Key Findings to Date in the Neoadjuvant Therapy of H2+ Breast Cancer Novel Preoperative Therapies for H2-Positive Breast Cancer Debu Tripathy, MD University of Southern California Norris Comprehensive Cancer Center Pathological complete response (pc) rate predicts longterm outcome, possibly to a greater extent than H2- (esp H+) cases H2+ cases exhibit greater pc rate than H2- cases with chemotherapy alone Addition of significantly improves pc rate and DFS when added to chemotherapy pc rates are greater in H-negative vs H+ cases for H2+ and the difference in outcome based on pc is greater in H- (as is the case with H2-negative) H2 Positivity Confers Higher pc ate But Worse DFS and OS with Standard Chemotherapy Multivariate Backward Stepwise # Analysis of Treatment and Baseline Factors* (n=5172 excluding treatment) N = 710, Stage II/III, standard preoperative chemotherapy pc Breast, Nodes H2-Negative 20/287 = 7% H2+ 12/51 = 23.5% P=0.0008 DFS % H + H2 - Negative P=0.0073 Months Penault-Llorca F, et al. Oncologist 2007; 12:390 # Dose-density, concomitant/sequential, histological type, triple (/P/H) receptor status were removed because of p>0.05 *Factors grouped as in histograms von Minckwitz G, et al SABCS 2008; abst. 79 Neoadjuvant Therapy with Higher pc with H-Negative Status DFS with Standard Anthracycline/Taxane Chemotherapy: esults from I SPY-1 Trial Based on Intrinsic Gene Profile Subsets Peintinger F, et al. Ann Oncol 2008; 19:2020 sserman, L and I SPY-1 Investigators, unpublished data 1
ffect of on Neo-Adjuvant Therapy for H2-Positive Disease pc (%) 90 80 70 60 50 40 30 20 10 0 95% CI (41 87%) p=0.02 25% n=16 66.7% n=18 DSMB reviewed data (n=34) 95% CI (43 84%) p=0.016 26.3% n=19 65.2% n=23 Final results (n=42) P + FC alone H + (P FC) Buzdar A, et al. JCO 2005; 23:3676 H + AT q3w x 3 cycles H + T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles Surgery followed by radiotherapy a NOAH Study Design H2-positive LABC (IHC 3+ or FISH+) T + AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles H2-negative LABC (IHC 0/1+) n=117 n=118 n=99 Surgery followed by radiotherapy a T + AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a H continued q3w to week 52 AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); H, (8 mg/kg loading dose then 6 mg/kg); T, paclitaxel (175 mg/m 2 ); a Hormone receptor-positive patients will receive adjuvant tamoxifen Gianni L, et al., Lancet 2010; 375:377 NOAH: pc: Intent-to-Treat Population NOAH: FS in H2+ Population Median F/U 3.2 yr 1.00 Patients, % 50 40 30 20 10 0 43% p = 0.0007 22% With H Without H H2- negative H2-positive pc p = 0.37 17% 38% p = 0.001 pc: pathologic complete response in breast tpc: total pathologic complete response in breast and nodes 19% With H Without H H2- negative H2-positive tpc p = 0.52 16% Gianni L, et al., Lancet 2010; 375:377 Probability vent Free Survival (FS) 0.75 0.50 0.25 H + CT CT 0.00 0 6 12 18 24 30 36 42 Months Months H + CT (n =115) CT (n = 112) H (95% CI) P value FS (events) 36 51 0.59 (0.38 0.90).013 OS (events) 18 26 0.62.114 Symptomatic CHF = 2% egimen 3 Yr FS 3 Yr OS H + CT 71% 87% CT 56% 79% Gianni L, et al., Lancet 2010; 375:377 Critical Questions and Hypothesis about H2-Directed Neoadjuvant Therapy Are anthracylines more effective in combination with and is the combination safe? Are H2+ tumors addicted to H2? Can bypass pathways be overcome by dual targeting? Is dual targeting safe? Can dual targeting replace chemotherapy? Concurrent Neoadjuvant and Anthracyline compared to TCH: MDACC xperience 2001-2009 PH FCH TCH N 235 65 pc 60.6% 43.3% p = 0.016 cc 80.8% 58.9% p = 0.006 3 Yr FS 93% 71% p < 0.001 3 Yr OS 96% 86% p = 0.008 Decline in LVF from baseline 0.08% 0.08% p = 0.52 Note: PH FCH Group was significantly younger and had lower tumor stage and less pre-existing cardiac disease Bayraktar S, et al., ASCO 2011; abstract 532 2
Lapatinib or Combined With Neoadjuvant Chemotherapy: The GeparQuinto Study (GBG 44) Neoadjuvant Chemotherapy Plus Lapatinib or : fficacy pc ate C D/ Lapatinib C D/ P Value ypt0, ypn0 22% 31% <.05 ypt0/is, ypn0 30% 45% <.05 ypt0/is, ypnx 35% 50% <.05 Breast Conservation ate 56% 66% N Untch et al. SABCS 2010; abstract S3-1 Untch et al. SABCS 2010; abstract S3-1 Invasive operable H2+ BC T > 2 cm (inflammatory BC excluded) LVF 50% N=450 Stratification: T 5 cm vs. T > 5 cm or Pg + vs. & Pg N 0-1 vs. N 2 Conservative surgery or not Neo ALTTO Study Design A N D O M I Z paclitaxel paclitaxel paclitaxel 6 wks + 12 wks S U G Y F C X 52 weeks of anti-h2 therapy 3 34 weeks Grade 3 Adverse vents No major cardiac events NeoALTTO: Safety Lapatinib/ (n = 152) Lapatinib (n = 154) (n = 149) Diarrhea 32 (21%) 36 (23%) 3 (2%) Liver 13 (9%) 20 (13%) 2 (1%) Neutropenia 13 (9%) 24 (16%) 4 (3%) Skin 10 (7%) 10 (7%) 4 (3%) Treatment Discontinuation Due to Adverse vent 33 (22%) 29 (19%) 2 (1%) 1 death on / arm immediately after treatment ended NeoALTTO fficacy pc and tpc pc by Hormone eceptor Status L: ; T: ; L+T: plus pc pathologic complete response H: hormone receptors L: ; T: ; L+T: plus pc pathologic complete response H: hormone receptors 3
CH-LOB Trial CH-LOB Trial: Toxicity Amended to 1250 mg Amended to 750 mg CH-LOB Trial: Cardiac Function CH-LOB Trial: fficacy pc = ypt0/tis, ypn0 ligibility criteria: Operable or locally advanced/ inflammatory H2 + breast cancer Chemonaive Primary tumors > 2 cm andomized Phase II Study of Neoadjuvant Pertuzumab Plus : NeoSphere A N D O M I Z Docetaxel (T) (H) Docetaxel (T) (H) Pertuzumab (P) (H) Pertuzumab (P) Docetaxel (T) Pertuzumab (P) (n = 96) Primary endpoint: pc ratesall q 3 weeks 4 Secondary endpoints including: clinical response S U G Y FC q 3 weeks 3 5-17 FC q 3 weeks 3 5-17 T q 3 weeks 4 FC q 3 weeks 3 5-17 FC q 3 weeks 3 5-21 FC: 5-fluorouracil/epirubicin/ cyclophosphamide NeoSphere: fficacy of Neoadjuvant Pertuzumab Plus Pathologic Complete esponse TH THP HP TP (n = 96) pc in Breast 29% 46% 17% 24% By Hormone eceptor Status + /Pg + 20% 26% 6% 17% /Pg 37% 63% 29% 30% By Nodal Status Node negative 21.5% 39% 11% 18% Node positive 7.5% 6.5% 6% 6% C + P + SD a 107 (100%) 106 (99%) 99 (92.5%) 94 (98%) a Investigator assessed 4
pc, % ± 95% CI NeoSphere pc rates: ITT Population Summary p = 0.0198 50 40 30 20 p = 0.0141 45.8 p = 0.003 29.0 10 24.0 16.8 0 TH THP HP TP H, ; P, pertuzumab; T, docetaxel NeoSphere: Safety of Neoadjuvant Pertuzumab Plus Grade 3 Adverse vents TH THP HP (n = 108) The incidence of other grade 3 adverse events, including asthenia, granulocytopenia, rash, and drug hypersensitivity, was < 5%. TP (n = 94) Neutropenia 57% 45% 1% 55% Febrile Neutropenia 7.5% 8% 0 7% Leukopenia 12% 5% 0 7% Diarrhea 4% 6% 0 4% No significant cardiac effect with combined and pertuzumab was noted over 4 cycles of neoadjuvant treatment. TBCC 006: Neoadjuvant Lapatinib + Without Chemotherapy: Study Schema [TITL] [TITL] Lapatinib (L) + (T) + ndocrine therapy if + Chang J, et. al. ASCO 2011 Abstr # 505 Amplified Not Amplified Not Amplified Chang J, et. al. ASCO 2011 Abstr # 505 Focal H-2 amplified clones (FHAC) accounts for 21% of the FISH+ /IHC - cases and 30% of the FISH+ / IHC equivocal (2+) cases Amplified Sukov W, et al. ASCO 2009, abstr 520 5
Loss of H2 Post Neoadjuvant Pre Treatment Post Treatment H2 FISH CP 17 FISH Fusion H2 and CP 17 FISH CH-LOB Trial: pc ate by p95 Status Mittendorf A, et al. Clinical Cancer es 2009;15:7381 Molecular ffects and pc to Neoadjuvant and Lapatinib [TITL] Holmes FA, et al. ASCO 2011 Abstr # 506 Molecular ffects and pc to Neoadjuvant and Lapatinib esistant tumors are more highly networked Holmes FA, et al. ASCO 2011 Abstr # 506 Strategies for H2+ Neoadjuvant Therapy For clinical care, use best adjuvant regimen Biomarker-driven therapies using neoadjuvant model for research Dual pathway blockade Lapatinib, pertuzumab mto, PI3K, Akt inhibitors IGF-1, H3, c-mt Angiogenesis inhibitors Stem cell targeting, epigenetic therapy Testing switching strategies in the case of resistance 6
I-SPY 2 Adaptive Trial: Learn, Drop, Graduate, and eplace Agents Over Time H 2 (+) andomize * * + New Agent A * + New Agent B Paclitaxel Taxol + + * + New Agent FC AC Surgery Learn, Adapt from each patient as we go along Pt is On Study andomize Paclitaxel *Or quivalent H 2 ( ) Paclitaxel Taxol + + New Agent CF Paclitaxel Taxol + + New Agent GH D New Agent AC Surgery 7