Her 2 Positive Metastatic Breast Cancer Alison Jones November 2013
Mrs Hermione Positive (then and now!) Diagnosed 2007 T2 N1 Mo ER ve; Her2 ve Mastectomy ANC; FEC/T Herceptin (12months) August 2010metastatic relapse node and lung PS1 Normal organ function What next?
Trastuzumab Combination Pivotal Trial: Overall Survival FISH FISH 1.0 Trast. CT (n = 176) CT (n = 169) 1.0 Trast. CT (n = 50) CT (n = 56) Probability of survival 0.8 0.6 0.4 20.0 mo 26.2 mo RR = 0.71 p = 0.007 0.8 0.6 0.4 19.8 mo 24.0 mo RR = 1.11 p = NS 0.2 0.2 0 0 10 20 30 40 50 0 0 10 20 30 40 50 Months Months Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.
Majority of patients with ErbB2-positive MBC responding to trastuzumab plus taxane or vinorelbine 1 st -line progress within 1 year 0 2 4 6 8 10 12 months 6 1 7.1 2,3* Median TTP 7.8 4 9.9 5 11.1 6 11.7 7 12.4 8 *ErbB2 IHC 3 subgroup 1. Burstein et al. Cancer 2007;110(5):965 72; 2. Slamon et al. N Engl J Med 2001;344:783 92; 3. Smith et al. Anticancer Drugs 2001;12(Suppl 4):S3 10; 4. Burstein et al. J Clin Oncol 2001;19:2722 30; 5. Gasparini et al. Breast Cancer Res Treat 2007;110(5):965 72; 6. Pegram et al. J Clin Oncol ASCO Annual Meeting Proceedings 2007;25(18S): Abstract #LBA1008; 7. Marty et al. J Clin Oncol 2005;23:4265 74; 8. Tedesco et al. J Clin Oncol 2004;22(6):1071 7
GBG-26 was the first randomised Phase III study to investigate continuation of Herceptin Progression under Herceptin-based 1st-line therapy taxane (n=114) a or progression under Herceptin monotherapy or non-taxane (n=42) R Xeloda 1,250 mg/m 2 bid d1-14 q21d continuation of Herceptin 6 mg/kg q3w (n=78) Xeloda 1,250 mg/m 2 bid d1-14 q21d (n=78) Primary endpoint: TTP a Includes 3 patients who received adjuvant Herceptin taxane R, randomisation von Minckwitz G et al ASCO 2008; Abs 26
Continuation of Herceptin prolongs time to progression by nearly 3 months Probability 1.0 Herceptin Xeloda (n=78) Xeloda (n=78) 0.8 0.6 0.4 X: 5.6 (4.2-6.3) mos XH: 8.2 (7.3-11.2) mos HR=0.69 (2-sided p=0.034; 1-sided p=0.015) 0.2 0.0 5.6 a 8.2 a 0 10 20 30 Time from 1st progression (months) 40 74 77 40 55 15 29 8 12 5 4 3 3 2 1 1 1 1 1 a Median TTP in months HR, hazard ratio von Minckwitz G et al ASCO 2008; Abs 26
Mrs Hermione Positive (situation in 2011) First line taxane plus herceptin with herceptin until disease progression At progression (outside CNS) apply for capecitabine plus lapatinib via Cancer Drugs fund At futher progrssion stop HER 2 targeted therapy (reluctantly) and unless there is a targeted trail available use standard@ chemotherapy and pray!
Mrs Hermione Positive (then and now!) Diagnosed 2010 T2 N1 Mo ER ve; Her2 ve Mastectomy ANC; FEC/T Herceptin (12months) August 2013 metastatic relapse node and lung PS1 Normal organ function What next?
CLEOPATRA (WO20698) HER2ve MBC (n=808) R Docetaxel trastuzumab placebo Docetaxel trastuzumab pertuzumab» Primary endpoint: PFS (independent review)» Secondary endpoints: Overall survival PFS (investigator assessment) Objective response rate and duration of response Safety profile Time to symptom progression (FACT Trial Outcome Index) Evaluate biomarkers and correlate with clinical outcomes» Enrolment stratified by: Prior treatment for breast cancer Geographic region FACT=Functional assessment of cancer therapy, PFS=progression-free survival
Primary endpoint: Independently assessed PFS n = 433 PFS events Progression-free survival (%) 100 90 80 70 60 50 40 30 20 10 0 n at risk Pla T D Ptz T D: median 18.5 months Pla T D: median 12.4 months 0 5 10 15 20 25 30 35 40 Time (months) 402 345 267 139 83 32 Ptz 10 T D 0 0 406 311 209 93 42 17 7 0 0 HR = 0.62 95% CI 0.51 0.75 p<0.0001 D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab = 6.1 months Stratified by prior treatment status and region
What to do at first relapse? Lapatinib plus capectiabine TDM-1? Trastuzumab plus laptinib? And then what to do at next relapse?
T-DM1 Structure Target expression: HER2 Monoclonal antibody: trastuzumab (Herceptin ) Cytotoxic agent: DM1 Highly potent cytotoxic agent Linker: MCC Systemically stable T-DM1 Average drug:antibody ratio 3.5:1 12
EMILIA Phase III (TDM4370g) HER2-positive (centrally confirmed) locally advanced or MBC (n=980) R T-DM1 q3w Lapatanib capecitabine q3w Treatment continues until disease progression or unmanageable toxicity No provision for crossover Primary endpoints: PFS (by IRF) OS Safety Secondary endpoints: QoL FACT-B Key inclusion criteria Prior treatment to include a taxane and trastuzumab in adjuvant, locally advanced or metastatic setting Documented progression of disease during or after treatment for advanced/metastatic disease, or within 6 months of completing adjuvant therapy Silent as to line of therapy but assume majority of patients will be 2 nd (or 2 nd /3 rd )-line PFS=progression-free survival; IRF=independent review facility; OS=overall survival; QoL=quality of life; FACT-B=functional assessment of cancer therapy for breast cancer
Key findings: progression-free survival by independent and investigator review Blackwell KL, et al. ASCO 2012;30:LBA1.
Special cases Relapse on or within 12months of adjuvant treatment (pertuzumab not available through CDF) ER HER2 metastatic breast cancer (role of dual targeting) CNS only metastases Can we ever stop Trastuzumab in the metstatic setting?
HER2 breast Cancer; Keep the brake on HER2!