NOVITA’ IN TEMA DI CARCINOMA GASTRICO

ROSA BERENATO

ONCOLOGIA MEDICA 1 FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI

MILANO

Little progress against mGC:

Median overall survival in most first-line large studies is 9–11 months

OS in first-line palliative setting

PROGRESS AGAINST METASTATIC GC

What do we have so far?

Trastuzumab + cisplatin + capecitabine/5FU in HER2+ GC as first-line

Ramucirumab +/- Paclitaxel in second-line

Bang YJ, et al. Lancet 2010 Wilke H, et al. Lancet Oncol 2014

Fuchs C, et al. Lancet 2014

STATUS OF TARGETED AGENTS IN GC

HOW CAN WE MOVE FORWARD?

• Targeting HER-2

• Targeting Angiogenesis

• Immune Checkpoint Inhibitors

HOW CAN WE MOVE FORWARD?

• Targeting HER-2

• Targeting Angiogenesis

• Immune Checkpoint Inhibitors

V325

ToGA

ToGa HER2 3+

8,6

11,1

11,8

0,6

2,7

4,2

Incremental survival gains: trastuzumab beats cytotoxics!

OS, months

Bang YJ, et al. Lancet 2010

1°LINE CHEMO PLUS TRASTUZUMAB

Dual HER2 blockade? 2° Line anti-HER2 Therapy?

Resistance mechanisms?

HOW TO MOVE ON AFTER ToGA TRIAL?

JACOB STUDY DESIGN

Treatment until disease progression

or unacceptable toxicity

Pertuzumab (840 mg) Trastuzumab (8 6 mg/Kg)

CDDP + 5-FU/cape

Placebo Trastuzumab (8 6 mg/Kg)

CDDP + 5-FU/cape

R A N D O M I Z E

(1:1)

Metastatic HER-2+ gastric/GEJ cancer

(n=780)

Secondary endpoints: PFS, ORR, PRO, Safety, PK, IG

Multicenter, randomized, double-blind, placebo-controlled phase III study

Primary endpoint: overall surival superiority

Secondary endpoint: PFS, ORR, duration-of-response, clinical benefit rate, safety, cardiac safety

Adaptative phase II/III study

Primary endpoint: overall surival

Secondary endpoint: PFS, ORR, duration-of-response, PRO, safety, and PK

Presented By Yoon-Koo Kang at 2016 ASCO GI

GATSBY STUDY DESIGN

Presented By Yoon-Koo Kang at 2016 ASCO GI

GATSBY STUDY: OVERALL SURVIVAL

OS: ITT population PSF ITT population

TyTAN STUDY: RESULTS

LOSS OF HER2 AS ACQUIRED RESISTANCE MECHANISM

HER2 IHC in baseline (A, B) and post-

progression samples (C, D) in a patient

receiving trastuzumab in association to

CDDP + 5FU followed by trastuzumab

maintenance until disease progression

HER2 positivity HER2 over-expression

Concordance Loss Concordance Loss

N % N % N % N %

Baseline HER2 IHC score

1 20 4 80 3 38 5 62 2+

3+ 12 86 2 14 12 86 2 14

All 13 68 6 32 15 68 7 32

p value* 0.008 0.025

HER2 status changes according to definition of HER2 positivity (IHC + ISH) and HER2 overexpression (IHC only)

Pietrantonio F, Berenato R, et al. Submitted

OS HER2 3+ PFS HER2 3+

TyTAN STUDY: HER2 STATUS AND RESULTS

An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients.

Piro G, et al. Clin Cancer Res 2016

TRASTUZUMAB RESISTENCE: FGFR3

TRASTUZUMAB RESITANCE : ONGOING TRIALS

Molecules Trial number Conditions Combined agents Phase

Afatinib NCT01743365 Her2 positive mGC 1° L CDDP + 5FU II

Afatinib NCT02274012 Her2 positive / Trastuzumab-refractory

Paclitaxel II

Afatinib NCT01522768 Her2 positive / Trastuzumab-refractory

Trastuzumab II

Poziotinib NCT01746771 Her2 positive mGC 1° L

Paclitaxel + Trastuzumab

I, II

Dacomitinib NCT01152853 Her2 positive / Trastuzumab-refractory

None II

Pertuzumab NCT01774786 Her2 positive mGC 1° L CDDP + 5FU III

HOW CAN WE MOVE FORWARD?

• Targeting HER-2

• Targeting Angiogenesis

• Immune Checkpoint Inhibitors

Study Treatment arms Line mOS ∆OS HR

RAINBOW (phase III)

Ramucirumab + paclitaxel Placebo + paclitaxel

2°L 9.6 7.4

1.2 0.807 (p 0.017)

REGARD (phase III)

Ramucirumab Placebo

2°L 5.2 3.8

1.4 0.776 (p 0.047)

Chinese (phase III)

Apatinib Placebo

3°L 6.5 4.7

1.8 HR= 0.70 (p 0.014)

INTEGRATE (phase II)

Regorafenib Placebo

2°L 5.8 4.5

1.3 HR=0.74 p 0.147

Primary endpoint PFS 58% cross-over

No biomarker for antiangiogenic tx is currently available

Wilke H, et al. Lancet Oncol 2014 Fuchs CS, et al. Lancet 2014 Li J, et al. J Clin Oncol 2016

Pavlakis N, et al. J Clin Oncol 2016

ANTI-VEGFR2 TARGETED THERAPY

Treatment until disease progression

or unacceptable toxicity

Ramucirumab 8mg/kg gg1,8 CDDP + 5-FU/cape

Placebo CDDP + 5-FU/cape

R A N D O M I Z E

(1:1)

Metastatic HER-2- gastric/GEJ cancer

(n=616)

Multicenter, randomized, double-blind, placebo-controlled phase III study

Primary endpoint: progression-free survival superiority

Secondary endpoint: OS, TTP ORR, duration-of-response, clinical benefit rate, safety, biomarkers

RAINFALL STUDY DESIGN

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Pro

gre

ssio

n-F

ree

Su

rviv

al

(%)

Time (months)

RAM+FOLFOX

Placebo+FOLFOX

Gastric/GEJ

HR 0.53 (0.29, 0.97)

P =.036 median 9.3 vs 7.6 mos

HR 1.10 (0.61, 1.97)

P =.746 median 5.8 vs 5.8 mos

Overall Survival Esophageal: HR 1.29 (0.75, 2.19); 10.5 vs 11.5 m Gastric/GEJ: HR 0.94 (0.55, 1.61); 14.6 vs 12.5 m

RAM + FOLFOX

Placebo + FOLFOX

Esophageal

Exploratory Analysis - PFS by tumor location

Presented by Yoon at ASCO2014

RAMUCIRUMAB IN FIRST LINE

FIRST-LINE STANDARD FOLFOX or CAPOX

X 3 months

Metastatic gastric/GEJ HER-2 neg

MAINTENANCE

Paclitaxel Ramucirumab

FOLFOX or CAPOX X 3 months

Then single agent fluoropyrimidine

PD

TOX

N=280

Multicenter, randomized, open-label, phase III no-profit study (35 centers in Italy)

Primary endpoint: superiority of progression-free survival

Secondary endpoint: OS, TTF, ORR, duration-of-response, safety, QoL (PRO)

Exploratory endpoints: tissue biomarkers, PGX, circulating biomarkers

If no PD RANDOM

Sc Reen I ng

Assessment of Ramucirumab plus paclitaxel as switch MANteInance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or

gastroesophageal junction cancers

ARMANI STUDY DESIGN

HOW CAN WE MOVE FORWARD?

• Targeting HER-2

• Targeting Angiogenesis

• Immune Checkpoint Inhibitors

Keynote-012 (n= 39) Decrease in target lesions 53% Objective response 23%

Muro K, et al. Lancet Oncol 2016

PEMBROLIZUMAB- ANTI-PD1

Immune-Related Progression Free Survival (irPFS)

irPFS was the primary endpoint of the study Median irPFS (95% CI), months: -Ipilimumab: 2.92 -BSC: 4.90 (HR = 1.44; p = 0.097)

Overall Survival (OS)

A randomized, open-label, two-arm, phase II trial comparing the efficacy of sequential ipilimumab versus best supportive care following first-line chemotherapy in patients with unresectable, locally advanced/metastatic gastric or gastroesophagel junction adenocarcinoma

Moehler M, et al. ASCO 2016; abs 4011

IPILIMUMAB IN GC

CHECKMATE 032 STUDY DESIGN

Janjigian Y, et al. ASCO 2016; abs 4010

Janjigian Y, et al. ASCO 2016; abs 4010

CHECKMATE 032 RESULTS

Janjigian Y, et al. ASCO 2016; abs 4010

CHECKMATE 032

PD-1 BLOCKADE IN H-MSI

Le DT et al, NEJM 2015

This is the first step to validation of MSI as predictive biomarker of benefit from PD-1

blockade

Bass et al. Nature 2014

NEW MOLECULAR SUBTYPES TGCA

Epstein–Barr virus (EBV)-positive

Microsatellite instability (MSI)

Genomically stable (GS) Chromosomal instability (CIN)

9% 22% 20% 50%

PIK3CA mutation Hypermutation Diffuse histology Intestinal histology

PD-L1/2 overexpression Gastric-CIMP CDH1, RHOA mutations TP53 mutation

EBV-CIMP MLH1 silencing CLDN18–ARHGAP fusion RTK-RAS activation

CDKN2A silencing Mitotic pathways Cell adhesion VEGF-A amplification

Immune cell signaling

Anti-CTLA4 or Anti PD1 or Anti-PDL1

Perioperative First-Line Second-Line Third-Line + Refractory to standard

Ipilimumab (BMS) Anti-CTLA4

Phase III Nivo Ipi vs CTX

Phase II Ipi vs Standard of care

Nivolumab (BMS) Anti-PD1

Phase III Nivo Ipi vs CTX

ONO-473 Phase III Nivo vs Taxanes

ONO-4538-07 Phase II Nivo

Pembrolizumab (MSD) Anti-PD1

KEYNOTE-062 Phase III Pembro vs Pembro + Cis + 5Fu vs Cis + 5FU

KEYNOTE-181 Phase III Pembro vs Standard of care KEYNOTE-061 Phase III Pembro vs Pacltaxel

KEYNOTE-180 Phase II Pembro

Durvalumab (AZ) Anti-PDL1

Phase II Maintenance Her2-: Durva vs Cape vs observation Her+: Tratuzumab +/- Durva

Atezolizumab (roche) Anti-PDL1

Phase II Perioperative FOLFOX/FLOT +/- Atezo

Phase I Her2-: CT + Atezo + Bev

Phase I Atezo + Bev +/- CT vs Atezo + CT

Avelumab (Pfizer) Anti-PDL1

JAVELIN GASTRIC 100 Phase III Maintenance after FOLFOX

JAVELIN GASTRIC 300 Phase III Avelumab

NCT02340975 (Ph I/II): Durva vs Treme vs Durva + treme

NCT02572687 (PhI): Durva + Ramucirumab

AFTER ASCO: EVEN MORE TRIALS FOR GC

IMAB362 ANTIBODY IN GC - FAST

• Chimeric IgG1 antibody • Highly specific for CLDN18.2 • Modes of action:

Antibody-dependent cellular cytotoxicity (ADCC)

Complement-dependent cytotoxicity (CDC)

In combination with chemo: enhances T-cell infiltration and induces pro-infiammatory cytokines

Presented By Salah-Eddin Al-Batran at 2016 ASCO Annual Meeting

Presented By Salah-Eddin Al-Batran at 2016 ASCO Annual Meeting

International, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophagel junction adenocarcinoma

PFS in all patients PFS in high expressor patients*

*CLDN18.2 in IHC 2+/3+ in >70% tumor cells

FAST STUDY: RESULTS

• Better patients selection in clinical trials

• Better understanding of tumor biology and heterogeneity

HOW CAN WE MOVE FORWARD?