ADVANCED GASTRIC CANCER Chemotherapy and anti-angiogenic Treatment Florian Lordick, MD, PhD University Cancer Center Leipzig (UCCL) University Hospital Leipzig, Germany Barcelona, 30 August 2019 DISCLOSURE OF INTEREST Florian 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 CANCER Epidemiology Age-standardised incidence of gastric cancer, 20181 Between 40 and 80% of patients with gastric cancer present with metastatic disease at diagnosis2 Over 1 million new cases in 2018 5th most common malignancy 3rd leading cause of cancer death ASR, age standardised incidence; Ctx, chemotherapy; FU, fluorouracil; LV, leucovorin 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. ADVANCED GASTRIC CANCER First-line Therapy 1ST-LINE TREATMENT ADVANCED GASTRIC CANCER Recommended Algorithm Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016;13:348–360 1ST-LINE TREATMENT ADVANCED GASTRIC CANCER FACTS • Chemo-Tx prolongs overall survival • Chemo-Tx improves symptom control • Combinations more effective than mono-Tx Wagner et al. J Clin Oncol 2006; 24: 2903-9 • Elderly patients (>70 years) benefit Trumper et al. Eur J Cancer 2006; 42: 827-34 1ST-LINE TREATMENT ADVANCED GASTRIC CANCER FACTS • Oxaliplatin can substitute for Cisplatin Potential advantage for elderly patients Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442 Cunningham et al. N Engl J Med 2008; 358: 36-46 • Capecitabin p.o. can substitute for i.v. 5-FU Gepoolte analysis: shows higher efficacy Kang et al. Ann Oncol 2009; 20: 666-673 Cunningham et al. N Engl J Med 2008; 358: 36-46 Okines et al. Ann Oncol 2009 [ePub ahead of print] • A 3rd drug (triplet) increases the activity and certainly the toxicity Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7 Wagner et al. J Clin Oncol 2006; 24: 2903-9 1ST-LINE CHEMOTHERAPY Doublet or Triplet? Docetaxel-CF (DCF) vs CF Response Rate 37% vs 25% p=0.01 Time to progression 5.6 vs 3.7 months p<0.001 Survival 9.2 vs 8.6 months p=0.02 Grade 3 /4 Toxicity 69% vs 59% p=0.02 Van Cutsem et al. J Clin Oncol 2006;24:4991–4997 1ST-LINE - JAPAN Doublet or Triplet? Yamada Y et al. Lancet Gastroenterol 2019;4:501–510 1ST-LINE - JAPAN Doublet or Triplet? Yamada Y et al. Lancet Gastroenterol 2019;4:501–510 1ST-LINE - ELDERLY Doublet or Triplet? FLOT 65+ Study (n=142, median 70 years) Progression-free survival among patients with metastatic disease Toxicity Grade 3/4 FLOT: 81.9% FLO: 38.6% (p<0.001) Deterioration on PFS EORTC Global Health Scale >10 points FLOT: 47.5% FLO: 20.5% (p<0.01) EORTC, European Organisation for Research and Treatment of Cancer; FLO: 5FU-Leucovorin-Oxaliplatin; FLOT: 5FU-Leucovorin-Oxaliplatin-Docetaxel. Al-Batran S et al., Eur J Cancer 2013;49:835–842 1ST-LINE – PLATINUM-FREE The Role of Irinotecan Time to treatment failure Time to treatment failure better with FOLFIRI but Overall survival equal: 9.5 vs. 9.7 months (p=0.95) N = 416 FOLFIRI versus ECX first-line Guimbaud R et al. J Clin Oncol 2014;32:3520–3526 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE – ELDERLY PATIENTS GO2 Study - Full or Reduced Dose Chemotherapy? Hall P et al., ASCO 2019; #4006 1ST-LINE CHEMOTHERAPY FOR ADVANCED GC Conclusions . 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 Lordick F et al. Gastric Cancer. 2014 Apr;17(2):213-2 ADVANCED GASTRIC CANCER Second-line Therapy 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER Recommended Algorithm Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016;13:348–360 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER Randomized Controlled Trials Study Drug Overall survival, months Improvement 1 Thuss-Patience Irinotecan 4.0 vs. 2.4 HR 0.48 AIO Study, Germany vs. BSC (p=0.012) ∆ 1.6 months (n=40) 2 Irinotecan or Kang 5.3 vs. 3.8 HR 0.657 Docetaxel Korean Study (p=0.007) ∆ 1.5 months (n=202) vs. BSC 3 Ford Docetaxel 5.2 vs. 3.6 HR 0.67 COUGAR-02, UK vs. BSC (p=0.01) ∆ 1.6 months (n=168) 4 Hironaka Paclitaxel 9.5 vs. 8.4 HR 1.13 WJOG, Japan vs. Irinotecan (p=0.38) No difference (n=219) 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. 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER Survival, Symptom Control, and Quality of Life Health-related QoL outcomes Overall survival Ford HER et al. Lancet Oncol 2014;15:78–86 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER Randomized Controlled Trials Study Drug Overall survival, months Improvement 1 Thuss-Patience Irinotecan 4.0 vs. 2.4 HR 0.48 AIO Study, Germany vs. BSC (p=0.012) ∆ 1.6 months (n=40) 2 Irinotecan or Kang 5.3 vs. 3.8 HR 0.657 Docetaxel Korean Study (p=0.007) ∆ 1.5 months (n=202) vs. BSC 3 Ford Docetaxel 5.2 vs. 3.6 HR 0.67 COUGAR-02, UK vs. BSC (p=0.01) ∆ 1.6 months (n=168) 4 Hironaka Paclitaxel 9.5 vs. 8.4 HR 1.13 WJOG, Japan vs. Irinotecan (p=0.38) No difference (n=219) Fuchs 5 Ramucirumab 5.2 vs. 3.8 HR 0.776 REGARD, Global vs BSC (p=0.047) (n=335) ∆ 1.4 months 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 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER Anti-Angiogenic Treatment Clarke JM et al. Expert Opin Biol Ther 2013;13:1187–1196 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER Rainbow – 2nd-line paclitaxel +/- ramucirumab Overall survival RAM + Placebo + HR paclitaxel paclitaxel p-value Pac-ramucirumab Response rate 28% 16% p=0.0001 PFS (med, months) 4.4 2.9 HR 0.635 9-month PFS (%) 22% 10% p<0.0001 Pac-placebo OS (med, months) 9.6 7.4 HR 0.807 12-month OS (%) 40% 30% p=0.0169 Wilke H et al.Lancet Oncol 201415:1224–1235 2ND-LINE TREATMENT ADVANCED GASTRIC CANCER RAMIRIS: Ramucirumab + FOLFIRI vs Ramucirumab + Paclitaxel Lorenzen S et al., ASCO 2019; abstract 4023 2ND-LINE CHEMOTHERAPY FOR ADVANCED GC Conclusions . 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 CANCER Third-line Therapy 3RD-LINE CHEMOTHERAPY FOR ADVANCED GC TAS-102 = Trifluridin (FTD) + Tipiracil (TPI) Fluorinated Thymidine Inhibits Thymidine-Phosphorylase2 Incorporation into DNA1 Prolongs FTD degradation2 DNA Dysfunction1 + FTD 1:0.5 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 3RD-LINE CHEMOTHERAPY FOR ADVANCED GC TAGS Study BID, twice daily; DCR, disease control response; FTD/TPI, trifluridine/tipiracil; QOL, quality of life Shitara K et al. Lancet Oncol. 2018;19:1437–1448 3RD-LINE CHEMOTHERAPY FOR ADVANCED GC TAGS Study – Baseline Demographics Patient characteristic FTD/TPI (n=337) Placebo (n=170) Age, years; median (range) 64.0 (24–89) 62.5 (32–82) Gender, % Male 75 69 Geographic region, % Japan 14 16 ROW 86 84 ECOG PS, % 0 36 40 1 64 60 Primary site, % Gastric 71 72 GEJ 29 28 Prior gastrectomy, % Yes 44 44 Number 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 Shitara K et al.