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Andrew D. Seidman , Adam Brufsky, Rafat H. Ansari,

Abstract 1000. Phase III Trial of Gemcitabine plus Docetaxel (GD) Compared to Capecitabine plus Docetaxel (CD) with Planned Crossover to the Alternate Single Agent in Metastatic Breast Cancer (MBC). Andrew D. Seidman , Adam Brufsky, Rafat H. Ansari,

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Andrew D. Seidman , Adam Brufsky, Rafat H. Ansari,

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  1. Abstract 1000 Phase III Trial of Gemcitabine plus Docetaxel (GD) Compared to Capecitabine plus Docetaxel (CD) with Planned Crossover to the Alternate Single Agent inMetastatic Breast Cancer (MBC) Andrew D. Seidman, Adam Brufsky, Rafat H. Ansari, James R. Rubinsak, Richard S. Stein, Lee S. Schwartzberg, John F. Stewart, Luping Zhao, John F. Gill, D. Fritz Tai

  2. DISCLOSURES This work was funded by Lilly USA, LLC. Dr. Seidman has been paid by Lilly and Sanofi-Aventis as a consultant and speaker. Dr. Brufsky has been paid by Lilly as a consultant and speaker. Drs. Ansari, Rubinsak, Stein, Schwartzberg, and Stewart have no disclosures. Drs. Zhao, Gill, and Tai are employees and shareholders of Lilly USA, LLC.

  3. BACKGROUND • Docetaxel (D) + capecitabine (C) improves response rate (RR) and time to progressive disease (TTP) over docetaxel as first-line treatment of MBC after prior anthracycline.1 • Paclitaxel + gemcitabine (G) improved RR and TTP over paclitaxel as first-line treatment of MBC after prior adjuvant anthracycline therapy.2 • GD and CD yielded nearly identical efficacy in anthracycline-pretreated MBC, but GD resulted in improved TTF due to toxicity-related treatment discontinuation with CD.3 • O’Shaughnessy J, et al. JCO 2002 • Albain KS, et al. JCO 2008 • Chan S, et al. JCO 2009

  4. RATIONALE Both combination and single-agent chemotherapy have a role in the management of MBC. Few large, randomized, Phase III trials have examined pre-planned crossover chemotherapy strategies in MBC. Prior Phase III trials of CD have been complicated by treatment-limiting palmar-plantar erythrodysesthesia (PPE), resulting in frequent capecitabine dose reduction outside the clinical trial setting. This study compared safety and efficacy of GD and CD in patients with MBC, where the alternate, crossover monotherapy (GDC or CDG) was predetermined.

  5. STUDY OBJECTIVES Primary TTP Secondary Toxicity Overall response rate (ORR) Progression-free survival (PFS) Overall survival (OS)

  6. STUDY DESIGN AND TREATMENT R A N D O MI Z E GD Induction: G 1000 mg/m2 IV on Days 1,8 + D 75 mg/m2 IV on Day 1 every 21 days until disease progression (PD) C Crossover: C 1000 mg/m2 PO BID on Days 1-14 every 21 days until PD Off study Follow-up (1:1) CD Induction: D 75 mg/m2 IV on Day 1 + C 1000 mg/m2 PO BID on Days 1-14 every 21 days until PD G Crossover: G 1000 mg/m2 IV on Days 1,8 every 21 days until PD Off study Follow-up • Patient Stratification Factors • First- versus second-line treatment • Prior anthracycline therapy • Visceral dominant disease • ECOG PS • Measurable versus non-measurable (evaluable) only disease

  7. MAJOR ELIGIBILITY CRITERIA Inclusion • Locally advanced or metastatic breast cancer. • No more than one prior course of chemotherapy for MBC. • Measurable and non-measurable (evaluable) disease. • Adequate renal, hepatic, and bone marrow function. • ECOG PS ≤ 1 Exclusion • Prior taxane therapy for MBC. • Prior gemcitabine or capecitabine therapy. • Concurrent trastuzumab therapy. • CNS metastases.

  8. STATISTICAL CONSIDERATIONS Using Freedman’s method, it was estimated that 442 patients (221 per arm) would be needed to obtain the 385 progression events required to observe a 2-month difference in TTP between GD and CD treatment arms with an 80% statistical power. Time‑to‑event analyses were estimated from date of randomization using the Kaplan-Meier method and results for each arm were compared by log-rank test. All 2‑sided statistical comparisons between the treatment arms were judged relative to a significance level of α=0.05. Data-lock for this final analysis was on 17 March 2009. Data management was performed by query analyses and data reviews. An exploratory, post-hoc analysis of the sum of induction and crossover TTP was performed.

  9. PATIENT DISPOSITION Patients randomly assigned (N = 475) Accrual: 15 February 2002 – 23 December 2008 ITT N = 475 CD Arm (n = 236) GD Arm (n = 239) Withdrew (n = 9) Withdrew (n = 3) Safety N = 463 GD Arm (n = 236) CD Arm (n = 227) Discontinued (n = 236) PD (n = 98) Adverse event (n = 43) Investigator decision (n = 40) Patient request (n = 38) Other (n = 17) Discontinued (n = 227) PD (n = 83) Adverse event (n = 67) Investigator decision (n = 31) Patient request (n = 27) Other (n = 19) Crossover N = 158 CDG (n = 81) GDC (n = 77) Withdrew (n = 1) Withdrew (n = 1) Discontinued (n = 76) PD (n = 50) Adverse event (n = 8) Investigator decision (n = 7) Patient request (n = 6) Other (n = 5) Discontinued (n = 80) PD (n = 53) Adverse event (n = 8) Investigator decision (n = 7) Patient request (n = 9) Other (n = 3) PD = Progressive Disease; ITT = Intent-to-Treat

  10. PHASE III MBC TRIALSPre-Planned Sequential Lines of Chemotherapy CEF = cyclophosphamide, epirubicin, 5-fluorouracil MV = mitomycin C, vinblastine GD = gemcitabine + docetaxel CD = capecitabine + docetaxel

  11. PATIENT CHARACTERISTICSBaseline ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PR = progesterone receptor

  12. PATIENT CHARACTERISTICSPrior Therapy

  13. DRUG ADMINISTRATION * Total number of patients with dose adjustment.

  14. DRUG-RELATED TOXICITY (Induction)Hematologic * Adverse events were defined using NCI-CTC, version 2.0. Prophylactic use of hematopoietic growth factors was not allowed

  15. DRUG-RELATED TOXICITY (Induction)Nonhematologic * Adverse events were defined using NCI-CTC, version 2.0. ALT = alanine aminotransferase; AST = aspartate aminotansferase

  16. EFFICACYTumor Response (Measurable Disease) * Fisher’s exact test

  17. OVERALL SURVIVAL 1.0 0.8 0.6 0.4 0.2 0.0 Survival Probability • Intent-to-treat population 0 6 12 18 24 30 36 42 48 54 60 66 72 Time to Death (Months)

  18. TIME TO PROGRESSIVE DISEASEInduction Phase 1.0 0.8 0.6 0.4 0.2 0.0 Despite over-accrual, censoring resulted in only 324 TTP events, compared to 385 planned events. Progression-Free Probability • Intent-to-treat population 0 6 12 18 24 30 36 42 48 54 60 66 72 Time to Progressive Disease (Months)

  19. TIME TO PROGRESSIVE DISEASECrossover Phase 1.0 0.8 0.6 0.4 0.2 0.0 Progression-Free Probability • Intent-to-treat population 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time to Progressive Disease (Months)

  20. PD Induction Crossover    Baseline Scan Scan Scan TTP1 TTP2 Patient 2 TTP1 Patient 1 Discontinued TTP INDUCTION-CROSSOVER SUMDefinition Further PD • TTP Induction-Crossover Sum is a sub-set analysis of only those patients who • received single-agent crossover therapy (C or G). • Induction TTP (TTP 1) was estimated for all patients from time of randomization • to first PD. • Crossover TTP (TTP2) was estimated for all crossover patients from the time of • first single-agent dose to further PD. • TTP Induction-Crossover Sum was calculated as TTP1 + TTP2.

  21. TIME TO PROGRESSIVE DISEASESummary * Exploratory, post-hoc analysis

  22. TIME TO PROGRESSIVE DISEASEInduction-Crossover Sum 1.0 0.8 0.6 0.4 0.2 0.0 • Exploratory, post-hoc analysis Progression-Free Probability • Treated Patients 0 6 12 18 24 30 36 42 48 54 60 66 72 Time to Progressive Disease (Months)

  23. PATIENT CHARACTERISTICSCrossover Population ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PR = progesterone receptor

  24. PATIENT CHARACTERISTICSPrior Therapy: Crossover Population

  25. PATIENT CHARACTERISTICSBaseline ECOG = Eastern Cooperative Oncology Group

  26. SUMMARY • ORR, TTP, and OS were not significantly different comparing GD and CD. • More Grade 3-4 fatigue, hepatotoxicity, neutropenia, and thrombocytopenia with GD; more Grade 3-4 PPE, gastrointestinal toxicity, and mucositis with CD (despite the lower capecitabine dose). • More patients in the CD arm discontinued therapy due to toxicity (28.4% versus 18.0%, p = .009). • In an exploratory analysis, the TTP sum from induction through crossover was 5.1 months greater for the GDC sequence compared to CDG, but did not reach statistical significance (p = .093).

  27. CONCLUSIONS • GD and CD had similar efficacy with toxicity profiles consistent with prior clinical experience. • In an exploratory, post-hoc analysis of patients who crossed over to the pre-specified second-line therapy, C crossover from GD trended toward greater clinical benefit compared to G crossover from CD. This suggeststhat the GDC sequence may be preferable. • This trial, like others that have attempted to prescribe 2 consecutive lines of therapy, had a modest rate of crossover.

  28. ACKNOWLEDGEMENTS • We are indebted to the patients who participated in this trial. • We thank the supporting institutions and all the health care professionals who provided care and collected data. • We thank Melissa Humbert and Jane Bromund for their diligence in trial management and data acquisition.

  29. BACK-UP SLIDES

  30. TIME TO TREATMENT FAILURE 1.0 0.8 0.6 0.4 0.2 0.0 Non-Failure Probability • Intent-to-treat population 0 6 12 18 24 30 36 42 48 54 60 66 72 Time to Treatment Failure (Months)

  31. PROGRESSION-FREE SURVIVALInduction Phase 1.0 0.8 0.6 0.4 0.2 0.0 Progression-Free Probability • Intent-to-treat population 0 6 12 18 24 30 36 42 48 54 60 66 72 Time to Progressive Disease (Months)

  32. DURATION FROM PD TO CROSSOVER • 5 patients who did not reach PD but received crossover therapy • were excluded from this analysis; 2 patients in GDC and 3 patients • in CDG. • 2 patients did not receive crossover therapy and were excluded from • this analysis.

  33. ECOG PERFORMANCE STATUSPatients at Baseline and at Crossover ECOG = Eastern Cooperative Oncology Group

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