Systemic therapy: HER-2 update Hans Wildiers Multidisciplinair Borst Centrum/Algemene medische oncologie UZ Leuven
New drugs Strategic issues
Specific anti-her2 drugs Lapa$nib /Nera$nib Baselga & Swain, Nature Reviews Cancer 2009
Pertuzumab: NeoSphere Patients with operable or locally advanced / inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417) TH (n=107) docetaxel + trastuzumab THP (n=107) docetaxel + trastuzumab + pertuzumab HP (n=107) trastuzumab + pertuzumab TP (n=96) docetaxel + pertuzumab S U R G E R Y FEC q3w x 3 trastuzumab q3w cycles 5 17 FEC q3w x 3 trastuzumab q3w cycles 5 17 docetaxel q3w x 4 FEC q3w x 3 trastuzumab q3w cycles 5 17 FEC q3w x 3 trastuzumab q3w cycles 5 21 Study dosing: q3w x 4 Lancet Oncol SABCS 2012 2010
Pertuzumab: NeoSphere pcr rates pcr, % 50 p = 0.0141 p = 0.0198 p = 0.003 40 30 45.8 20 29.0 10 24.0 16.8 0 TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel
Pertuzumab with anthracyclines Very little cardiac toxicity pcr 57-66% Tryphaena study SABCS 2011
Pertuzumab metastatic 1st line: CLEOPATRA study Max 1 line of hormone therapy (Neo)adj therapy interval 12 Mo NEJM 2011
Pertuzumab metastatic 1st line: CLEOPATRA study RR 80,2% vs 69,3%
Pertuzumab (P) after Trastuzumab (T) 29 pts progressive during T Start P monotherapy: ORR 3% (1 pt), CBR 10% Re-addition of T : ORR 17%, CBR 41% P + T more active than monotherapy! JCO 212 Cortez.
T-DM1 Single agent activity - 112 pts with progression after at least one line of antiher2 therapy (median of 5 prior systemic agents in metastatic setting) - ORR 26% - PFS 4,6 months - Toxicity limited: hypokalemia, thrombocytopenia, liver test disturbance JCO 2011 Burris
T-DM1 PFS Hurvitz, ESMO 2011
T-DM1 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD ESMO 2012
T-DM1 EMILIA results ORR 43,6% vs 30,8% Duration of Response 12,6 vs 6,5 months Much less toxic!
Lapatinib: NEO-ALLTO trial 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 SABCS 2010
Lapatinib: Neo-ALLTO pcr rates Lancet 2012
Lapatinib More toxic: diarrhea (21% gr III), rash, (liver) Waiting ALLTO trial: Lapatinib alone inferior! Other trials showing inferiority of L vs T (e.g. Capecitabine L vs T) L + T remains interesting
Neratinib Irreversible panher TKI High activity: RR 24% if prior Trast. RR 56% in Trast-naïve pts Toxicity: up to 30% gr III-IV diarrhea Ann Oncol 2010
New drugs Strategic issues
Adjuvant treatment in HER2+ Anthracycline Taxane or TCH chemo Trastuzumab 1y = standard potentially useful from 0.5 cm (pt1bn0) If chemo possible, best to combine T with chemo T concomitant with Taxanes > sequential Other antiher2 drugs: wait for ALLTO and Aphinity trial
Update on duration of Trast. ESMO 2012 HERA: 2y = 1y Phare: 6 Mo non inferior to 12 Mo 1y Trast. remains standard
Metastatic Increasing chaos Number of drugs Number of patients Availability (reimbursement) = suboptimal
ER pos HER2 pos Chemo + T as efficient as in ER neg Hormone therapy JCO 2005 Cui et al Tamoxifen: relative resistance? Anastrozole +/- T: PFS 4.8 vs 2.4 mo Letrozole +/- L: PFS 8.2 vs 3.0 mo PFS in HER2+ (no benefit in HER2 neg)
Metastatic: hormoneinsensitive/resistant R/ options Taxane-T Monotherapie: RR ± 50-80% Vinorelbine T vs Docetaxel (30-35 mg/m2) (100 mg/m2) T TTP 15.3 vs 12.4 md OS 38.8 vs 35.7 md FN 10 % vs 36 % (p <0.05) Capecitabine + L < Capecitabine + H L + T platinum, gemcitabine, liposomal anthracycline (+/- T) Andersson. JCO 2011
Near future Cortes ESMO 2012
Reimbursement in Belgium Taxanes: fortunately solved recently Trastuzumab: Monotherapy after failure of anthracyclines and taxanes With paclitaxel 1 st line if anthracycline are not considered With docetaxel 1 st line if docetaxel is reimbursed Aromatase inhibitors: after anti-e Lapatinib: + Letrozole in ER+ At this moment no indication for chemo AND no previous trastuzumab or chemo for MBC AND contraindication for anti-estrogeen AND contraindication for trastuzumab (report from cardiologist) + Capecitabine, after failure of anthracycline-taxane-trastuzumab Pertuzumab/T-DM1: let s cross fingers!
Predictive markers of response? HERA trial: DFS by central FISH ratio HERA trial: SABCS 2007)
Predictive markers of response? Neosphere: selection of biomarkers IGF1R HER1 HER2 HER3 Y HER2 NK cell FcGR HER ligands p95 HER2 ER PTEN mtor p27 FKHR PI3K Akt GSK3 BAD ER Grb2 Shc Sos Grb2 Sos Ras Raf MEK 1/2 Cyclin D1, E Cell- cycle progression Cell survival Nucleus c- myc MAPK Cell prolifera$on
Predictive markers of response? Conclusions from NeoSphere biomarker analyses HER2 expression (H-score) associated with sensitivity to pertuzumab PIK3CA mutations in exon 9 linked to lack of sensitivity to HER2-directed MAb s Intrinsic differences between HER2-positive tumors based on hormone receptor status No predictive role for truncated forms of the HER2 receptor including p95 HER2 So far none of the analyses provided clinically useful assays for patient and/or regimen selection in addition or alternative to the conventional assessment of HER2 by IHC or FISH 2
Conclusions: HER2+ breast cancer Wealth of drugs available (more and more specific with limited toxicity) Major challenge is how to use/combine/ sequence these drugs Drug availability/reimbursement is a threat Can we get rid of chemo?