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2 nd annual San Antonio breast cancer symposium review january 28, 2012. Sponsored By:. SABCS 2011 Review: HER2-Directed Therapy in Breast Cancer. Chau Dang, MD Assistant Professor of Medicine Weill Cornell Medical College Breast Cancer Medicine Service
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2nd annual San Antonio breast cancer symposium reviewjanuary 28, 2012 Sponsored By:
SABCS 2011 Review:HER2-Directed Therapy in Breast Cancer Chau Dang, MD Assistant Professor of Medicine Weill Cornell Medical College Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center January 28, 2012
Objectives • Overview on Trastuzumab • Lapatinib • Goss et al (abstract # S4-7) • Neratinib • Martin et al (abstract # S5-7) • Pertuzumab • Baselga et al (abstract # S5-5) • Schneeweiss et al (abstract # S5-6) • pCR as predictor of outcomes • Loibl et al (abstract # S5-4)
HER2-“Positive” Breast Cancer • 20-25% of invasive breast cancers • Overexpression can activate signaling • Promotes cell proliferation and survival Hudis NEJM 2007
Trastuzumab in First-Line Treatment AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin + cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR, response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant 1Slamon DJ et al. N Engl J Med. 2001:344(11):783-792; 2Vogel CL et al. J Clin Oncol. 2002;20:719-726; 3Burstein HJ et al. J Clin Oncol. 2003;21(15):2889-2895; 4Marty M et al. J Clin Oncol. 2005;23(19):4265-4274; 5Kaufman B et al. J Clin Oncol. 2009;27(33):5529-5537; 6Valero V et al. J Clin Oncol. 2011;29:149-156.
“Other” HER Targeted Strategies Anti-ligand blocking antibodies Tyrosine kinase Inhibitors neratinib lapatinib erlotinib gefitinib Anti-EGFR blocking antibodies cetuximab HER dimerization inhibitors pertuzumab Ligand- or Ab-toxin conjugates T-DM1 Adapted from Noonberg and Benz. Drugs. 2000;59:753.
Targets intracellular kinase domain of HER1 and HER2 Reversible inhibition of HER1 and HER2 homo and heterodimer formation Inhibits growth in trastuzumab conditioned cell lines Lapatinib 1+1 2+2 1+2 Courtesy of E. Winer
Clinical Activity of Lapatinib in HER2+ MBC • 1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4Geyer NEJM 2006; 5Cameron BrCancerResTreat 2008; 6Di leo JCO 2008
TEACH trial: Tykerb Evaluation After Chemotherapy • Randomized, double-blind, placebo-controlled, phase III trial to evaluate the effects of delayed adjuvant lapatinib monotherapy • More than 3000 women • completed neo-adjuvant or adjuvant chemotherapy, • did not receive trastuzumab and • NED • Randomized to lapatinib or placebo for up to 12 months or until a DFS event • Median time from diagnosis to study entry: 3 years Goss abs S4-7
Delayed Adjuvant Lapatinib Results • Median follow up of 4 years • DFS events were 13% vs. 17% in favor of lapatinib vs placebo (HR = 0.83 95% CI, 0.70 to 1.00; 2 sided p=0.053), but not statistically significant. • No role for “delayed” lapatinib in the adjuvant setting ! • What about “upfront” lapatinib in ALTTO ? Goss abs S4-7
ALTTO Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Neo (adj) anthracycline-based chemo THL (12 wks) HL (40 wks) (L =1000 mg qd) TL (12 wks) L (40 wks) (L =1500 mg qd) TH (12 wks) TH (12 wks) H (40 wks) Washout (6 wks) L (34 wks) (L =1500 mg qd) T=paclitaxel, H=trastuzumab, L=lapatinib • Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years • Radiotherapy if indicated
Lapatinib vs Neratinibin HER2+ MBC • 1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4 Burstein JCO 2010
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Study Design Neratinib 240 mg/day n = 117 R A N D O M I Z E Phase 2, open-label trial in HER2+ locally advanced or metastatic BC patients L + C L 1,250 mg/day + C 2,000 mg/m2 per day n = 116 1○- PFS 2○ - ORR, CBR, OS, Safety G 3/4 Diarrhea and PPE • Neratinib was administered orally at 240 mg/day continuously • L 1,250 mg/day was administered orally continuously; • C 2,000 mg/m2 was administered orally on D1 to 14 of each 21-day cycle • Martin et al, SABC 2011 abstract # S5-7 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Key Eligibility Criteria Women with HER2+ locally advanced or metastatic BC not amenable to curative therapy Disease progression on or following 1 to 2 prior trastuzumab-based regimens Prior treatment with a taxane regimen Prior anthracycline treatments at or below the maximum cumulative dose of 400 mg/m2 for doxorubicin, 800 mg/m2 for epirubicin, or equivalent dose for other anthracycline derivatives Measurable disease (≥1 measurable lesion), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Baseline Characteristics This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
PFS: ITT Population 100 90 80 70 60 50 40 30 20 10 0 0 5 10 15 20 25 30 San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Neratinib L + C Non-inferiority of neratinib vs L+C could not be demonstrated. Probability of PFS (%) Time since randomization (mo) This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Overall Survival: ITT Population 100 90 80 70 60 50 40 30 20 10 0 0 5 10 15 20 25 30 San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Neratinib L + C Probability of OS (%) Time since randomization (mo) This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Best Overall Response: ITT L=lapatinib, C=capecitabine The ORR was 40% in L+C arm vs 29% in neratinib arm. The CBR was 63% in L+C arm vs 44% in neratinib arm.
Selected Treatment-related AEs (All Grades) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 There was a low incidence of cardiac events in both treatment arms: neratinib, 7%; L + C, 6% Diarrhea was transient and manageable. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Conclusions Neratinib did not demonstrate non-inferiority for PFS against L+C. Med PFS was numerically (not statistically) superior with L+C (6.8 mo vs 4.5 mo). Diarrhea was the most frequently reported AE. The ORR of neratinib in heavily pretreated patients was 29%, consistent with results from the preceding single-arm trial.1 Continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC ? San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 1. Burstein HJ, et al. J Clin Oncol. 2010;28(8):1301-1307. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
HER2-Targeted Therapy with Pertuzumab • Monoclonal antibody and pan-HER inhibitor • Binds to a distinct epitope on the HER2 extracellular domain • Prevents dimerization Pertuzumab Trastuzumab
Pertuzumab Activity 1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022
Pertuzumab Activity 1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022
CLEOPATRA: CLinical Evaluation Of Pertuzumab And TRAstuzumab CLEOPATRA
Eligibility Criteria • Centrally confirmed HER2+ (IHC 3+ and/or FISH > 2.0) • Locally recurrent, un-resectable, or MBC • Measurable and/or non-measurable • 1 prior hormone Rx for MBC allowed • Prior neoadj/adj chemo and trastuzumab allowed if DFI > 12 mo • LVEF > 50% • No h/o CHF or LVEF < 50% during/after prior trastuzumab
Data immature but Baselga abs #S5-5
Grade 3/4 Adverse Events(incidence > 5%) G 3/4 diarrhea was low !
Cardiac Safety *LVSD=left ventricular systolic dysfunction, defined as NYHA class III/IV
Conclusions • CLEOPATRA met its primary endpoint w/ a statistically significant PFS improvement from 12.4 to 18.5 months w/ addition of pertuzumab (HR 0.62, p < 0.0001). • OS data immature • Pertuzumab well tolerated • No increased cardiac toxicity • May be practice changing !
Questions • Safe in combination with other chemotherapy foundations? • Adjuvant/neoadjuvant studies ? • Continuation beyond progression ?
MSKCC IRB# 10-142 THP Schema Accrual Goal = 69 patients N = 69 HER2 + 0-1 prior Rx Tissue bx optional 1° endpoint=6 mo PFS q week …………………………… q 3 weeks…………………………. q 3 weeks…………………………. ♥ ♥ every 4 cycles………………….. TNI, BNP, NRG-1ß every 2 cycles………………………… Paclitaxel at 80 mg/m2 ♥ ECHO w/ strain imaging Pertuzumab at 840mg load → 420 mg q 3 w Trastuzumab at 8 mg/kg load → 6 mg/kg q 3 w PI: Dang
APHINITY: Adjuvant PertuzumabAnthracycline-Based S R F O L L O W U P 10 yrs R A N D O M I Z E AC/EC x 4 or FEC/FEC x 3-4 T x 3-4 S U R G E R Y Trastuzumab q 3 wks x 52 wks Pertuzumab q 3 wks x 52 wks Centrally Confirm HER2 AC/EC x 4 or FEC/FEC x 3-4 T x 3-4 Trastuzumab q 3 wks x 52 wks Placebo q 3 wks x 52 wks Breast/chest RT and endocrine Rx as appropriate after chemo completion Start w/i 1 wk of randomization Randomize w/i 7 wks of surgery
APHINITY: Adjuvant PertuzumabNon-Anthracycline Based S R F O L L O W U P 10 yrs R A N D O M I Z E TC x 6 S U R G E R Y Trastuzumab q 3 wks x 52 wks Pertuzumab q 3 wks x 52 wks Centrally Confirm HER2 TC x 6 Trastuzumab q 3 wks x 52 wks Placebo q 3 wks x 52 wks Breast/chest RT and endocrine Rx as appropriate after chemo completion Start w/i 1 wk of randomization Randomize w/i 7 wks of surgery
Can HER2-targeted antibody therapies be administered safely with anthracyclines?
Study Endpoints Primary endpoint: • Cardiac safety • Symptomatic LVSD (grade ≥3) • LVEF declines (≥10 percentage points and below 50%) Secondary endpoints: • Toxicity • pCR • Clinical response rate • Rate of BCS • DFS, OS • Biomarker evaluation Schneeweiss abs #S5-6
Eligibility Criteria Centrally confirmed HER2-positive locally advanced, inflammatory, or early-stage breast cancer Primary tumor ≥2 cm Baseline LVEF ≥55% ECOG PS 0 or 1 No previous anticancer therapy or radiotherapy for any malignancy Adequate bone marrow, liver, and renal function Schneeweiss abs #S5-6
Breast Conserving Surgery When Mastectomy Was Planned* * Patients in ITT population w/ T2-3 tumors for whom mastectomy was planned.