Trial Design

Unscheduled DSMB Review October 2003

Why: High overall complete pathological response rate (47%)Findings: Treatment Pathological CR P FEC alone (N=16) 25% P FEC + H (N=18) 66.7% Additional 8 patients were still on study final N = 42 DSMB decision: Trial should be closed evident superiority of P FEC + H.Rationale: If accrual to 164 patients - 95% probability P FEC + H superior (Bayesian predictive probability)

Pathological Complete Response Rates

26.3% N=19

65.2% N=23

25% N=16

66.7% N=18

P=0.016

95% CI (41%-87%)

95% CI (43%-84%)

Pathological Complete Response Rates by Hormonal Receptor Status

27.2% N=11

61.5% N=13

25% N=8

70% N=10

Adverse Events Cardiac Safety Data

EventsP FEC aloneP FEC + H N=19 N=23CHF00 >10% Decrease in ejection fraction57 - Decrease on paclitaxel04 - Decrease on FEC53

Improvement in ejection fraction on follow-up evaluation23

Abnormal Troponin-T01

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 cancerAddition of trastuzumab resulted in significantly higher incidence of neutropenia11 vs 21, p .03No clinical cardiac toxicity was observedWhere should we go from here? Not a regimen to take home yet! Consider use of Herceptin off protocol for LABC Adjuvant data to follow

Conclusion

Dose Dense Sequential Chemotherapy with ETC: The AGO Trial. Mobus et al, #51326.4% required transfusions in the phase I/II study of dose density

Time to Relapse and RFS Subgroup AnalysisTime to relapse 127 vs 94 mo (p = .0009)No impact on TTR of epoietinLess transfusions28 v 12%One patient died of AML in the ETC armHazard ratio 0.64

Take Home PointsDose dense and dose intense sequential ETC is better than standard EC followed by T in women with > 4 + axillary lymph nodesThis is the first large study to show survival benefit in patients with high risk node positive diseaseShort 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 densityTreatment is reasonably well tolerated with growth factor supportChemotherapy can be given safely every 2 weeks, this shortens duration of treatmentEpo had no effect on survivalContrary to prior studies suggesting worse outcome with epo

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 objectivesWeekly (q1w) paclitaxel (P) improves response in MBC as compared to q3w PAdding trastuzumab (T) to q1w or standard (q3w) P improves response for HER2 normal MBCSecondary objectiveTTP and OS are better with weekly paclitaxel compared with every three week dosing

Seidman et al, ASCO 2004

CALGB 9342To reduce patients required for study endpoints, and study costs, 158 patients were borrowed (total 738)

175 mg/m2210 mg/m2250 mg/m2Response

TTP

OSWiner E et al. J Clin Oncol 22: 2061-2068, 200423%26%21%Multivariate p =NS0.120.303.9 mos4.1 mos4.9 mos11 mos12 mos14 mos

= paclitaxel 80 mg/m2* qw vs 175 mg/m2 q 3w= trastuzumab 4mg/kg load, 2 mg/kg/w** CALGB 9840: DesignMBC with 0-1 Prior Chemotherapy for MBC, > 12 mo Since Adjuvant Taxaneq3w Pq1w P1998-2000(n=171; HER2 unknown)*first 116 pts at 100 mg/m2 x 6, then all pts 80 mg/m2 qw**Her 2 + receive trastuzumab, Her 2 randomized to T or no T

CALGB 9840Tumor Response100

80

60

40

20

0q1w P q3w PT No T40% 28%35% 29%(OR=1.61, p=0.017)(p=0.34)Percentagen = 344 373 112 111(all patients)(HER2 normal patients)

CALGB 9840Time to Progression 121110987654321q1w P q3w PT No T9 mos 5 mos7 mos 6 mos(Adjusted HR=1.45, p=0.0008)(p=0.09)months74/11382/115221/350324/385n (events/pts) =(all patients)(HER2 normals)

CALGB 9840: ConclusionsWeekly 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 MBCCompanion correlative studies are pendingLess neutropenia in the weekly arm5 vs 15% grade 3-4More sensory neuropathy in the weekly arm30% - 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 lineWithout those patients, trend toward improved response, significant improvement in TTP

Phase III Study of Gemcitabine plus Paclitaxel versus Paclitaxel as Frontline Therapy for MBC: Albain et al, ASCO 2004Treat until documented PD

All sites of disease assessed every 8 weeks Paclitaxel 175 mg/m2 (3 hr)

Gemcitabine 1250 mg/m2 Paclitaxel 175 mg/m2 (3 hr) GT arm (21-day cycle) T arm (21-day cycle) Day 1: Day 1: Gemcitabine 1250 mg/m2Day 8:RANDOMIZEStandard paclitaxel premedicationsELIGIBILITYUnresectable, locally recurrent or metastatic measurable diseaseNo prior chemotherapy for advanced diseasePrior adjuvant chemotherapy (anthracycline-based, unless contraindicated)98 centers, 19 countries

JHQG Planned Interim AnalysisEndpoint GT T p-valueResponse rate 40.8% 22.1%