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Abstract 1000 Phase III Trial of Gemcitabine plus Docetaxel (GD) Compared to Capecitabine plus Docetaxel (CD) with Planned Crossover to the Alternate Single.

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Presentation on theme: "Abstract 1000 Phase III Trial of Gemcitabine plus Docetaxel (GD) Compared to Capecitabine plus Docetaxel (CD) with Planned Crossover to the Alternate Single."— Presentation transcript:

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 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 Good morning. On behalf of my co-investigators, I am pleased to present the results of this study.

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. I have been remunerated by Eli Lilly Company and Sanofi-Aventis for consulting and speaking services; other disclosures are as noted.

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 In patients with prior anthracycline exposure, the addition of capecitabine to docetaxel and the addition of gemcitabine to paclitaxel has resulted in improved response rates and TTP compared to the taxane monotherapy arm. As recently reported, the doublet of docetaxel plus gemcitabine yielded nearly identical RR and PFS as docetaxel plus capecitabine, with superior TTF for GD due to greater toxicity-related treatment discontinuation with CD. 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. Despite much debate on the issue, both poly- and mono-chemotherapy play a role in the management of MBC. Few randomized phase III trials have examined pre-planned crossover chemotherapy strategies in MBC. Prior phase III trials of docetaxel plus capecitabine have been notable for treatment-limiting PPE resulting in frequent capecitabine dose reduction outside the clinical trial setting. This study compared the safety and efficacy of GD and CD among patients with MBC where the alternate crossover monotherapy was predetermined. 4

5 STUDY OBJECTIVES Primary Secondary TTP Toxicity
Overall response rate (ORR) Progression-free survival (PFS) Overall survival (OS) The primary objective of this trial was time to disease progression. Secondary objectives were to compare toxicity, response rate, PFS and OS. 5

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 R A N D O MI Z E GD Induction: G 1000 mg/m2 IV on Days 1, D 75 mg/m2 IV on Day 1 every 21 days until disease progression (PD) 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: IV on Days 1,8 every 21 days until PD C Crossover: Off study Follow-up (1:1) After stratification for line of therapy, prior anthracycline exposure, visceral dominant disease, performance status, and measurable vs. evaluable-only disease, patients were randomized 1:1 to GD induction to be followed by capecitabine upon PD or prohibitive toxicity or CD induction to be followed by gemcitabine monotherapy upon PD or prohibitive toxicity. The docetaxel-gemcitabine regimen has docetaxel at 75 mg/m2 every 3 weeks, with gemcitabine 1000 mg/m2 days 1 and 8 every 3 weeks. The docetaxel-capecitabine arm employs a 20% lower dose of capecitabine than in both the O’Shaughnessy and Chan trials, given the high incidence of prohibitive hand-foot syndrome in those trials. At crossover, the monotherapy regimens were identical to the single agent non-taxane components of the induction doublets. Treatment was to progression or prohibitive toxicity. 6

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 Eligible patients had locally advanced or metastatic breast cancer, no more than one prior chemotherapy regimen for metastatic disease, measurable or evaluable disease, adequate end-organ function and performance status. Patients were excluded if they had prior taxane for MBC, prior gemcitabine or capecitabine, concurrent trastuzumab or central nervous system metastases. 7

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. The sample size was driven by the comparison in TTP between the GD and CD arms. Using Freedman’s method, it was estimated that 442 patients would be needed to obtain the 385 progression events required to observe a 2-month difference in TTP between treatment arms with 80% statistical power. Time to event analyses were estimated from the date of randomization using the Kaplan-Meier method, and results were compared by log-rank test. 2-sided statistical comparisons between treatment arms were judged relative to an alpha of Data lock for this final analysis was on March 17th, 10 weeks ago. Finally, an exploratory, post-hoc analysis of the sum of induction and crossover TTP was performed. 8

9 Patients randomly assigned
PATIENT DISPOSITION Patients randomly assigned (N = 475) Accrual: 15 February 2002 – 23 December 2008 GD Arm (n = 239) ITT N = 475 CD Arm (n = 236) Withdrew (n = 3) Withdrew (n = 9) 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 GDC (n = 77) CDG (n = 81) In a trial such as this where two lines of therapy are planned, a careful accounting of patient disposition is critical. 475 patients comprised the intent-to-treat population, and 463 were evaluable for safety. 43 patients (point) exited the trial due to an adverse event during first-line therapy with GD, while 67 patients (point) stopped protocol therapy due to an adverse event on the CD arm. Other reasons for patient removal from the trial were fairly balanced. A total of 158 patients (point), or one-third of the ITT population, proceeded to the crossover monotherapy. The majority of patients receiving monotherapy discontinued it due to disease progression (point), in contrast to the induction phase patients above. 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 9

10 PHASE III MBC TRIALS Pre-Planned Sequential Lines of Chemotherapy
Study First-Line Therapy Second-Line % Crossover Second-Line/First-Line Sledge et al. JCO, 2003 Doxorubicin Paclitaxel 129/245 (52.6%) 128/242 (52.9%) Paridaens et al. JCO 2000 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%) Several prior phase III trials have attempted to deliver two consecutive sequential lines of chemotherapy for metastatic breast cancer. In the ECOG 1193 trial, and the EORTC trial studying sequential doxorubicin and paclitaxel, approximately 50% of the study population actually crossed over to the designated second-line therapy. In the Joensuu trial, after combination chemotherapy, about one-half of patients went on to receive the preplanned subsequent single agent regimen. In the current trial, only about one-third of patients crossed over from the induction taxane-based combination to the designated preplanned monotherapy. CEF = cyclophosphamide, epirubicin, 5-fluorouracil MV = mitomycin C, vinblastine GD = gemcitabine + docetaxel CD = capecitabine + docetaxel 10

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 (%) 1 175 (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 (%) 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) The median ages for patients on the GD and CD arms were 57 and 54, respectively. Approximately three quarters of patients had an ECOG PS of 0. Treatment arms were well-balanced for hormone receptor status, and approximately 2/3 of patients in each arm had visceral-dominant disease. ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PR = progesterone receptor 11

12 PATIENT CHARACTERISTICS Prior Therapy
Parameter GD N=239 CD N=236 Prior chemotherapy for MBC, n (%) Yes 26 (10.9) 25 (10.6) No 211 (88.3) 208 (88.1) Prior anthracycline therapy, n (%) 136 (56.9) 133 (56.4) 99 (41.4) 99 (41.9) Prior hormonal therapy, n (%) 135 (57.2) 101 (42.3) 100 (42.4) Prior adjuvant taxane therapy, n (%) 46 (19.2) 47 (19.9) 31 (13.0) Unknown 162 (67.8) 164 (69.5) The large majority of patients treated were to receive first and second-line chemotherapy on this trial; about 11% (point) were intended to receive protocol therapy as second- and third-line chemotherapy. More than half of all patients had prior anthracycline (point), and the arms were well-balanced for prior antiestrogen therapy and prior taxane exposure. 12

13 DRUG ADMINISTRATION * Total number of patients with dose adjustment.
Parameter GD N=237 CD N=226 GDC N=77 CDG N=79 Total cycles received, n 1768 1668 390 344 Mean cycles received, n 7.5 7.4 5.1 4.4 Median cycles received, n 6 3 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, % 91.0 91.7 Relative dose intensity, gemcitabine, % 72.5 87.5 Relative dose intensity, capecitabine, % 77.4 92.8 Patients received a median of 6 cycles of combination chemotherapy and 3 cycles of subsequent monotherapy. Docetaxel dose reduction or delay occurred in less than half of patients on both induction arms (point). Dose adjustments for gemcitabine and capecitabine were also made in over 80% of patients in the combination arms (point), and in approximately half of patients during subsequent monotherapy with these agents (point). Despite this, the relative dose intensity for docetaxel was over 90% (point). The RDI for the non-taxane components in the combination phase was approximately 75% (point), and approximately 90% during the crossover monotherapy phase (point). * Total number of patients with dose adjustment. 13

14 DRUG-RELATED TOXICITY (Induction) Hematologic
Adverse event, n (%)* GD N=237 CD N=226 P Grade 3-4 neutropenia 181 (76.4) 69 (30.5) < .001 Grade 3-4 leukopenia 68 (28.7) 17 (7.5) Grade 3-4 thrombocytopenia 19 (8.0) 0 (0.0) Grade 3-4 anemia 10 (4.2) 8 (3.5) .812 Grade 3-4 febrile neutropenia 17 (7.2) 14 (6.2) .713 Grade ¾ neutropenia, leukopenia, and thrombocytopenia were statistically more common with GD than CD. There was no difference in the incidence of grade ¾ anemia nor in the incidence of febrile neutropenia. Prophylactic hematopoietic growth factor support was not allowed. * Adverse events were defined using NCI-CTC, version 2.0. Prophylactic use of hematopoietic growth factors was not allowed 14

15 DRUG-RELATED TOXICITY (Induction) Nonhematologic
Adverse event, n (%)* GD N=237 CD N=226 P Grade 3-4 fatigue 25 (10.5) 12 (5.3) .041 Grade 3-4 ALT/AST increased 6 (2.5) 0 (0.0) .031 Grade 3-4 nausea/vomiting 8 (3.4) 18 (8.0) .042 Grade 3-4 hand-foot syndrome 3 (1.3) 57 (25.2) < .001 Grade 3-4 mucositis 10 (4.4) .049 Grade 2-4 diarrhea 54 (22.8) 50 (22.1) .912 Grades ¾ non-hematologic toxicities are shown here. Fatigue and elevation of hepatic transaminase was more common with GD. Nausea and vomiting, hand-foot syndrome, and mucositis were more common with CD. * Adverse events were defined using NCI-CTC, version 2.0. ALT = alanine aminotransferase; AST = aspartate aminotansferase 15

16 EFFICACY Tumor Response (Measurable Disease)
Best Overall Response GD CD P* Induction patients, n 207 191 Induction response, n (%) 72 (34.8) 78 (40.8) .216 GDC CDG Crossover patients, n 72 70 Crossover response, n (%) 11 (15.3) 5 (7.1) .184 A total of 398 patients with measurable disease were evaluable for response to induction therapy, and 142 for the subsequent monotherapy phase. 34.8% of patients responded to GD, and 40.8% to CD, a non-significant difference. 15.3% patients who crossed over after GD responded to capecitabine, whereas 7.1% of patients who crossed over from CD to gemcitabine responded to this single agent, a non-significant difference. * Fisher’s exact test 16

17 Patients censored, n (%)
OVERALL SURVIVAL 1.0 0.8 0.6 0.4 0.2 0.0 OS, months GD (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 Survival Probability Intent-to-treat population The intent-to-treat survival curves for patients in this trial are virtually superimposable, and was just under 2 years. Time to Death (Months) 17

18 TIME TO PROGRESSIVE DISEASE Induction Phase
1.0 0.8 0.6 0.4 0.2 0.0 TTP, months GD (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 Despite over-accrual, censoring resulted in only 324 TTP events, compared to 385 planned events. Progression-Free Probability Intent-to-treat population Similarly, there was no significant difference in median time to progression between the GD and CD induction arms; 9.3 months for GD and 8.9 months for CD. Despite over-accrual, censoring resulted in 324 TTP events compared to the 385 planned events. Time to Progressive Disease (Months) 18

19 TIME TO PROGRESSIVE DISEASE Crossover Phase
1.0 0.8 0.6 0.4 0.2 0.0 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 Progression-Free Probability Intent-to-treat population The median TTP on capecitabine montherapy for those 77 patients who did indeed crossover after GD was 4.5 months. The median TTP on gemcitabine montherapy for the 81 patients who crossed over from CD was 2.3 months, a non-significant difference. Time to Progressive Disease (Months) 19

20 TTP INDUCTION-CROSSOVER SUM Definition
Further PD Crossover Baseline Scan Induction PD Patient 1 TTP1 Discontinued Patient 2 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. In an exploratory analysis, we examined the Summation Time to Progression for those patients who received single agent crossover therapy. Induction TTP, or TTP1, was estimated for all patients from time of randomization to first progression. Crossover TTP, or TTP2, was from the time of first single agent dose to further disease progression. The 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 239 236 Induction, median, months (95% CI) 9.3 (7.7, 10.8) 8.9 (7.4, 11.1) .385 Crossover patients, n 76 80 Crossover, median, months 4.5 (2.1, 7.8) 2.3 (2.0, 3.8) .145 Induction-crossover sum* patients, n Induction-crossover sum,* median, months 14.3 (10.4, 17.8) 9.2 (7.1, 11.6) .093 Recognizing that only one-third of the population crossed over from induction phase to crossover monotherapy, we nevertheless analyzed the sum of TTP for crossover patients in the two arms. (POINT) The median induction-crossover summation TTP was 14.3 months for the GD to C patients, and 9.2 months for the CD to G patients, with a p-value of * Exploratory, post-hoc analysis 21

22 TIME TO PROGRESSIVE DISEASE Induction-Crossover Sum
1.0 0.8 0.6 0.4 0.2 0.0 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 Exploratory, post-hoc analysis Progression-Free Probability Treated Patients The Kaplan-Meier time to progressive disease curves from protocol initiation through two lines of chemotherapy are shown here for those patients who indeed crossed over. Recognizing that crossover patients might not be balanced for prognostic features, we examined this possibility (next slide)…. Time to Progressive Disease (Months) 22

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 (%) 1 61 (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 (%) 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) While this is an exploratory analysis, it is noteworthy that the patients who crossed over were well-balanced for baseline demographic features such as age, performance status (which was also balanced at crossover), hormone receptor status and the presence of visceral dominant disease. ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PR = progesterone receptor 23

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) No 73 (94.8) 74 (91.4) Prior anthracycline therapy, n (%) 39 (50.6) 50 (61.7) 37 (48.1) 30 (37.0) Prior hormonal therapy, n (%) 42 (54.5) 42 (51.9) 34 (44.2) 38 (46.9) Prior adjuvant taxane therapy, n (%) 16 (20.8) 14 (17.3) 7 (9.1) 10 (12.4) Unknown 54 (70.1) 57 (70.4) Crossover patients were also balanced for line of therapy, and prior exposure to anthracycline, antiestrogen, and taxane. (While we unfortunately failed to capture prior adjuvant taxane use for a significant proportion of the study population, it is noteworthy that prior taxane exposure did not seem to bias against benefit from paclitaxel and bevacizumab in ECOG 2100). 24

25 PATIENT CHARACTERISTICS Baseline
All Patients Crossover Patients Parameter GD N=239 CD N=236 GDC N=77 CDG N=81 ECOG performance status, n (%) 1 175 (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 (%) 158 (66.1) 79 (33.1) 161 (68.2) 73 (30.9) 55 (71.4) 22 (28.6) 55 (67.9) 26 (32.1) Finally, the one-third of patients crossing over in this study had similar baseline performance status, line of therapy and likelihood of visceral-dominant disease as compared to the overall study population. ECOG = Eastern Cooperative Oncology Group 25

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). In summary (read) -

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. GD and CD had similar efficacy with toxicity profiles consistent with prior clinical experience. This trial, like others that have attempted to prescribe 2 consecutive lines of therapy, had a modest rate of crossover. This illustrates the practical issues inherent in such a trial design, an observation that has implications for the design of future clinical trials. In an exploratory, post-hoc analysis of patients who crossed over to the prespecified second-line therapy, C crossover from GD trended toward greater clinical benefit compared to G crossover from CD, suggesting that this sequence may be preferable.

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. We thank the patients who participated in this trial, the supporting institutions and health care professionals in The U.S., Taiwan, Mexico, Argentina, Australia, South Korea and Brazil who provided care and collected data, and Melissa Humbert and Jane Bromund for their diligence in trial management and data acquisition. THANK YOU VERY MUCH.

29

30 BACK-UP SLIDES

31 TIME TO TREATMENT FAILURE
1.0 0.8 0.6 0.4 0.2 0.0 TTF, months GD (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 Non-Failure Probability Intent-to-treat population Time to Treatment Failure (Months) 31

32 PROGRESSION-FREE SURVIVAL Induction Phase
1.0 0.8 0.6 0.4 0.2 0.0 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 Probability Intent-to-treat population Time to Progressive Disease (Months) 32

33 DURATION FROM PD TO CROSSOVER
Parameter GD N=74 CD N=77 Median duration from PD to crossover, days 14 10 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

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 (%) 1 61 (79.2) 14 (18.2) 65 (80.2) 15 (18.5) ECOG performance status at crossover, n (%) 63 (84.0) 12 (16.0) 63 (78.8) 17 (21.3) ECOG = Eastern Cooperative Oncology Group 34


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