novita’ in tema di - aiommedia.aiom.it/.../slide/20160709_62_berenato.pdf · what do we have so...
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![Page 1: NOVITA’ IN TEMA DI - AIOMmedia.aiom.it/.../slide/20160709_62_Berenato.pdf · What do we have so far? Trastuzumab + cisplatin + capecitabine/5FU in HER2+ GC as first-line Ramucirumab](https://reader035.vdocument.in/reader035/viewer/2022070811/5f0a8c967e708231d42c2e14/html5/thumbnails/1.jpg)
NOVITA’ IN TEMA DI CARCINOMA GASTRICO
ROSA BERENATO
ONCOLOGIA MEDICA 1 FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI
MILANO
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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
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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
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HOW CAN WE MOVE FORWARD?
• Targeting HER-2
• Targeting Angiogenesis
• Immune Checkpoint Inhibitors
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HOW CAN WE MOVE FORWARD?
• Targeting HER-2
• Targeting Angiogenesis
• Immune Checkpoint Inhibitors
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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
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Dual HER2 blockade? 2° Line anti-HER2 Therapy?
Resistance mechanisms?
HOW TO MOVE ON AFTER ToGA TRIAL?
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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
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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
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Presented By Yoon-Koo Kang at 2016 ASCO GI
GATSBY STUDY: OVERALL SURVIVAL
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OS: ITT population PSF ITT population
TyTAN STUDY: RESULTS
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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
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OS HER2 3+ PFS HER2 3+
TyTAN STUDY: HER2 STATUS AND RESULTS
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An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients.
Piro G, et al. Clin Cancer Res 2016
TRASTUZUMAB RESISTENCE: FGFR3
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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
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HOW CAN WE MOVE FORWARD?
• Targeting HER-2
• Targeting Angiogenesis
• Immune Checkpoint Inhibitors
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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
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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
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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
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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
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HOW CAN WE MOVE FORWARD?
• Targeting HER-2
• Targeting Angiogenesis
• Immune Checkpoint Inhibitors
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Keynote-012 (n= 39) Decrease in target lesions 53% Objective response 23%
Muro K, et al. Lancet Oncol 2016
PEMBROLIZUMAB- ANTI-PD1
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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
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CHECKMATE 032 STUDY DESIGN
Janjigian Y, et al. ASCO 2016; abs 4010
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Janjigian Y, et al. ASCO 2016; abs 4010
CHECKMATE 032 RESULTS
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Janjigian Y, et al. ASCO 2016; abs 4010
CHECKMATE 032
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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
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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
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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
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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
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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
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• Better patients selection in clinical trials
• Better understanding of tumor biology and heterogeneity
HOW CAN WE MOVE FORWARD?