ASCO 2005 Adjuvant Breast Cancer Update Lori J. Goldstein, MD Director, Breast Evaluation Center Leader, Breast Cancer Research Program Fox Chase Cancer Center Philadelphia, PA

ASCO 2005 Breast Cancer Update Abstract #/ Session Title/ Subject 512 E2197: Adjuvant AT vs. AC 513 ECTO: A->CMF vs AT->CMF MoAB Ed N9831/ NSABP B31 Joint Analysis – Adjuvant Trastuzumab MoAB Ed N9831 – Adjuvant Trastuzumab MoAB Ed HERA: Adjuvant Trastuzumab MoAB Ed E2100: T +/- bevacizumab MBC

E2197: Phase III AT vs. AC in the Adjuvant Treatment of Node Positive and High Risk Node Negative Breast Cancer Goldstein LJ, O’Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE. On behalf of ECOG and the US Intergroup, thank you for allowing me to present the first results of E2197, a randomized trial comparing adriamycin plus docetaxel to adriamycin plus cyclophosphamide for node positive and hi risk node negative breast cancer.

E2197 Rationale Phase II Studies Anthracyline + Taxane Study A/Por D mg/m2 RR % CHF % Gianni/ 60/P200 80-90 20 Dombernowsky Sledge E1193 50/P150 47 9.8 Sparano E4195 60/P200 57 6 Sparano E1196 60/D60 57 6 Cresta 60/D60 63 10 Misset 50/D75 81 0 Given their single agent activity, relative non-cross resistance, partially non-overalpping toxicities and different mechanisms of action, there was a clear rationale for combining the taxanes with doxorubicin. The encouraging results of the combination of doxorubicin and palcitaxel were associated with a risk of cardiac toxicity related to cumulative doxorubicin dose and alteration of doxorubicin pharmacokinetcs by paclitaxel which was highly sequence dependent Here are some of the Phase II trial s in metastatic breast cancer. The combination of doxorubicin and docetaxel was selected for E2197 based on the relative cardiac safety of this combination.

E2197 Rationale Phase III Studies:Anthracyline + Docetaxel MBC AT (50/75) AC (60/600) RR% 60 47 p=.012 TTPwk 37.1 31.9 p=.015 CHF % 2 4 FN% 33 10 No difference OS Nabholtz JCO 2003 TAC vs. FAC MBC Mackey ASCO 2002 Increase RR with TAC; no difference in TTP or OS TAC vs. FAC Adjuvant: Nabholtz ASCO 2002 TAC increase DFS/ OS Subsequent to the initiation of E2197 several randomized trials were published supporting the investigation of this combination in the adjuvant treatment of early stage breast cancer. Here one can see that AT resulted in an increased response rate and time to tumor progression compared to AC in metastatic breast cancer with a low incidence of CHF. As you can also see the AT combination is associated with significant febrile neutropenia when given without growth factor support. These data are also supported by the comparison of TAC vs FAC. While TAC resulted in an increased response rate there was no improvement in time to progression when compared to FAC in metastatic breast cancer. However, in the adjuvant setting, TAC was superior to FAC in terms of both disease free and overall survival.

E2197: Schema R A N D O M I Z E IV q 3wk x 4 Cipro 500mg po. bid D8 x 10d Adriamycin 60mg/m2 Docetaxel (T) 60mg/m2 T1-3 N0-1 M0 No then T> 1.0cm Adriamycin 60mg/m2 Cyclophosphamide 600mg/m2 IV q 3wk x 4 Tamoxifen 20mg daily x 5 years post chemotherapy for ER and/or PR positive tumor Stratified: Nodal Status HR Status (ER+PR+,ER+PR-, ER-PR+,ER- PR-,ER/PR unknown) Menopausal Status *G-CSF - per ASCO guidelines

E2197: Objectives To determine whether AT will improve DFS and OS To compare toxicity of AT vs. AC No difference in LVEF between AT and AC reported ASCO 2003. At ASCO 2003 we reported no difference in LVEF bewteen AT and AC.

E2197: Study Design Primary endpoint: DFS-recurrences, new breast primaries, or death without recurrence whichever comes first. Design: 83% power to detect a 25% reduction of the DFS failure hazard rate (5% absolute improvement in 5 yr DFS from 78% to 83% by using AT) Sample size: 2778 including an estimated 10% ineligible Primary Analysis: Intent-to-treat analysis on eligible patients. The primary endpoint was DFS defined a recurrence, new breast cancer, or death without recurrence. With 2778 patients (inlcuding 10% ineligible) this study had 83% power to detect a 25% reduction in DFS hazard rate using AT This was an intent to treat analysis. __________________________________________________________________________________________________________________ (assuming a 5 yr 78% DFS on the AC arm OR The ability to detect a 5% absolute improvement in 5 yr DFS from 78% to 83%. 2 interims and a final analysis planned (total information=420 DFS failures) The information time was defined by the number of eligible patients who recur, have a new breast cancer primary or die without recurrence whichever occurred first.

E2197:Results Opened 7/30/98; closed 1/21/00 2952 entered through the collaborative effort of ECOG, CALGB, NCCTG, SWOG and EPP. 3% Ineligibility rate 2885 eligible and analyzable

E2197: Patient Characteristics Balanced for age, HR, menopause, nodes, surgery, grade and size Age range 24-85 yo, Median age 51 64% ER + 65% LN- Grade: 10% low, 38% int., 46% high Size: 0.1 – 12.5 cm; Median – 2.0 cm The arms were balanced for age, hormone receptors, menopause, nodes, surgery, grade and size. The Age range was 24-85 , with a Median age of 51 64% were ER + 65% were LN- For Grade: 10% were low, 38% int., and 46% high For Size:the range was 0.1 – 12.5 cm; with a Median size of 2.0 cm

E2197: Toxicity Summary AT AC Feb/Infxn/N 28% 10% AML/MDS 7 7 Lethal Events Related 4 Unrelated 2 2 As noted in other studies of the AT combination, the neutropenia associated with fever and infection was significant at 28% compared to AC where the rate was 10%. Again noted is that growth factor was not given prophylactically, but rather by ASCO guidelines. There were 7 cases of AML/MDS on each arm. There were 7 deaths during or within 30 days of chemo and One death at 42 days. 4 were related to treatment with AT, one with visceral ishcemia( ischemic bowel), 2 secondary to sepsis and one cardiac in a patient with a cardiac history. Ages 62-70). AT Unrelated: Cardiac – h/o cardiac disease (77) Sudden death (60) AC Unrealted Angioedema of the larynx post endoscopy MI post chemo

E2197 Cardiac Safety AT AC Grade 3 4 5 3 4 CHF 15 2 1 10 Total 18 10 % .01 .006 No statistically significant difference There 18 and 10 cases of CHF on the AT and AC arms respectively, with no significant difference between the 2 arms.

E2197: DFS Fall 2004 DMC (409/ 420 DFS failures) O’Brien-Fleming boundary had not been crossed, there was not enough evidence to suggest a significant difference April 2005 - Median follow-up = 59 months 432/ 2885 (15%) recurred, developed second breast cancer or died. At the Fall 2004 DMC, the study was at full information and the ECOG DMC released the study for presentation and publication. The current data are as of April 2005. At 59 month median follow-up, 432 of 2885 patients recurred, developed second breast cancers or died.

E2197: DFS/OS Hazard Ratio HR > 1 favors AT HR (adjusted) DFS 1.03 (0.86-1.25), p=0.70 OS 1.09 (0.85-1.40), p=0.49 As of 4/4/05, 242 deaths With a Hazard ratio greater than 1 favoring AT there was no significant difference in disease free or overall survival between the 2 arms. The Hazard ratio was adjusted for age, nodes, ER, menopausal status, surgery, grade, size. The unadjusted HR’s were not significantly different.

E2197 Disease-Free Survival Percent 10 20 30 40 50 60 70 80 90 100 Months 12 24 36 48 72 AT AC 1444 213 1441 219 N Events 87 (1) 4-Yr % (S.E.) E2197 Disease-Free Survival The K-M curves are overlappiing for a disease free survival. The 4 year DFS was 87% for both arms.

Percent 10 20 30 40 50 60 70 80 90 100 Months 12 24 36 48 72 AT AC 1444 117 1441 125 N Events 94 (1) 93 4-Yr % (S.E.) E2197 Overall Survival Similarly, the curves overlap for overall survival with 94% survival at 4yrs.

E2197: DFS Subgroup Analysis No significant effect within any of the following subgroups : Nodes Size Age Menopausal Status Grade Type of Surgery Race No significant effect was observed within any of the following subgroups : Nodes Size Age Menopausal Status Grade Type of Surgery Race NB: There were no significant interactions between treatment and any of these variables.

E2197 Disease-Free Survival:ER-/PR- 10 20 30 40 50 60 70 80 90 100 100 90 80 70 60 Percent Percent 50 40 30 20 10 12 24 36 48 60 72 12 24 36 48 60 72 Months Months N Events 4-Yr % (S.E.) N Events 4-Yr % (S.E.) AT 454 85 83 83 83 (2) (2) (2) AT 52 14 77 (6) AC 463 109 79 79 79 79 79 79 79 79 (2) (2) (2) (2) (2) (2) (2) (2) AC 38 3 95 (4) E2197 Disease-Free Survival:ER+/PR- E2197 Disease-Free Survival:ER+/PR+ 100 100 90 90 80 80 70 70 60 The ER/PR subgroups were prespecified stratification groups at randomization designed to balance the treatment arms. And are not powered to detect differences between the subgroups. While there is no statistically significant difference in the ER+ and ER- tumors, these curves illustrate the 4 prespecified ER/PR subgroups. In the ER-/PR- and the ER+/PR – seen on the left side of the slide, there were fewer events in the AT arm. For the ER-/PR- group, the 4 yr DFS was 83% for AT and 79% for AC. For the ER+/PR- group, the DFS was 90 % and 83% respectively for AT and AC, acknowledging that this subgroup is quite small. On the top right, the ER-/PR+ subgroup was extremely small and may represent lab error for ER and therefore this curve could be collapsed into the ER+/PR+ curve below it showing no difference between the 2 arms, and this represents the majority of patients. 60 Percent 50 Percent 50 40 40 30 30 20 20 10 10 12 24 36 48 60 72 12 24 36 48 60 72 Months Months N Events 4-Yr % (S.E.) N Events 4-Yr % (S.E.) AT 162 22 90 (2) AT 767 91 90 90 90 90 90 90 90 (1) (1) (1) (1) (1) (1) (1) AC 164 34 81 83 81 (3) (3) (3) AC 770 73 92 92 92 92 92 92 92 (1) (1) (1) (1) (1) (1) (1)

Disease Free Survival ER-/PR- 1.30 (0.96, 1.70) ER-/PR+ 0.30 (0.10, 0.95) ER+/PR- 1.64 (0.96, 2.80) Here the same subgroup data are illustrated in this forest plot of DFS where anything to the right of 1 favors AT. Again the largest group is the ER+/PR+ group with the very small ER-/PR+ group likely collapsing into it. This again suggests that the PR – tumors may potentially benefit from AT but the study was not powered to statistically detect these differences. The same pattern is seen for OS, data not shown. These data support the hypothesis presented by Don Berry at San Antonio, that the in the ER positive tumors the large benefit provided by Tamoxifen, overwhelms the potential benefit to chemo, or that the prognosis of these tumors is so good it is difficult to detect a difference between the 2 chemotherapy arms. Taken together along with the Genomic Health data, this data supports the hypothesis that the biology of the tumor may predict the benefit to individual therapies. ER+/PR+ 0.79 (0.58, 1.10) 0.1 0.2 0.5 1 2 5 Favors AC Favors AT

E2197 Conclusions These results show a better than expected outcome for both regimens. 87%(obs) vs 78% (expected for AC) DFS at 4 yrs. At 59 mo median follow-up, there is no difference in DFS or OS between AT and AC. Prespecified stratifications at randomization: LN, menopause, ER/PR – no significant difference between the 2 treatment arms. In PR negative tumors, a potential benefit to AT may be suggested. These results show a better than expected outcome for both regimens. 87%(obs) vs 78% (expected for AC) DFS at 4 yrs. At 59 mo median follow-up, there is no difference in DFS or OS between AT and AC. Prespecified stratifications at randomization: LN, menopause, ER/PR – no significant difference between the 2 treatment arms. In PR negative tumors, a potential benefit to AT may be suggested.

E2197: Issues for Discussion Would longer f/u change these results? Unlikely Observed DFS = 87% at 4 yrs. Expected DFS = 78% at 4yrs. Aromatase Inhibitor Affect: 60% on Tam; Median 41 mo; AI info collected; future analysis Subset analysis of prespecified ER/PR stratifications: Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies. Central review of ER/PR/Her 2 pending Genomic Health/ Sanofi-Aventis Analysis: Oncotype Genomic profiling Use as training set for validation with E1199 Pharmacogenomics PACCT- 1 Trial Would longer f/u change these results? Unlikely Observed DFS = 87% at 4 yrs. Expected DFS = 78% at 4yrs. The better than anticipated DFS may represent the continued improved prognosis over time that we have observed in Intergroup trials. In fact the predecessor to this trial, 9313, there was an 80% 5 yr DFS. What about the Aromatase Inhibitor Affect: 60% started Tam; About half have finished; with a Median of 41 mo on tamoxifen; AI info collected since 2004 for future analysis Subset analysis of prespecified ER/PR stratifications: lead to the Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies. Central review of ER/PR/Her 2 is ongoing With support from Genomic Health and Sanofi-Aventis we will perform the following analyses Oncotype Genomic profiling to Use these data as training set for validation with E1199 In addition to Pharmacogenomics In addition, These data support the design of the PACCT –1 trial Program for the assessment of clinical cancer tests – Phase III validation study of genomic profiling ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Intergroup 9313 AC vs. A->C; at median f/u of 5.3 yrs,, the estimated 5 yr DFS was 80%. Refer to NSABP studies of eight + years f/u to see differences in low risk population of tumors< 1 cm. B 13, 19, 14 and 20. Fisher at al. JNCI 93(2): 112-20. Jan 17, 2001 Prognosis and treatment of patient with breast tumors one cm or less and negative axillary nodes. ER - = 235: surgery +/- ctx ER + = 1024: surgery, tam +/- ctx 8yr RFS for ER -: Surgery = 81%; surgery + ctx = 90%; p=.06 Survival similar in both groups: 93 and 91%; p= .65. 8 yr RFS for ER+: Surgery = 86% Surgery/tam = 93%; p= .01 Surgery/tam/ctx = 95%; p= .07 compared with tam Survival was 90%, 92% ( p=,41). and 97% respectively. P=.01 in the latter 2 groups. Although the majority of tumor recurrences occur in the first decade of f/u, the proportion of recurrences that occur in the second decade of f/u increases in women with small tumors. Consequently a follow-up longer than 8 years is likely necessary to allow for a more meaningful assessment of the outcome of these patients. Mortality at 8 yrs f/up was 8% for t< 1 cm. I/2 of deaths were related to breast cancer. Therefore the findings in these patients with short follow-up should be viewed with caution. Would longer follow-up change these results? Statistically no, even though the entire group did better that anticipated compared to historical controls. PACCT-1 Program for the assessment of clinical cancer tests – Phase III validation study of genomic profiling

Anne O’Neill, Deborah Namande, Eric Ross Thank You Patients Data managers/ CRA’s CALGB, NCCTG, SWOG, EPP Anne O’Neill, Deborah Namande, Eric Ross