Positive HER-2 tumor. How to incorporate the new drugs into neoadjuvance

Transcription

1 Oncology Department Vall d Hebron University Hospital Barcelona. Spain Positive HER-2 tumor. How to incorporate the new drugs into neoadjuvance Javier Cortés June/2013

2 MD Anderson experience Buzdar et al. JCO 2005

3 pcr according to hormone receptor status Positive Negative Buzdar et al. JCO 2005

4 Efficacy of neoadjuvant trastuzumab in patients with HER-2 positive breast cancer: the NOAH (Neoadjuvant Herceptin) Phase III trial Gianni, et al. Lancet 2010

5 NOAH: the largest neoadjuvant trial in HER2-positive breast cancer HER2-positive LABC (IHC 3+ and / or FISH+) HER2-negative LABC (IHC 0/1+) n=115 H + AT q3w x 3 H + T q3w x 4 H q3w x 4 + CMF q4w x 3 Surgery followed by radiotherapy a H continued q3w to Week 52 AT q3w x 3 T q3w x 4 CMF q4w x 3 n=113 Surgery followed by radiotherapy a AT q3w x 3 T q3w x 4 CMF q4w x 3 n=99 Surgery followed by radiotherapy a a Hormone receptor-positive patients receive adjuvant tamoxifen; LABC, locally advanced breast cancer; H, trastuzumab (8 mg/kg loading then 6 mg/kg); AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); T, paclitaxel (175 mg/m 2 ); CMF, cyclophosphamide, methotrexate, fluorouracil

6 Interim efficacy analysis Primary end point (final analysis) event-free survival defined by either progression on therapy or relapse after surgery in patients with HER2-positive breast cancer Secondary end points (interim efficacy a and final analysis) overall response rate pcr rate safety and tolerability a Interim analysis of response rate is triggered once all patients have undergone surgery pcr, pathological complete response

7 NOAH: trastuzumab improves pcr rates in patients with HER2-positive LABC 50 p=0.002 Patients with pcr (%) p= With H Without H HER2 negative HER2 positive pcr = pathological CR Gianni, et al. Lancet 2010

8 NOAH: EFS (HER2-positive population) 1.00 Probability of EFS H + CTx CTx Events year EFS HR % CI p value* Months Median follow-up 3 years *Unadjusted for stratification variables: adjusted HR=0.55, p= EFS = event-free survival; CTx = chemotherapy Gianni, et al. Lancet 2010

9 New Neoadjuvant Trials To Consider R Trast + Docetaxel Pertuz + Docetaxel Pertuz + Trast + Docetaxel Pertuz + Trast NEO- SPHERE n~400 R Trast Trast + Paclitaxel Lapatinib Lapatinib + Paclitaxel Trast/Lap Trast/Lap + Paclitaxel NEO- ALTTO n~450 R EC + Trast Docetaxel + Trast EC + Lapatinib Docetaxel + Lapatinib GEPAR- QUINTO n~600

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16 NeoALLTO: 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

17 Efficacy pcr and tpcr L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pcr pathologic complete response

18 Efficacy Overall (Clinical) Response at 6 weeks (w/o chemo) and at surgery L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab

19 Safety Number (%) of patients with AEs at Grade 3 L (N= 154) T (N= 149) L+T (N= 152) Diarrhea 36 (23%) 3 (2%) 32 (21%) Hepatic * 20 (13%) 2 (1%) 13 ( 9%) Neutropenia 24 (16%) 4 (3%) 13 ( 9%) Skin disorders 10 (7%) 4 (3%) 10 (7%) * Includes 2 patients with Hy s Law criteria in T, and one patient in L No major cardiac dysfunction One death in L+T immediately after end of treatment (unrelated cardiac arrest) L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab

20 R A N D O M I Z C O R E B I S U R G A B CHER-LOB Study: Design 121 pts 5 FU 600 mg/m 2 Epi 75 mg/m 2 CTX 600 mg/m 2 Paclitaxel 80 mg/m 2 Trastuzumab 2 mg/kg Z A T I O N Lapatinib 1000 mg CDD Lapatinib 1500 mg continuous daily dose (CDD) I O P S Y G E R Y B C LVEF Guarneri V, et al. JCO 2012

21 Efficacy Breast & Axillary pcr rate % % 27.8% 0 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) pcr= ypt0/yptis + ypn0 T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib

22 NSABP B-41 Study: Design Tissue for Biomarkers Tissue for Biomarkers Operable Breast Cancer HER-2 neu Positive R AC WP+T AC WP+L AC WP+T+L WP=Weekly Paclitaxel S U R G E R Y Trastuzumab for a total of 1 year N= 529 Endpoints: pcr, cardiac events, DFS, OS Robidoux A, et al. ASCO 2012

23 NSABP B-41 Primary Aims To determine whether AC WP + T + L increases pcr in the breast compared to AC WP + T To determine whether AC WP + L increases pcr in the breast compared to AC WP + T

24 NSABP B-41 pcr Breast and Negative Nodes P=0.056 P=0.78

25 NSABP B-41 Diarrhea (%) AC WP+T (178) AC WP+L (173) AC WP+T+L (173) Grade % 80% 73% Grade 3 2% 20% 27% P<0.001

26 Neoadjuvant trastuzumab and pertuzumab Study WO20697 / NEOSPHERE HER2+ LABC and large stage II breast cancer (n=400) Trastuzumab + docetaxel q3w x 4 Trastuzumab + pertuzumab + docetaxel q3w x 4 Trastuzumab + pertuzumab q3w x 4 Pertuzumab + docetaxel q3w x 4 Surgery Surgery Surgery Surgery FEC q3w x 3 trastuzumab q3w until Week 52 End points: pcr biomarker analysis FEC q3w x 3 trastuzumab q3w until Week 52 Docetaxel + trastuzumab q3w x 4 FEC q3w x 3 trastuzumab q3w until Week 52 FEC q3w x 3 trastuzumab q3w until Week 52

27 NeoSphere pcr rates: ITT population summary p = p = p = pcr, % ± 95 5% CI H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP

28 NeoSphere: pcr and hormone receptors status pcr, % ± 95 5% CI H, trastuzumab; P, pertuzumab; T, docetaxel ER or PR pos ER and PR neg TH THP HP TP

29 Tolerability of neoadjuvant treatment by arm 10 most common grade 3 adverse events TH (n=107) Patients, % THP (n=107) HP (n=108) TP (n=94) Neutropenia Febrile neutropenia Leukopenia Diarrhea Aesthenia Granulocytopenia Rash Menstruation irregular Drug hypersensitivity ALT increased AE, adverse event; ALT, alanine aminotransferase H, trastuzumab; P, pertuzumab; T, docetaxel

30 TRYPHAENA Study diagnosis epirubi/cyclo x 3 // docetaxel x 3 plus trastuzumab /pertuzumab docetaxel x 3 plus Epirubi/cyclo X3 trastuzu/ pertuzu SURGE ERY / XRT Trastuzumab + pertuzumab to 1 year Trastuzumab + pertuzumab to 1 year Docetaxel / carboplatin Trastuzumab /pertuzumab (TCH) X 6 Trastuzumab + pertuzumab to 1 year Additional chemorx if required Schneeweiss, et al. SABCS 2011

31 Cardiac events in the treatment period FEC+H+P x3 T+H+P x3 n = 72 FEC x3 T+H+P x3 n = 75 TCH+P x6 n = 76 Symptomatic LVSD (grade 3), n (%) 2 (2.7) 1 (1.3) LVSD (all grades), n (%) 5 (6.9) 3 (4.0) 5 (6.6) LVEF decline 10% points from baseline to <50%, n (%) 5 (6.9) 5 (6.7) 5 (6.6) FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab Schneeweiss, et al. SABCS 2011

32 Pathological complete response ypt0/is ypt0 ypn0 Pathological comp plete response (%) 61.6 [ ] [ ] [ ] 51.9 FEC+H+P x3 T+H+P x3 (n = 73) FEC x3 T+H+P x3 (n = 75) TCH+P x6 (n = 77) FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab Schneeweiss, et al. SABCS 2011

33 TBCRC 006: Study Design Neoadjuvant Lapatinib & Trastuzumab Without Chemotherapy : Study Schema Lapatinib (1000 mg/day) Trastuzumab (4 mg/kg load, 2 mg/kg q-weekly) S u r g e r y Bx Weeks Lap (L) + Tras (T) + Endocrine Rx if ER+

34 Pathologic Response Evaluated after completion of neoadjuvant therapy Definition: pcr (path complete response): Absence of invasive cancer in breast npcr (near path complete response): Residual disease (<1 cm) in breast

35 Pathologic Response pcr pcr+npcr pcr (%) % 21% 40% 53% 56% 48% 0 All ER+ ER - All ER+ ER-

36 Adverse Events (N=65) Discontinued therapy: 5 (8%) Grade 1-2: Gastrointestinal Diarrhea: 43 (66%) Nausea: 20 (31%) Skin Acneiform rash: 30 (46%) Abnormal LFTs: 16 (25%) Grade 3-4 Abnormal LFTs: 3 (<5%)

37 Neoadjuvant Studies I NOAH GeparQuinto NeoAltto CHER-LOB NSABP B-41 Scheme Ch + T Ch + T Ch + L Ch + T Ch + L Ch + TL Ch + T Ch + L Ch + TL Ch + T Ch + L Ch + TL Primary endpoint EFS pcr breast & axilla* pcr breast pcr breast & axilla pcr breast n pcr (%) breast pcr (%) breast & axila NR NR NR *pcr excludes ducatl in situ carcinoma Ch, chemotherapy; EFS, event free-survival; L, lapatinib; n, sample; pcr, pathological complete response; T, trastuzumab

38 Neoadjuvant Studies II Neosphere Tryphaena TBCRC-006 Scheme Primary endpoint Ch + T Ch + P Ch + TP TP Ch + TP pcr breast Cardiotoxicity pcr breast TL n pcr (%) breast pcr (%) breast & axila NR Ch, chemotherapy; L, lapatinib; n, sample; P, pertuzumab; pcr, pathological complete response; T, trastuzumab

39 HannaH Phase III Study SC trastuzumab HER2- positive EBC (N=596) Clinical stage Ic to IIIc including IBC R 1:1 IV trastuzumab Neoadjuvant Surgery pcr Adjuvant 18 cycles/ 1 year Follow-up: 24 mo Docetaxel FEC 75 mg/m 2 500/75/500 Trastuzumab IV 6 mg/kg q3w (8 mg/kg loading dose) Trastuzumab SC 600 mg/5 ml q3w (fixed dose) Objective: Show non-inferiority of SC vs. IV based on co-primary endpoints PK: observed trastuzumab C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pcr) in the breast IBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide Jackisch C, et al. EBCC 2012

40 PK Results Primary endpoint Observed C trough pre-dose Cycle 8 Trastuzumab IV n=235 Trastuzumab SC n=234 Geometric mean (µg/ml) Geometric mean ratio 1.33 (90% CI) (1.24; 1.44) Non-inferiority of SC vs IV demonstrated as lower bound of 90% CI > than pre-specified non-inferiority margin of 0.8 Secondary endpoints Patients > 20 µg/ml pre-dose Cycle (98.7%) 227 (97.0%) AUC at Cycle 7 Geometric mean (µg/ml*day) Geometric mean ratio (90% CI) Pharmacokinetic per protocol population 20 µg/ml is the therapeutic target threshold 1.07 (1.01; 1.12) 20 µg/ml is the therapeutic target threshold Jackisch C, et al. EBCC 2012

41 Efficacy Results Primary endpoint Trastuzumab IV n=263 No. (%) Trastuzumab SC n=260 No. (%) pcr in the breast * 107 (40.7%) 118 (45.4%) Difference in pcr rates (95% CI)* 4.7% (-4.0%; 13.4%) Non-inferiority of SC vs IV demonstrated as lower bound of 95% CI > than pre-specified non-inferiority margin -12.5% Secondary endpoints pcr in breast and axilla (tpcr) * 90 (34.2%) 102 (39.2%) Difference in tpcr (95% CI) 5.01% (-3.5%; 13.5%) Overall response rate 231 (88.8%) 225 (87.2%) Median time to response 6 weeks 6 weeks Efficacy per protocol population. Pathological tumor response was assessed locally. Difference in pcr/tpcr calculated as SC- IV pcr defined as absence of invasive neoplastic cells in the breast. Residual ductal carcinoma in situ (DCIS) is acceptable for pcr Jackisch C, et al. EBCC 2012

42 Predictive value of pcr CMTN HER2

43 Predictive value of pcr Ki67 <13%; HER2[-] Ki67 >13%; HER2[-] HER2

44 CONCLUSIONS 1. 1-year Trastuzumab is the standard of care in patients treated a. In adjuvant b. In neoadjuvant 2. Lapatinib or Pertuzumab in combination with Trastuzumab seems to be the new upcoming SOC in the neoadjuvant setting 3. SC Trastuzumab might be a more convenient strategy to administer trastuzumab