gastric cancer: second and later line therapy · eox xp flo folfiri fufiri s-1 ... p = 0.007 ford h...

GASTRIC CANCER: Second and Later Line Therapy

David H. Ilson, M.D., Ph.D.

Attending Physician

Memorial Sloan-Kettering Cancer Center

New York

Disclosure

Consulting

– AMGEN

– Bayer

– Lilly/Imclone

– Pieris

– Roche Genentech

– Astra Zeneca

– Bristol Myers Squibb

Esophago-Gastric Cancer: Metastatic Disease

• CIV 5-FU + cisplatin

• 4-5 day 5-FU infusion

• RR 20-30%

• Med S 8-9 months

• Capecitabine = CIV 5-FU, Oxaliplatin = Cisplatin

• Superior toxicity for CRC scheduling (every 2 week schedule)

• 2 Drug regimens preferred

Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use?

Oxali:

EOX or

EOF

Cape:

ECX or EOX XP FLO FOLFIRI FUFIRI

S-1 Cis DCF ECF

Pts 489 513 160 109 209 170 305 221 126

%RR 44% 45% 41% 34% 39% 32% 54% 36% 45%

TTP, months

6.7 6.5 5.6 5.5 5.3 5.0 6.0 5.6 7.4

OS, months

10.9 10.4 10.5 10.7 9.5 9.0 13.0 9.2 8.9

Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol

19:450;2008 Koizumi Lancet Oncol 9:215;2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997

Second Line Chemo Gastric Cancer Phase III Trials Improved Survival

Docetaxel

vs

BSC Docetaxel

or

Irinotecan

vs

BSC Paclitaxel

vs

Irinotecan

Patients 84 84 133 69 111 112

RR % 7% -- 13%

17%/10%

-- 21% 14%

PFS 12.2 wks NS NS NS 3.6 mo 2.3 mo

OS 5.2 mo 3.6 mo 5.3 mo

(5.2-6.5)

3.8 mo 9.5 mo 8.4 mo

Significance HR 0.67

P = 0.01

HR 0.657

P = 0.007

Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012 Ueda JCO 31: 4438;

2013

Docetaxel/Irinotecan vs BSC Docetaxel vs BSC

Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012

Second Line Chemo Gastric Cancer Phase III Trials Taxanes or Irinotecan Improve Survival

FIRST LINE

SECOND LINE

THIRD LINE

Targeted Agents

The only success story to date is HER2 and VEGF

The only validated biomarker is HER2

No biomarker selection for VEGF directed therapy

Immunotherapy

– MSI high status

– PDL-1

– Candidate gene signatures

HER2

Trastuzumab has modest first line activity

– TOGA: Cape-Cis + trastuzumab improved RR, PFS, OS

– JACOB: Cape-Cis-Trastuzumab + Pertuzumab Failed--ESMO

Lapatinib failed to improve OS + Cape-Ox first line (LOGIC)

Second line: trastuzumab emtansine (TDM-1) was no better than paclitaxel

Up front and acquired resistance are likely

Bang Lancet 376: 1302; 2010, Hecht JCO 34: 443; 2016, Thuss-PatientceLancet Oncol 18: 540; 2017

2:1 RANDOMIZATION

Locally advanced or

metastatic gastric cancer or

GEJ adenocarcinoma

With disease progression on or after

• 4 months of 1st-line platinum or

fluoropyrimidine-based

chemotherapy or

• 6 months of adjuvant chemotherapy

Second Line, VEGFR2, Ramucirumab: 1000

patients on two multinational, double-blind

phase III trials

©2014 Eli Lilly and Company

REGARD2

Monotherapy plus BSC (n=355)

PRIMARY ENDPOINT:OVERALL SURVIVAL

Ramucirumab**†

+ BSC (n=238)

Placebo + BSC

(n=117)

*8 mg/kg IV every 2 weeks, or placebo, plus PTX (80 mg/m2 days 1, 8, and 15 of a 4-week cycle); no prior paclitaxel use

**8 mg/kg IV every 2 weeks or placebo†Until disease progression, unacceptable toxicity, or death

1:1 RANDOMIZATION

Locally advanced or

metastatic gastric cancer or

GEJ adenocarcinoma

With disease progression on or after

4 months of 1st-line platinum and

fluoropyrimidine-based chemotherapy

No prior paclitaxel use

RAINBOW1

Combination therapy (n=665)

PRIMARY ENDPOINT:OVERALL SURVIVAL

Ramucirumab +

paclitaxel*†

(n=330)

Placebo +

paclitaxel*†

(n=335)

BSC: best supportive care; GEJ: gastroesophageal junction.

1. Wilke H et al. Lancet Oncol 2014;15:1224–1235

2. Fuchs CS et al. Lancet 2014;383:31–39

REGARD: Monotherapy, Progression-free survival

Months

Pro

gre

ssio

n-f

ree s

urv

ival (%

)

1.3 MONTHS

2.1MONTHS

CI: confidence interval; HR: hazard ratio; PFS: progression-free survival.

Fuchs CS et al. Lancet 2014;383:31–39


REGARD: Overall survival

Months

Overa

ll surv

ival (%

)

5.2MONTHS

3.8MONTHS

Overa

ll surv

ival (%

)

CI: confidence interval; HR: hazard ratio; OS: overall survival.

Fuchs CS et al. Lancet 2014;383:31–39


5.2

3.8

5.2

3.6

Ramucirumab vs PBO (BSC)

(N = 355)

Docetaxel vs ASC

(N = 131)

Docetaxel or Irinotecan vs

BSC

(N = 202)

Irinotecan vs BSC

(N = 40)

5.3

Median OS in Randomized Second-Line Gastric Cancer Studies Presented/Published in 2009-2013

Ford HER, et al. The Lancet Oncology. 2014;15(1):78-86.

Kang JH, et al. J Clin Oncol. 2012;30(13):1513-1518.

Thuss-Patience PC, et al. Eur J Cancer. 2011;47(15):2306-2314.

0 1 2 3 4 5 6

Median OS (months) by study arm

Active Treatment BSC

3.8

4.0

2.4

RAINBOW: Paclitaxel + Ramucirumab,

Progression-free survival

Months

Overa

ll surv

ival pro

babili

tyP

rogre

ssio

n-f

ree s

urv

ival (%

)

4.4MONTHS

2.9MONTHS

CI: confidence interval; PBO: placebo; PTX: paclitaxel; RAM: ramucirumab.

Wilke H et al. Lancet Oncol 2014;15:1224–1235


RAINBOW: Overall survival

Months

Overa

ll surv

ival

9.6MONTHS

7.4 MONTHS

CI: confidence interval; PBO: placebo; PTX: paclitaxel; RAM: ramucirumab.



RAINBOW: Improved tumor response rate


Disease control:

Ramucirumab + paclitaxel 80%

Placebo + paclitaxel 64% (p<0.0001)


Recent Negative Second Line Trials

DREAM: DHP-107 (Oral Taxane) vs paclitaxel, PFS, 238 pts

GOLD; Paclitaxel + / - PARP Inhibitor Olaparib, OS, 644 pts

– Trend toward improved OS in ATM negative pts

BRIGHTER: Paclitaxel + / - STAT3 inhibitor BBI608

EGFR Inhibition: Irinotecan + / - Nimotuzumab

Ongoing Second or Later Line Trials

TAS102: Placebo vs TAS102 third or later line

Integrate II: Placebo vs Regorafenib third line

Apatinib vs Placebo

Blocking CTLA-4 and PD-1

T cellTumor cell

MHCTCR

PD-L1PD-1

- - -T cell

Dendritic

cell

MHCTCR

CD28

B7 CTLA-4- - -

Activation

(cytokines, lysis, proliferation,

migration to tumor)

B7+++

+++

CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)

anti-CTLA-4anti-PD-1

Tumor Microenvironment

+++

PD-L2PD-1

anti-PD-1

- - -

LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477

PD-L1 and PD-L2 Expression Are

Elevated in Gastric Cancer

CIN = chromosome instability; EBV = Epstein-Barr virus; GS = gnomically stable; MSI = microsatellite instability.

Presented with permission from Bass A. Comprehensive molecular characterization of gastric cancer. Presented

at: TCGA Symposium, May 13, 2014.

PD-L2 (PDCD1LG2)

3.5

3.0

2.5

2.0

1.5

1.0

0.5

mR

NA

Ex

pre

ssio

n (

RN

A S

eq

RP

KM

)(lo

g2

)

CIN EBV GS MSI

Molecular Subtype

PD-L1 (CD274)

7

6

5

4

3

2

1

0

mR

NA

Ex

pre

ssio

n (

RN

A S

eq

RP

KM

)(lo

g2

)

CIN EBV GS MSI

Molecular Subtype

Immunotherapy Pivotal Trials

Second or Later Line

– Pembrolizumab vs Paclitaxel (KEYNOTE 61) Failed

– Pembrolizumab vs Physician Choice (KEYNOTE 181)

– Avelumab vs Physician Choice (Javelin 300) Failed

Pembro, Nivo only superior to no therapy and best supportive care

Atezolizumab, Durvalumab / Tremelimumab, phase I-II

Modulation agents: IDO inhibitors, co stimulatory pathways, others + anti PD-1, PD-L1

Gastric Cancer: Summary

Metastatic Disease

– Two drug alternatives (FOLFOX, FOLFIRI, Cape-Cis or Oxali) less toxic

– Second Line: taxane or irinotecan

Targeted therapies

– VEGFR2: Ramucirumab improves outcome second line, alone or with paclitaxel

Paclitaxel + Ramucirumab benchmark 9.6 month OS

Concern about second line paclitaxel alone control arms

– HER2: Trastuzumab emtansine no better than paclitaxel

Genomic data: resistance pathways, networks

Checkpoint Inhibitors: clear signal of activity in late line therapy

– MSI high, PDL-1 positive: U.S. approval for Pembrolizumab

– Checkpoint inhibitors NO BETTER than chemotherapy in second and third line

– IT better only against no therapy

gastric cancer: second and later line therapy · eox xp flo folfiri fufiri s-1 ... p = 0.007 ford h...

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