Novel Preoperative Therapies for HER2-Positive Breast Cancer. Debu Tripathy, MD University of Southern California Norris Comprehensive Cancer Center

Transcription

1 Novel Preoperative Therapies for HER2-Positive Breast Cancer Debu Tripathy, MD University of Southern California Norris Comprehensive Cancer Center

2 Key Findings to Date in the Neoadjuvant Therapy of HER2+ Breast Cancer Pathological complete response (pcr) rate predicts longterm outcome, possibly to a greater extent than HER2- (esp HR+) cases HER2+ cases exhibit greater pcr rate than HER2- cases with chemotherapy alone Addition of trastuzumab significantly improves pcr rate and DFS when added to chemotherapy pcr rates are greater in HR-negative vs HR+ cases for HER2+ and the difference in outcome based on pcr is greater in HR- (as is the case with HER2-negative)

3 HER2 Positivity Confers Higher pcr Rate But Worse DFS and OS with Standard Chemotherapy N = 710, Stage II/III, standard preoperative chemotherapy pcr Breast, Nodes HER2-Negative 20/287 = 7% HER2+ 12/51 = 23.5% P= DFS % HER + HER2 - Negative P= Months Penault-Llorca F, et al. Oncologist 2007; 12:390

4 Multivariate Backward Stepwise # Analysis of Treatment and Baseline Factors* (n=5172 excluding trastuzumab treatment) # Dose-density, concomitant/sequential, histological type, triple (ER/PR/HER) receptor status were removed because of p>0.05 *Factors grouped as in histograms von Minckwitz G, et al SABCS 2008; abst. 79

5 Neoadjuvant Therapy with Trastuzumab Higher pcr with HR-Negative Status Peintinger F, et al. Ann Oncol 2008; 19:2020

6 DFS with Standard Anthracycline/Taxane Chemotherapy: Results from I SPY-1 Trial Based on Intrinsic Gene Profile Subsets Esserman, L and I SPY-1 Investigators, unpublished data

7 Effect of Trastuzumab on Neo-Adjuvant Therapy for HER2-Positive Disease % CI (41 87%) p= % CI (43 84%) p=0.016 P + FEC alone H + (P FEC) pcr (%) % n= % n= % n= % n=19 0 DSMB reviewed data (n=34) Final results (n=42) Buzdar A, et al. JCO 2005; 23:3676

8 NOAH Study Design HER2-positive LABC (IHC 3+ or FISH+) HER2-negative LABC (IHC 0/1+) H + AT q3w x 3 cycles n=117 n=118 n=99 T + AT q3w x 3 cycles T + 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 T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a 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, trastuzumab (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

9 NOAH: pcr: Intent-to-Treat Population Patients, % % p = p = % p = p = % 17% 19% 16% 0 With H Without H HER2- negative HER2-positive With H Without H HER2- negative HER2-positive pcr tpcr pcr: pathologic complete response in breast tpcr: total pathologic complete response in breast and nodes Gianni L, et al., Lancet 2010; 375:377

10 NOAH: EFS in HER2+ Population Median F/U 3.2 yr Probability Event Free Survival (EFS) H + CT CT Regimen 3 Yr EFS 3 Yr OS H + CT 71% 87% CT 56% 79% Months H + CT (n =115) CT (n = 112) HR (95% CI) P value Months EFS (events) ( ).013 OS (events) Symptomatic CHF = 2% Gianni L, et al., Lancet 2010; 375:377

11 Critical Questions and Hypothesis about HER2-Directed Neoadjuvant Therapy Are anthracylines more effective in combination with trastuzumab and is the combination safe? Are HER2+ tumors addicted to HER2? Can bypass pathways be overcome by dual targeting? Is dual targeting safe? Can dual targeting replace chemotherapy?

12 Concurrent Neoadjuvant Trastuzumab and Anthracyline compared to TCH: MDACC Experience PH FECH TCH N pcr 60.6% 43.3% p = ccr 80.8% 58.9% p = Yr RFS 93% 71% p < Yr OS 96% 86% p = Decline in LVEF from baseline 0.08% 0.08% p = 0.52 Note: PH FECH Group was significantly younger and had lower tumor stage and less pre-existing cardiac disease Bayraktar S, et al., ASCO 2011; abstract 532

13 Lapatinib or Trastuzumab Combined With Neoadjuvant Chemotherapy: The GeparQuinto Study (GBG 44) Untch et al. SABCS 2010; abstract S3-1

14 Neoadjuvant Chemotherapy Plus Lapatinib or Trastuzumab: Efficacy pcr Rate EC D/ Lapatinib EC D/ Trastuzumab P Value ypt0, ypn0 22% 31% <.05 ypt0/is, ypn0 30% 45% <.05 ypt0/is, ypnx 35% 50% <.05 Breast Conservation Rate 56% 66% NR Untch et al. SABCS 2010; abstract S3-1

15 Neo ALTTO Study Design Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF 50% N=450 Stratification: T 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR N 0-1 vs. N 2 Conservative surgery or not R A N D O M I Z E lapatinib paclitaxel trastuzumab paclitaxel lapatinib trastuzumab paclitaxel 6 wks + 12 wks S U R G E R Y F E C X 3 lapatinib trastuzumab lapatinib trastuzumab 34 weeks 52 weeks of anti-her2 therapy Baselga J et al. SABCS 2010; abstract S3-3

16 NeoALTTO: Safety Lapatinib/ Trastuzumab (n = 152) Lapatinib (n = 154) Trastuzumab (n = 149) Grade 3 Adverse Events 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 Event 33 (22%) 29 (19%) 2 (1%) No major cardiac events 1 death on lapatinib/trastuzumab arm immediately after treatment ended Baselga J et al. SABCS 2010; abstract S3-3

17 NeoALTTO Efficacy pcr and tpcr L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pcr pathologic complete response HR: hormone receptors Baselga J et al. SABCS 2010; abstract S3-3

18 pcr by Hormone Receptor Status L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pcr pathologic complete response HR: hormone receptors Baselga J et al. SABCS 2010; abstract S3-3

19 CHER-LOB Trial Amended to 1250 mg Amended to 750 mg Guarneri V, et al. ASCO 2011 Abstr # 507

20 CHER-LOB Trial: Toxicity CT = Chemotherapy; T = Trastuzumab; L = Lapatinib Guarneri V, et al. ASCO 2011 Abstr # 507

21 CHER-LOB Trial: Cardiac Function CT = Chemotherapy; T = Trastuzumab; L = Lapatinib Guarneri V, et al. ASCO 2011 Abstr # 507

22 CHER-LOB Trial: Efficacy CT = Chemotherapy; T = Trastuzumab; L = Lapatinib pcr = ypt0/tis, ypn0 Guarneri V, et al. ASCO 2011 Abstr # 507

23 Eligibility criteria: Operable or locally advanced/ inflammatory HER2 + breast cancer Chemonaive Primary tumors > 2 cm Randomized Phase II Study of Neoadjuvant Pertuzumab Plus Trastuzumab: NeoSphere R A N D O M I Z E Primary endpoint: pcr rates Secondary endpoints including: clinical response Docetaxel (T) Trastuzumab (H) (n = 107) Docetaxel (T) Trastuzumab (H) Pertuzumab (P) (n = 107) Trastuzumab (H) Pertuzumab (P) (n = 107) Docetaxel (T) Pertuzumab (P) (n = 96) All q 3 weeks 4 S U R G E R Y FEC q 3 weeks 3 H q 3 weeks, cycles 5-17 FEC q 3 weeks 3 H q 3 weeks, cycles 5-17 T q 3 weeks 4 FEC q 3 weeks 3 H q 3 weeks, cycles 5-17 FEC q 3 weeks 3 H q 3 weeks, cycles 5-21 FEC: 5-fluorouracil/epirubicin/ cyclophosphamide Gianni et al. SABCS 2010; abstract S3-2

24 NeoSphere: Efficacy of Neoadjuvant Pertuzumab Plus Trastuzumab Pathologic Complete Response TH (n = 107) THP (n = 107) HP (n = 107) TP (n = 96) pcr in Breast 29% 46% 17% 24% By Hormone Receptor Status ER + /PgR + 20% 26% 6% 17% ER /PgR 37% 63% 29% 30% By Nodal Status Node negative 21.5% 39% 11% 18% Node positive 7.5% 6.5% 6% 6% CR + PR + SD a 107 (100%) 106 (99%) 99 (92.5%) 94 (98%) a Investigator assessed Gianni et al. SABCS 2010; abstract S3-2

25 NeoSphere pcr rates: ITT Population Summary p = p = p = pcr, % ± 95% CI TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel Gianni et al. SABCS 2010; abstract S3-2

26 NeoSphere: Safety of Neoadjuvant Pertuzumab Plus Trastuzumab Grade 3 Adverse Events TH (n = 107) THP (n = 107) HP (n = 108) 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% The incidence of other grade 3 adverse events, including asthenia, granulocytopenia, rash, and drug hypersensitivity, was < 5%. No significant cardiac effect with combined trastuzumab and pertuzumab was noted over 4 cycles of neoadjuvant treatment. Gianni et al. SABCS 2010; abstract S3-2

27 [TITLE]

28 TBCRC 006: Neoadjuvant Lapatinib + Trastuzumab Without Chemotherapy: Study Schema [TITLE] Lapatinib (L) + Trastuzumab (T) + Endocrine therapy if ER+ Chang J, et. al. ASCO 2011 Abstr # 505

29 Chang J, et. al. ASCO 2011 Abstr # 505

30 Amplified Not Amplified Not Amplified Amplified Focal HER-2 amplified clones (FHAC) accounts for 21% of the FISH+ /IHC - cases and 30% of the FISH+ / IHC equivocal (2+) cases Sukov WR, et al. ASCO 2009, abstr 520

31 Loss of HER2 Post Neoadjuvant Trastuzumab Pre Treatment Post Treatment HER2 FISH CEP 17 FISH Fusion HER2 and CEP 17 FISH Mittendorf EA, et al. Clinical Cancer Res 2009;15:7381

32 CHER-LOB Trial: pcr Rate by p95 Status CT = Chemotherapy; T = Trastuzumab; L = Lapatinib Guarneri V, et al. ASCO 2011 Abstr # 507

33 [TITLE]

34 Molecular Effects and pcr to Neoadjuvant Trastuzumab and Lapatinib Holmes FA, et al. ASCO 2011 Abstr # 506

35 Molecular Effects and pcr to Neoadjuvant Trastuzumab and Lapatinib Resistant tumors are more highly networked Holmes FA, et al. ASCO 2011 Abstr # 506

36 Strategies for HER2+ Neoadjuvant Therapy For clinical care, use best adjuvant regimen Biomarker-driven therapies using neoadjuvant model for research Dual pathway blockade Lapatinib, pertuzumab mtor, PI3K, Akt inhibitors IGF-1R, HER3, c-met Angiogenesis inhibitors Stem cell targeting, epigenetic therapy Testing switching strategies in the case of resistance

37 I-SPY 2 Adaptive Trial: Learn, Drop, Graduate, and Replace Agents Over Time HER 2 (+) Randomize Paclitaxel + Trastuzumab* Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + Trastuzumab* + New Agent B Paclitaxel Taxol + + Trastuzumab* + New Agent FC AC Surgery Learn, Adapt from each patient as we go along Pt is On Study Randomize Paclitaxel *Or Equivalent HER 2 ( ) Paclitaxel Taxol + + New Agent CF Paclitaxel Taxol + + New Agent GH D Paclitaxel + New Agent E AC Surgery