbB1,2 VEGFR-2/EGFR VEGFR, c-kit VEGFR1,2; PDGFR, c-kit VEGFR1,2 VEGFR2, FGFR VEGFR, FGFR, PDGFR Phase III* Phase II/III Phase II Phase II/III Phase III** Phase II/III Phase I/II Phase II/III Phase II/III Phase II/III Phase I/II Phase II Phase II Pfizer Pfizer Pfizer GSK Bayer/Onyx Novartis Novartis Astra Zeneca Astra Zeneca Amgen Abbott BMS Novartis

4 Phase III Trial with Bevacizumab Therapy in Metastatic Breast Cancer Previously treated MBC R A N D O M I Z A T I O N Capecitabine (n=230) Capecitabine + bevacizumab (15 mg/kg q3w) (n=232) PD PD Capecitabine alone Capecitabine + bevacizumab P Value Overall response rate (%) Progression-free survival (mo) Overall survival (mo) Miller et al. JCO 23: , 2005.

5 E2100: Supported Accelerated Approval in 2008 MBC not previously treated with chemotherapy (N = 722) Stratification - Disease-free interval - Adjuvant therapy - ER +, ER, unknown - Number of metastatic sites R Paclitaxel: 90 mg/m 2 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 Paclitaxel: 90 mg/m 2 IV infusion over 1 hr weekly x 3 wk followed by 1 wk of rest Miller K, et al. NEJM, 2007.

6 Proportion without event E2100 PFS by IRF (Kaplan-Meier) Paclitaxel (n = 354) Paclitaxel + Bevacizumab (n = 368) HR = (0.385, 0.607) Log-rank test, p Miller K, et al. NEJM 2007, JCO 2008 Time, mo

7 Patient Disposition, IRF Review of E % had at least one image 82% had both baseline/post baseline radiographic data 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: by American Society of Clinical Oncology

8 3 Randomized Phase III Trials in Previously Untreated MBC N=2,447 patients from 3 trials Control (n=1,008); BV + chemo (n=1,439) Previously untreated MBC E2100 Paclitaxel AVADO Docetaxel RIBBON-1 Capecitabine, Taxane, or Anthracycline R A N D O M I Z E Chemo + No Bev Chemo + Bev Treat until PD Optional second-line Chemo + Bev (AVADO and RIBBON-1 only)* *~ 50% of patients received bevacizumab at crossover PFS primary endpoint HR for PFS relatively similar across trials

9 PFS estimate PFS estimate PFS estimate PFS estimate Bevacizumab And Chemotherapy in the First-Line Setting: PFS E2100 (IRF assessment) Paclitaxel (n=354) Bevacizumab + paclitaxel (n=368) HR=0.48* ( ) p< RIBBON-1 : taxane/anthracycline cohort Placebo + docetaxel (n=207) Bevacizumab + taxane/ anthracycline (n=415) HR=0.64* ( ) p< Time (months) AVADO Placebo + docetaxel (n=241) Bevacizumab 15mg/kg q3w + docetaxel (n=247) HR=0.67* ( ) p= Time (months) RIBBON-1 : capecitabine cohort Placebo + capecitabine (n=206) Bevacizumab + capecitabine (n=409) HR=0.69* ( ) p= Time (months) Time (months)

10 Secondary Endpoint: Overall Survival (OS) RIBBON-1 3 E AVADO 2 Capecitabine T/anthr Pac Bev + pac Placebo + doc Bev* + doc Placebo + cap Bev + cap Placebo + T/a Bev + T/a Median OS, months HR 0.87 p= p= p= p= year OS rate, % p=0.017 p=0.02 p=0.076 p=0.44 *15mg/kg q3w; Exploratory p values

11 Pooled Safety Analysis of Bevacizumab + Chemotherapy vs Chemotherapy Alone Select Grade 3 Adverse Event,* % Chemotherapy + Bevacizumab (n = 1679) Chemotherapy Alone (n = 982) Neutropenia Sensory neuropathy Hypertension Febrile neutropenia Venous thromboembolic event Proteinuria Total deaths MBC Treatment-related Other *Occurring in 2% of pts in either arm O Shaughnessy et al. ASCO Abstract 1005.

12 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) 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.

13 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 RIBBON I (2:1) Weekly paclitaxel/ anthracycline Weekly taxane (exploratory) CALGB Weekly paclitaxel 283 (paclitaxel arm only) (10.7 IRC) TURANDOT Weekly paclitaxel Rugo et al, ASCO 2012, Zielinski et al, ESMO 2012, abstract 3170

14 All Patients GEPARquinto NSABP B-40 No Bev (969) Bev (956) No Bev (595) Bev (584) pcr (inv) in breast (%) P=0.02 pcr (inv) breast/node pcr (inv/noninv) breast/node 0.07 P= (HR1.29; ) TN Disease TN HR+ pcr (inv) in breast (%) P=.022 P=.34 P=.007 pcr breast/node Inv only in NSABP P=.059 P=.458 P=.03 pcr (inv/noninv) breast/node von Minckwitz et al, NEJM 2012; Bear et al, NEJM Both trials: significant increase in pcr in tumors P=.003 with high grade histology Test for homogeneity NS

15 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!

16 Subsets and Biomarkers: Can clinical and biologic markers predict response? 16

17 expression Higher intratumoral VEGF levels in TNBC Linderholm et al. Ann Oncol Hypoxic Signatures and Basal-like Tumors VEGF 13-gene VEGF-signature Hypoxia related features are common in basal-like tumors; 13 gene hypoxia signature correlates with poor outcome, includes VEGF and HIF-1a related genes. Hu et al., BMC Medicine 2009

18 TNBC population: PFS Estimated probability PFS BEV + CT (n=112) PLA + CT (n=47) Events, n (%) 94 (84) 42 (89) Median, months HR a (95% CI) Log-rank test ( ) p= a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) Time (months) No. at risk: BEV + CT Placebo + CT

19 Cameron et al., SABCS 2012; abstract S6-5 BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer BEATRICE study design Eligibility criteria: Resected triple-negative (centrally confirmed) invasive early breast cancer Primary endpoint: DFS Secondary endpoints: OS, breast cancer-free interval, DFS, distant DFS, safety, biomarkers (N=2591) R A N D O M I Z E 4-8 cycles of standard chemotherapy (investigator s choice) 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)

20 BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer Efficacy 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 ( ).18 OS ( ).23 None of the subgroups examined (age, baseline ECOG performance status, region, race, menopausal status, tumor size, # of positive LNs, Chemo adjuvant alone chemotherapy, HR status, and surgery) showed a significant effect on invasive DFS Adverse events, % of patients Any Safety AE results Grade 3 AE Grade 5 AE AE leading to chemo and/or bev discontinuation AE leading to bev discontinuation (n=1271) 99% 57% 0.2% 2% -- Chemo + bevacizumab (n=1288) 99% 72% 0.3% 20% 18% Cameron et al., SABCS 2012; abstract S6-5

21 BEATRICE Trial: Biomarker Results 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 Baseline Plasma Concentration HR* P-Value Median VEGF-A High 0.81 Low rd Quartile VEGF-A High 0.64 Low 0.92 Median VEGFR-2 High.61 Low 1.24 * HR <1.0 indicates CT plus Bev better than CT alone Carmeliet et al., SABCS 2012; abstract P

22 R A N D O M I Z E D Confirmatory Study Schema: MERiDiAN MBC, HER2-Negative Chemo-naïve N=480 Paclitaxel 90 mg/m2 weekly x 3 q4 weeks / Bevacizumab 10 mg/kg q2w Stratification VEGF-A (low/high) Adjuvant therapy (yes/no) Hormonal status (ER +/-) Paclitaxel 90mg/m2 weekly x 3 q4 weeks / Placebo 10 mg/kg q2w Co-Primary Endpoints: PFS (All Patients), PFS (VEGF high subset) Secondary Endpoints: OS; ORR; Symptoms/QoL; Safety

23 LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced Breast Cancer Design 380 patients, first line therapy, post-menopausal women Results: Outcome 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 Endocrine therapy Endocrine therapy + bevacizumab HR (95% CI) P-value Median PFS 13.8 months 18.4 months 0.83 ( ).14 Median OS 42 months 41 months 1.18 ( ).47 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

24 CALGB 40503: First-line Endocrine Rx +/- Bevacizumab ER or PR+ MBC 1st line Rx +/- Measurable Post-Menopausal or Ovarian suppression Endocrine therapy + Bevacizumab (15mg/kg IV q3wks) Endocrine therapy + Placebo 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

25 Phase II Trial: Capecitabine/Sorafenib vs. Capecitabine/Placebo as First- or Second-Line Therapy for Locally Advanced or Metastatic BC: Results Endpoint Capecitabine/ Sorafenib (n = 115) Capecitabine/ Placebo (n = 114) HR P Value Median PFS 6.4 months 4.1 months First-line 7.5 months 4.1 months Second-line 5.7 months 4.1 months Overall Response Rate 38% 31% NR.1229 CR 2% <1% NR NR PR 36.5% 30% NR NR 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 Baselga et al. J Clin Oncol: May, 2012.

26 Phase III trial of Docetaxel +/- Ramicirumab (IMC 1121B) as First-Line Therapy in HER2-Negative, Unresectable LABC or MBC (closed to accrual) Eligibility criteria: HER2 disease First-line treatment Locally recurrent or metastatic breast cancer Docetaxel (75 mg/m 2 ) Placebo q3w Docetaxel (75 mg/m 2 ) Ramucirumab (10 mg/kg) q3w (n = 1113) VEGFR-2 directed recombinant human monoclonal antibody (IgG1) Endpoints Primary: Progression-free survival Secondary: Time to treatment failure, overall survival PI: John Mackey

27 Angiopoietins (Ang)/Tie2 signaling pathway and its functions on vascular remodeling. Cascone T, Heymach J V JCO 2012;30: by American Society of Clinical Oncology

28 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 (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)

29 Paraphrasing William Osler: Antiangiogenic therapy still holds promise for the treatment of breast cancer The benefit of experience is not in treating everyone, but in treating wisely. 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?