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