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Phase III Trial of Gemcitabine plus Docetaxel (GD) Compared to Capecitabine plus Docetaxel (CD) with Planned Crossover to the Alternate Single Agent in.

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Presentation on theme: "Phase III Trial of Gemcitabine plus Docetaxel (GD) Compared to Capecitabine plus Docetaxel (CD) with Planned Crossover to the Alternate Single Agent in."— Presentation transcript:

1 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, James R. Rubinsak, Richard S. Stein, Lee S. Schwartzberg, John F. Stewart, Luping Zhao, John F. Gill, D. Fritz Tai Abstract 1000

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 1.O’Shaughnessy J, et al. JCO Albain KS, et al. JCO 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 Patient Stratification Factors First- versus second-line treatment Prior anthracycline therapy Visceral dominant disease ECOG PS Measurable versus non-measurable (evaluable) only disease RANDOMIZERANDOMIZE GD Induction: G 1000 mg/m 2 IV on Days 1,8 + D 75 mg/m 2 IV on Day 1 every 21 days until disease progression (PD) CD Induction: D 75 mg/m 2 IV on Day 1 + C 1000 mg/m 2 PO BID on Days 1-14 every 21 days until PD G Crossover: G 1000 mg/m 2 IV on Days 1,8 every 21 days until PD C Crossover: C 1000 mg/m 2 PO BID on Days 1-14 every 21 days until PD Off study Follow-up Off study Follow-up (1:1)

7 MAJOR ELIGIBILITY CRITERIA Prior taxane therapy for MBC. Prior gemcitabine or capecitabine therapy. Concurrent trastuzumab therapy. CNS metastases. Inclusion Exclusion 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

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

10 PHASE III MBC TRIALS Pre-Planned Sequential Lines of Chemotherapy Study First-Line Therapy Second-Line Therapy % Crossover Second-Line/First-Line Sledge et al. JCO, 2003 Doxorubicin Paclitaxel Doxorubicin 129/245 (52.6%) 128/242 (52.9%) Paridaens et al. JCO 2000 Doxorubicin Paclitaxel Doxorubicin 77/165 (46.7%) 91/166 (54.8%) Joensuu et al. JCO 1988 CEF Epirubicin MV Mitomycin C 88/150 (58.7%) 74/153 (50.3%) Seidman et al. ASCO 2009 GD CD Capecitabine Gemcitabine 77/237 (32.5%) 79/226 (35.0%) CEF = cyclophosphamide, epirubicin, 5-fluorouracil MV = mitomycin C, vinblastine GD = gemcitabine + docetaxel CD = capecitabine + docetaxel

11 PATIENT CHARACTERISTICS Baseline Parameter GD N=239 CD N=236 Age, median (range)57 (27-81)54 (27-82) Age group, n (%) ≤65 years >65 years 188 (78.7) 51 (21.3) 193 (81.8) 43 (18.2) ECOG performance status, n (%) (73.2) 60 (25.1) 176 (74.6) 55 (23.3) ER status, n (%) Positive Negative 135 (56.5) 89 (37.2) 134 (56.8) 80 (33.9) PR status, n (%) Positive Negative 102 (42.7) 114 (47.7) 115 (48.7) 102 (43.2) Visceral dominant disease, n (%) Yes No 158 (66.1) 79 (33.1) 161 (68.2) 73 (30.9) ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PR = progesterone receptor

12 PATIENT CHARACTERISTICS Prior Therapy Parameter GD N=239 CD N=236 Prior chemotherapy for MBC, n (%) Yes 26 (10.9) 25 (10.6) No211 (88.3)208 (88.1) Prior anthracycline therapy, n (%) Yes136 (56.9)133 (56.4) No 99 (41.4) 99 (41.9) Prior hormonal therapy, n (%) Yes136 (56.9)135 (57.2) No101 (42.3)100 (42.4) Prior adjuvant taxane therapy, n (%) Yes 46 (19.2) 47 (19.9) No 31 (13.0) 25 (10.6) Unknown162 (67.8)164 (69.5)

13 DRUG ADMINISTRATION Parameter GD N=237 CD N=226 GD  C N=77 CD  G N=79 Total cycles received, n Mean cycles received, n Median cycles received, n6633 Dose adjustments, docetaxel, n (%) *117 (49.4)106 (46.9)-- Dose adjustments, gemcitabine, n (%)211 (89.0)--39 (49.4) Dose adjustments, capecitabine, n (%)-190 (84.1)40 (51.9)- Relative dose intensity, docetaxel, % Relative dose intensity, gemcitabine, % Relative dose intensity, capecitabine, % * Total number of patients with dose adjustment.

14 DRUG-RELATED TOXICITY (Induction) Hematologic Adverse event, n (%)* GD N=237 CD N=226 P Grade 3-4 neutropenia181 (76.4)69 (30.5)<.001 Grade 3-4 leukopenia 68 (28.7)17 (7.5)<.001 Grade 3-4 thrombocytopenia 19 (8.0) 0 (0.0)<.001 Grade 3-4 anemia 10 (4.2) 8 (3.5).812 Grade 3-4 febrile neutropenia 17 (7.2)14 (6.2).713 * 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 event, n (%)* GD N=237 CD N=226 P Grade 3-4 fatigue25 (10.5)12 (5.3).041 Grade 3-4 ALT/AST increased6 (2.5)0 (0.0).031 Grade 3-4 nausea/vomiting8 (3.4)18 (8.0).042 Grade 3-4 hand-foot syndrome3 (1.3)57 (25.2)<.001 Grade 3-4 mucositis3 (1.3)10 (4.4).049 Grade 2-4 diarrhea54 (22.8)50 (22.1).912 * Adverse events were defined using NCI-CTC, version 2.0. ALT = alanine aminotransferase; AST = aspartate aminotansferase

16 EFFICACY Tumor Response (Measurable Disease) Best Overall ResponseGDCDP*P* Induction patients, n Induction response, n (%)72 (34.8)78 (40.8).216 GD  CCD  G P*P* Crossover patients, n7270 Crossover response, n (%)11 (15.3)5 (7.1).184 * Fisher’s exact test

17 OVERALL SURVIVAL Survival Probability Time to Death (Months) OS, monthsGD (N=239)CD (N=236)P Patients censored, n (%)75 (31.4)72 (30.5) Median, (95% CI)23.0 (18.8, 25.7)23.3 (18.6, 25.5).785 Intent-to-treat population

18 Progression-Free Probability Time to Progressive Disease (Months) TTP, monthsGD (N=239)CD (N=236)P Patients censored, n (%)68 (28.5)83 (35.2) Median, (95% CI)9.3 (7.7, 10.8)8.9 (7.4, 11.1).385 TIME TO PROGRESSIVE DISEASE Induction Phase Intent-to-treat population Despite over-accrual, censoring resulted in only 324 TTP events, compared to 385 planned events.

19 Progression-Free Probability Time to Progressive Disease (Months) TTP, months GD  C (n=77) CD  G (n=81) P Patients censored, n (%)13 (16.9)10 (12.3) Median, (95% CI)4.5 (2.1, 7.8) 2.3 (2.0, 3.8).145 TIME TO PROGRESSIVE DISEASE Crossover Phase Intent-to-treat population

20 TTP INDUCTION-CROSSOVER SUM Definition Further PD Crossover Baseline Scan Induction   PD Scan Patient 1 TTP1 Discontinued Patient 2 TTP1 TTP2 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 DISEASE Summary Parameter GD GD  C CD CD  G P Induction patients, n Induction, median, months (95% CI) 9.3 (7.7, 10.8) 8.9 (7.4, 11.1).385 Crossover patients, n7680 Crossover, median, months (95% CI) 4.5 (2.1, 7.8) 2.3 (2.0, 3.8).145 Induction-crossover sum* patients, n7680 Induction-crossover sum,* median, months (95% CI) 14.3 (10.4, 17.8) 9.2 (7.1, 11.6).093 * Exploratory, post-hoc analysis

22 Progression-Free Probability Time to Progressive Disease (Months) TTP, months GD  C (N=76)CD  G (N=80) P Patients censored, n (%)13 (17.1)10 (12.5) Median, (95% CI)14.3 (10.4, 17.8)9.2 (7.1, 11.6).093 TIME TO PROGRESSIVE DISEASE Induction-Crossover Sum Treated Patients Exploratory, post-hoc analysis

23 PATIENT CHARACTERISTICS Crossover Population Parameter GD  C N=77 CD  G N=81 Age, median (range)56 (27-74)54 (27-82) Age group, n (%) ≤65 years >65 years 65 (84.4) 12 (15.6) 68 (84.0) 13 (16.1) ECOG performance status, n (%) (79.2) 14 (18.2) 65 (80.2) 15 (18.5) ER status, n (%) Positive Negative 40 (51.9) 31 (40.3) 40 (49.4) 29 (35.8) PR status, n (%) Positive Negative 33 (42.9) 35 (45.5) 34 (42.0) 36 (44.4) Visceral dominant disease, n (%) Yes No 55 (71.4) 22 (28.6) 55 (67.9) 26 (32.1) ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PR = progesterone receptor

24 PATIENT CHARACTERISTICS Prior Therapy: Crossover Population Parameter GD N=77 CD N=81 Prior chemotherapy for MBC, n (%) Yes 4 (5.2) 7 (8.6) No73 (94.8)74 (91.4) Prior anthracycline therapy, n (%) Yes39 (50.6)50 (61.7) No37 (48.1)30 (37.0) Prior hormonal therapy, n (%) Yes42 (54.5)42 (51.9) No34 (44.2)38 (46.9) Prior adjuvant taxane therapy, n (%) Yes16 (20.8)14 (17.3) No7 (9.1)10 (12.4) Unknown54 (70.1)57 (70.4)

25 PATIENT CHARACTERISTICS Baseline All PatientsCrossover Patients Parameter GD N=239 CD N=236 GD  C N=77 CD  G N=81 ECOG performance status, n (%) (73.2) 60 (25.1) 176 (74.6) 55 (23.3) 61 (79.2) 14 (18.2) 65 (80.2) 15 (18.5) Prior chemotherapy for MBC, n (%) Yes No 26 (10.9) 211 (88.3) 25 (10.6) 208 (88.1) 4 (5.2) 73 (94.8) 7 (8.6) 74 (91.4) Visceral dominant disease, n (%) Yes No 158 (66.1) 79 (33.1) 161 (68.2) 73 (30.9) 55 (71.4) 22 (28.6) 55 (67.9) 26 (32.1) 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 suggests that 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.

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30 BACK-UP SLIDES

31 TIME TO TREATMENT FAILURE Non-Failure Probability Time to Treatment Failure (Months) TTF, monthsGD (N=239)CD (N=236)P Patients censored, n (%)43 (18.0)51 (21.6) Median, (95% CI)6.7 (6.2, 8.3)5.1 (4.4, 6.2).784 Intent-to-treat population

32 Progression-Free Probability Time to Progressive Disease (Months) PFS, months GD (n=239) CD (n=236)P Patients censored, n (%)64 (26.8)80 (33.9) Median, (95% CI)9.0 (7.7, 10.5)8.9 (7.3, 10.9).361 PROGRESSION-FREE SURVIVAL Induction Phase Intent-to-treat population

33 DURATION FROM PD TO CROSSOVER Parameter GD N=74 CD N=77 Median duration from PD to crossover, days 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.

34 ECOG PERFORMANCE STATUS Patients at Baseline and at Crossover Parameter GD  C N=77 CD  G N=81 ECOG performance status at baseline, n (%) (79.2) 14 (18.2) 65 (80.2) 15 (18.5) ECOG performance status at crossover, n (%) (84.0) 12 (16.0) 63 (78.8) 17 (21.3) ECOG = Eastern Cooperative Oncology Group


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