ESMO Preceptorship Programme

To trastuzumab resistance and beyond

Valeria Merz, MD – University of Verona (Italy)

Gastric Cancer – Valencia, 28 -29 September 2018

ESMO PRECEPTORSHIP PROGRAMME

No conflicts of interest.

Gastric Cancer – Valencia, 28 -29 September 2018

To trastuzumab resistance and beyond

ESMO PRECEPTORSHIP PROGRAMME

P. C., male, 62 years old

July 2011 Diagnosis of adenocarcinoma

of gastric cardia cT3N2M0 HER2 3+

July – September 2011 weekly TCF

RT (50,4 Gy) + weekly TCF

ESMO PRECEPTORSHIP PROGRAMME

Predictive role of HER2 to peri-operative chemotherapy in the MAGIC trial

Okines, Ann Oncol 2013

10.4%

HER2

positive

ESMO PRECEPTORSHIP PROGRAMME

EORTC 1203

INNOVATION trial

Perioperative treatment ongoing trials

• phase II

• HER2 gastric or

GEJ

adenocarcinoma

• stage Ib-II

R

perioperative CT

perioperative CT + trastuzumab

perioperative CT trastuzumab+ + pertuzumab

FLOT6

PETRARCA trial

CT: XP or FOLFOX or FLOT

• phase II/III

• HER2 resectable

gastric cancer R

perioperative FLOT

(4 + 4 cycles)

perioperative FLOT

(4 + 4 cycles)trastuzumab pertuzumab+ +

Primary endpoint: major

pathological response rate

Primary endpoint:

- phase II: pCR rate

- phase III: mPFS

ESMO PRECEPTORSHIP PROGRAMME

P. C., male, 62 years old, ECOG PS 0

July 2011 Diagnosis of adenocarcinoma

of gastric cardia cT3N2M0 HER2 3+

July – September 2011 weekly TCF

RT (50,4 Gy) + weekly TCF

November 2011 Subtotal

esophagectomy with mediastinic

and abdominal D2 node dissection

pCR

ESMO PRECEPTORSHIP PROGRAMME

March 2012

March 2012 PD (single liver metastasis) CDDP + 5-FU + trastuzumab

ESMO PRECEPTORSHIP PROGRAMME

ToGA trial

median number of cycles of

trastuzumab: 8 (1 – 49)

Bang, Lancet 2010

ESMO PRECEPTORSHIP PROGRAMME

March 2012

March 2012 PD (single liver metastasis) CDDP + 5-FU + trastuzumab

July 2012 Liver metastasectomy maintenance with trastuzumab

January 2014 Pulmonary PD right atypical metastasectomy (HER2+)

maintenance with trastuzumab

October 2015 Pulmonary PD 2 cycles of CDDP + 5-FU + trastuzumab

February 2016 PR maintenance with trastuzumab

January 2014 October 2015

ESMO PRECEPTORSHIP PROGRAMME

May 2016 Right VATS with metastasectomy; EI: R1; HER2+ maintenance with

trastuzumab

December 2016 PD in previous surgical site 3 cycles of CDDP + 5-FU +

trastuzumab

March 2017 PR maintenance with trastuzumab

December 2017 Pulmonary PD right

middle lobectomy maintenance with

trastuzumab

18/06/18 Last CT scan: still negative

until now

ESMO PRECEPTORSHIP PROGRAMME

What if he will eventually develop trastuzumab resistance?

Satoh, JCO 2014

TyTAN trial

Lapatinib

+

paclitaxel

Paclitaxel

Prior

trastuzumab

therapy8 (6%) 7 (5%)

ESMO PRECEPTORSHIP PROGRAMME

Thuss-Patienc, Lancet Oncol 2017

GATSBY trial

Taxane TD-M1

Prior

trastuzumab

therapy93 (79%) 173 (76%)

What if he will eventually develop trastuzumab resistance?

ESMO PRECEPTORSHIP PROGRAMME

d26 d94 d129

Piro G, et al. Clin Cancer Res 2016

In vivo selection of four gastric cancer models with

acquired resistance to trastuzumab

ESMO PRECEPTORSHIP PROGRAMME

An FGFR3 autocrine loop sustains acquired

resistance to trastuzumab in gastric cancer patients

NCI-N

87

N87

-TR1

N87

-TR2

N87

-TR3

N87

-TR4

0

50

100

150FGF9

Fo

ld C

ha

ng

e (

2- D

DC

T)

NCI-N

87

N87

-TR1

N87

-TR2

N87

-TR3

N87

-TR4

0

1000

2000

3000 FGFR3

Fo

ld C

ha

ng

e (

2- D

DC

T)

Piro G, et al. Clin Cancer Res 2016

ESMO PRECEPTORSHIP PROGRAMME

FGFR3/AKT sustains acquired resistance to

trastuzumab in gastric cancer patients

Piro G, et al. Clin Cancer Res 2016

ESMO PRECEPTORSHIP PROGRAMME

Study Title: A phase II trial of the FGFR inhibitor INCB54828 in patients with HER2-positive advanced

EGJ/Gastric cancer Trastuzumab Resistant: the FiGhTeR trial

Indication: HER2-positive advanced EGJ/gastric cancer progressed to Trastuzumab

Country/Site: Italy (Verona)

Other Sites

Number of sites: 1

Design:

This will be a phase II, single-arm, open-label trial to assess the safety, the tolerability and the activity of INCB54828 as second-line treatment strategy in advanced EGJ/gastric cancer patients refractory to first-

line trastuzumab-containing therapies.

Principal Investigator: Davide Melisi

ESMO Preceptorship Programme