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Maintenance Therapy With PLD Following Standard Chemotherapy for MBC Significantly Prolongs TTP in a Multicenter Phase III Randomized Trial: GEICAM 2001-01.

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Presentation on theme: "Maintenance Therapy With PLD Following Standard Chemotherapy for MBC Significantly Prolongs TTP in a Multicenter Phase III Randomized Trial: GEICAM 2001-01."— Presentation transcript:

1 Maintenance Therapy With PLD Following Standard Chemotherapy for MBC Significantly Prolongs TTP in a Multicenter Phase III Randomized Trial: GEICAM Study E. Alba (1), M. Ruiz-Borrego (2), M. Martín (3), M. Margelí (4), Á. Rodríguez-Lescure (5), P. Sánchez-Rovira (6), A. Ruiz (7), N. Ribelles (1), E. Calvo (2), A. Casado (3) (1) Hospital U. Virgen de la Victoria, Málaga, Spain; (2) Hospital U. Virgen del Rocío, Sevilla, Spain; (3) Hospital U. Clínico San Carlos, Madrid, Spain; (4) Hospital Germans Trias i Pujol, Badalona, Spain; (5) Hospital Gral. U. de Elche, Elche, Spain; (6) Complejo Hospitalario de Jaén, Jaén, Spain; (7) Instituto Valenciano de Oncología, Valencia, Spain

2 Role of Maintenance Therapy for MBC  Randomized trials demonstrate consistent benefit favoring prolonged vs standard duration of chemotherapy  Meta-analysis revealed a reduction in hazard of death 1  Maintenance therapy offers a strategy to prolong time to progression, but must be weighted against side effects  Optimal duration of treatment a matter of debate  No benefit in MANTA 1 trial of maintenance paclitaxel after 1 st -line regimen of anthracycline/paclitaxel 2  Trial stopped early  Confounding variables 1 Coates et al. Am Soc Clin Oncol Ed Book. 2003;pp ; 2 Gennari et al. J Clin Oncol. 2006;24:

3 Randomized Studies of Chemotherapy Duration in MBC StudyTreatment SchedulesN TTP, median (months) Coates (1987)AC/CMF until PD vs AC x 33056* vs 4 Muss (1991)FAC x 6 → CMF x 12 vs FAC x * vs 3.2 Ejlertsen (1993)FEC x 18 (+ TAM) vs FEC x 6 (+ TAM)25414* vs 10 Gregory (1997)VAC/VEC x 6 → MMM x 6 vs VAC/VEC/MMM x * vs 7 Falkson (1998)A x 6 → CMFPTH x 8 vs A x * vs 7.8 FESG (2000)FEC-75 x 11 vs FEC-100 x 4 → FEC-50 x 8 vs FEC-100 x vs 8.3 vs 6.2 Nooij (2003)CMF until PD vs CMF x * vs 3.5 Gennari (2006)AP/EP x 6-8 → P x 8 vs AP/EP x † 8 vs 9 *Statistically significant; † assessed in futility analysis.

4 Pegylated Liposomal Doxorubicin (PLD) as Maintenance Therapy  Anthracyclines are cornerstone of treatment for breast cancer  Conventional anthracyclines limited by cardiac toxicity  PLD has comparable efficacy and significantly improved safety profile compared with conventional doxorubicin in MBC 1 –Significantly less cardiotoxicity –Less nausea/vomiting, alopecia, and myelosuppression 1 O’Brien et al. Ann Oncol. 2004;15:

5 GEICAM Background and Aim  Regimen choice for this trial based on GEICAM –A→T equally effective, less toxic compared with concomitantly administered AT –Significantly reduced rate of febrile neutropenia –Based on these results, considered a regimen of choice for 1 st -line treatment of MBC  Trial utilizes 1 st -line standard GEICAM regimen and assesses the role of maintenance therapy, utilizing pegylated liposomal anthracycline, or no maintenance therapy as an approach to 1 st -line MBC 1 Alba et al. J Clin Oncol. 2004;22:

6 GEICAM Study Design *Patients assessed at same time points in both study arms. PLD 40mg/m 2 q 28daysx 6cycles* Observation* CR PR SD R A N D O M I Z A T I O N Design  Phase III trial  Multicenter Eligibility  MBC after 1 st -line induction chemotherapy with A → T

7 Study Endpoints  Primary –Time to progression (TTP)  Secondary –Toxicity –Overall survival (OS)

8 Study Assessments  Prior to randomization –Response to induction chemotherapy 6 wks after last dose and within 8 wks prior to study registration  After randomization –All patients followed q 28 days during the first 6 months –Disease status assessed in all patients (without signs or symptoms of progression) at 3-mo intervals up to 24 mo –Patients followed until disease progression documented or until study completed  Cardiotoxicity –LVEF by echocardiography or MUGA at baseline, cycle 3, cycle 6, and every 6 months thereafter

9 Statistical Methodology  Sample size: –Assuming an increase of median TTP of 66% (log-rank test) –With an alpha error of 0.01 (1-sided) and a power of 80%, 77 patients per arm needed  Statistical analysis: –ITT population –Log-rank test for treatment arm comparisons –Cox regression model to control risk factors

10 Eligibility  Key Inclusion Criteria –Women with MBC with response (CR or PR) or SD after first-line induction therapy –Age > 18 years –ECOG PS 0, 1, or 2 –At least one measurable lesion by RECIST –Normal cardiac function  Key Exclusion Criteria –Previous grade II or higher cardiac dysfunction as assessed by NYHA criteria or congestive cardiac failure –Hypersensitivity to anthracyclines or Cremophor ® –Radiation therapy in previous 4 weeks –Symptomatic brain metastases

11 Patient Registration and Randomization 288 Patients Registered 155 Randomized 133 (46.2%) Not randomized Progression/death: 63 Toxicity: 14 Patient refusal: 25 Logistics/scheduling: 9 Unknown/other: 22 PLD: 78Observation: 77

12 Patient and Disease Characteristics Characteristic PLD (n=78) Observation (n=77) P-value Age, median ECOG PS Unknown 45 (58%) 20 (26%) 5 (6%) 8 (10%) 43 (56%) 28 (36%) 2 (3%) 4 (5%).209 Hormonal status ER+ and/or PR+ ER- and/or PR- Unknown 53 (68%) 17 (22%) 8 (10%) 56 (73%) 15 (19%) 6 (8%).654 Dominant site of disease Visceral Non-visceral Unknown 46 (59%) 31 (40%) 1 (1%) 43 (56%) 31 (40%) 3 (4%).839

13 Patient and Disease Characteristics Characteristic PLD (n=78) Observation (n=77) P-value Response status at randomization Complete response Partial response Stable disease 3 (4%) 38 (49%) 37 (47%) 7 (9%) 47 (61%) 23 (30%).055 Prior adjuvant/neo-adjuvant therapy Chemotherapy Hormonal therapy 48 (62%) 33 (42%) 44 (57%) 32 (42%) Prior adjuvant anthracycline23 (30%)27 (35%).186

14 Maintenance Treatment Description Characteristic PLD (n=78) Cycles Mean Median (range) (0-6) Patients completing all planned cycles39 (50%) Discontinuation reason PD or death Toxicity Other 21 (54%) 8 (20%) 10 (26%)

15 Time to Progression – From Randomization % Progression–Free Survival PLD maintenance median: 8.38 months Observation median: 5.06 months Months P-value (log-rank test) =.0006 HR = 0.54 (95% CI, ) 0 – 6 m6 -12 m m18 – 24 m PLD Observation

16 % Progression–Free Survival P-value (log-rank test) =.0005 HR = 0.53 (95% CI, ) Months PLD maintenance median: months Observation median: months Time to Progression – From Initial Induction Treatment

17 Maintenance Treatment: Hematologic Toxicity (NCI-CTC.2) Toxicity % of Patients PLD (n=78) Observation (n=77) Grade 1 / 2Grade 3 / 4Grade 1 / 2Grade 3 / 4 Neutropenia Anemia  Febrile neutropenia occurred in only 2.6% of PLD patients

18 Maintenance Treatment: Non-Hematologic Toxicity (NCI-CTC.2) Toxicity % of Patients PLD (n=78) Observation (n=77) Grade 1 / 2Grade 3 / 4Grade 1 / 2Grade 3 / 4 Nausea/vomiting Fatigue Alopecia Infusion reaction Mucositis PPE * *Grade 3 only

19 Cardiotoxicity PLD (n=78) Observation (n=77) Median LEVF at cycle 661%60% Decrease in LVEF ≥ 10%5 (6%)1 (1%) Drop of LVEF < 50%2* (3%)0 Congestive heart failure00 *LVEF value at cycle 6 → 47% and 44%

20 Conclusions  Maintenance therapy with PLD significantly prolongs TTP (3.33 months)  Most progressions are avoided while the patients are on treatment with PLD  Toxicity is infrequent and manageable, especially subjective toxicity (eg, nausea/vomiting and alopecia)  Cardiotoxicity incidence has not been relevant  Maintenance therapy with PLD is a therapeutic option in non-progressing patients with MBC after first-line chemotherapy  Based on these results, adding PLD to responding MBC patients, will be the standard arm on future GEICAM studies

21 Acknowledgements  All the women who participated in this trial  GEICAM personnel  Investigators and their support staff who enrolled patients onto the trial Emilio Alba – Hospital Virgen de la Victoria Manuel Ruiz Borrego – Hospital Virgen del Rocío Miguel Martín – Hospital Clínico San Carlos Mireia Margeli – Hospital Trias i Pujol Rodríguez Lescure – Hospital General de Elche Mel Lorenzo – Hospital Xeral Calde Amparo Ruíz – Instituto Valenciano de Oncología Pedro Sánchez – Hospital Ciudad de Jaén Ramos Vázquez – Centro Oncológico de Galicia Carlos Jara – Fundación Hospital Alcorcón López Vega – Hospital Marques de Valdecilla Lourdes Calvo – Complejo Hospitalario Juan Canalejo Antonio Antón – Hospital Miguel Servet Ricardo Cubedo – Clínica Puerta de Hierro Isabel Moreno – Hospital de Badalona Enrique Aranda – Hospital Provincial Reina Sofia Antonio Fernandez – Hospital General de Albacete Cesar Mendiola – Hospital Universitario 12 de Octubre GEICAM Investigators


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