Clinical Updates

Advances in Targeted Therapies for Breast Cancer

A Report From SABCS 2009 Kathy D. Miller, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Cancer Center Indianapolis, IN

Discussion Topics

• HER2 positive disease – Growing number of options • Angiogenesis – Bevacizumab questions answered and rephrased – Small molecule success and disappointment

HER2: What We Knew Before SABCS

• Trastuzumab – Active as single agent and adds to chemo/HRT – Effective with chemo beyond PD – Adds to lapatinib monotherapy (ORR, PFS) • Lapatinib – Active as single agent and adds to chemo/HRT – Effective with chemo after PD on trastuzumab • MULTIPLE new agents in development

Case 1

• 54 year old woman with newly diagnosed stage II breast cancer s/p lumpectomy and axillary dissection – Primary tumor 1.9 cm – Involves 1 of 14 LN (1/2 SN, 0/12 additional LN) – Grade III – ER+ 15%, PR – HER2 2+ by IHC (intense staining in 20% of cells) – FISH equivocal with ratio 2.15

• Do you recommend adjuvant trastuzumab?

Background

• In 2007, ASCO/CAP recommended new guidelines to define HER2 positivity by both IHC 3+* and FISH+** – 3+ IHC: Uniform intense membrane staining of > 30% of invasive tumor cells – FISH+: HER2/CEP17 ratio > 2.2

• Original HER2 eligibility criteria in the pivotal N9831 Phase III Adjuvant HER2 Trial – 3+ IHC: Uniform intense membrane staining of > 10% of invasive tumor cells – FISH+: HER2/CEP 17 ratio ≥ 2.0

HerceptTest DAKO, Carpenteria, CA; FISH: PathVysion, Abbott Molecular; Masood S et al. Ann Clin Lab Sci 1998;28(4):215-223; Perez EA et al. SABCS 2009 #701

N9831 DFS Based on Original Criteria:

HER2 Non-positive* vs. HER2+** * HER2 Non positive (IHC ≤ 10 and FISH Ratio < 2.0) ** HER2+ (IHC > 10 or FISH Ratio ≥ 2.0) Perez EA et al. SABCS 2009 #701

N9831 DFS Based on 2007 ASCO/CAP:

HER2 Non-positive* vs. HER2+** * HER2 Non positive (IHC ≤ 30 and FISH Ratio ≤ 2.2) ** HER2+ (IHC >30 or FISH Ratio > 2.2) Perez EA et al. SABCS 2009 #701

Conclusions

• A small percentage (by IHC:3.7%, FISH 1.4%, both:1.7%) of N9831 pts did not meet ASCO/CAP 2007 HER2 positivity guidelines when applied retrospectively • Trastuzumab effect appeared similar for HER2+ pts regardless of ASCO/CAP or originally used FDA approved guidelines • Data support determining eligibility for trastuzumab based on the original definition of HER2 positivity (IHC 3+, >10% staining; FISH ratio>2.0).

Perez EA et al. SABCS 2009 #701

Case 1

• 54 year old woman with newly diagnosed stage II breast cancer s/p lumpectomy and axillary dissection – Primary tumor 1.9 cm – Involves 1 of 14 LN (1/2 SN, 0/12 additional LN) – Grade III – ER+ 15%, PR – HER2 2+ by IHC (intense staining in 20% of cells) – FISH equivocal with ratio 2.15

• Do you recommend adjuvant trastuzumab?

– YES

IHC or FISH

Adjuvant Trastuzumab

NCCTG N9831 BCIRG 006 FISH IHC or FISH NSABP B-31

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation

IHC or FISH HERA Observation 1 v 2 years AC P D DCarbo Standard Trastuzumab 1 year

BCIRG 006 DFS Events

First / Second / Third Planned Efficacy Analyses (cutoff dates: 30June2005 / 01Nov2006 / 16Oct2009 ) • Median follow-up time = 23 / 36 / 65 months • 322 / 462 / 656 DFS events (42% additional events) – Breast cancer relapse – Second primary malignancy – Death • 84 / 185 / 348 deaths (88% additional deaths)

Current BCIRG 006 Disease-Free Survival – 3

rd

Planned Analysis

Current BCIRG 006 Overall Survival – 3

rd

Planned Analysis

Cardiac Deaths and CHF as per Independent Review Panel

Therapeutic Index – Most Recent Data

Control (A)*

vs AC → T

Sequential (B)* AC → T → H

Efficacy Analysis *Patients eligible for crossover censored Data frozen on 11/3/2009 Perez EA et al, SABCS 2009

Control

vs

Sequential

Alive and disease free (%) 100

AC → T → H (164 events)

90 80

85.2% 79.7%

70

AC → T (222 events)

60 Log rank

P

=0.0005

50

1097 1087

40 0

735 728

1

675 643

2

624 581

3

586 529

4 Years from randomization

80.1% 71.9% 513 447

5 No. at risk Perez EA et al, SABCS 2009

Sequential (B)* AC → T → H

vs

Concurrent (C) AC → T+H → H

Efficacy Analysis *Censoring based on temp closure of C, and eligibility for crossover Data frozen on 11/3/2009 N9831 Perez EA et al, SABCS 2009

Sequential vs Concurrent 1st Interim Analysis

• At 50% of planned number of events (312 events) – 1,903 pts, median follow-up: 5.3 yr – 75% of pts followed for 5 yr • DFS may differ with respect to the timing of trastuzumab’s addition to AC → T – Log rank P=0.019 (HR 0.77; 95% CI 0.61-0.96) • Not crossing the boundary for statistical significance, pre-set at 0.00116

Perez EA et al, SABCS 2009

Sequential

vs

Concurrent

Alive and disease free (%) 100 90 80 89.1% AC →T+ H → H (138 events) 84.2% 85.7% AC → T → H (174 events) 79.8% 70 60 Logrank p=0.0190

50 40 0 949 954 837 830 1 788 766 740 705 676 641 2 3 Years from randomization 4 456 418 5 No. at risk Perez EA et al, SABCS 2009

Conclusions

• DFS is significantly improved with the addition of 52 wks of trastuzumab to AC  T • There is a statistically significant 33% reduction in the risk of an event with the sequential addition of trastuzumab following AC  T – 5 yr DFS: 72% vs. 80% • There is a strong trend for a 25% reduction in the risk of an event with starting trastuzumab concurrently with taxane relative to sequentially – 5 yr DFS: 80% vs. 84% Perez EA et al, SABCS 2009

Trastuzumab DFS

HERA Combined analysis BCIRG 006 AC DH BCIRG 006 DCarboH FinHER VH / DH CEF Median follow-up 1 year 2 years 2 years 2 years 3 years 0 Favors Trastuzumab 1 Favors no Trastuzumab 2 HR Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005

Adjuvant Trastuzumab

• Test everyone for HER2, inquire about testing quality and look carefully at ‘equivocal’ results – Most important message -> Give Trastuzumab!

– Either TCH or AC>TH supported by data – Differences between regimens modest • Slightly more recurrence with TCH balanced by increased cardiac and long-term marrow toxicity with AC>TH • Give concurrently with chemo unless there is a compelling reason not to

Case 2

• 74 year old presents with 5 cm primary breast mass with associated axillary adenopathy. – ER-, PR-, HER2 3+ by IHC (FISH ratio 8.9) – Staging finds several liver lesions, largest 2.2 cm • Biopsy of liver lesion confirms MBC, HER2+ • LFTs normal • LVEF 62% • She refuses chemotherapy but will consider other options, family supports her wishes • What would you recommend?

Lapatinib

Pathway Activation HER Ligands

Trastuzumab

Lapatinib + Trastuzumab

EGF104900

Heavily pretreated patients with HER2-positive MBC and progression on trastuzumab (N = 296) Lapatinib 1500 mg PO QD (n = 148) Optional crossover to trastuzumab arm if PD after 4 wks (n = 77) Lapatinib 1000 mg PO QD + Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV wkly (n = 148)

Stratified by visceral disease and hormone receptor status

PO, orally; QD, once daily.

Primary endpoint: PFS Secondary endpoints: OS ORR CBR Blackwell K, et al. SABCS 2009 # 61.

Lapatinib + Trastuzumab

52% of patients crossed over from single-agent lapatinib to combination therapy on progression.

Blackwell K, et al. SABCS 2009 # 61.

Lapatinib + Trastuzumab Safety Update

• Most AEs reported in ≥ 10% of patients were grade 1/2 • Diarrhea was the only grade 3/4 AE reported in ≥ 5% of patients – 8% of patients receiving lapatinib plus trastuzumab vs 7% receiving lapatinib alone • 1 fatal cardiac event in combination arm

Cardiac AEs N

Any, N Grade 3/4 Serious events* Treatment-related events

Lapatinib + Trastuzumab (n = 149)

11 3 10 10

Lapatinib (n = 146)

3 1 3 2 * Defined as grade ≥ 3 LV dysfunction, LVEF decrease ≥ 20% from baseline and below lower limit of normal defined by institution. Blackwell K, et al. SABCS 2009 # 61.

Lapatinib + Trastuzumab

• Lapatinib + trastuzumab associated with 26% improvement in OS vs lapatinib alone – Significant survival benefit despite 52% crossover – Supports combination arm of ALTTO • Lapatinib plus trastuzumab well tolerated – AEs comparable to lapatinib alone • Offers possible options for heavily pretreated patients who progress on trastuzumab Blackwell K, et al. SABCS 2009 # 61.

T-DM1

• T-DM1, an antibody-drug conjugate, combines biologic effect of trastuzumab against HER2-expressing cells with highly potent antimicrotubule agent DM1 – MOA likely involves receptor mediated internalization of T-DM1 after binding to HER2, resulting in intracellular release of DM1 Austin CD et al. Mol Biol Cell. 2004;15:5268-5282.

T-DM1 Monotherapy

• Multicenter, single arm (N=110) • Primary endpoint – ORR by IRF at 24 weeks • Eligibility – Prior anthracycline, taxane, capecitabine, trastuzumab, lapatinib – Active disease progression on last therapy – LVEF 50% or better Krop I, et al. SABCS 2009.#5090.

T-DM

1

Monotherapy

• ORR (by independent review) 32.7% • Clinical benefit rate (by independent review) 44.5% • Median PFS 7.3 months • T-DM1 well tolerated – Thrombocytopenia • Offers a very real option for additional therapy for HER2+ patients Krop I, et al. SABCS 2009 #5090.

Response Rates for Novel HER2-Targeting Agents After Progression on Trastuzumab

P<0.0001

Modi et al, ASCO 2008; Gelmon et al, ASCO 2008; Swaby et al, ASCO 2009; Burris et al, ESMO 2009.

Topics

• HER2 positive disease – Growing number of options • Angiogenesis – Bevacizumab questions answered and rephrased – Small molecule success and disappointment

Angiogenesis

• Angiogenesis is important for tumor growth • Highly regulated, multiple redundant pathways – VEGF among the most potent and frequently overexpressed • Bevacizumab – Modest activity as monotherapy – Disappointing results in initial randomized trial – E2100, then AVADO and RIBBON-1 • Now RIBBON-2

E2100

R A N D O M I Z E

Paclitaxel + Bevacizumab Paclitaxel

Stratify: • DFI < 24 mos. vs. > 24 mos.

• < 3 vs. > 3 metastatic sites • Adjuvant chemotherapy: yes vs. no • ER+ vs. ER- vs. ER unknown 28-day cycle: • Paclitaxel 90 mg/m 2 D1, 8 and 15 • Bevacizumab 10 mg/kg D1 and 15 Miller K, et al.

N Engl J Med.

2007;357:2666-2676

AVADO

1 st -line locally recurrent or mBC (n=705) Stratification factors: • region • prior taxane/time to relapse since adjuvant chemo • measurable disease • hormone receptor status Docetaxel* 100mg/m + placebo q3w Docetaxel* + 2 bevacizumab 7.5mg/kg q3w Docetaxel* + bevacizumab 15mg/kg q3w Treat with placebo/ bevacizumab to disease progression All patients given option to receive bevacizumab with 2 nd -line chemotherapy • Primary endpoint: progression-free survival • Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life *Docetaxel was administered for a maximum of nine cycles, but earlier discontinuation was permitted Miles D, et al.

J Clin Oncol.

2008;26(18S). LBA 1011.

RIBBON-1

Previously untreated MBC (n=1,237) Stratification Factors: • Disease-free interval • Previous adjuvant chemotherapy • Number of metastatic sites • Cape, T or Anthra CHOICE OF CHEMO BY INVESTIGATOR Capecitabine or Taxane or Anthracycline Chemo + bevacizumab q3w Chemo + placebo q3w • Capecitabine (1000 mg/m 2 BID x 14d) • Taxane (docetaxel or protein-bound paclitaxel) • Anthracycline-based chemotherapy (AC, EC, FAC, FEC) • Placebo or bevacizumab (15 mg/kg) Treat until PD Optional 2nd-line Chemo + bevacizumab Robert et al, ASCO 2009 #1005

Study Design

E2100 1 AVADO 2 RIBBON-1: Cape RIBBON-1: A/T Placebo Controlled Chemotherapy Dose of Bevacizumab Primary Endpoint IRF review

No Yes Yes Yes Weekly paclitaxel q3w docetaxel Capecitabine 10 mg/kg q2wk 7.5 or 15 mg/kg q3wk 15 mg/kg q3wk q3w doce/nabP AC/FAC/EC/FEC 15 mg/kg q3wk PFS Retrospective PFS (IRF) Yes PFS (Inv) Yes PFS (Inv) Yes 1 Miller K, et al.

N Engl J Med.

2007;357:2666-2676; 2 Miles D, et al.

J Clin Oncol.

39

Patient Population

N ER-/PR > 3 sites Measureable disease Adjuvant Chemo/Taxane E2100 1

673 35% 45% 73% 65%/16%

AVADO 2

736 22% 46% 83% 66%/15%

RIBBON-1: Cape

615 23% 44% 80% 72%/40%

RIBBON-1: A/T

622 24% 45% 84% 45%/15% 1 Miller K, et al.

N Engl J Med.

2007;357:2666-2676; 2 Miles D, et al.

J Clin Oncol.

2008;26(18S). LBA 1011.

ORR PFS (months) HR OS (months) HR E2100

Efficacy

AVADO

D+Pl D+B

RIBBON-1: Cape

C+Pl C+B

RIBBON-1: A/T

P P+B A/T + Pl A/T+B 25% 25.2

49% 49% 55%/63% 24% 35% Relative increase in RR 20-50% 38% 5.9

11.8

0.60

P

<0.0001

26.7

8.0

8.7/8.8

0.79 (7.5 mg)

P

0.72 (15 mg)

P

= 0.0099

NR NR 5.7

21.2

0.69

8.6

29 8.0

9.2

0.64

P

<0.0001

23.8

51% 25.2

0.88

P

= 0.16

0.92 (7.5 mg) 0.86 (15 mg) 0.85

P

= 0.27

1.03

P

= 0.83

Case 3

• 63 year old with metastatic breast cancer consults you for advice on additional therapy – Initial diagnosis 6 years ago, adjuvant AC x 4 cycles followed by AI for stage I disease (T2.1 cm, LN-, G2, ER+, PR-, HER2-) – Metastatic disease identified with bone invovlement and mediastinal and SC adneopathy ~28 months ago • Initially treated with fulvestrant > PR lasting 12 months • Tamoxifen > SD lasting 6 months • Exemestane > PD after 2 months • Capecitabine > PR lasting 8 months, now with PD

Case 3

• Currently has minimally symptomatic bone involvement (does not require narcotics) with asymptomatic mediastinal nodes and new pulmonary nodules (largest 1.6 cm) • PS = 1 • Local oncologist has recommended taxane based therapy • Would you add bevacizumab?

Ribbon 2

Second-line HER (-) Chemotherapy of choice † Randomize 2:1 Bevacizumab 10 mg/kg q2w (Bevacizumab 15 mg/kg q3w) Chemotherapy of choice † Placebo † Docetaxel, paclitaxel (qw or q3w), nab-paclitaxel, gemcitabine, vinorelbine, or capecitabine.

National Cancer Institute. Clinical Trials (PDQ). Available at: http://www.cancer.gov/search/clinical_trials/.

Key Eligibility Criteria

• One prior cytotoxic treatment for MBC • ECOG performance status (PS) 0 or 1 • HER2-negative or HER2 status unknown • No prior therapy with bevacizumab or other VEGF pathway- target therapy

Primary Endpoint of PFS (ITT Population)

Brufsky et al, SABCS 2009 #42

Cohort-Specific Analyses of PFS (ITT Population)

Brufsky et al, SABCS 2009 #42

What We’ve Learned

• Bevacizumab is an important component of initial chemotherapy for metastatic HER2- breast cancer – Increases RR – Prolongs PFS • Adds to second-line chemo in patients who didn’t get bevacizumab with initial chemo • Toxicity differs among reported regimens – Bevacizumab associated toxicity consistent

Remaining Questions

• Combine with anti-HER2 and hormonal therapies • Optimal duration of therapy • Why have we failed to demonstrate a difference in OS?

In Search of OS

• There is no difference • Subsequent therapy obscures benefit of 1st line therapy • Reported trials individually underpowered – Amenable to meta-analysis (see ASCO 2010) • Resistance to bevacizumab = more aggressive disease • Rapid regrowth of vasculature after stopping bevacizumab

Remaining Questions

• Combine with anti-HER2 and hormonal therapies • Optimal duration of therapy • Why have we failed to demonstrate a difference in OS?

• Does the choice of chemotherapy matter?

Does the Choice of Chemo Matter?

• HR broadly similar but absolute improvements in PFS gain differ widely – Ability to continue combined therapy – Interval censoring • May depend on mechanism(s) of action?

– Inherent anti-angiogenic effect of chemotherapy – Chemotherapy induced release of bone marrow progenitors – Role of VEGF on tumor cells

TKI Alternatives: Sorafenib

Targets Both Tumor-Cell Proliferation and Angiogenesis Wilhelm et al, SABCS 2009 #42

TIES Program

Trials to Investigate the Efficacy of Sorafenib in Breast Cancer

A Multinational Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo when Administered in Combination with Capecitabine in Patients with Locally Advanced Metastatic Breast Cancer Baselga et al, SABCS 2009 #45

A Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo when Administered in Combination with Paclitaxel in Patients with Locally Advanced Metastatic Breast Cancer http://www.clinicaltrials.gov/ct/show/NCT00499525 Gradishar et al, SABCS 2009 #44

Top Line Efficacy and Safety

(SOLTI-0701 & NU 07B1) Median PFS, * mos TTP, * mos Overall response rate, * % On-study deaths, * n (%) Subjects with AE leading to discontinuation of study treatment, * n (%) Baselga et al.

(Capecitabine+/- Sorafenib) 4.1 vs. 6.4

HR=0.576;

P

=0.0006** 4.2 vs. 6.8 (P=0.0005**) HR=0.562 (0.394, 0.799) 31 vs 38

P

=0.1229** 5 (4.5) vs 5 (4.5) 9 (8) vs 14 (13.4) Gradishar et al.

Paclitaxel +/- Sorafenib 5.6 vs. 6.9

HR=0.788;

P

=0.09** 5.6 vs. 8.1 (

P

=0.0171**) 0.674 (0.465, 0.975) 54 vs 67

P

=0.0234** 4 (3) vs 16 (14) 12 (10) vs 35 (30) * Chemotherapy + placebo vs chemotherapy + sorafenib ** One-sided

Adverse Event Rates

(Safety Population)

Overall incidence ≥ 10% and Grade 3/4 ≥ 3% in either teratment arm Baselga et al.

Gradishar et al.

HFSR S+C N=112 All (%) Grade 3 (%) 89 45 Pl+C All (%) N=112 Grade 3 (%) 63 13 S+P All (%) N=115 Grade 3 (%)

55

30 Pl+P N=118 All (%) Grade 3 (%) 7 3 Diarrhea 53 5 30 5

37

3 25 3 Asthenia Fatigue Dyspnea Neutropenia 24 14 12 11 0 2 5 4 27 13 12 4 2 1 3 2

29 14 13 24

7 3 1 10 21 20 14 19 3 2 3 4 P=Paclitaxel, S=Sorafenib, C=Capecitabine, Pl=Placebo

PFS: ITT Population

SABCS 2009 #45

SOLTI-0701: Capecitabine +/- Sorafenib

• 42% reduction in risk of disease progression or death – PFS benefit observed in subgroup analyses – PFS benefit noted in both first-line and second-line therapy • Increased incidence of hand-foot syndrome – Attention to dose modification critical • Phase III registration trial planned for sorafenib/capecitabine in advanced breast cancer

Motesanib Blocks More Than One Mechanism Involved in Tumorigenesis

Study Design

Objective Response Rate (ITT Population)

Progression-Free Survival (ITT Population)

Progression-Free Survival (ITT Population)

Mackey et al, SABCS 2009 #47

Phase III Sunitinib vs. Capecitabine

• HER2 negative, prior anthracycline and taxane required • N=483 • ORR 11.3 % vs. 16.4% • PFS 2.8 months vs. 4.2 months Favors Capecitabine Barrios et al, SABCS 2009 #46

Conclusions

• Bevacizumab is an important component of initial chemotherapy for patients with HER2- disease – Some benefit in second line if not given prior • All bevacizumab containing regimens are not equal – Toxicity differences clear – Efficacy?

– Differences in chemotherapy affects may be important • Small molecule VEGF TKIs have some activity as well but toxicity troublesome

The Future Is Possible

I don’t know if heavier than air flight is possible, but I’m committed to living my life dedicated to its possibility.

Wilbur Wright