New Information About The Use Of Adjuvant Trastuzumab From The 2005 San Antonio Breast Cancer Symposium

BCIRG-006, FinHer, HERA, cMYC/Her2 NSABP B31, Cardiac Safety N9831.

A review of data, and reflections on their implications.

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The 5 Adjuvant Trastuzumab Trials

Trial B31+9831 9831 Post C HERA BCIRG 006 FinHer Control CA*4+T*4 all Q3W CA*4+T*4 all Q3W Any prior adj. chemo.

CA*4+D*4 all Q3W D or V + FEC*3 Exp Arm Same + Tras 1y Same + Tras 1y + Tras 1y Same + Tras 1y CbD + Tras 1y Same + Tras 9w Conc ?

Y N N Y Y Y N = , fu = 3,351; 2y ~1,860; 1.5y

3,387; 1y 3,222; 2y 3,222; 2y 232; 3y Relapse 52 13 46 51 39 58 Mortality 33 15 24 - - 59

Numbers in red had p < 0.05. Numbers in blue had p = 0.06 – 0.10. Numbers in black had p > 0.10.

Abstract 1: Oral Presentation Thursday 9:45am Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC ® T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC ® TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Slamon D, Eiermann W, Robert N, et al.

BCIRG 006 (n = 3222 , fu = 23 months)

Will trastuzumab improve adjuvant therapy?

Will a non-anthracycline adjuvant regimen have less cardiac toxicity ?

Arm 1 Arm 2 Arm 3 AC q 3 wk * 4 = docetaxel q 3 wk * 4 = trastuzumab q 1 w = docetaxel/platinum q 3 wk * 6 = trastuzumab q 3 w

Eligibility

Node Positive or High Risk Node Negative Her2 amplification

Detailed criteria not in abstract or presentation Almost certainly included exclusion of patients with cardiac risk factors.

Patient / Tumor: Characteristics No Imbalances Between Treatment Arms

(numbers shown are % of total) Age < 50 > 50 Nodes N0 NP (1-3) NP (4-9) NP (> 9) 53 47 29 39 23 9 Tumor Size T < 2cm T 2.1-5.0 cm T > 5 cm 40 54 6 ER and PgR Status ER + or PgR+ 54

Treatment CA*4 + D*4 CA*4 + D*4 With Tras.

CbD * 6 With Tras.

BCIRG – 006 Trial

DFS Results n = 1073 DFS (3 yr) 77 % 1074 86 % 1075 80 % HR - 0.49

0.61

p value < 0.001

< 0.001

There was a trend for the non-anthracycline plus trastuzumab arm (Carbo/ Docetaxel/Trastuzumab) be less effective than the anthracycline plus trastuzumab arm; p = 0.16.

BCIRG – 006 Trial Risk of Grade 3 / 4 Toxicity

Neutropenia Neutropenic fever Neutropenic Infection Anemia Platelets Mylagia Fatigue Nausea Vomiting AC –T AC-TH 63 10 11 3 1 5 7 6 6 71 11 11 3 1 5 7 6 7 CbTH 66 9 10 6 5 2 7 5 3

BCIRG – 006 Trial All Grades (in % risk)

Sensory Neuropathy Motor Neuropathy Nail Changes Myalgia Renal Failure AC –T AC-TH CbTH 46 5 47 53 0 46 6 40 54 0 31 4 23 37 0.1

BCIRG – 006 Trial Cardiac Events

Grade 3 / 4 AC –T AC-TH CbTH Cardiac Death CHF Cardiac Ischemia/Infarc.

Arrythmias Total 0 3 0 7 10 0 17 4 4 25 0 4 1 9 14

BCIRG – 006 Trial Cardiac Events

Grade 3 / 4 Events AC –T AC-TH CbTH Total % of patients with event 10 1.0% 25 2.3% 14 1.3% p = 0.02

p = 0.54

p = 0.11

Authors’ Conclusions / Comments

1) At 23 months median follow-up, AC-TH and TCH provide over AC-T: Primary endpoint: Disease-Free Survival Statistically significant improvement: Secondary endpoint: Overall Survival - data not mature enough at the present time 2) Statistically significant higher incidence of cardiac events: in AC-TH in comparison to AC-T, but not in TCH in comparison to AC-T.

3) There is also a statistically significant higher incidence of asymptomatic and persistent LVEF declines in AC TH in comparison to AC-T and TCH

Abstract 2: Oral Presentation Thursday 10:00am Trastuzumab in combination with docetaxel or vinorelbine as adjuvant treatment of breast cancer: the FinHer Trial. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Blanco G, Isola J. Helsinki University Central Hospital, Helsinki, Finland.

Analysis of 4 Treatments of FinHer

Patients either NP or NN with tumor size > 2 cm and PgR negative. Her2 amplification determined by CISH.

Arm A Arm B n = 1,010; median follow-up 3.2 yr All patients were randomized between docetaxel and vinorelbine.

Her amplified patients (n = 232) were randomized between additional trastuzumab or not. Docetaxel 100 mg/m2 Q3W * 3 Vinorelbine 25 mg/m2 Q1W * 3 FEC 600/60/600 mg/m2 Q3W * 3 = trastuzumab Q1W * 9

Eligibility

Node Positive or High Risk Node Negative Age < 65 PS = 1 No Cardiac Failure Of Any Degree No Severe Cardiac Disease Or Hypertension

Patient / Tumor: Characteristics

Balanced (Except For Tumor Size) (numbers shown are % of total) Tumor Size T < 2cm T > 2.0

41 / 46 59 / 54 ER and PgR Status ER + or PgR+ 72 Her2 Amplified Yes 23 Nodes N0 NP (1-3) NP > 3 11 61 28

Endpoint RFS OS

In FinHer

Docetaxel vs Vinorelbine Docetaxel / FEC n = 502 Vinorelbine/ FEC n = 507 n = 42 n = 71 n = 20 n = 30 HR 0.58

0.66

p value 0.005

0.15

Endpoint RFS OS

In FinHer

Trastuzumab vs Control Trastuzu mab n = 115 n = 12 Control n = 116 n = 27 n = 6 n = 14 HR 0.42

0.41

p value 0.01

0.07

Docetaxel

(80/100)

Vinorelbine

Neutropenia Neutropenic fever Gr 1/2 (%) Gr 3/4 (%) Gr 1/2 (%) Gr 3/4 (%) 2 98 29 58 24 3 Stomatitis Alopecia 71 98 3 40 53 0 Nail problems Rash/Skin toxicity Allergic reaction Neuropathy (motor) Edema Phlebitis 56 56 12 31 62 9 1 2 1 2 9 21 3 18 30 31 1 0 2 0 LFT elevation 19 0 47 1

In FinHer Cardiac Safety

Trastuzumab vs Control

Trastuzumab CHF LVEF Decrease > 15% From Baseline 0 (0%) 4 (3%) Control 1 (1%) 7 (6%)

Authors’ Conclusions / Comments

Adjuvant docetaxel improves RFS compared with vinorelbine, but at the expense of more adverse effects.

Brief use of adjuvant trastuzumab administered concomitantly with docetaxel or vinorelbine is well tolerated and effective for HER2-positive BC.

Study limitations were limited follow-up, and small study size Randomized comparison of the brief and 1-yr regimens appears warranted Potential advantages: Few patient visits, lower costs and less cardiotoxicity.

Abstract 11. Oral Presentation Thursday 3:00pm Trastuzumab (H: Herceptin®) following adjuvant chemotherapy (CT) significantly improves disease free survival (DFS) in early breast cancer (BC) with HER2 overexpression: the HERA Trial. The HERA Study Team.

HERA Trial HERA

(Randomization after chemotherapy) Arm A No Herceptin Arm B Arm C (1 yr) (2 yr) Only Arms A and B analyzed in this interim analysis n = 3,307, median follow-up ~ 1 year

Eligibility HERA Trial

1) Definitively resected primary adenocarcinoma of the breast.

2) Received and completed neoadjuvant and/or adjuvant chemotherapy. Chemotherapy must have been at least 4 cycles of an approved regimen.

3) If node negative tumor size must have been T1c or larger (for adjuvant patients).

4) Normal LVEF by MUGA or echo of > 55%.

5) Her2 IHC +++ or FISH + by central lab.

6) Known (and centrally reviewed ER status).

HERA Trial: Patient / Tumor: Characteristics No Imbalances Between Treatment Arms

(numbers shown are % of total) Age < 50 50 - 59 > 59 Nodes N0 NP (1-3) NP > 4 NeoAdj 51 32 16 33 29 28 11 Adjuvant Regimen Anthracyclines Anthra + Taxane No A or Taxane 68 26 6 ER and PgR Status ER + ER 51 49 Endocrine Adj If HR+ * Tam AI Ovarian Suppr.

80 18 17 None 9 *some pts got > 1 endocrine therapy

DFS: HERA Trial

% alive and disease free 100 90 80 70 60 50 40 30 20 10 0 0 No. at risk 1694 1693 Trastuzumab 1 yr Observation Events 127 220 2-yr DFS % HR [95% CI] p value 85.8

77.4

0.54

[0.43, 0.67] <0.0001

25 5 10 15 20 Months from randomization 1472 1428 1067 994 629 580 303 280 102 87

Efficacy In HERA

Endpoint DFS Trastuzu mab n = 127 DDFS n = 89 OS Contralat BC n = 29 n = 6 Control n = 220 n = 171 n = 37 n = 7 HR 0.54

0.49

0.76

- p value < 0.001

< 0.001

ns --

DFS In Patient Subsets: HERA Trial

Hazard ratio Nodal status Any, neo-adjuvant chemotherapy 0 pos, no neo-adjuvant chemotherapy 1-3 pos, no neo-adjuvant chemotherapy



4 pos, no neo-adjuvant chemotherapy Anthracycline, no taxane Anthracycline + taxane Pos + no endocrine therapy Pos + endocrine therapy Age group <35 yrs 35-49 yrs 50-59 yrs



60 yrs 358 1100 972 953 203 2307 467 1234 1490 1091 0.53

0.52

0.51

0.53

0.64

0.43

0.49

0.68

0.52

0.53

0 Trastuzumab Better 1 Observation Better 2

Overall Safety in HERA

(very early 1 year median follow-up report) Observation N=1708 1 Year trastuzumab N=1678 >1 Grade 3/4 AE 4.4 % 7.9 % Fatal AE 0.2 % a 0.4 % b AE, adverse event a Cardiac failure, suicide, unknown b Cerebral haemorrhage, cerebrovascular accident, sudden death, appendicitis, 2 unknown Treatment withdrawals in trastuzumab group in 8.5% of patients. Safety in 5.5%, refusal in 2.5%, other in 0.5%

Cardiac Safety in HERA

(very early 1 year median follow-up report) LVEF < 50% and decrease by



10 EF points CHF grade III/IV, and / or cardiac death Observation N=1736 2.3 % 1 Year trastuzumab p < 0.001

N=1677 7.4 % 0 % 0.6 % p < 0.001

Authors’ Conclusions / Comments

Trastuzumab following adjuvant CT significantly prolongs DFS in women with HER2-positive breast cancer Trastuzumab significantly reduces the risk of distant metastases Trastuzumab after chemotherapy is associated with a low incidence of severe CHF (0.6%) Long-term follow-up will provide clarification of the survival gain further safety data information on trastuzumab treatment duration (1 vs 2 years)

Abstract 46: Oral Presentation Thursday 10:45am Trastuzumab sensitivity of breast cancer with coamplification of HER2 and cMYC suggests pro apoptotic function of dysregulated cMYC in vivo.

Kim C, Bryant J, Horne Z, Geyer CE, Wickerham DL, Wolmark N, Paik S. NSABP Operations and Biostatistical Center, Pittsburgh, PA

cMYC: Initial Hypothesis

cMYC disregulation (amplification) would provide an alternative path to drive cell proliferation from that of the Her2 system. Prediction: In Her2 + / cMYC + tumors trastuzumab will be less effective than in Her2+ / cMYC tumors. This prediction was tested using tumor material and data from NSABP B31

NSABP trial B-31

Control: AC



T Experimental arm: AC



TH = doxorubicin/cyclophosphamide (AC) 60/600 mg/m 2 q 3 wk x 4 = paclitaxel (T) 175 mg/m 2 q 3 wk x 4 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

%

Combined Analysis for

DFS

of NSABP B-31 / NCCTG – N9831

AC



TH 87% 85% AC



T 75% 67% AC



T AC



TH N 1679 1672 Events 261 134 HR=0.48, 2P=3x10 -12 Years From Randomization

Time to First Recurrence, B31 (N=1549) Just The Opposite of Prediction!

0 MYC+,AC->TH n = 237 MYC-,AC->TH n = 538 MYC-,AC->T n = 540 MYC+,AC->T If cMYC+ HR = 0.24, p < 0.001

If cMYC – HR = 0.63, p = 0.01

Test for interaction p = 0.01

n = 234 1 2 3 4 5

cMYC Theorey

cMYC +: Drives both proliferation and Subsequent apoptosis But in the presence of apoptosis blocker

(such as overexpression of Her2?)

cMYC + Her2+: Drives proliferation only But in the presence of apoptosis blocker blocker (such as trastuzumab) cMYC + Her2 + Trastuzumab: Drives proliferation and Drives subsequent cell death

Authors’ Comments / Conclusions

1) Contrary to our a priori hypothesis, patients with tumors that had cMYC amplification derived more benefit from adding trastuzumab to AC->T regimen 2) This data suggests that HER2 may contribute to carcinogenesis by suppressing pro-apoptotic function of deregulated cMYC 3) Inhibition of HER2 signaling by trastuzumab may turn on pro-apoptotic function of cMYC in such tumors 4) It may be more effective to target cooperating oncogenes than cMYC itself and take advantage of pro-apoptotic function of cMYC

Abstract 2038. Poster Presentation. Friday 7 am poster presentation Exploratory analysis from NCCTG N9831: do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy?

Perez EA, Suman VJ, Davidson NE, Kaufman PA, Martino S, Dakhil SR, Ingle JN, Rodeheffer RJ, Gersh BJ, Jaffe AS. NCCTG, Rochester, MN; ECOG, Philadelphia, PA; CALGB, Chicago, IL; SWOG, San Antonio, TX

Analysis of Three Arms of N9831

n = 3,505; median follow-up 1.5 yr

NCCTG N9831

Arm A Arm B Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m 2 q 3 wk x 4 = paclitaxel (T) 175 mg/m 2 q 3 wk x 4 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

LVEF was checked Pre AC, Post AC, and 3, 6, and 15-18 months post starting paclitaxel.

N9831 Cardiac Eligibility

LVEF within institutional normal range as assessed either by MUGA or ECHO No active cardiac disease

N9831: Effect of AC * 4 on LVEF

Control Sequential Concurrent Total LVEF drops > 15% LVEF drops < 15 but below LLN Prohibited from continuing 3.8 % 3.1 % 6.9 % 1.7 % 2.5 % 4.2 % 2.3 % 1.6 % 3.9 % 2.6 % 2.4 % 5.0 % Of course no differences would be expected. A nearly identical result was obtained in NSABP B-31 in which 4% of patients were prohibited from going on post AC * 4.

Patient / Tumor: Characteristics For Patients Getting Post AC Therapy (No Imbalances Between Treatment Arms)

Median Age Meds for hypertension Radiation to Right Chest Radiation to Left Chest Median Pre AC * 4 LVEF Median Post AC * 4 LVEF 48 years 17 % 36 % 33 % 63 % 62 %

N9831: Post AC * 4 Cardiac Issues

Control Sequential Concurrent CHF LVEF drops > 15 % Cardiac Death 0.2 % 7 % 0.2 % 2.2 % 14 % 0.2 % 3.5 % 17 % 0.2 % All cardiac events out to 3 years of follow-up. ~ 3 % CHF rate similar to that of NSABP B-31 In this N9831 “cardiac events” only included CHF and cardiac death. (LVEF falls were not “events”)

Cardiac Safety Concurrent Arm

: N9831 Age and Post AC LVEF were predictors of the risk of a cardiac event (at 2 yrs fu) Post AC LVEF < 55% Initial LVEF >/= 55% Risk of Cardiac Event (%) Age younger than 60 Age 60 and older 1.7 % 1.7 % 2.4 % 8.5 %

These patients got the same treatment as on B31 but for reasons that are unclear, there was not a high risk of cardiac events in the older patients who started on with LVEF of < 55% (in the NSABP study 20% of the patients in this category developed CHF).

Cardiac Safety Sequential Arm

: N9831 Age and Post AC LVEF were predictors of the risk of a cardiac event (at 2 years of fu) Post AC LVEF < 55% Initial LVEF >/= 55% Risk of Cardiac Event (%) Age younger than 60 Age 60 and older 3.6 % 0 % 2.1 % 4.5 %

There was no comparable arm in B-31.

Authors’ Comments / Conclusions

1) Trastuzumab increases risk of cardiac events about 2.5 to 3.5 % in this selected population. 2) CHF that developed improved with treatment. 3) Trend to more risk with age 4) Radiation therapy, post AC LVEF has no effect on risk 5) No differences in average post treatment LVEF between control and trastuzumab arms. 6) About 15% of patient on the concurrent arm had to discontinue trastuzumab therapy because of cardiac events.

Impact Of New Information About The Use Of Adjuvant Trastuzumab From The 2005 San Antonio Breast Cancer Symposium 1) Consolidates observation that concurrent chemo/trastuzumab has a major effect on DFS which is likely to translate into a OS advantage.

2) Leaves open the question that whether trastuzumab is as dramatically effective when used after chemotherapy, or when used concurrently with a non-anthracycline based regimen. 3) Consolidates observation that concurrent chemo/trastuzumab modestly increases risk of CHF and cardiac events.

4) Suggests that short course, or sequential trastuzumab has better cardiac safety profile, but provides no evidence that these strategies are safe in women with preexisting cardiac disease.