NOVITA’ DAGLI STUDI DI TERAPIA ADIUVANTE PER IL

CARCINOMA MAMMARIO HER2+: RILEVANZA CLINICA

Mirco Pistelli Clinica di Oncologia Medica

A. O. Ospedali Riuniti Ancona

Perugia, 6 luglio 2018

Anti-HER2 adjuvant therapy: CHALLENGES WITH EVIDENCE

• Less chemotherapy (de-escalation)

• Duration of Trastuzumab: longer versus shorter

• Addition of other agents (escalation)

• ER+ HER2+

Impact of adjuvant trastuzumab on long-term outcome in early-stage HER2-positive breast cancer

1986-1992

2004-2008

Cossetti RJ et al JCO 2015

7178 pazienti- stadio I-III

Adjuvant Trastuzumab Trials: >13,000 Patients 2005 Was a Good Year

Anti-HER2 adjuvant therapy: CHALLENGES WITH EVIDENCE

• Less chemotherapy (de-escalation)

• Duration of Trastuzumab: longer versus shorter

• Addition of other agents (escalation)

• ER+ HER2+

Less chemotherapy: anthracyclines, yes or not?

Less chemotherapy: anthracyclines, yes or not?

Less chemotherapy: anthracyclines, yes or not?

Less chemotherapy: anthracyclines, yes or not?

Less chemotherapy: anthracyclines, yes or not?

Tolaney et al, NEJM 2015 & ASCO 2017

Less chemotherapy: anthracyclines, yes or not?

Less chemotherapy: anthracyclines, yes or not?

Tolaney et al, NEJM 2015 & ASCO 2017

Less chemotherapy: anthracyclines, yes or not?

Tolaney et al, NEJM 2015 & ASCO 2017

Less chemotherapy: anthracyclines, yes or not?

Tolaney et al, NEJM 2015 & ASCO 2017

Less chemotherapy: anthracyclines, yes or not?

Tolaney et al, NEJM 2015 & ASCO 2017

Adjuvant chemotherapy: yes or not?

Adjuvant chemotherapy is standard of care

Anti-HER2 adjuvant therapy: CHALLENGES WITH EVIDENCE

• Less chemotherapy (de-escalation)

• Duration of Trastuzumab: longer versus shorter

• Addition of other agents (escalation)

• ER+ HER2+

Just one year ago…

Just 7 months ago…

Just 1 month ago…

6 vs 12 months (DFS)

9 weeks vs 12 months (DFS)

HORG=481 pz

p=ns p=ns

PHARE=3380 pz

p=0.01

PERSEPHONE=4089 pz

Short-HER=1253 pz

p=ns

SOLD=2176 pz

p=ns

Short-HER=1253 pz PHARE=3380 pz PERSEPHONE=4089 pz

Subgroup analysis (DFS)

Slide 31

Presented By Martine Piccart-Gebhart at 2018 ASCO Annual Meeting

Anti-HER2 adjuvant therapy: CHALLENGES WITH EVIDENCE

• Less chemotherapy (de-escalation)

• Duration of Trastuzumab: longer versus shorter

• Addition of other agents (escalation)

• ER+ HER2+

Addition of other agents: Lapatinib

Martine Piccart, JCO 2016

Addition of other agents: Lapatinib

DFS L+T vs T=+2% (4y) p=ns OS L+T vs T=+1% (4y) p=ns

Addition of other agents: Neratinib

Martin M, Lancet Oncology 2017

Addition of other agents: Neratinib

DFS N+T vs T=+2.5% (5y) p=0.008

Martin M, Lancet Oncology 2017

Martin M, Lancet Oncology 2017

Addition of other agents: Neratinib

DFS N+T vs T=+4.4% (5y) p=0.002 DFS N+T vs T=+0.1% (5y) p=ns

Addition of other agents: Pertuzumab

(expected 89.2%)

Addition of other agents: Pertuzumab

* statistically signicant

ALTTO (N=8381) ExteNET (N=2840) APHINITY (N=4805)

T >2 cm 4199 (50.1%) 1401 (49.3%) 2879 (59.9%)

N+ (%) 4323 (51.6%) 2169 (76.4%) 3007 (62.6%)

DFS (control group) 86% (4y) 87.7% (5y) 90.6% (4y)

OS (control group) 94% (4y) nr nr

HR 0.84 0.73 0.81

in favour of «more» (ALL) +2% +2.5%* +1.7%*

in favour of «more» (ER+) +2% +4.4% * +1.4%

in favour of «more» (ER-) +3% +0.1% +2.3%

in favour of «more» (N0) nr Nr +0.5%

in favour of «more» (N+) nr nr** +3.2%*

** HR=0.67 (0.46-0.96) N>4

Addition of other agents: does it really benefit?

• Lapatinib: not approved for adjuvant treatment

• Neratinib: approved by FDA, rejected by EMA

• Pertuzumab: approved by FDA and EMA, waiting for AIFA.

Addition of other agents: where are we now?

Anti-HER2 adjuvant therapy: CHALLENGES WITH EVIDENCE

• Less chemotherapy (de-escalation)

• Duration of Trastuzumab: longer versus shorter

• Addition of other agents (escalation)

• ER+ HER2+

• We may (and probably are) over-treating a subgroup of ER+ HER2+ BC in the (neo-) adjuvant setting.

• Inhibition of HER2 without inhibition of ER may increase ER signaling allowing ER to act as an escape mechanism. This could contribute to the lower pCR seen in ER+HER2+ BC. Crosstalk could explain worse outcome in the ExteNET.

• There may be a subset of ER+HER2+ BC where ER inhibition is critical and more important than chemotherapy.

Why is this important?

• The use of Trastuzumab-based chemotherapy has dramatically improved outcome for patients with early stage HER2+ BC; patients in more recent trials have lower recurrence rates than in earlier trials.

• For the present, chemotherapy is a key component and standard of care for the treatment of early stage HER2+ BC.

• Further follow-up from APT trial demonstrates very favorable outcome with low rates of distant recurrence; thus can be considered for stage I HER2+ BC.

• A short duration of adjuvant Trastuzumab (< 12-mo) should be considered (especially if cardiac risk factors) and patients who cannot complete 12-mo can be reassured.

• Addition of pertuzumab to adjuvant regimens improves DFS but restricted to high risk patients (especially N+). However, don’t forget to select N+ HER2+ BC for neo-adjuvant treatment (pCR= ↑OS).

• ER+ HER2+ BC are heterogeneous and further therapeutic de-escalation could be evalueted.

Thoughts to take home