Terapia Neoadiuvante Revisione delle evidenze scientifiche Valentina Guarneri Nonantola, 19 Novembre 2011

Preoperative vs postoperative, Overall Survival DDFS o OS??? The Cochrane Library, Issue 3, 2008

pCR vs residual disease, Overall Survival The Cochrane Library, Issue 3, 2008

Buzdar AU, Clin Cancer Res 2007 NEOADJUVANT P-FEC TRASTUZUMAB IN HER2+ OPERABLE BREAST CANCER T-FEC 19 pts T-FEC + H 23 pts pCR 26.3 % 65.2 % pCR ER pos 27 % 61 % pCR ER neg 25 % 70 % pN0 78.9 % 86.9 % In particular, the DMC requested that they be presented with a calculation of the probability of eventually (ie, after the full sample size of 164 patients), showing statistical significance in pCR rates favoring the trastuzumab plus chemotherapy arm, based on the currently available information. This probability was 95%. TheDMCfound this to be compelling evidence that the study had reached its primary objective and recommended that accrual be suspended. The pCR data for the first 34 patients, as reviewed Buzdar, J Clin Oncol 2005 Buzdar AU, Clin Cancer Res 2007 4

NOAH HER2-positive LABC (IHC 3+ or FISH+) AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles HER2-negative LABC (IHC 0/1+) Surgery followed by radiotherapya (n=99) (n=115) (n=113) H + AT q3w x 3 cycles AT q3w x 3 cycles H + T q3w x 4 cycles T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles CMF q4w x 3 cycles Surgery followed by radiotherapya Surgery followed by radiotherapya H continued q3w to week 52 19 crossed over to H 5 5 5

Gianni L, Lancet 2010

HR negative, or HR+ with cN+

GEPAR-QUATTRO: EFFICACY OUTCOMES 80 70 60 50 40 30 20 10 ypT0 ypTis ypT0/is, N0 ypN0 Untch M, J Clin Oncol 2010

Untch M et al, J Clin Oncol 2011

NEO-ALTTO STUDY DESIGN R G E Y A N D O M I Z E lapatinib trastuzumab paclitaxel + 12 wks 6 wks Stratification: T ≤ 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR – N 0-1 vs. N ≥ 2 Conservative surgery or not Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N=450 lapatinib FEC X 3 trastuzumab lapatinib trastuzumab 34 weeks 52 weeks of anti-HER2 therapy Baselga J et al. SABCS 2010 14

Neo-ALLTO: PATHOLOGIC RESPONSE L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response Baselga J et al. SABCS 2010 15

CHER LOB Trial: study plan RANDOMI ZATI ON Lapatinib 1000 mg/daily Lapatinib 1500 mg/daily CORE BI OPSY S URGE RY  Chemotherapy A B C TXL 80 mg/m2 Trastuzumab 2 mg/kg 5 FU 600 mg/m2 Epi 75 mg/m2 CTX 600 mg/m2 Guarneri V, ASCO 2011

CHER-LOB: EFFICACY OUTCOMES 10 20 30 40 50 60 70 80 90 Arm A:CT + trastuzumab Arm B: CT + lapatinib Arm C: CT + trastuzumab/lapatinib pCR (breast & axilla) Node negativity Breast conservation Guarneri V, ASCO 2011

NEOSPHERE: STUDY DESIGN TH (n=107) docetaxel + trastuzumab S U R G E Y FEC q3w x 3 trastuzumab q3w cycles 5–17 trastuzumab q3w cycles 5–21 Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) THP (n=107) docetaxel + trastuzumab + pertuzumab HP (n=107) trastuzumab + pertuzumab docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17 TP (n=96) docetaxel + pertuzumab Study dosing: q3w x 4 BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L et al. SABCS 2010 18

NEOSPHERE: pCR RATES pCR, %  95% CI 45.8 29.0 24.0 16.8 50 40 30 20 The main therapeutic result showed a very high rate of tumor eradication in th breast when pertuzumab was added to the conventional trastuzumab and docetaxel combination: 46.8 % for the triplet regimen and 29 % for the comparator arm. pCR accounted for 16.8% in women receiving the two monoclonals without chemotherapy, and 24% when pertuzumab and docetaxel were used 20 29.0 24.0 10 16.8 H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP Gianni L et al. SABCS 2010 6 19

HORMONE RECEPTOR STATUS AND pCR Trial/author pts # Regimen HR + % % pCR HR- HR+ Kemeny 54 FACVb 66 20.0 7.7 Ring 435 CMF, A/E 71 21.6 8.1 Bear 1211 AC 59 13.6 5.7 565 AC+T 57 22.8 14.1 GEPARDO 250 ddAD+/-T 56 15.4 1.1 GEPARDUO 913 ddAD/CA-D 74 6.2 GEPARTRIO 286 TAC/TAC-NX 68 36.6 10.1 Guarneri 1731 FAC+/-P 23.8 7.8 Gianni 438 A+/P/CMF 63 42.2 11.6 201 FEC/ET/GET 16.6 3.5 Colleoni 399 ECF/EC/ET/ViFuP 33.3 7.6 20

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 21

CHER-LOB: pCR rate by HR 25% 22.7% 10 20 30 40 50 60 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) 26.6% 35.7% 56.2% HR+ HR- T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib 22

NEOSPHERE: pCR AND HORMONE RECEPTORS STATUS 70 60 ER or PR pos ER and PR neg 50 63.2 40 pCR, %  95% CI 30 . 20 36.8 30.0 10 29.1 26.0 20.0 5.9 17.4 H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP Gianni L et al. SABCS 2010 23

Chang, ASCO 2011

Chang, ASCO 2011

PST IN HER2+ OPERABLE BREAST CANCER: KEY FINDINGS Patient selection is mandatory for the integration of novel agents in cancer treatment Chemotherapy + trastuzumab is the gold standard Double-HER2 blockade increases the pCR rate Endocrine pathway is still important even in presence of HER2 co-expression A dual anti-HER2 blockade + endocrine therapy is promising The preoperative setting is ideal to test new combinations through the “window of opportunity model”