Hans Wildiers Multidisciplinair Borst Centrum/Algemene medische oncologie

UZ Leuven

Systemic therapy: HER-2 update

• New drugs

•  Strategic issues

Specific anti-HER2 drugs

Lapa$nib  /Nera$nib  

Baselga  &  Swain,  Nature  Reviews  Cancer  2009  

Pertuzumab: NeoSphere

THP (n=107) docetaxel + trastuzumab + pertuzumab

HP (n=107) trastuzumab + pertuzumab

TP (n=96) docetaxel + pertuzumab

S

U

R

G

E

R

Y

docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17

FEC q3w x 3 trastuzumab q3w cycles 5–17

FEC q3w x 3 trastuzumab q3w cycles 5–17

FEC q3w x 3 trastuzumab q3w cycles 5–21

Study dosing: q3w x 4

TH (n=107) docetaxel + trastuzumab

Patients with operable or

locally advanced /inflammatory*

HER2-positive BC

Chemo-naïve & primary tumors >2cm (N=417)

SABCS 2010 Lancet Oncol 2012

H, trastuzumab; P, pertuzumab; T, docetaxel

Pertuzumab: NeoSphere pCR rates

p = 0.0141 50

40

30

20

10

0 TH THP HP TP

pCR, % p = 0.0198

p = 0.003

29.0

45.8

16.8 24.0

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

RR 80,2% vs 69,3%

Pertuzumab metastatic 1st line: CLEOPATRA study

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%

JCO 212 Cortez.

→ P + T more active than monotherapy !

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

EMILIA Study Design

1:1

HER2+ (central) LABC or MBC

(N=980)

•  Prior taxane and trastuzumab

•  Progression on metastatic tx or within 6 mos of adjuvant tx

PD

T-DM1

3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD

T-DM1

ESMO 2012

ORR 43,6% vs 30,8% Duration of Response 12,6 vs 6,5 months Much less toxic !

T-DM1 EMILIA results

Lapatinib: NEO-ALLTO trial

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

34 weeks 52 weeks of anti-HER2 therapy

lapatinib

trastuzumab

lapatinib trastuzumab

FEC X 3

S U R G E R Y

R A N D O M I Z E

lapatinib

trastuzumab

lapatinib trastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks 6 wks

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.

•  HERA: 2y = 1y

•  Phare: 6 Mo non inferior to 12 Mo

→ 1y Trast. remains standard

ESMO 2012

Increasing chaos …

•  Number of drugs ↗  •  Number of patients ↘  •  Availability (reimbursement) =

‘suboptimal’

Metastatic

ER pos HER2 pos

•  Chemo + T as efficient as in ER neg

•  Hormone therapy – 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)

JCO 2005 Cui et al

R/ options •  Taxane-T Monotherapie: RR ± 50-80% •  Vinorelbine (30-35 mg/m2) –T vs Docetaxel (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

Metastatic: hormoneINsensitive/resistant

Near future

Cortes ESMO 2012

Reimbursement in Belgium •  Taxanes: fortunately solved recently

•  Trastuzumab: –  Monotherapy after failure of anthracyclines and taxanes –  With paclitaxel 1st line if ‘anthracycline are not considered’ –  With docetaxel 1st 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 !

HERA trial: DFS by central FISH ratio

HERA trial: SABCS 2007)

Predictive markers of response?

Neosphere: selection of biomarkers

ER

Nucleus  

c-­‐myc  

Raf  

MEK  1/2  

MAPK

Akt  

GSK3   BAD  

Cell-­‐cycle  progression  

PTEN  

mTOR  

p27  

Cyclin  D1,  E  

FKHR  

Grb2   Sos  

Cell  survival  

Ras  

Shc   Sos  Grb2  

PI3K  

Cell  prolifera$on  

HER  ligands  NK  cell  

FcGR  Y

ER

p95HER2  

HER2  HER1   HER2   HER3  IGF1R  

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 p95HER2 •  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  

Predictive markers of response?

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?