Sun Young RHAYonsei Cancer Center

Yonsei University College of Medicine

Chemotherapy for metastatic Gastric Cancer

ESMO GI preceptorship 2019

Disclosures

• Research grants and research support: MSD, BMS, GSK, Eli Lilly, Boehringer Ingelheim

• Consultation/advisory role: MSD, Celltrion, Ipsen, Daiichi Sankyo, Eisai

• Speaker bureau: Eli Lilly, Ipsen

Differences in global outcome:Five-year survival of gastric cancer (Korea, US, Ca nada and Japan) 1

35.1%

75.8%

32.1%

25%

64.6%

Korea

('06-'10)

Korea

('12-'16)

US

('08-'14)

Canada

('06-'08)

Japan

('06-'08)

Mortality-to-incidence ratio 2

World 0.76

USA 0.55

Canada 0.58

Japan 0.49

Korea 0.34

1. National Cancer Statistics, Korea, 2016. Available at http://ncc.re.kr/main.ncc?uri=english/sub04_Statistics (accessed on July 25, 2019); 2. Tsai et al. World J Gastroenterol 2017;23:7881–7.

Factors affecting outcomes between East vs West

1) Tumor characteristics - different proportion of subgroup 2) Host characteristics including pharmacogenetics/

pharmacogenomics and tumor microenvironment -> different toxicity profiles, dosing & schedule

3) Treatment and practice pattern: more doublets, sequential treatment, better supportive care -> more subsequent treatment -> impact on OS

4) Cultural(Pts, Drs)5) Regulatory and political issues -> different drug availability

-> affects treatment outcomes

-> Study design issues in global clinical trials-> Careful interpretation of global clinical trials-> Rational application in the clinical practice

• QoL maintenance: better PS

• Survival prolongation: longer PFS

• Conversion to surgery in oligometastasis: chance for cure

Goals of palliative chemotherapy

5-Fluorouracil/platinum(+/- docetaxel) 5–7 Mo

Paclitaxel oririnotecan (3–5 Mo)

+ trastuzumab in HER2 + Ramucirumab + paclitaxel

90% 60–65% 30–40%

Supportive2nd line Tx (3rd – 4th line Tx)1st line Tx

Chemotherapy

Apatinib / trifluridine/tipiracil?

� Ethnic differences (Asians vs. Westerns): treatment pattern, drug toxicity� Systemic chemotherapy is the main Tx

� Doublet vs. triplet� Various doublets are similar� Sequential treatment improved survival

� Role of molecular targeted agents?� Angiogenesis inhibitor showed benefit in 2nd line and more� IO showed the potential benefit� New strategy: conversion surgery, IP chemotherapy

pembrolizumab in PD-L1 +Nivolumab, pembrolizumab in PD-L1 +

Multidisciplinary approach!

Maintain QoL with the best supportive care is important!

Current treatment of metastatic GC in Asia (median 16–18 months)

MSI-H/dMMRPembrolizumab in MSI-H/dMMR

39-year-old female, elementary school teacher• CC: indigestion 1 month• FHx/PHx: none• PEx: ECOG PS 0• Lab: WNL except Hb 11.2 • Tumour markers: CEA, 0.6 ng/mL; CA 19-9, 6.7 U/mL; CA 72-4, 1.41 U/mL; CA 125, 190.8 U/mL

• EGD with biopsy: adenocarcinoma, poorly differentiated

• AP CT: AGC with peritoneal carcinomatosis, direct invasion of T-mesocolon, seeding mets of T-colon, Lt para-aortic LN, Lt obstructive hydronephrosis

• PET-CT: AGC with carcinomatosis, no systemic mets

Molecular characterization• Gastric cancer panel by IHC

with EGD biopsy tissue

– HER2 (-)

– EBV-associated type (-)

– MSI-high type (-)

– EGFR (-)

– c-MET (-)

– PTEN (intact)

– PD-L1 (22C3) (-)

Genome stable type

• Tissue NGS

Adapted from Cancer Genome Atlas Research Network. Nature 2014;513:202–9.

Baseline

After 4 cycles of 1 st line chemotherapy: increasing SD

Lt ureteral stent was inserted

Rt ureteral stent was inserted

Palliative 1st line chemotherapy with S-1 and cisplatin

ECOG PS 1; CA 125, 90.8 U/mL

Images are property of Prof. Rha.

PD after SP 8 cycles

2nd line palliative Tx with paclitaxel + ramucirumab

Repeated EGD biopsy: signet ring cell type (PD-L1, CPS 1%)

PD after 4 cycles

3rd line palliative Tx with FOLFIRI

PD after 3 rd line FOLFIRI 2 cycles: T Bil, 3.1 mg/dL; ALP, 704 IU/L; G-GT, 1109 IU/L;

Cr, 8.19 mg/dL; eGFR 5 mmol/L

PTBD → internal stentLt PCN

→ Start palliative 4th line with FOLFOX

EGD due to complaint of esophageal discomfort

Currently ongoing with improved status of ECOG PS 0 and normalized labs

Esophageal candidiasis → improved after fluconazole treatment

S-1 + cisplatinPaclitaxel +

ramucirumab

Hospice2nd line Tx (3rd – 4th line Tx)1st line Tx

8 months4.5 months

1.5 months>2 months

FOLFIRI FOLFOX

12M 24M

CapecitabineDocetaxelEpirubicin

---Clinical trials

----

Lt ureteralstent

Rt ureteralstent

PTBDLt PCN

EGD with molecular subtyping

Repeated EGD*

Repeated EGD*

Current OS: >16 months

Progress summary of the patient

*Research purposes

Multidisciplinary approach (I)

• Surgery: palliative resection, bypass surgery

• Radiotherapy: primary tumour, bone metastasis, brain metastasis

• Gastric stent, ureteral stent, ascites control, PTBD, etc….

• Nutritional support

1) Disease control: proper drug selection

2) Maintain organ function: proper palliative care

Approved/available agents for mGC

Chemotherapeutics

+ trastuzumab(2010)

+ ramucirumab(2015)

Targeted/immune agents

Nivolumab/pembrolizumab

(2017)

DocetaxelPaclitaxel

Doxorubicin/epirubicinirinotecan

5-FUS-1

Capecitabine

CisplatinOxaliplatin

� Various regimens with different MoA

Monotherapy < Doublet << Triplet

Increasing efficacy

Increasing toxicity & decreasing tolerability

1st line Tx

� Are there any superior regimens?

� Is the more the better?

� Any role of targeted agents?

Indirect evidence of similar efficacies of 1 st line doublets: FP = XP = SP = SOX = CAPOX (XELOX)

Trial Arm RR (%) PFS (months) OS (months)

ML17032 FP 5.0 9.3

Korean; Kang, 2009 XP 5.6 10.5

Japanese XP 43.2 5.8 13.8

Retrospective; Shitara, 2013 SP 50 5.2 13.5

G-SOX SP 52.2 5.4 13.1

Yamada, 2015 SOX (100) 55.7 5.5 14.1

Korean RPII SOX (130) 40 6.2 12.4

Kim, 2012 CAPOX (130) 44 7.2 13.3

� Similar toxicity (more G1/2 HFS in capecitabine-containing arm)

Doublet is tolerable and better than monotherapyVarious combinations of platinum and 5-FU analogues are similar

� 5-FU ci -> oral 5-FU analogue� FP -> SP/XP� Cisplatin -> oxaliplatin� Role of taxanes

Kang et al. Ann Oncol 2009;20:666–73; Shitara et al. Int J Clin Oncol 2013;18:539–46; Yamada et al. Ann Oncol 2015;26:141–8; Kim et al. Eur J Cancer 2012;48;518–26.

Comparison of 4 doublets (FOLFOX, XELOX, SP, XP) at Yonsei Cancer Center (2012 –2017): PFS (n=841)

Group Total PD CensoredmPFS

(95% CI)

FOLFOX169

(20.10%)114

55(32.54%)

6.266(5.333, 7.100)

XELOX286

(34.01%)208

78(27.27%)

7.133(6.400, 8.133)

SP321

(38.17%)219

102(31.78%)

7.233(6.333, 8.200)

XP65

(7.73%)50

15(23.08%)

4.600(2.966, 6.366)

Group Total PD CensoredmPFS

(95% CI)

XELOX +FOLFOX

455(54.10%)

322133

(29.23%)6.866

(6.133, 7.466)

SP + XP386

(45.90%)269

117(30.31%)

7.000(6.066, 7.666)

P-value = 0.0001 P-value = 0.3657

Rha et al. Unpublished data.

Comparison of 4 doublets (FOLFOX, XELOX, SP, XP) at Yonsei Cancer Center (2012 –2017): OS (n=841)

Group Total Death CensoredmOS

(95% CI)

FOLFOX169

(20.10%)150

19(11.24%)

19.600(13.933, 24.467)

XELOX286

(34.01%)222

64(22.38%)

19.700(17.833, 22.833)

SP321

(38.17%)274

47(14.64%)

20.733(17.567, 22.967)

XP65

(7.73%)56

9(13.85%)

16.267(12.267, 22.500)

Group Total Death CensoredmOS

(95% CI)

XELOX +FOLFOX

455(54.10%)

37283

(18.24%)19.700

(17.833, 21.900)

SP + XP386

(45.90%)330

56(14.51%)

19.833(17.167, 22.400)

P-value = 0.4349 P-value = 0.5384

Rha et al. Unpublished data.

Oxaliplatin based(n=372, mOS 19.7m) = Cisplatin based (n= 386, mOS 19.8m)

FLOT4 Study Design

Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

Doublet vs Triplet? Phase III, DCF vs. CF (V325), JCO 2006

N ORR PFS/TTP OS

Docetaxel/irinotecan/oxaliplatin1 40 50% 6.5 mo 11.5 mo

Paclitaxel/cisplatin/5-FU2 45 51.2% 6.9 mo 12.7 mo

Docetaxel/cisplatin/S-13 34 87.1% 7.4 mo 22.6 mo

Docetaxel/cisplatin/5-FU/LV4 46 61% 8.9 mo 17.6 mo

Docetaxel/oxaliplatin/5-FU5 89 46.6% 7.7 mo 14.6 mo

Docetaxel/oxaliplatin/capecitabine5 86 25.6% 5.6 mo 11.3 mo

Docetaxel/cisplatin/5-FU6 31 33% 6.5 mo 12.6 mo

Modified DCF6 54 49% 9.7 mo 18.8 mo

Irinotecan/oxaliplatin/5-FU/LV7 63 33% 7.5 mo 12.1 mo

Paclitaxel/cisplatin/S-18 44 59.1% 9.4 mo 11.2 mo

Irinotecan/oxaliplatin/S-19 44 75% 10.2 mo 17.6 mo

Docetaxel/cisplatin/S-110 49 81% 8.7 mo 18.5 mo

Docetaxel/oxaliplatin/capecitabine11 55 43% 6.9 mo 13.0 mo

Docetaxel/oxaliplatin/S-112 44 54.5% 7.6 mo 12.0 mo

1Di Lauro L et al, Br J Cancer 2007;97:593, 2Hwang J et al, J Korean Med Sci 2008;23:586, 3Sato Y et al, Cancer Chemother Pharmacol 2010;66:721, 4Tomasello G et al, Gastric Cancer 2014;17:711, 5Van Cutsem et al, Ann Oncol 2015;26:149, 6Shah MA, et al, J Clin Oncol 2015;33:3874, 7Comella P, et al, Cancer Chemother Pharmacol 2009;64:893, 8Kim JY, et al, Cancer Chemother Pharmacol 2011;67:527, 9Park SR, Ann Oncol 2011;22:890,

10Koizumi, W et al, Cancer Chemother Pharmacol 2014;69:407, 11Stein A et al, Acta Oncol 2014;53:392, 12Kim HS, et al. Gastric Cancer 2016;19:579, Van Cutsem, et al. J Clin Oncol 2006;24:4991-4997

Phase II Studies of Triplet Regimens

Doublet is preferred based on benefit-risk ratio

• For palliation– Symptom control in patients with severe symptoms

associated with high tumor burden

• For prolongation of survival – Patients with rapidly progressing disease

• For cure– Locally advanced unresectable or borderline

resectable disease– Metastatic disease with the possibility of conversion

surgery

When needs high antitumor activity

Sequential Tx improves outcome!

Not overlapping MoANo cumulative toxicity

Phase III Korean Study: Salvage Chemo + vs. BSC Alone • Primary endpoint: OS

Patients with metastatic gastric

cancer, 1-2 previous chemo* regimens,

ECOG PS 0-1(N = 202)

Treatment continued until progression, toxicity, or withdrawal

Docetaxel 60 mg/m2 on Day 1 q3w or Irinotecan 150 mg/m2 q2w

(n = 133)

Best Supportive Care †

(n = 69)

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

*Fluoropyrimidines and/or platinum agents.†Including analgesics, paracentesis, psychosocial care, nutritional support, blood transfusion, palliative radiotherapy, or nonprotocol BSC measures.

Phase III UK trial (COUGAR -02)• Primary endpoint: OS

Patients with metastatic esophagus,

EGJ, or gastric cancer, 1 previous chemo regimens,

ECOG PS 0-2(N = 168)

Treatment continued until progression, toxicity, or withdrawal

Docetaxel 75 mg/m2

on Day 1 q3w(n = 84)

BSC(n=84)

Lancet Oncol 2014; 15: 78–86

Phase III Japan trial (WJOG 4007)Paclitaxel vs. Irinotecan

• Primary endpoint: OS

Patients with metastatic gastric cancer, 1 previous chemo regimens,

ECOG PS 0-2(N = 223)

Treatment continued until progression, toxicity, or withdrawal

Paclitaxel 80 mg/m2

on Day 1,8, 15 q 4wks(n = 108)

irinotecan 150 mg/m2 on days 1 and 15, q 4 wks

(n=111)

J Clin Oncol. 2013;31:4438-4444.

2nd line chemotherapy

Study Regimen Survival, months Improvement

Thuss-Patience et al.Eur J Cancer 2011, AIO (n=40)

Irinotecan vs. BSC

4.0 vs. 2.4(p=0.012)

HR 0.48∆ 1.6 months

Kang et al.J Clin Oncol 2012, Korea (n=202)

Irinotecan or docetaxelvs. BSC

5.3 vs. 3.8(p=0.007)

HR 0.657∆ 1.5 months

Ford et al.Lancet Oncol 2014 (n=168)

Docetaxelvs. BSC

5.2 vs. 3.6(p=0.01)

HR 0.67∆ 1.6 months

Fuchs et al.Lancet 2014 (n=223)

Ramucirumabvs. BSC

5.2 vs. 3.8(p=0.047)

HR 0.776∆ 1.4 months

Wilke et al.Lancet Oncol 2014 (n=665)

Ramucirumab + paclitaxelvs. PBO + paclitaxel

9.6 vs. 7.4(p=0.017)

HR 0.807∆ 2.2 months

Li et al. J Clin Oncol 2016 (n=273)

Apatinibvs. BSC

6.5 vs. 4.7(p=0.015)

HR 0.709∆ 1.8 months

Thuss-Patience et al. Eur J Cancer 2011;47:2306–14; Kang et al. J Clin Oncol 2012;30:1513–8; Ford et al. Lancet Oncol 2014;15:78–86;Fuchs et al. Lancet 2014;383:31–9; Wilke et al. Lancet Oncol 2014;15:1224–35; Li et al. J Clin Oncol 2016;34:1448–54.

GC treatment guidelinesESMO guidelines Pan-Asian adopted ESMO guidelines

Adapted from Smyth et al. Ann Oncol 2016;27(suppl 5):v38–v49; Muro et al. Ann Oncol 2019;30:19–33.Please refer to prescribing information in each country for details on the approved indications.

Korean Practice Guideline for Gastric Cancer 2018 Treatment algorithm for palliative systemic therapy

Korean Gastric Cancer Association (KGCA) et al. J Gastric Cancer 2019;19:1–48.

HER2 negative

HER2 positive

5FU analogue +/-platinum

Irinotecan

5-FU analogue +/- platinum

XP/FP (SP)+Trastuzumab

Gastric cancer treatment guideline ver. 4. 2014 (additional information)

1st-line 2 nd-line 3 rd-line

90-95% 60-70% 40-50%

Paclitaxel/Docetaxel

Irinotecan

Ramucirumab

Paclitaxel+Ramucirumab

Palliative sequential treatments in Asia

Paclitaxel/Docetaxel

5-FU analogue +/- platinum

� Oral fluoropyrimidine monotherapy for elderly or poor PS

Multidisciplinary approach (II): maintain QoL from systemic Tx• Cytotoxic chemotherapeutics: targeting proliferating cells

� Non-specific

� Drug specific

• Targeted agents (drug specific, on-target side effects)� Trastuzumab

� Ramucirumab

• IO (checkpoint inhibitor; nivolumab, pembrolizumab)� Immune-related toxicities

� Proper evaluation- Severity/duration- Monitoring plan

� Proper management- Multidisciplinary approach- Education

• Nutritional support• Nephropathy/neuropathy

management• Oesophageal candidiasis

• Cardiac function evaluation and proper management

• HiBP/TE • Non-infectious pneumonitis • Endocrinologic dysfunction

• Trifluridine/tipiracil (Lonsurf ): trifluridine(a nucleoside analog) + tipiracil(thymidine phosphorylase inhibitor, prevents rapid metabolism of trifluridine)

• approved by the U.S. FDA (Sep 2015) and EMA (April 2016) for refractory CRC

Recent trial with new chemotherapeutics in mGC

TAGS: a phase 3, randomised, double-blind study of trifluridine/ tipiracil (TAS-102) versus placebo in patients with refractory mGC

• PRIMARY ENDPOINT : OS• SECONDARY ENDPOINTS: PFS, ORR, DCR, QoL, time to ECOG PS ≥2, safety

R

PD

Stratification

• ECOG PS (0 vs. 1)

• Region (Japan vs. rest of world)

• Prior ramucirumab (yes vs. no)

TFD/TPI (TAS-102) + BSC35 mg/m2 bid orally on D1–5 and 8–12

of each 28-day cycle (n=337)

Key patient inclusion criteria

• Metastatic gastric/GEJ cancer

• ≥2 prior regimens

• Age ≥18 years (≥20 years in Japan)

• ECOG PS 0/1

(n=507)PD

Placebo + BSC bid orally on D1–5 and 8–12

of each 28-day cycle (n=170)

J Tabenero et al. WGIC 2018, Arkenau H, et al. ESMO 2018

LBA25: TAGS: a phase 3, randomised, double-blind st udy of trifluridine/ tipiracil (TAS-102) versus placebo in patients with refractory mGC

aITT population; bstratified log-rank testArkenau H, et al. Ann Oncol 2018;29(suppl 5):abstr LBA25

TFD/TPI(n=337)a

Placebo(n=170)a

Events, n (%) 244 (72) 140 (82)

mOS, months 5.7 3.6

HR (95%CI) 0.69 (0.56, 0.85)

One-sided p-valueb 0.0003

Two-sided p-valueb 0.0006

OS100

Time, months

00

80

60

40

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

337170

328158

282131

240101

20171

16160

12447

10240

8034

6629

5117

4012

3110

229

167

115

92

72

70

70

40

40

40

30

10

00

12-month OS: 21%

12-month OS: 13%

OS

, %

No. at riskTFD/TPIPlacebo

S-1/CDDP

IP PTX + S-1/PTX

Gastric cancer withperitoneal metastasis

R

1

2

Key Eligibility Criteria• No or <2mo prior chemo.• No other distant metastasis• No prior gastrectomy• No frequent ascites drainage

Stratification• Institution• Prior chemo. +/-• Peritoneal meta.

P1/P2-3

Primary Endpoint• Overall survival

Secondary Endpoints• Response rate• Safety

• Hironori Ishigami Japan intraperitoneal chemotherapy study group (JIPG), Cancer 2013, ASCO 2016

Phase III study of intraperitoneal paclitaxel plus S-1/paclitaxel compared with S -1/cisplatin in GC pts with peritoneal metastasis: PHOENIX -GC trial

Efficacy

Sur

viva

l Rat

e

Time (Months)

HR=0.72 (95% CI: 0.49–1.04) P=0.081

Median OS, months (95% CI)

IP : 17.7 (14.7–21.5)

SP : 15.2 (12.8–21.8)

Disappeared Decreased No change IncreasedMantel

test

IP (n=38) 15 (39%) 18 (47%) 3 (8%) 2 (5%)P=0.001

SP (n=7) 0 (0%) 2 (29%) 3 (43%) 2 (29%)

• Evaluation of ascites by CT

� Slightly increased neutropenia, diarrhea and neuropathy

Summary and Conclusion� Sequential treatment is important

� Proper toxicity management is essential for oncologic outcome

� Need complete understanding of the treatment regimen/schedule

� Education of doctors/nurses and the patients/caregivers

• No homogeneous Tx: Ethnicity-based diverse strategy

• More understanding of host characteristics (PK/TME) for personalized treatment

� Effort for proper patient selections

– Molecular subtype (no proven marker for IOs)

– Pharmacogenomic study

– AI-based approach?