1 / 18

P Fumoleau, 1 A Wardley, D Miles, S Verma, K Gelmon, D Cameron, L Gianni, PF Conte, G Ross, V McNally, J Baselga

Safety of pertuzumab plus trastuzumab in a Phase II trial of patients with HER2-overexpressing metastatic breast cancer which had progressed during trastuzumab therapy. P Fumoleau, 1 A Wardley, D Miles, S Verma, K Gelmon, D Cameron, L Gianni, PF Conte, G Ross, V McNally, J Baselga

sandra_john
Download Presentation

P Fumoleau, 1 A Wardley, D Miles, S Verma, K Gelmon, D Cameron, L Gianni, PF Conte, G Ross, V McNally, J Baselga

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Safety of pertuzumab plus trastuzumab in a Phase II trial of patients with HER2-overexpressing metastatic breast cancer which had progressed duringtrastuzumab therapy P Fumoleau,1 A Wardley, D Miles, S Verma, K Gelmon, D Cameron, L Gianni, PF Conte, G Ross, V McNally, J Baselga 1Centre Georges-François-Leclerc, Dijon, France

  2. Pertuzumab background • Pertuzumab, a humanized monoclonal antibody, is a HER2 dimerization inhibitor • HER2 is the preferred co-receptor for HER1, HER3 and HER4 dimers • HER signaling is implicated in cancer cell proliferation and survival • Pertuzumab inhibits both HER2 homodimerization and heterodimerization, blocking multiple HER signaling pathways HER, human epidermal growth factor receptor

  3. Rationale for this study • Pertuzumab and trastuzumab bind distinct and non-overlapping epitopes of HER2 • The addition of pertuzumab post-progression to ongoing trastuzumab in xenografts synergistically increased tumor inhibition compared with trastuzumab alone • Patients with disease progression during trastuzumab treatment have high unmet need • An understanding of the adverse event profile of this combination, particularly cardiac safety, is of importance

  4. YES NO Study design Simon-type two-stage design Stage 2 (n=66) ≥2 R or 1 R + 12 SDor 13 SD Safety evaluationfor IDSMB Stage 1 (n=24)Trastuzumab +pertuzumaba Stop trial • There have been no safety objections raised by the IDSMB regarding continuing the study into stage 2 • n=58 fully evaluable patients needed aTrastuzumab: 4 mg/kg loading dose  2 mg/kg qw or 8 mg/kg loading dose  6 mg/kg q3w;Pertuzumab: 840 mg loading dose  420 mg q3w IDSMB, International Data Safety Monitoring Board

  5. Main eligibility criteria • Up to 3 lines of prior cytotoxic therapies and / or trastuzumab (including in the adjuvant setting) • Disease progression during trastuzumab as most recent treatment for metastatic disease • No brain metastases • Baseline LVEF ≥55% • No decrease of LVEF to <50% during prior trastuzumab treatment • Within 9 weeks of last trastuzumab treatment LVEF, left ventricular ejection fraction

  6. Recruitment end 10 July, 2007 Patientsenrolled 70 Stage 2: 39 patients have received treatment 60 50 Stage 1: 27 patients have received treatment 40 30 20 Planned cumulative 10 Actual cumulative 0 Mar06 Apr06 May06 Jun06 Jul06 Aug06 Sep06 Oct06 Nov06 Dec06 Jan07 Feb07 Mar07 Apr07 May07 Jun07 Jul07 Study fully recruited • Efficacy population n=33 • all patients who received 2 cycles of study treatment and an end of cycle 2 tumor assessment at April ASCO snapshot (no other planned efficacy cuts) • Safety population n=61 • all patients randomized and received study treatment at last IDSMB snapshot in August

  7. Safety population • 61 patients had received at least one dose of study medication at thetime of the data cut-off • all 61 patients are included in the safety population • median cycles received = 4 • range of cycles received = 1-16 • 64% of patients received prior anthracyclines

  8. Patient characteristics Characteristic No. patients No. patients Age (years), median (range) ECOG performance status 0 / 1 (%) Organ site (target and non-target lesions), n (%) Visceral Lung Liver Bone Lymph nodes Soft tissue Other ER status (%) +ve / -ve Total lesions (target and non-target), median (range) 61 54 (25-85) 70 / 16 48 (78) 24 (39) 32 (53) 16 (26) 24 (39) 10 (16) 7 (11) 48 / 51 3.5 (1-14) ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor

  9. All adverse events Adverse event (AE) Diarrhea Skin (other than rash) Nausea / vomiting Mucositis Pain Rash Fatigue Deep vein thrombosis (DVT), ejection fraction decreased, hypersensitivity, hypertension, hypomagnesemia Incidenceall grades (%) n=61 35 (59) 19 (31) 22 (36) 20 (33) 26 (43) 18 (30) 17 (28) 1 each (2) IncidenceGrade 3 / 4 (%) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) 0 (0) 1 DVT (2)

  10. Treatment-related adverse events: grade ≥3 Adverse event(n=1; 2%) Diarrhea Grade 3 Outcome Resolved Treatmentcontinued Yes

  11. Aftercycle 1 n= 54 Aftercycle 2 n= 51 Aftercycle 4 n= 35 Aftercycle 6 n= 23 Aftercycle 8 n= 14 Aftercycle 12 n= 10 Summary of the mean change in LVEF from baseline over time: local reading Baseline mean: 61.1% (SEM 0.67); median 60.0% (range 51-75) Mean absolute change in LVEF (%)

  12. Summary of LVEF data over time: local reading Baseline mean: 61% (SD 5.17); median 60.0% (range 51-75) Aftercycle 1 2 4 6 8 12 16 n 54 51 35 23 14 10 4 Increase, n/c,or change ≤10% 53 (98%) 50 (98%) 34 (97%) 22 (96%) 13 (93%) 9 (90%) 4 (100%) ≤50% &≥10% 1 (2%) ≤50% &≥15% Othera 1 (2%) 1 (3%) 1 (4%) 1 (7%) 1 (10%) aReading taken but the result invalid

  13. Patient with falling LVEF(local vs central reading) • Only 2 patients had a falling LVEF (≤50% and ≥10%) • Patient 1 remained asymptomatic; withdrawn from study at cycle 3 for disease progression Cycle Patient 1 Screening 1 2 Final visit LVEFLocala 56 50 42 42 LVEFCentralb 63 56 56 54 Changefrom baselinea -6% -14% -14% Changefrom baselineb -6.4% -6.6% -8.8% aLocal reading (patients managed according to local reading); bCentral reading

  14. Patient with falling LVEF(local vs central reading) • Only 2 patients had a falling LVEF (≤50% and ≥10%) • Patient 2 remained asymptomatic; withdrawn from study at the end of cycle 4 for disease progression Cycle Patient 2 Screening 1 2 4 LVEFLocala 60 56 60 55 LVEFCentralb 71 53 46 70 Changefrom baselinea -4% 0% -5% Changefrom baselineb -18% -25% -1% aLocal reading (patients managed according to local reading); bCentral reading

  15. Interim efficacy data as presented at ASCO 07 • n=33 • Overall response rate = 18.2% • Clinical benefit rate = 39.4% • Efficacy results updated for all 66 patients in trial will be reported in 2008 Baselga et al ASCO 2007

  16. CLEOPATRA : Phase III studyof trastuzumab + pertuzumab in HER2+ MBC Trastuzumab + docetaxel + placebo 1:1 randomization HER2+ MBC n = 800 Trastuzumab + docetaxel + pertuzumab An international Phase III randomized, double-blind, placebo-controlled study (approximately 250 sites worldwide) • Endpoints: • Progression-free survival • Overall survival • Quality of life • Biomarker analysis

  17. Neoadjuvant trastuzumab and pertuzumab HER2+ LABC and large stage II breast cancer (n=400) Trastuzumab + pertuzumab + docetaxelq3w x 4 Trastuzumab + docetaxelq3w x 4 Trastuzumab + pertuzumabq3w x 4 Pertuzumab + docetaxelq3w x 4 Surgery Surgery Surgery Surgery FEC q3w x 3 trastuzumab q3w until Week 52 FEC q3w x 3 trastuzumab q3w untilWeek 52 FEC q3w x 3 trastuzumab q3w untilWeek 52 Docetaxel + trastuzumab q3wx 4 FEC q3w x 3 trastuzumab q3w until Week 52 • Endpoints: • pCR • Biomarker analysis

  18. Conclusions • Pertuzumab is a promising agent with a new mechanism of action • Pertuzumab plus trastuzumab is active and well tolerated in patients with HER2-positive breast cancer • No significant cardiac events have been observed in 61 patients in this study • The trial is ongoing, with an additional pertuzumab monotherapy arm

More Related