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?