personalizing therapy for gastroesophageal adenocarcinoma

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

Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.

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


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



CPS<50.89 AC + SCC

SCC?AC?

Abstract 4003

18



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



Abstract 4003

Sources: 21


Abstract 4003

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


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


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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


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


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

Thank You

personalizing therapy for gastroesophageal adenocarcinoma

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