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Sun Young RHAYonsei Cancer Center
Yonsei University College of Medicine
Chemotherapy for metastatic Gastric Cancer
ESMO GI preceptorship 2019
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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
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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.
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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
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• QoL maintenance: better PS
• Survival prolongation: longer PFS
• Conversion to surgery in oligometastasis: chance for cure
Goals of palliative chemotherapy
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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
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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
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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.
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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.
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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
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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
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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
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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
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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
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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
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1st line Tx
� Are there any superior regimens?
� Is the more the better?
� Any role of targeted agents?
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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.
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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.
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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)
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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
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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
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Doublet is preferred based on benefit-risk ratio
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• 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
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Sequential Tx improves outcome!
Not overlapping MoANo cumulative toxicity
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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.
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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
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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.
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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.
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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.
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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.
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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
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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
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• 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
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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
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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
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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
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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?