biologic targeted agents in gc - european society for ......expand study 5 cisplatin 80mg/m2 d1...

Biologic Targeted Agents in GC- HER2, EGFR, Angiogenesis -

Florian LordickDirector of the University Cancer Center Leipzig (UCCL)

Professor of Oncology – University of Leipzig

ESMO Preceptorship, Valencia

06 October 2017

Disclosures

© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 2

Honoraria for advisory role, membership in data safety board or lectures for Astellas, Astra Zeneca, Amgen, Biontech, BMS, Elsevier,

MSD, Roche, Servier

Amplification of RTK’s as Potential Drug Targets


Genomic DNA were extracted from flash-frozen tissues or cell

pellets using a Qiagen genomic DNA extraction kit (Qiagen,

Hilden, Germany), and profiled on Affymetrix SNP 6.0 arrays

(Affymetrix, Santa Clara, California, USA)

Dr. Patrick Tan

Duke Univ. Singapore

Deng N, et al. Gut 2012;61:673-84

Receptor Tyrosine Kinase-directed Therapy


Genomic DNA were extracted from flash-frozen tissues or cell

pellets using a Qiagen genomic DNA extraction kit (Qiagen,

Hilden, Germany), and profiled on Affymetrix SNP 6.0 arrays

(Affymetrix, Santa Clara, California, USA)

Deng N, et al. Gut 2012;61:673-84

Anti-EGFR

negative phase-3: EXPAND, REAL3Lordick et al. Lancet Oncol 2013

Waddell et al. Lancet Oncol 2013

Anti-MET

negative phase-3: MetMab, RiloMetShah et al. ASCO 2015

Cunningham et al. ASCO 2015

anti-FGFR

preliminary phase-2: ShineBang et al. ASCO 2015

KRAS

non druggable (?)

HER2

positive phase-3: ToGABang et al. Lancet 2010

EXPAND Study

5

Cisplatin 80mg/m2 d1

Capecitabine 1000mg/m2 2 x / day.; d1-14

q3wR

A

N

D

O

M

• Until radiographic progression or toxicity-related end of treatment

• Primary endpoint: Progression-free survival (PFS)

Cisplatin 80mg/m2 d1

Capecitabine 1000mg/m2 2 x tgl.; d1-14

q3w

Cetuximab 400mg/m2 loading dose,

then 250mg/m2 / week

Lordick et al., Lancet Oncol. 2013; 14: 490-499

© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick

EXPAND Study

6



EXPAND Study

7



HER2-positive Gastric Cancer


▪ Significant HER2 positivity: ~16%

▪ Proximal > distal gastric cancer

▪ Intestinal >> diffuse gastric cancer

Bang Y, et al. Lancet 2010;376:687–97

Survival advantage with trastuzumab in HER2+ gastric cancer

CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio.

Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016

Anti-HER2 antibody trastuzumab prolongs survival in selected patients

© Universitätsklinikum Leipzig AöR: University Cancer Center Leipzig (UCCL), Prof. Dr. F. Lordick 9

ToGA HER2 Results and Trastuzumab Efficacy

Bang Y et al. Lancet 2010; 376: 687-697

Treatment Algorithm 1st line for Gastric Cancer


HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridisation. Lordick F, Janjigian YY. Nat Rev Clin Oncol. 2016 Jun;13(6):348-60

HER2-directed Treatment


The mechanism of action of pertuzumab and trastuzumab. Trastuzumab binds to the ECD IV of the HER2 receptor,

preventing the spontaneous formation of homodimers (HER2–HER2) and ligand-independent heterodimers

(HER2–HER3 and also HER2–HER1 and HER2–HER4). Pertuzumab binds to the dimerization domain of the HER2 receptor

(ECD II), preventing the formation of ligand-induced HER2 heterodimers.

Metzger-Filho O, et al. Clin Cancer Res 2013; 19: 5552-5556

HER2-double Targeting in Gastric Cancer


R

A

N

D

O

M

1:1 primary endpoint: survival

Stomach

and EGJ

Stage IV

1st-line

Chemo-naive

Multinational

MulticentreTrastuzumab + Pertuzumab + Cisplatin/FP

q3w 6 cycles

Trastuzumab/Pertuzumab until progression

Trastuzumab + Cisplatin/FP

q3w 6 cycles

Trastuzumab until progression

JACOB Study

Tabernero J et al. Ann Oncol 2017;28(Suppl 5):Abstr 616O




Key results

• OS not statistically significant: 16% reduction in risk of death; 3.3-month increase in mOSP

rob

ab

ility

of P

FS

Time, months

1.0

0.8

0.6

0.4

0.2

00

388

392

6

323

306

2

363

359

4

342

339

8

297

279

14

209

175

10

266

252

12

243

221

16

175

143

22

92

76

18

149

118

20

114

95

24

67

60

26

54

47

28

36

38

34

10

14

30

27

31

32

16

23

36

6

7

4238

4

4

40

3

2

Arm A (n=388)

Arm B (n=392)

Censored

No. at risk

Arm A

Arm B

ITT population

Arm A

(n=338)

Arm B

(n=392)

Events, n 242 262

Median, months 17.5 14.2

HR (95%CI) 0.84 (0.71, 1.00)

p-value (log-rank) 0.0565

Median duration of survival follow-up

• Arm A: 24.4 months (min–max 22.3–26.1)

• Arm B: 25.0 months (min–max 22.3–28.9)

OS

Arm A (n=388) Arm B (n=392) HR (95%CI)

mPFS, months 8.5 7.0 0.73 (0.62, 0.86)




Key results (cont.)

Conclusions

• The JACOB study did not meet the primary endpoint of OS

– A treatment effect trend with pertuzumab + trastuzumab + CT was observed

• OS was generally consistent in the subgroups*

• Key secondary endpoints of PFS and ORR showed similar trends, but statistical

significance could not be concluded due to hierarchical testing

• Safety was comparable between treatment arms, apart from diarrhoea*

– Diarrhoea incidence increased with pertuzumab; however, there were no pertuzumab

discontinuations due to diarrhoea

ORR in patients with measurable disease at baseline

Arm A(n=351)

Arm B(n=352)

Objective response, % 56.7 48.3

Difference, % (95%CI)8.4

(0.9, 15.9)

Median duration of objective

response, months (95%CI)

10.2

(8.4, 10.7)

8.4

(6.8, 10.7)

Anti-HER2 – Trastuzumab / Pertuzumab Periop.

15

Currently ongoing Studies

EORTC 1203 - INNOVATION

FLOT / FOLFOX +/- Trastuzumab +/- Trastuzumab/Pertuzumab

AIO-FLOT6 - PETRARCA

FLOT +/- Trastuzumab/Pertuzumab

RTOG 1010 (USA)

Carbo/Paclitacel + RTX +/- Trastuzumab in AEG

JCOG1301 (Trigger Study, Japan).

Cisplatin/S-1 +/- Trastuzumab neoadjuvant in nodal + GC

© Universitätsklinikum Leipzig AöR: University Cancer Center Leipzig (UCCL), Prof. Dr. F. Lordick

HER2-double Targeting in Localized Gastric Cancer


EORTC – INNOVATION Study – ongoing

HER2 Focal Expression in GC (Heterogeneity)


HER2, human epidermal growth factor receptor 2. Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016

Heterogeneity and Sampling Errors

Warneke VS… Röcken C. Ann Oncol 2013 Mar;24(3):725-33

2230 core biopsies from TMA‘s of 454 tumor probes

D

D


Heterogeneity and Sampling Errors

Warneke VS… Röcken C. Ann Oncol 2013 Mar;24(3):725-33

D

D

2230 core biopsies from TMA‘s of 454 tumor probes


HER2 Evolution in Gastric Cancer


Janjigian YY. ESMO Congress, Copenhagen 2016

Anti-HER2 Treatment 2nd line


Thuss-Patience P, et al. Lancet Oncol 2017 May;18(5):640-653

Trastuzumab-Emtansine Conjugate


Anti-HER2 Treatment 2nd line - GATSBY



HER-2 Directed Treatment in Gastric Cancer

All studies apart from ToGA (Trastuzumab) negative

HER2 TKI Lapatinib Ph-2 und Ph-3 GastroLap, TYTAN und LOGIC

HER2 mAB Pertuzumab 1st-line Phase-3 JACOB

HER2-Konjugat

Trastuzumab-Emtansine (TDM-1) 2nd-line Phase-3 GATSBY

Lorenzen S….Lordick F. Eur J Cancer 2015 Mar;51(5):569-76

Satoh T et al. J Clin Oncol 2014: 32:2039-2049

Hecht JR et al. J Clin Oncol. 2016 Feb 10;34(5):443-51

Tabernero J et al. ESMO 2017; abstract 616-O

Thuss-Patience P et al. Lancet Oncol 2017 May;18(5):640-653


Molecular Classification of Esophago-Gastric Cancer


The Cancer Genome Atlas Research Network. Nature 2017; 541: 169 ff.

Anti-Angiogenic Approach (1)


Dr. Judah Folkman, Boston 1933–2008

http://3quarksdaily.blogs.com/3quarksdaily/images/12folkman_1.jpg

Folkman J, et al. N Engl J Med 1971;285:1182–6

Folkman’s Hypothesis

Anti-Angiogenic Approach (2)


Lordick F, Janjigian YY. Nat Rev Clin Oncol. 2016 Jun;13(6):348-60

2nd-line Gastric Cancer – Randomised Studies


Study Drug Survival Improvement

Thuss-Patience PC, et al.

Eur J Cancer

2011;47:2306–14.

AIO, Germany (n=40)

Irinotecan

vs. BSC

4.0 vs. 2.4

(p=0.012)

HR 0.48

∆ 1.6 months

Kang JH, et al. J Clin

Oncol 2012;30:1513–8.

Korea (n=202)

Irinotecan or

Docetaxel

vs. BSC

5.3 vs. 3.8

(p=0.007)

HR 0.66

∆ 1.5 months

Ford HE, et al. Lancet

Oncol 2014;15:78–86.

COUGAR-02, UK (n=168)

Docetaxel

vs. ASC

5.2 vs. 3.6

(p=0.01)

HR 0.67

∆ 1.6 months

Fuchs CS, et al. Lancet

2014;383:31–9.

REGARD, global (n=335)

Ramucirumab

+BSC

vs. Placebo

+BSC

5.2 vs. 3.8

(p=0.047)

HR 0.776

∆ 1.4 months

ASC, active symptom control; BSC, best supportive care; HR, hazard ratio.

Ramucirumab 2nd-line (REGARD)


Fuchs CS, et al. Lancet 2014;383:31–9

Median: 3.8 vs. 5.2 monthsN=355; 119 centres

Stage IV, Stomach / EGJ

Adenocarcinoma

2nd-line after platinum-

or fluorpyrimidine-

containing

chemotherapy

5FU, fluorouracil; CI, confidence interval; EGJ, oesophageal junction; HR, hazard ratio.

Ramucirumab 2nd-line (RAINBOW)


Wilke H, et al. Lancet Oncol 2014;15:1224–35

R

A

N

D

O

M

1:1

Primary endpoint: survival

N=665

Stomach

and EGJ

Stage IV

2nd-line

after platinum/5FU

170 centres

27 countries

Ramucirumab 8 mg/kg d1+15 q4w

Paclitaxel 80 mg/m² d1,8+15 q4wuntil progression

Placebo q2w

Paclitaxel 80 mg/m² d1,8+15 q4wuntil progression

5FU, fluorouracil; EGJ, oesophageal junction.

Ramucirumab 2nd-line (RAINBOW)


RAM +

Paclitaxel

Placebo +

Paclitaxel

HR

p-value

Response rate, % 28 16 p=0.0001

Median PFS, months

(9-month PFS, %)4.4 (22) 2.9 (10)

HR 0.635

p<0.0001

Median OS, months

(12-month OS, %)9.6 (40) 7.4 (30)

HR 0.807

p=0.017

Wilke H, et al. Lancet Oncol 2014;15:1224–35

CI, confidence interval; HR, hazard ratio; OS, overall survival;

PFS, progression-free survival; RAM, ramucirumab.

Ramucirumab 2nd-line (RAINBOW) – Quality of Life


Al-Batran SE, et al. Ann Oncol. 2016 Apr;27(4):673-9

CI, confidence interval; HR, hazard ratio; PBO, placebo;

PTX, paclitaxel; RAM, ramucirumab

Favours PBO+PTXFavours RAM+PTX

Diarrhoea

Dyspnoea

Treatment Algorithm for Gastric Cancer 2nd-line


ECOG, Eastern Cooperative Oncology Group; PS, performance status. Lordick F, Janjigian YY. Nat Rev Clin Oncol. 2016 Jun;13(6):348-60

Dose-response Relationship in Asian Patients


Kim TY. Gastric Cancer 2017 Jun 20. doi: 10.1007/s10120-017-0737-2. [Epub ahead of print]

Ramucirumab is Active in HER2 Positive Cancers


Fuchs C et al Brit J Cancer 2016 Oct 11;115(8):974-982

Anti-Angiogenesis - Apatinib 3rd-line


Li J, et al. J Clin Oncol 2016; 34:1448-1454

Anti-VEGFR Ramucirumab 1st line Stage IV

38

Yoon HH et al. Ann Oncol 2016 Dec;27(12):2196-2203

OS

OS


RAINFALL: Phase 3 Evaluation of Ramucirumab / Capecitabine-Cisplatin

Compared With Placebo / Capecitabine-Cisplatin in Patients With No Prior

Cytotoxic Therapy for Advanced Gastric / GEJ Adenocarcinoma


Ramucirumab 8 mg/kg IV day 1 & day 8, Q 21d until PD

Cisplatin 80 mg/m² IV day 1, Q 21d, 6 cyclesRANDOMIZE

Inclusion:

• Metastatic Gastric or GEJ adenocarcinoma

• No prior systemic chemoRx except for (neo)adjuvant

• ECOG PS: 0-1

• Measurable or non-measurable but evaluable disease

Exclusion:

• Inadequate nutritional status (albumin less than 2.5 g/dl in non-dehydrated state)

• CNS mets

• HER2+ tumor

1° Endpoint: PFS 2° Endpoints: OS, PFS2, TTP, ORR, DCR, DOR, Safety, QOL, PK, IG Exploratory objectives: Biomarkers

Capecitabine*1000 mg/m² b.i.d., PO, d1-14 Q 21d, until PD

A

BCisplatin 80 mg/m² IV day 1, Q 21d, 6 cycles

Capecitabine*1000 mg/m² b.i.d., PO, d1-14 Q 21d, until PD

Placebo 8 mg/kg IV day 1 & day 8, Q 21d until PD

* Patients unable to take capecitabine may be considered for treatment with IV continuous 5-FU, 800 mg/m²/day, d1-5. No changeover during the trial.

1:1 N~616

ClinicalTrials.gov Identifier: NCT02314117

RAINSTORM: Phase 2 Evaluation of S-1 and Oxaliplatin With or Without

Ramucirumab in Patients With No Prior Cytotoxic Therapy for Advanced

Gastric / GEJ Adenocarcinoma


Screen

Patients

♦ ≥20 years

♦ Metastatic gastric or GEJ

adenocarcinoma

♦ No prior first-line systemic

therapy

♦ Not HER2 positive

R

A

N

D

O

M

I

Z

E

1:1

Primary endpoint Progression-free survival

Secondary endpoints 2nd documentation of PFS, OS, ORR, DCR, PK, anti-ramucirumab antibodies

NCT02539225, I4T-JE-JVCW

This clinical trial is being conducted in Japan and Korea

Ramucirumab

IV (Days 1 and 8) + S-1

by mouth (Days 1-14) and

oxaliplatin IV (Day 1)

of each 21-day cycle

Placebo

IV (Days 1 and 8) + S-1

by mouth (Days 1-14) and

oxaliplatin IV (Day 1)


Part A (first line)

Ramucirumab IV (Days 1

and 15) + paclitaxel IV

(Days 1, 8, and 15)


Part B (second line)

As S-1 is part of the standard of care regimen in Japan, a study to assess ramucirumab

in addition to the combination of S-1 and platinum is being undertaken

Pre

tre

atm

en

tp

erio

d o

f P

art

B

Stratification

♦ Geographic region (Japan / Korea)

♦ ECOG PS (0 / 1)

♦ Disease measurability

(measureable / nonmeasurable)

Ramucirumab IV (Days 1

and 15) + paclitaxel IV

(Days 1, 8, and 15)


Combinations: Immunotherapy and Angiogenesis

Ipilimumab

Nivolumab



Future of Immune Therapy in GC – Combinations

Chau I et al. ASCO 2017; abstract 4046 (poster board 38)

Tumor Response Over Time in Patients with 1st-Line G/GEJ Adenocarcinoma: Ramucirumab + Pembrolizumab – Phase 1

% C

han

ge

in

Tu

mo

r S

ize

Analysis Relative Time (Weeks)

Be

st %

Ch

an

ge

fro

m B

aselin

e in

Tu

mo

r S

ize

Patients

Duration of Treatment

Of patients with assessable disease,

77% experienced a decrease in

target lesion(s) size

Summary


Receptor Tyrosine Kinases (RTK)

• Anti-EGFR negative

• Positive data only for 1st line trastuzumab + chemo

• Pertuzumab 1st-line negative

• Lapatinib 1st and 2nd line negative

• TDM-1 negative

Anti-Angiogenesis

• Positive data for Ramucirumab 2nd-line

• Positive data for Apatinib 3rd line

• 1st-line Ramucirumab: data coming soon

biologic targeted agents in gc - european society for ......expand study 5 cisplatin 80mg/m2 d1...

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