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

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.

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 2002

2. Albain KS, et al. JCO 2008

3. Chan S, et al. JCO 2009

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 (GDC or CDG) was predetermined.

STUDY OBJECTIVES

• Primary– TTP

• Secondary– Toxicity– Overall response rate (ORR)– Progression-free survival

(PFS)– Overall survival (OS)

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

RANDOMIZE

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)

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

C Crossover: C 1000 mg/m2

PO BID on Days 1-14 every 21 days until PD

Off studyFollow-up

Off studyFollow-up

(1:1)

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

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.

PATIENT DISPOSITIONAccrual: 15 February 2002 –

23 December 2008

Patients randomly assigned(N = 475)

ITTN = 475

SafetyN = 463

GD Arm(n = 239)

GD Arm(n = 236)

GDC(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)

CDG(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)

CrossoverN = 158

PD = Progressive Disease; ITT = Intent-to-Treat

Withdrew (n = 1)Withdrew (n = 1)

PHASE III MBC TRIALSPre-Planned Sequential Lines of Chemotherapy

StudyFirst-LineTherapy

Second-Line

Therapy

% CrossoverSecond-Line/First-

Line

Sledge et al. JCO, 2003

Doxorubicin

Paclitaxel

Paclitaxel

Doxorubicin

129/245 (52.6%)

128/242 (52.9%)

Paridaens et al. JCO 2000

Doxorubicin

Paclitaxel

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-fluorouracilMV = mitomycin C, vinblastineGD = gemcitabine + docetaxelCD = capecitabine + docetaxel

PATIENT CHARACTERISTICSBaseline

Parameter GDN=239

CDN=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 (%) 0 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 (%) 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

PATIENT CHARACTERISTICSPrior Therapy

Parameter GDN=239

CDN=236

Prior chemotherapy for MBC, n (%)

Yes 26 (10.9)

25 (10.6)

No 211 (88.3)

208 (88.1)

Prior anthracycline therapy, n (%)

Yes 136 (56.9)

133 (56.4)

No 99 (41.4)

99 (41.9)

Prior hormonal therapy, n (%)

Yes 136 (56.9)

135 (57.2)

No 101 (42.3)

100 (42.4)

Prior adjuvant taxane therapy, n (%)

Yes 46 (19.2)

47 (19.9)

No 31 (13.0)

25 (10.6)

Unknown 162 (67.8)

164 (69.5)

DRUG ADMINISTRATION

ParameterGD

N=237 CD

N=226GDCN=77

CDGN=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 6 3 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 -

* Total number of patients with dose adjustment.

DRUG-RELATED TOXICITY (Induction)Hematologic

Adverse event, n (%)*GD

N=237CD

N=226P

Grade 3-4 neutropenia 181 (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

DRUG-RELATED TOXICITY (Induction)Nonhematologic

Adverse event, n (%)*GD

N=237CD

N=226P

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 3 (1.3) 10 (4.4) .049

Grade 2-4 diarrhea 54 (22.8) 50 (22.1) .912* Adverse events were defined using NCI-CTC, version 2.0.

ALT = alanine aminotransferase; AST = aspartate aminotansferase

EFFICACYTumor Response (Measurable Disease)

Best Overall Response GD CD P*

Induction patients, n 207 191

Induction response, n (%) 72 (34.8) 78 (40.8) .216

GDC CDG P*

Crossover patients, n 72 70

Crossover response, n (%) 11 (15.3) 5 (7.1) .184

* Fisher’s exact test

OVERALL SURVIVALS

urv

ival

Pro

bab

ilit

y

Time to Death (Months)

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66 72

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

• Intent-to-treat population

0 6 12 18 24 30 36 42 48 54 60 66 72

1.0

0.8

0.6

0.4

0.2

0.0

Pro

gre

ssio

n-F

ree

Pro

bab

ilit

y

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 DISEASEInduction Phase

• Intent-to-treat population

Despite over-accrual, censoring resulted in only 324 TTP events, compared to 385 planned events.

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

1.0

0.8

0.6

0.4

0.2

0.0

Pro

gre

ssio

n-F

ree

Pro

bab

ilit

y

Time to Progressive Disease (Months)

TTP, months GDC (n=77)

CDG (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 DISEASECrossover Phase

• Intent-to-treat population

TTP INDUCTION-CROSSOVER SUMDefinition

FurtherPDCrossover

BaselineScan

Scan

Induction PD

Scan

Patient 1 TTP1Discontinued

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.

TIME TO PROGRESSIVE DISEASESummary

Parameter GD

GDCCD

CDGP

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(95% CI)

4.5(2.1, 7.8)

2.3(2.0, 3.8)

.145

Induction-crossover sum* patients, n 76 80

Induction-crossover sum,* median, months(95% CI)

14.3(10.4, 17.8)

9.2(7.1, 11.6)

.093* Exploratory, post-hoc analysis

0 6 12 18 24 30 36 42 48 54 60 66 72

1.0

0.8

0.6

0.4

0.2

0.0

Pro

gre

ssio

n-F

ree

Pro

bab

ilit

y

Time to Progressive Disease (Months)

TTP, months GDC (N=76)CDG

(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 DISEASEInduction-Crossover Sum

• Treated Patients

• Exploratory, post-hoc analysis

PATIENT CHARACTERISTICSCrossover Population

Parameter GDCN=77

CDGN=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 (%) 0 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 (%) 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

PATIENT CHARACTERISTICSPrior Therapy: Crossover Population

Parameter GDN=77

CDN=81

Prior chemotherapy for MBC, n (%)

Yes 4 (5.2)

7 (8.6)

No 73 (94.8)

74 (91.4)

Prior anthracycline therapy, n (%)

Yes 39 (50.6)

50 (61.7)

No 37 (48.1)

30 (37.0)

Prior hormonal therapy, n (%)

Yes 42 (54.5)

42 (51.9)

No 34 (44.2)

38 (46.9)

Prior adjuvant taxane therapy, n (%)

Yes 16 (20.8)

14 (17.3)

No 7 (9.1) 10 (12.4)

Unknown 54 (70.1)

57 (70.4)

PATIENT CHARACTERISTICSBaseline

All PatientsCrossover Patients

ParameterGD

N=239CD

N=236GDCN=77

CDGN=81

ECOG performance status, n (%) 0 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 (%) 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

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 GDC sequence compared to CDG, but did not reach statistical significance (p = .093).

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 GDC sequence may be preferable.

• This trial, like others that have attempted to prescribe 2 consecutive lines of therapy, had a modest rate of crossover.

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.

BACK-UP SLIDES

TIME TO TREATMENT FAILUREN

on

-Fai

lure

Pro

bab

ilit

y

Time to Treatment Failure (Months)

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66 72

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

• Intent-to-treat population

1.0

0.8

0.6

0.4

0.2

0.0

Pro

gre

ssio

n-F

ree

Pro

bab

ilit

y

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 SURVIVALInduction Phase

• Intent-to-treat population

0 6 12 18 24 30 36 42 48 54 60 66 72

DURATION FROM PD TO CROSSOVER

ParameterGD

N=74CD

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 GDC and 3 patients in CDG.

• 2 patients did not receive crossover therapy and were excluded from this analysis.

ECOG PERFORMANCE STATUSPatients at Baseline and at Crossover

ParameterGDCN=77

CDGN=81

ECOG performance status at baseline, n (%) 0 1

61 (79.2)

14 (18.2)

65 (80.2)

15 (18.5)

ECOG performance status at crossover, n (%) 0 1

63 (84.0)

12 (16.0)

63 (78.8)

17 (21.3)

ECOG = Eastern Cooperative Oncology Group