Slide 1

Update on Breast Cancer: ASCO 2004 Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast Oncology Clinical Trials Program University of California San Francisco Comprehensive Cancer Center

Slide 2

ASCO Update: Breast Cancer Chemotherapy Neoadjuvant therapy Herceptin for HER2 positive disease Adjuvant therapy Dose dense therapy for high risk node positive disease Metastatic disease Weekly vs every three week paclitaxel Gemcitabine plus paclitaxel vs paclitaxel Novel cytotoxics Abraxane Targeted therapy/surrogate endpoints Prognostic factors Gene analysis Circulating tumor cells

Slide 3

Risk of relapse at 5 years Update on MA.17 Effects of exemestane on bone and cardiovascular endpoints Exemestane as first-line therapy for metastatic disease ASCO Update: Breast Cancer Hormone Therapy

Slide 4

Neoadjuvant Chemotherapy for Breast Cancer in HER2 Positive BC Trastuzumab improves survival when added to chemotherapy for MBC Remarkable synergy exists when combined with doxorubicin Limited by significant cardiac toxicity Is there a way to capitalize on the benefits of both agents without increasing the risk of cardiac damage?

Slide 5

ObjectivesObjectives Compare the pathologic complete response rate in patients receiving chemotherapy with or without trastuzumab Compare the pathologic complete response rate in patients receiving chemotherapy with or without trastuzumab Histologically confirmed invasive breast cancer T 1-3, N 0-1, M 0 Histologically confirmed invasive breast cancer T 1-3, N 0-1, M 0 Her-2 + by FISH or IHC 3+ Her-2 + by FISH or IHC 3+ Significantly Higher Pathological Complete Remission (PCR) Rate Following Neoadjuvant Therapy with Trastuzumab [Herceptin (H)], Paclitaxel (P) and Anthracycline-Containing Chemotherapy (CT): Initial Results of a Randomized Trial in Operable Breast Cancer (BC) with HER-2 Positive Disease Buzdar et al, ASCO 2004

Slide 6

Paclitaxel: 225 mg/m 2 over 24 h FEC: 75mg/m 2 epirubicin

Slide 7

Slide 8

Slide 9

Slide 10

Slide 11

The addition of trastuzumab to taxane and anthracycline-containing chemotherapy as utilized in this trial significantly increased the pathological complete response rates in patients with HER-2 positive breast cancerThe addition of trastuzumab to taxane and anthracycline-containing chemotherapy as utilized in this trial significantly increased the pathological complete response rates in patients with HER-2 positive breast cancer Addition of trastuzumab resulted in significantly higher incidence of neutropeniaAddition of trastuzumab resulted in significantly higher incidence of neutropenia 11 vs 21, p.0311 vs 21, p.03 No clinical cardiac toxicity was observedNo clinical cardiac toxicity was observed Where should we go from here?Where should we go from here? Not a regimen to take home yet! Not a regimen to take home yet! Consider use of Herceptin off protocol for LABC Consider use of Herceptin off protocol for LABC Adjuvant data to follow Adjuvant data to follow

Slide 12

26.4% required transfusions in the phase I/II study of dose density Dose Dense Sequential Chemotherapy with ETC: The AGO Trial. Mobus et al, #513

Slide 13

Slide 14

Time to Relapse and RFS Subgroup Analysis Time to relapse 127 vs 94 mo (p =.0009) No impact on TTR of epoietin Less transfusions 28 v 12% One patient died of AML in the ETC arm Hazard ratio 0.64

Slide 15

Slide 16

Take Home Points Dose dense and dose intense sequential ETC is better than standard EC followed by T in women with > 4 + axillary lymph nodes This is the first large study to show survival benefit in patients with high risk node positive disease Short follow-up (28 months) Unclear whether benefits are due to the dose-density or the dose-intensity of the regimen Superior arm had higher doses as well as higher density Treatment is reasonably well tolerated with growth factor support Chemotherapy can be given safely every 2 weeks, this shortens duration of treatment Epo had no effect on survival Contrary to prior studies suggesting worse outcome with epo

Slide 17

CALGB 9840: Phase III study of weekly vs. every third week paclitaxel in the treatment of metastatic breast cancer, with trastuzumab for HER2 + MBC and randomized for trastuzumab for HER2 normal MBC Primary objectives Weekly (q1w) paclitaxel (P) improves response in MBC as compared to q3w P Adding trastuzumab (T) to q1w or standard (q3w) P improves response for HER2 normal MBC Secondary objective TTP and OS are better with weekly paclitaxel compared with every three week dosing Seidman et al, ASCO 2004

Slide 18

CALGB 9342 To reduce patients required for study endpoints, and study costs, 158 patients were borrowed (total 738) 175 mg/m 2 210 mg/m 2 250 mg/m 2 Response TTP OS Winer E et al. J Clin Oncol 22: 2061-2068, 2004 23%26% 21% Multivariate p = NS 0.12 0.30 3.9 mos4.1 mos4.9 mos 11 mos12 mos14 mos

Slide 19

= paclitaxel 80 mg/m 2 * qw vs 175 mg/m 2 q 3w = trastuzumab 4mg/kg load, 2 mg/kg/w** CALGB 9840: Design CALGB 9840: Design MBC with 0-1 Prior Chemotherapy for MBC, > 12 mo Since Adjuvant Taxane q3w P q1w P 1998-2000 (n=171; HER2 unknown) q3wP+T q1wP+T 2000-2003 (n=406; HER2 known) H E R 2 (+) H E R 2 (-) *first 116 pts at 100 mg/m 2 x 6, then all pts 80 mg/m 2 qw **Her 2 + receive trastuzumab, Her 2 randomized to T or no T

Slide 20

CALGB 9840 Tumor Response 100 80 60 40 20 0 q1w P q3w PT No T 40% 28%35% 29% (OR=1.61, p=0.017)(p=0.34) Percentage n = 344 373 112 111 (all patients) (HER2 normal patients)

Slide 21

CALGB 9840 Time to Progression 12 11 10 9 8 7 6 5 4 3 2 1 q1w P q3w PT No T 9 mos 5 mos7 mos 6 mos (Adjusted HR=1.45, p=0.0008)(p=0.09) months 74/11382/115221/350324/385 n (events/pts) = (all patients)(HER2 normals)

Slide 22

CALGB 9840: Conclusions Weekly P is superior to every 3 week P for response and time to progression in MBC, there was no difference in overall survival (24 vs 16 mo) Trastuzumab does not improve outcome when added to P for HER2 normal MBC Companion correlative studies are pending Less neutropenia in the weekly arm 5 vs 15% grade 3-4 More sensory neuropathy in the weekly arm 30% - 100 mg weekly (n116); 19% - 80 mg weekly (n228) 12% - q 3 weeks (n224) Do the borrowed patients affect the observed outcome? 75 v 20% second line Without those patients, trend toward improved response, significant improvement in TTP

Slide 23

Treat until documented PD All sites of disease assessed every 8 weeks Paclitaxel 175 mg/m 2 (3 hr) Gemcitabine 1250 mg/m 2 Paclitaxel 175 mg/m 2 (3 hr) GT arm (21-day cycle) T arm (21-day cycle) Day 1: Gemcitabine 1250 mg/m 2 Day 8: RANDOMIZERANDOMIZE Standard paclitaxel premedications Phase III Study of Gemcitabine plus Paclitaxel versus Paclitaxel as Frontline Therapy for MBC: Albain et al, ASCO 2004 ELIGIBILITY Unresectable, locally recurrent or metastatic measurable disease No prior chemotherapy for advanced disease Prior adjuvant chemotherapy (anthracycline-based, unless contraindicated) 98 centers, 19 countries

Slide 24

JHQG Planned Interim Analysis Endpoint GT T p-value Response rate 40.8% 22.1%