advanced gastric cancer - oncologypro · 2019. 9. 5. · advanced gastric cancer. chemotherapy and...
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ADVANCED GASTRIC CANCERChemotherapy and anti-angiogenic Treatment
Florian Lordick, MD, PhD
University Cancer Center Leipzig (UCCL)University Hospital Leipzig, Germany
Barcelona, 30 August 2019
DISCLOSURE OF INTERESTFlorian Lordick
Personal financial interests: Astra Zeneca, Amgen, Astellas, Biontech, BMS, Eli Lilly, Elsevier, Infomedica, Medscape, Medupdate, Merck, MSD, Promedicis, Roche, Servier, Springer-Nature, StreamedUp, Zymeworks
Leadership roles: ESMO (Director of Education Elect), EORTC (Chairman of the GI Tract Cancer Group), German Cancer Society (Secretary), International Gastric Cancer Association (President)
ADVANCED GASTRIC CANCEREpidemiology
Over 1 million new cases in 2018 5th most common malignancy 3rd leading cause of cancer death
1. GLOBOCAN. http://gco.iarc.fr/today/online-analysis; 2. Ebinger S, et al. Gastric Cancer. 2016;19:723-34; 3. Riihimäki M, et al. Oncotarget. 2016;7:52307-16; 4 Dassen A, et al. Eur J Cancer. 2010;46:1101-10.
Age-standardised incidence of gastric cancer, 20181
ASR, age standardised incidence; Ctx, chemotherapy; FU, fluorouracil; LV, leucovorin
Between 40 and 80% of patients with gastric cancer present with metastatic disease at diagnosis2
ADVANCED GASTRIC CANCERFirst-line Therapy
1ST-LINE TREATMENT ADVANCED GASTRIC CANCERRecommended Algorithm
Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016;13:348–360
1ST-LINE TREATMENT ADVANCED GASTRIC CANCERFACTS
Wagner et al. J Clin Oncol 2006; 24: 2903-9
• Chemo-Tx prolongs overall survival• Chemo-Tx improves symptom control• Combinations more effective than mono-Tx
• Elderly patients (>70 years) benefitTrumper et al. Eur J Cancer 2006; 42: 827-34
1ST-LINE TREATMENT ADVANCED GASTRIC CANCERFACTS
• Oxaliplatin can substitute for CisplatinPotential advantage for elderly patients
• Capecitabin p.o. can substitute for i.v. 5-FUGepoolte analysis: shows higher efficacy
• A 3rd drug (triplet) increases the activity and certainly the toxicity
Wagner et al. J Clin Oncol 2006; 24: 2903-9
Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442Cunningham et al. N Engl J Med 2008; 358: 36-46
Cunningham et al. N Engl J Med 2008; 358: 36-46Kang et al. Ann Oncol 2009; 20: 666-673
Okines et al. Ann Oncol 2009 [ePub ahead of print]
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
1ST-LINE CHEMOTHERAPYDoublet or Triplet?
Van Cutsem et al. J Clin Oncol 2006;24:4991–4997
Time to progression5.6 vs 3.7 months p<0.001
Survival9.2 vs 8.6 months p=0.02
Response Rate37% vs 25% p=0.01
Docetaxel-CF (DCF) vs CF
Grade 3 /4 Toxicity69% vs 59% p=0.02
1ST-LINE - JAPANDoublet or Triplet?
Yamada Y et al. Lancet Gastroenterol 2019;4:501–510
1ST-LINE - JAPANDoublet or Triplet?
Yamada Y et al. Lancet Gastroenterol 2019;4:501–510
1ST-LINE - ELDERLYDoublet or Triplet?
Al-Batran S et al., Eur J Cancer 2013;49:835–842
Toxicity Grade 3/4 FLOT: 81.9%FLO: 38.6%
(p<0.001)
Deterioration onEORTC Global Health Scale >10 pointsFLOT: 47.5%FLO: 20.5% (p<0.01)
PFS
FLOT 65+ Study (n=142, median 70 years)
Progression-free survival among patients with metastatic disease
EORTC, European Organisation for Research and Treatment of Cancer; FLO: 5FU-Leucovorin-Oxaliplatin; FLOT: 5FU-Leucovorin-Oxaliplatin-Docetaxel.
1ST-LINE – PLATINUM-FREEThe Role of Irinotecan
Guimbaud R et al. J Clin Oncol 2014;32:3520–3526
N = 416FOLFIRI versus ECX first-line
Time to treatment failure better with FOLFIRIbutOverall survival equal: 9.5 vs. 9.7 months (p=0.95)
Time to treatment failure
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE – ELDERLY PATIENTSGO2 Study - Full or Reduced Dose Chemotherapy?
Hall P et al., ASCO 2019; #4006
1ST-LINE CHEMOTHERAPY FOR ADVANCED GCConclusions
Lordick F et al. Gastric Cancer. 2014 Apr;17(2):213-2
Doublets (Platinum-Fluoropyrimidine) are standard
No scientific justification for epirubicine-containing triplets
Docetaxel-containing triplets (DCF, FLOT, …) are indicated in specific situations,e.g. if rapid tumor shinkage is needed, or if there is an option for secondary resection
FOLFIRI is a valid alternative to platinum/FP first-line CTx (but not approved in many countries)
Consider upfront dose-reduction (80% - 60%) in frail and elderly population
ADVANCED GASTRIC CANCERSecond-line Therapy
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERRecommended Algorithm
Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016;13:348–360
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERRandomized Controlled Trials
BSC, best supportive care. 1. Thuss-Patience PC et al. Eur J Cancer 2011;47:2306–2314; 2. Kang JH et al. J Clin Oncol 2012;30:1513–1518; 3. Ford HE et al. Lancet Oncol 2014;15:78–86; 4. Hironaka S, et al. J Clin Oncol 2013;31:4438–4444.
Study Drug Overall survival, months Improvement
Thuss-Patience1
AIO Study, Germany(n=40)
Irinotecanvs. BSC
4.0 vs. 2.4(p=0.012)
HR 0.48∆ 1.6 months
Kang2
Korean Study(n=202)
Irinotecan orDocetaxelvs. BSC
5.3 vs. 3.8(p=0.007)
HR 0.657∆ 1.5 months
Ford3
COUGAR-02, UK(n=168)
Docetaxelvs. BSC
5.2 vs. 3.6(p=0.01)
HR 0.67∆ 1.6 months
Hironaka4
WJOG, Japan(n=219)
Paclitaxelvs. Irinotecan
9.5 vs. 8.4(p=0.38)
HR 1.13No difference
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERSurvival, Symptom Control, and Quality of Life
Ford HER et al. Lancet Oncol 2014;15:78–86
Overall survivalHealth-related QoL outcomes
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERRandomized Controlled Trials
BSC, best supportive care. 1. Thuss-Patience PC et al. Eur J Cancer 2011;47:2306–2314; 2. Kang JH et al. J Clin Oncol 2012;30:1513–1518; 3. Ford HE et al. Lancet Oncol 2014;15:78–86; 4. Hironaka S, et al. J Clin Oncol 2013;31:4438–4444; 5. Fuchs C et al. Lancet 2014;383:31–339
Study Drug Overall survival, months Improvement
Thuss-Patience1
AIO Study, Germany(n=40)
Irinotecanvs. BSC
4.0 vs. 2.4(p=0.012)
HR 0.48∆ 1.6 months
Kang2
Korean Study(n=202)
Irinotecan orDocetaxelvs. BSC
5.3 vs. 3.8(p=0.007)
HR 0.657∆ 1.5 months
Ford3
COUGAR-02, UK(n=168)
Docetaxelvs. BSC
5.2 vs. 3.6(p=0.01)
HR 0.67∆ 1.6 months
Hironaka4
WJOG, Japan(n=219)
Paclitaxelvs. Irinotecan
9.5 vs. 8.4(p=0.38)
HR 1.13No difference
Fuchs 5REGARD, Global(n=335)
Ramucirumabvs BSC
5.2 vs. 3.8(p=0.047)
HR 0.776∆ 1.4 months
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERAnti-Angiogenic Treatment
Clarke JM et al. Expert Opin Biol Ther 2013;13:1187–1196
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERRainbow – 2nd-line paclitaxel +/- ramucirumab
Wilke H et al.Lancet Oncol 201415:1224–1235
Overall survival
Pac-ramucirumab
Pac-placebo
RAM + paclitaxel
Placebo + paclitaxel
HRp-value
Response rate 28% 16% p=0.0001
PFS (med, months)9-month PFS (%)
4.422%
2.910%
HR 0.635p<0.0001
OS (med, months)12-month OS (%)
9.640%
7.430%
HR 0.807p=0.0169
2ND-LINE TREATMENT ADVANCED GASTRIC CANCERRAMIRIS: Ramucirumab + FOLFIRI vs Ramucirumab + Paclitaxel
Lorenzen S et al., ASCO 2019; abstract 4023
2ND-LINE CHEMOTHERAPY FOR ADVANCED GCConclusions
2nd-line treatment should be offered to patients who are motivated to receive further treatment
Robust evidence for 2nd-line mono chemotherapy (Evidence IA, ESMO recommendation A)
Phase-III-data suggest the combination of ramucirumab + paclitaxel to the best availabe option
Some evidence for using 2nd-line combinations (like e.g. FOLFIRI)
ADVANCED GASTRIC CANCERThird-line Therapy
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAS-102 = Trifluridin (FTD) + Tipiracil (TPI)
1. Gottschling H & Heidelberger C. J Mol Biol 1963;7:541–560; 2. Fukushima M, et al. Biochem Pharmacol. 2000;59:1227–1236. Images via Wikipedia
+
1:0.5FTD TPI
Fluorinated ThymidineIncorporation into DNA1
DNA Dysfunction1
Inhibits Thymidine-Phosphorylase2
Prolongs FTD degradation2
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAGS Study
BID, twice daily; DCR, disease control response; FTD/TPI, trifluridine/tipiracil; QOL, quality of lifeShitara K et al. Lancet Oncol. 2018;19:1437–1448
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAGS Study – Baseline Demographics
Shitara K et al. Lancet Oncol. 2018;19:1437–1448
Patient characteristic FTD/TPI (n=337) Placebo (n=170)Age, years; median (range) 64.0 (24–89) 62.5 (32–82)Gender, % Male 75 69Geographic region, % Japan 14 16
ROW 86 84ECOG PS, % 0 36 40
1 64 60Primary site, % Gastric 71 72
GEJ 29 28Prior gastrectomy, % Yes 44 44Number of prior regimens, % 2 37 38
3 40 35≥4 23 27
ITT population; ECOG PS, Eastern Co-operative Oncology Group Performance Status; FTD/TPI, trifluridine/tipiracil; GEJ, gastroesophageal; ROW, rest of world
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAGS Study – Disease Characteristics
Shitara K et al. Lancet Oncol. 2018;19:1437–1448
Patient characteristic FTD/TPI (n=337) Placebo (n=170)Number ofmetastatic sites, %
1–2 46 42≥3 54 58
HER2 status, % Positive 20 16Negative 61 62Not assessed 18 22
Prior systemiccancer therapeuticagents, %
Fluoropyrimidine >99a 100Platinum 100 100Irinotecanb 54 58Taxaneb 92 87Ramucirumab 34 32Immunotherapy (anti-PD-1/PD-L1) 7 4
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAGS Study – Survival Outcomes
Shitara K et al. Lancet Oncol. 2018;19:1437–1448
Overall survival
FTD/TPI(n=337)
Placebo(n=170)
Events, no. (%) 244 (72) 140 (82)
Median, months 5.7 3.6
HR (95% CI) 0.69 (0.56-0.85)
1-sided Pa 0.0003
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAGS Study – Adverse Events in >10% of patients
Shitara K et al. Lancet Oncol. 2018;19:1437–1448
All treated patientsFTD/TPI, trifluridine/tipiracil
FTD/TPI (n=335) Placebo (n=168)Any grade, % Grade ≥3, % Any grade, % Grade ≥3, %
Nausea 37 3 32 3Decreased appetite 34 9 31 7Fatigue 27 7 21 6Vomiting 25 4 20 2Diarrhoea 23 3 14 2Asthenia 19 5 24 7Abdominal pain 16 4 18 9Constipation 13 1 15 2Dyspnoea 7 2 10 4General physical deterioration 7 7 10 9
3RD-LINE CHEMOTHERAPY FOR ADVANCED GCTAGS Study – Hematological Adverse Events
Shitara K et al. Lancet Oncol. 2018;19:1437–1448
aTreated patients with ≥1 post-baseline measurementFTD/TPI, trifluridine/tipiracil
Grade ≥3 febrile neutropenia was reported in 6 patients (2%) treated with FTD/TPI
FTD/TPI (n=328a) Placebo (n=162a)Grade 3, % Grade 4, % Grade 3/4, % Grade 3, % Grade 4, % Grade 3/4, %
Neutropenia 27 11 38 0 0 0Leukopenia 19 2 21 0 0 0Lymphocytopenia 17 2 19 8 0 8Anaemia 19 NA 19 7 NA 7Thrombocytopenia 4 2 6 0 0 0
CONCLUSIONS FOR TREATMENT OF ADVANCED GCMy Best Choice
• First-line Platinum-Fluoropyrimidin-Doublet (triplet = exception)– Irinotecan-5-FU: is an alternative (not approved) in Platin-pretreated pts
• Plan for sequential treatment lines• Second-line Paclitaxel-Ramucirumab (standard)• Third-line TAS-102 (now FDA approved, positive EMA CHMP opinion)• Personalized therapy
– HER2-positive: Chemo + Trastuzumab (only first-line)– Anti-Claudin18.2 (Zolbetuximab) in clinical trials– Immunotherapy in selected pts in clinical trials