personalizing therapy for gastroesophageal adenocarcinoma
TRANSCRIPT
Daniel Catenacci, MD
Personalizing Therapy for
Gastroesophageal Adenocarcinoma
Associate Professor
Director, GI Medical Oncology
University of Chicago
Gastric Cancer• 24,590 new cases/year
• 10,720 deaths/year
Esophageal Cancer(70% EGJ Adenocarcinoma)
• 16,980 new cases/year
• EGJ 400% increase in last decades
• 15,590 deaths/year
Gastroesophageal Adenocarcinoma
Epidemiology US 2015
Worldwide Gastroesophageal Cancer 2018:
• All Cancer: 18,078,957 incidence; 9,555,027 deaths
• 1,605,735 incidence; 1,292270 deaths
• (13% of all cancer deaths)
• 3rd cancer incidence
• 2nd cancer death
Bray et al. Ca Cancer J Clin 2018;
Fitzmaurice et al. JAMA ONC. 2018;
www.cancer.org
Seigel et al. Ca Cancer J Clin 2015;
www.cancer.org.
EGJ AC
Gastric(non-Cardia)
AC
Esophagus (SCC)
Diaphragm
Gastroesophageal Junction (GEJ)Fundus
Lesser curvature
Duodenum
Cardia
Body
PyloricAntrum
Greater curvature
Gastroesophageal Cancer
Angular notch(incisura angularis)
Pylorus
Esophageal (SCC)
Type I SeiwertTYPE I
TYPE IITYPE III
Esophageal vs. Gastric Adenocarcinoma 7th edition 2010 AJCC/UICC Staging
Gastric or Stomach Cancer
Sehdev A, Catenacci DVT. Gastroesophageal Adenocarcinoma: Focus on Epidemiology, Classification and Staging. Discov Med 2013
Esophagus (Adenocarcinoma)
Type II Seiwert
Type III Seiwert
GEA
TCGA Gastric cancer. Nature 2014
TCGA Esophageal cancer. Nature 2017
I
II
III
50%
9%
22%
20%
95%
1%
1%
3%
EGJ GC
Stage I-III
Stage IV
mostly
CIN & GS
Heterogeneity:
• Histology
SCC vs Adeno
diffuse vs intestinal types
• Anatomy
EGJ AC vs GC
• BiologyCIN v GS v MSI-H v EBV
intrapatient
GC AC
Eso AC
Previous
IO studies
Recent ESMO
ASCO studies
Eso SCC
Locally Advanced
GEC
GEJ AC
FLOT4
CROSS
CM577
CM
-577 y
pT
+/N
+ R
0Ongoing
StudiesESOPEC
TOPGEAR
NeoAegis
FLOT4
CROSS
KN585
HER2+HER2-
PE
TR
AR
CA
RT
OG
101
0
KN975 dCRT
SKYSCRAPER-07 dCRT
INNOVATION
ST
03
MATTERHORN
RA
MS
ES
DANTE EA2174ATTRACTION
-05
mOS ≈ 45 months mOS ≈ 43 months
Perioperative Therapy EGJ AC: DFS, OS
Al-Batran et al. Phase III FLOT4. Lancet 2019Cunningham et al. Phase III MAGIC. NEJM 2006
van Hagen et al. Phase III CROSS. NEJM 2012Shapiro et al. Phase III CROSS. Lancet Oncol 2015
LN+ disease: 78%T4 disease: 8%
LN+ disease: 65%T4 disease: 0%
FLOT
ECFSurgery Only
CRT
EGJ AC FLOT > MAGIC > Surgery
HR 0.76 HR 0.74
EGJ ACCROSS > just surg
HR 0.75
N=275N=398
Forthcoming Head to Head Phase III studies
Neo-AEGIS
• ECX/EOX/FLOT vs CROSS
• Ireland, UK, Denmark
• N= 540 , EGJ (I/II) only
• HR 1.02, terminated for futility at second interim analysis
• >85% MAGIC, prior to amendment for FLOT
ESOPEC
• FLOT vs CROSS
• Germany
• N=438, EGJ (I/II) only
• Target HR 0.645 (!)
TOPGEAR
• ECX/FLOT +/- neoCRT
• Australia, New Zealand
• N=620, GC/EGJ, not type I
• Target HR 0.76
Leong et al. BMC Cancer 2015 Heoppneret al. BMC Cancer 2016Reynolds et al. BMC Cancer 2017
Daniel Catenacci
EGJ AC FLOT > MAGIC > Surgery
HR 0.76 HR 0.74
EGJ ACCROSS > Surgery
HR 0.75
716 pts
Slide 4
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Abstract 4004
Abstract 4004
If MAGIC > Surgery (HR ~0.75) (MAGIC study 2006, N=503)
& CROSS > Surgery (HR ~0.74) (CROSS study 2012, N=368)
& MAGIC = CROSS (HR ~1.02) (NeoAegis study 2021, N=319)
& if FLOT > MAGIC (HR ~0.76) (FLOT4 study 2019, N=738)
Can we solve for Y?
FLOT vs CROSS (HR Y) (ESOPEC study, XX, N=438)
Neoadj MAGIC/FLOT +/-RT, adj MAGIC/FLOT (TOPGEAR, XX, N=620)
Abstract 4004
11
Daniel Catenacci, MD
Perioperative anti-HER2 studies
Safran et al. RTOG1010 Phase III. ASCO 2020 Hofheinz et al. PETRARCA Phase II. ASCO 2020
RTOG1010
N=194
PETRARCA
N=81
Primary
Endpoint:
Phase 2:
pCR rate
Phase 3:
DFS
Primary
Endpoint:
DFS
0
Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer following neoadjuvant chemoradiotherapy: expanded efficacy and safety analyses from CheckMate 577Ronan J. Kelly,1 Jaffer A. Ajani,2 Jaroslaw Kuzdzal,3 Thomas Zander,4 Eric Van Cutsem,5
Guillaume Piessen,6 Guillermo Mendez,7 Josephine Feliciano,8 Satoru Motoyama,9 Astrid Lièvre,10
Hope Uronis,11 Elena Elimova,12 Cecile Grootscholten,13 Karen Geboes,14 Jenny Zhang,15
Samira Soleymani,15 Ming Lei,15 Prianka Singh,15 James M. Cleary,16 Markus Moehler17
1The Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas, TX; 2The University of Texas MD Anderson Cancer Center, Houston, TX; 3Jagiellonian University, John Paul II Hospital, Cracow, Poland; 4University Hospital of Cologne, Cologne, Germany; 5University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven, Belgium; 6University of Lille, Claude Huriez University Hospital, Lille, France; 7Fundacion Favaloro, Buenos Aires, Argentina; 8Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 9Akita University Hospital, Akita, Japan; 10CHU Pontchaillou, Rennes 1 University, Rennes, France; 11Duke Cancer Institute, Durham, NC; 12Princess Margaret Cancer Centre, Toronto, ON, Canada; 13Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; 14UZ Gent, Gent, Belgium; 15Bristol Myers Squibb, Princeton, NJ; 16Dana Farber Cancer Institute, Boston, MA; 17Johannes-Gutenberg University Clinic, Mainz, Germany
Abstract 4003
CM 577(Adj EsoSCC/EsoAC/GEJAC)
15
TGFb TIGIT LAG-3 IO Bisp.
4003: Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT)
Abstract 4003
Sources: 16
CM 577(Adj EsoSCC/EsoAC/GEJAC)
• CPS <5?
• AC?
• GEJ?
• Longer DFS/OS f/u
TPS not CPS!!
Abstract 4003
17
TGFb TIGIT LAG-3 IO Bisp.
4003: Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT)
CPS<50.89 AC + SCC
SCC?AC?
Abstract 4003
18
TGFb TIGIT LAG-3 IO Bisp.
4003: Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT)
Abstract 4003
Progression-free survival 2 (PFS2)
Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.Abstract 4003
20
TGFb TIGIT LAG-3 IO Bisp.
4003: Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT)
Abstract 4003
Sources: 21
4003: Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT)
Abstract 4003
22
If MAGIC > Surgery (HR ~0.75) (MAGIC study 2006, N=503)
& CROSS > Surgery (HR ~0.74) (CROSS study 2012, N=368)
& MAGIC = CROSS (HR ~1.02) (NeoAegis study 2021, N=319)
& if FLOT > MAGIC (HR ~0.76) (FLOT4 study 2019, N=738)
Can we solve for Y?
FLOT vs CROSS (HR Y) (ESOPEC study, XX, N=438)
Neoadj MAGIC/FLOT +/-RT, adj MAGIC/FLOT (TOPGEAR, XX, N=620)
CROSS → nivo vs CROSS (HR OS?) (CM577, XX, N=532)
CF/FLOT-pembro vs CF/FLOT (HR OS?) (KN585, XX, N=1007)
FLOT-durva vs FLOT (HR OS?) (MATTERHORN, XX, N=900)
Adj S1/CapeOx-nivo vs Adj S1/CapeOx (HR OS?) (ATTRACTION-05, XX, N=700)
FLOT-atezo vs FLOT (DANTE/FLOT8, XX, N=295)
CROSS-nivo vs CROSS → nivo vs nivo-ipi (EA2174, XX, N=278)
June 22, 2021
First Line Management of Advanced Gastroesophageal Adenocarcinoma
1. Murad, et al. Cancer 1993
2. Vanhoefer, et al. JCO 2000
3. Ajani, et al. ASCO 2009
4. Van Cutsem, et al. JCO 2006
5. Dank, et al. Ann Oncol 2008
6. Cunningham, et al. NEJM 2008
7. Kang, et al. Ann Oncol 2009
8. Guimbaud, et al. JCO 2014
9. Shah, et al. JAMA ONC 2016
BSC = best supportive care;
MTX = methotrexate; S = S-1; A = doxorubicin
F = 5-FU; C/P = cisplatin; I = irinotecan;
E = epirubicin; O = oxaliplatin; D = docetaxel
mOS Months
BSC 1
60 2 4 128 10
FAMTX 2
SP 3
EOX 6
XP 7
FP 4
IF 5
EOF 6
DCF 4
ECF 6
ECX 6
FOLFIRI 8
FOLFOX 9
mOS = ~10-11m
1yr OS = ~40%
2yr OS = ~15-20%
5yr OS < ~2%
GEA: A Molecularly Heterogeneous Disease
TCGA. Integrated genomic characterization of oesophageal carcinoma. Nature 2017 TCGA. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014
Gene Amplification is a hallmark of CIN
~10% Gastric
~15% EGJ
Gajria, Chandarlapaty. HER2-amplified Breast Cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther 2011.
Tucatinib
afatinib
ADCs
TDM1
Ds8201a
ZW49
ZW25
Anti-HER2 therapies
HER2 amp
~10-15% GEA
~10% Gastric
~15-20% EGJ
The ToGA phase III study
Bang et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA):
a phase 3, open-label, randomised controlled trial. Lancet 2010
mOS Months
BSC 1
60 2 4 128 10
FAMTX 2
SP 3
EOX 6
XP 7
FP 4
IF 5
EOF 6
DCF 4
ECF 6
ECX 6
FOLFIRI 8
1. Murad, et al. Cancer 1993 2. Vanhoefer, et al. JCO 2000 3. Ajani, et al. ASCO 2009 4. Van Cutsem, et al. JCO 2006
5. Dank, et al. Ann Oncol 2008 6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 2009 8. Guimbaud, et al. JCO 2014
9. Shah et al. JAMA Oncol 2016. 10. Bang et al. Lancet 2010.
X/FP+/-T10
X/FP+/-T10
HER2 IHC3+ or IHC2+/FISH+
HER2 (+) (IHC0-3+/FISH+)
X/FP+/-T10 HER2 IHC3+/FISH+
+T
+T
14 16 18
FOLFOX 9
+T
All-comers
mOS = ~10-11m
1yr OS = ~40%
2yr OS = ~15-20%
5yr OS < ~2%
HER2+
mOS = ~14-16m
1yr OS = ~55-65%
2yr OS = ~25-30%
5yr OS < ~10-15%
Antiangiogenesis for EGA: 2L RAINBOW
Paclitaxel/Ramucirumab vs Paclitaxel
Wilke et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW):
a double-blind, randomised phase 3 trial. Lancet Oncol 2014
Trifluridine/Tipuracil 3L+
Shitara et al. Trifluridine/tipiracil v placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018
Third Line – Trastuzumab Deruxtecan
Shitara et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. NEJM 2020
Irinotecan or paclitaxel
N= 125 pts
R 2:1
100% Asian
40%
14%
Shitara et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. NEJM 2020
DESTINY-Gastric01: TRAE in ≥20% of Pts
Shitara K, et al. ASCO 2020. Abs 4513.
Pneumonitis:
12 patients (9.6%)
G1/2: 9 (7.2%)G1: 3 (2.4%)G2: 6 (4.8%)
G3/4: 3 (2.4%)G3: 2 (1.6%)G4: 1 (0.8%)
Tras-Derux in Asian phase 2 study in 3L+ (~55% 3L, 45% 4L+)
ORR, PFS, and OS compared to taxane/irinotecan MD choice.
📌 Approved in Japan for 3L+ 9/25/20
📌 Approved in US by FDA for 2L+ 1/15/21.
DESTINY-Gastric01
Black Box: ILD, Pt Selection Reassess HER2 status!
Le et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017
N= 86 MSI-H pts12 different tumor types
GEA:
TCGA 23%
Stage IV <3%
FDA Approves Pembrolizumab for Microsatellite Instability-High and Mismatch Repair Deficient Cancers. May 23, 2017
• ORR 3/5 = 60%
FDA approval 2L+ Pan-tumor
N=149, historical control
Immune Checkpoint
Blocakade for EGA
MSI-High
Chao et al. Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-
061, and KEYNOTE-062 Clinical Trials. JAMA Oncol 2021
0 6 12 18 24 30 360
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
12-moRate
Median, mo(95% CI)
71% NR (1.1-NR)
Eventsn (%)
3 (43%)
No. at risk
7 5 4 4 1 05Pembro
0 6 12 18 24 30 360
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
12-moRate
Median, mo(95% CI)
25% 5.5 (4.2-6.7)
Eventsn (%)
235 (91%)
No. at risk
259 118 43 32 16 463Pembro
0 6 12 18 24 30 36 420
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
14 13 11 10 9 4 2 019 13 9 7 4 3 0 0
No. at risk
Median, mo(95% CI)
Pembro
Eventsn (%)
12-moRate
Chemo
5 (36%)15 (79%)
79% NR (10.7-NR)8.5 (5.3-20.8)47%
0 6 12 18 24 30 360
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
296 155 101 53 16 0296 191 83 36 12 0
12-moRate
Median, mo(95% CI)
34% 6.7 (5.4-8.9)
Events,n, %
239 (81%)28% 8.3 (7.7-8.8)262 (89%)
PembroChemo
00
0 6 12 18 24 30 360
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
15 12 11 6 3 0 012 8 3 1 0 0 0
PembroChemo
12-moRate
Median, mo(95% CI)
59% NR (5.6 to NR)
Events,n (%)
6 (40%)25% 8.1 (2.0-16.7)10 (83%)
0 6 12 18 24 30 36 420
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at Risk
256 162 120 94 59 23 4 0250 192 114 75 38 15 2 0
PembroChemo
12-moRate
Median, mo(95% CI)
47% 10.6 (7.7-13.8)
Events,n, %
201 (79)46% 11.1 (9.2-12.8)216 (86)
KEYNOTE-059 (3L+)
KEYNOTE-061 (2L)
KEYNOTE-062 (1L)
ITT MSI-High (~2-3%)
ITT = any PDL1
ITT2 = PDL1 CPS>1
ITT = PDL1 CPS>1
MSI-High: negative prognostic & positive predictive biomarker
Anti-PD1/PDL1 Trials: Gastroesophageal Cancer IV
3L+
KN-059
ATTRACTION-2
JAVELIN-300
2L
KN-061
KN-181 (AC 36% SCC 64%)
ATTRACTION-3 (SCC 100%)
1L Maintenance
KN-062
KN-590 (AC 23%, SCC, 73%)
CM-649
ATTRACTION-4
JAVELIN-100
(KN859)
(CM-648 SCC)
(KN811)
(MAHOGANY)
…
Co
mp
lete
dO
ng
oin
g
PDL1 testing
PDL1 CPS < 1
Poor PS, Adeno
High Volume Dz
??
Higher PDL1 CPS
MSI-high, PS 0 , SCC, Asian
EBV+, Low disease
??
ITT
0 6 12 18 24 30 360
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
15 12 11 6 3 0 012 8 3 1 0 0 0
PembroChemo
12-moRate
Median, mo(95% CI)
59% NR (5.6 to NR)
Events,n (%)
6 (40%)25% 8.1 (2.0-16.7)10 (83%)
KN61
PDL1 CPS >10
MSI-high
Catenacci DVT, Hochster H, Klempner S. Keeping Checkpoint Inhibitors in Check. JAMA Netw Open 2019
Anti-PD1/PDL1 monotherapy
KN61
PDL1 CPS 0
Gastroesophageal Cancer: 1L IO + Chemotherapy
1 KEYNOTE 062
2 KEYNOTE 590
3 CHECKMATE 649
4 ATTRACTION 4
Histology: SCC > AC
PDL1: > 10 > 5 > 1
Geography: Asian > non Asian
First line Immunotherapy
+
Chemotherapy
AC
CPS>1
AC, SCC
Any PDL1
AC
CPS>5
AC
Any PDL1
KN 590 (1L EsoSCC/EsoAC/GEJAC) (Similar eligibility to 2L KN 181)
286 pts +262 pts
CPS>10 All
HR 0.57 → 0.72
Pts# 286 → 286+262
SCC CPS<10
??
262
KN 590 (1L EsoSCC/EsoAC/GEJAC) (Similar eligibility to 2L KN 181)
383/730 CPS>10
=52.5%
286 CPS>10 SCC
286/548= 52%
383-286
=97 CPS>10 AC
97/201 = 48%
First evidence of
no benefit from
IO+Chemo in
Low/neg PDL1
• Especially CPS 0
• Especially ACAC CPS<10
201- 97
= 104/201 (52%)
HR??
Listed in NCCN guidelines 12/2020, CPS >5 platinum+pembro, esophageal/GEJ (SCC or AC)
FDA approved 3/22/21 for all-comers (any PDL1)
EMA esophageal/GEJ (SCC or AC), CPS PDL1 > 10
First-line nivolumab plus chemotherapy vs chemotherapy in advanced gastric cancer/ gastroesophageal junction cancer/esophageal adenocarcinoma: expanded efficacy and safety <br
/>data from CheckMate 649
Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.
Abstract 4002
CM 649 (1L EsoAC/GEJ AC/GC AC) FOLFOX +/- Nivolumab
Moehler et al. ESMO 2020
CM 649 (1L GEJ AC/GC AC)
CPS>5 CPS>1 All
HR 0.71 → 0.77 → 0.8
Pts# 473 → 473+168 → 641+148
First evidence that
Chemo+IO not effective in
CPS <5 tumors
• Especially CPS 0
Listed in NCCN guidelines 12/2020, CPS >5 FOLFOX+Nivo, GC, EGJ AC
FDA approved 4/16/21 for all-comers (any PDL1)
EMA no decision yet
CPS 1-5
??
168
CPS 0
??
148
CPS <5
??
316
Moehler et al. ESMO 2020
Initially
Not
Reported
Efficacy subgroup analysis by PD-L1 CPS in all randomized patients
Moehler et al. ASCO 2021
Abstract 4002
Sources:
ATTRACTION04 (1L GEJ AC/GC AC)
NCCN Guidelines: 6/22/21 (Version 3.2021)
PDL1 CPS 0 is not recommended to receive first-line anti-PD1 therapy for GC/GEJ/Eso for either AC or SCC!!
Category 1Category 2ACategory 2B
Anti-HER2 + IO Combination?
Anti-HER2 Ab
CD16A (FCGR3)
V allele – high affinity
F allele – low affinity
VV = ~15%
VF
FF= ~85%
trastuzumab vs
margetuximab
Catenacci et al. MAHOGANY: margetuximab combination in HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma. Future Oncol 2021
Anti-HER2 + IO Combination
Janjigian et al. Lancet Oncol 2020 Catenacci et al. Lancet Oncol 2020
Second Line: Margetuximab/PembrolizumabFirstLine: Chemo/Trastuzumab/Pembrolizumab
KN-811 1L Phase IIIChemo/trastruzumab +/- pembrolizumab
MAHOGANY 1L Phase II/IIIA) margetuximab + retifanlimab (IHC3+ & PDL1 CPS>1)
B) Chemo/margetuximab +/- retifanlimab
With Number of Subjects at Risk
Product-Limit Survival Estimates
24 24 22 22 22 21 21 18 18 16 13 12 11 10 9 8 8 8 8 8 5 4 3 3 3 1 1 1 1 1 0
32 32 31 29 28 28 25 25 22 20 17 13 13 12 10 9 8 6 6 5 4 2 1 1 0
8 7 6 6 6 6 6 6 5 3 3 3 3 3 2 1 0
6 6 5 4 3 1 1 0
IHC3+/PDL1+IHC3+/PDL1-IHC2+/PDL1+IHC2+/PDL1-
01
23
45
67
89
1011
1213
1415
1617
1819
2021
2223
2425
2627
2829
30
OS: Months from treatment initiation
0.0
0.2
0.4
0.6
0.8
1.0
Surv
ival
Pro
bab
ility
01
23
45
67
89
1011
1213
1415
1617
1819
2021
2223
2425
2627
2829
30
OS: Months from treatment initiation
0.0
0.2
0.4
0.6
0.8
1.0
Surv
ival
Pro
bab
ility
+ Censored
IHC3+/PDL1+
IHC3+/PDL1-
IHC2+/PDL1+IHC2+/PDL1-
FDA accelerated
Approval 5/2021
• N=264
• 52% vs 74% ORR
Janjigian et al. ASCO 2021 Abstr
First Line – Margetuximab/Retifanlimab
Catenacci et al. Margetuximab plus pembrolizumab for previously treated, HER2-positive GEA (CP-MGAH22–05): a single-arm, phase 1b–2 trial. Lancet Oncology 2020
Maron et al. Targeted therapies for targeted populations: Anti-EGFR therapy for EGFR amplified gastroesophageal adenocarcinoma. Can Discov 2018.
EGFR amplification8/148 ~6% (259/4645 5.6%)
57% ORR
100% DCR
AMG337 phase II study in MET amp
Van Cutsem et al. Gastric Cancer. A Multicenter Phase 2 Study of AMG 337 in Patients With MET-Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma or Other MET-Amplified Solid Tumors.
Clin Can Res 2018.
ORR - 8/45 = ~18%
mDOR = 6 months
DCR 24/45 = 53%
mOS = ~8 months
Amgen: Closed Early (45 of 100 planned)
Deemed ineffective and
too small a subset to proceed (?!)
1L 0%
2L 27%
3L 31%
4L+ 42%
Monotherapy late line AMG337
Screened: 2101 patients
Identified: 132 MET++
Enrolled: 60 (45 in GEA, cohort 1)
56
FIGHT: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY OF BEMARITUZUMAB (BEMA) COMBINED WITH MODIFIED FOLFOX6 IN 1L FGFR2B+ ADVANCED GASTRIC/GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA (GC) (NCT03694522)
Authors: Catenacci DV1, Kang YK2, Saeed A3, Yamaguchi K4, Qin S5, Lee KW6, Kim IH7, Oh SC8, Li J9, Turk HM10, Teixeira AC11, Borg C12, Hitre E13, Udrea AA14, Cardellino GG15, Guardeño Sanchez R16, Mitra S17, Yang Y17, Enzinger PC18, Wainberg ZA19
1University of Chicago, Chicago, USA; 2Asan Medical Center, Seoul, South Korea; 3Kansas University Cancer Center, Westwood, KS, USA; 4The Cancer Institute Hospital of JFCR, Koto-Ku , Tokyo, Japan; 581 Hospital Nanjing University of Chinese Medicine, Nanjing, China; 6Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, South Korea; 7The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea; 8Korea University Guro Hospital, Seoul, South Korea; 9Shanghai East Hospital, Shanghai, China; 10Department of Medical Oncology, Bezmialem Vakif University, School of Medicine, Istanbul, Turkey; 11Hospital Senhora Da Oliveira, Guimarães, Portugal; 12Centre Hospitalier Régional Universitaire de Besançon, Besançon France; 13National Institute of Oncology, Budapest, Hungary; 14SC Medisprof SRL, Cluj-Napoca, Romania; 15Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy; 16Institut Català d’Oncologia, Girona, Spain; 17FivePrime Therapeutics, Inc., South San Francisco, USA; 18Dana Farber Cancer Institute, Boston, USA; 19University of California, Los Angeles, USA
Presenter: Daniel Catenacci, MDUniversity of Chicago
Abstract 4010
57
Bemarituzumab blocks growth factor signaling
Bemarituzumab: IgG1 Ab Specific to FGFR2b Receptor
ADCC, antibody-dependent cell-mediated cytotoxicity; FGF, fibroblast growth factor; IgG1, immunoglobulin G1; NK, natural killer; TKIs, tyrosine kinase inhibitors. 1. Catenacci D, et al. J Clin Oncol. 2020.
18% overall response rate in late-line FGFR2b+ gastroesophageal cancer1
Daniel Catenacci, MD
Bemarituzumab enhances ADCC
Selectivity avoids electrolyte abnormalities seen with FGFR TKIs
Abstract 4010
58
FGFR2 Amplification: Bemarituzumab
Catenacci DVT. Phase I Escalation & Expansion Study of Bemarituzumab (FPA144) in Pts With Advanced Solid Tumors and FGFR2b-Selected Gastroesophageal Adenocarcinoma JCO 2020
Catenacci DVT. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design. Future Oncol 2019
N=28 pts
ORR 18%
DCR 64%
Abstract 4010
Daniel Catenacci, MD
59
FIGHT Phase 2 Study Design
*Bemarituzumab dosing: 15 mg/kg Q2W beginning cycle 1 day 1 (plus 1 dose of 7.5 mg/kg on day 8 of cycle 1 only). FOLFOX6 dosing: standard fixed doses Q2W.
FGFR2b, fibroblast growth factor receptor 2b.
Primary endpoint
• PFS
Secondary endpoints
• OS
• Response rate
Bemarituzumab*
+ mFOLFOX6
(n = 77)
Placebo +
mFOLFOX6
(n = 78)
1:1 VS
• No prior therapy for unresectable, locally advanced or metastatic gastric/GEJ adenocarcinoma
• RECIST v1.1 evaluable disease
• FGFR2b overexpression and/or FGFR2 gene amplification
• Not HER2-positive
Key Eligibility Criteria
• Geographic region
• Single dose of FOLFOX while screening
• Prior perioperative chemotherapy
Stratification Factors
Randomization
Daniel Catenacci, MD
Treatment may continue until progression, unacceptable
toxicity, or the patient meets other withdrawal criteria
Abstract 4010
60
IHC 2+/3+ >5% (N = 118)
Median OS Reached With Longer Follow-up
*ITT = includes 149 patients with IHC 2+/3+ and 6 with IHC <2+ or not available who were enrolled based on ctDNA alone. NR, not reached.
Median Follow-up 12.5 months
Daniel Catenacci, MD
ITT* (N = 155) IHC 2+/3+ >10% (N = 96)
OS Median (95% CI)
Bema: 19.2 (13.6–NR)
Pbo: 13.5 (9.3–15.9)
HR: 0.6 (0.38–0.94)
OS Median (95% CI)
Bema: NR (13.8–NR)
Pbo: 12.5 (8.8–15.0)
HR: 0.52 (0.30–0.91)
OS Median (95% CI)
Bema: 25.4 (13.8–NR)
Pbo: 11.1 (8.4–13.8)
HR: 0.41 (0.23–0.74)
BemaPlacebo
Addition of Bemarituzumab Showed a +5.7 Month Improvement in Median OS
*Based on February, 28th 2021 data cut
Abstract 4010
Claudin 18.2: Overexpressed in ~35% GEA
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Sahin et al. FAST: A randomised phase II study of zolbetuximab (IMAB362) plus EOX vs EOX alone for first-line treatment of advanced CLDN18.2 positive gastric and gastro-oesophageal adenocarcinoma. Annals Oncol 2021
ITT
CLDN18.2 >70% extensity
CLDN18.2 40-69% extensity
PFS OS
PANGEA Strategy
Primary endpoint: OS in PANGEA1 strategy (A)
Catenacci et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase 2 study evaluating an individualized treatment strategy for metastatic disease. Cancer Discovery 2021
Secondary Endpoint: OS in top tier vs lower tier groups within PANGEA strategy (C)
Secondary Endpoint: mPFS1 (A)Secondary Endpoint: ORR1/DCR1 (B)
Catenacci et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase 2 study evaluating an individualized treatment strategy for metastatic disease. Cancer Discovery 2021
ITT: mPFS1 8.2 months (95% CI 7.3 - 9.6)Non-ITT: mPFS1 6.7 months (95% CI 2.9-10.6)
p=0.17
A
B
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