Systemic treatment in early and advanced gastric cancer

Transcription

1 Systemic treatment in early and advanced gastric cancer Andrés Cervantes Professor of Medicine

2 Classical approach to localised gastric cancer n Surgical resection n Pathology assessment and estimation of risk n Treatment based upon classical TNM stage n Postoperative chemotherapy of doubtful versus no value n Postoperative chemoradiation

3 Meta-analysis of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer-1 Meta-analysis Year No. trials No. pts Odds Ratio 95% CI Conclusions Hermanns (1) J Clin Oncol No benefit Earle (2) Eur J Cancer Small survival benefit In N+ patients Mari (3) Ann Oncol Small survival benefit Janunger (4) Eur J Surg Western Very heterogeneous group of trials Asian Hermanns J et al. J Clin Oncol, 1993, vol11, no 8, Earle CC et al. Eur J Cancer 1999; 35 (7): Mari e et al. Ann Oncol 2000; 11(7): Janunger KG et al. Eur J Surg 2002; 168(11):

4 Meta-analysis of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer-2 Meta-analysis Year No. trials No. pts Odds Ratio 95% CI Conclusions Zhao et al. (1) Cancer Investigation Liu et al. (2) Eur J Surg Oncol Marginal, though significant benefit P: Marginal, though significant benefit P< Gastric Group (3) JAMA P< Zhao SL et al. Cancer Invest. 2008;26: Liu TS, et al. Eur J Surg Oncol 2008;34: The Gastric Group. Jama 2010: 303:

5 Why has adjuvant chemotherapy failed to show any positive effect after surgery in gastric cancer? n Non standard surgery n High risk of local relapse n Chemotherapy nor very active in advanced disease: Complete response rate less than 10% n Heterogeneous samples, low size samples, most patients n- n Inadequate statistical design n Prolonged and slow accrual

6 Meta-analysis of individual data of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer n Overall survival estimate after any chemotherapy or surgery alone truncated at 10 years Any chemotherapy Surgery alone Survival (%) Log-rank P< Time from randomisation (years) No. at risk Any chemotherapy Surgery Redrawn from The Gastric Group. JAMA 2010;303:

7 Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy versus surgery alone: 5-year follow-up of a randomised phase III trial Noh SH, et al. Lancet Oncol 2014;15: , (2014), with permission from Elsevier

8 Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy versus surgery alone: 5-year follow-up of a randomised phase III trial Noh SH, et al. Lancet Oncol 2014;15: , (2014), with permission from Elsevier

9 Study design The role of radiation in the postoperative setting: Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial SURGERY NO TREATMENT STRATIFICATION T 1 4 NODES 0, 1 3, >3 CT+ CT-RT + CT MacDonald JS, et al. N Engl J Med 2001;345:

10 Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial MacDonald JS, et al. N Engl J Med 2001;345: Copyright (2001) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

11 Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial MacDonald JS, et al. N Engl J Med 2001;345: Copyright (2001) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

12 Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: Long term data of a randomised Phase III Trial Smalley S, et al. J Clin Oncol 2012;30: Reprinted with permission. (2012) American Society of Clinical Oncology. All rights reserved.

13 The role of Radiation in the Postoperative Setting Adjuvant Cisplatin and Capecitabine versus Chemoradiation for Gastric Cancer after Surgery: A Randomized phase III Trial Park SH, et al. J Clin Oncol 2015; 33:

14 The role of radiation in the postoperative setting: Adjuvant cisplatin and capecitabine versus chemoradiation for gastric cancer after surgery: A randomised Phase III Trial Lee J, et al. J Clin Oncol 2012;30: Reprinted with permission. (2012) American Society of Clinical Oncology. All rights reserved.

15 The role of Radiation in the Postoperative Setting Adjuvant Cisplatin and Capecitabine versus Chemoradiation for Gastric Cancer after Surgery: A Randomized phase III Trial Park SH, et al. J Clin Oncol 2015; 33:

16 The role of radiation in the postoperative setting: Adjuvant cisplatin and capecitabine versus chemoradiation for gastric cancer after surgery: A randomised Phase III Trial Park SH, et al. J Clin Oncol 2015; 33:

17 Localised gastric cancer: Aims of neoadjuvant therapy n To increase R0 resection rate n Early treatment of micrometastaes n To reduce locoregional relapses n Biological studies

18 Study design Eligible patients: Adenocarcinoma of the stomach or lower third of the oesophagus (from 1999), suitable for curative resection Non-metastatic disease Stage II or greater Study entry and randomisation S arm N=253 CSC arm N=250 Primary Overall survival Secondary Progression-free survival Surgical resectability Quality of Life Chemotherapy (ECF): Epirubicin 50 mg/m 2, IV day 1 Cisplatin 60 mg/m 2, IV day 1 5-FU 200 mg/m 2 /day, continuous infusion, days 1-21 (cycles repeated every 3 weeks) Recruitment: July 1994-April 2002 Cunningham D, et al. N Engl J Med 2006;355:11 20 Surgery Pre-operative chemotherapy: ECFx3 Surgery 3-6 weeks 6-12 weeks Post-operative chemotherapy: ECFx3

19 MAGIC Trial results PFS* Overall Logrank p-value = Hazard Ratio = 0.66 (95% CI ) Logrank p-value = Hazard Ratio = 0.75 (95% CI ) EventsTotal CSC S Months from randomisation 2 year survival 5 year survival Median survival CSC 50% 36% 24 mo S 41% 23% 20 mo Benefit to CSC arm 9% 13% 4 mo n n EventsTotal CSC S Months from randomisation On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender Hazard ratio for death n Adjusted: 0.74 (95%CI: ) n Unadjusted: 0.75 Cunningham D, et al. N Engl J Med 2006;355: Copyright (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

20 Summary of trials of perioperative chemotherapy for localised gastric cancer Trial CT No. pts control No. pts CT 5-year survival control 5-year survival CT HR (CI at 95%) Cunningham N Eng J Med 2006 ECF 253 No CT % 36 % p=0.009 Ychou J Clin Oncol 2011 CDDP 5-FU 111 No CT % 38% p= Cunningham D, et al. N Engl J Med 2006;355:11 20; 2. Ychou M, et al. J Clin Oncol 2011;29:

21 Neoadjuvant chemotherapy in gastric cancer: Conclusions n Perioperative chemotherapy: n Induces downstaging n May increase the R0 resection rate n Prolongs disease free survival n Improves overall survival n Evidence level I based upon 2 well designed and properly conducted randomised trials n Preoperative therapy is better tolerated than postoperative n Localised gastric cancer requires a multidisciplinary team approach n Further research on biological predictive factors is needed n Radiotherapy should be considered experimental

22 Currently recommended approach to localised gastric cancer n Clinical assessment and staging n Multidisciplinary team discussion n Preoperative treatment in all patients with clinical stage II and III n Surgical resection after chemotherapy n Pathology assessment and estimation of risk n Postoperative chemotherapy if tolerated n Participation in trials

23 Treatment for localised gastric cancer: What is standard of care? n Algorithm for the management of gastric cancer Gastric cancer (adenocarcinoma) Operable Stage T1N0 Preferred pathway Operable Stage >T1N0 Consider endoscopic/ limited resection Preoperative chemotherapy Surgery Surgery Adjuvant chemoradiation Adjuvant chemotherapy Post-operative chemotherapy Waddell T, et al. Ann Oncol 2013;24 (Suppl 6): By permission of T. Waddell and Oxford University Press/on behalf of ESMO

24 Treatment for localised gastric cancer: Relevant experimental questions n The addition Bevacizumab in the neoadjuvant treatment of gastric cancer n Should Docetaxel-based scheduled should be used in the neoadjuvant treatment of gastric cancer n The addition of Radiotherapy in the neoadjuvant treatment of gastric cancer

25 ST03 TRIAL DESIGN MAGIC-Bevacizumab Histologically confirmed, resectable (MDT review) stage Ib-IV adenocarcinoma of the lower oesophagus, OGJ or stomach Randomised 1:1 Chemotherapy regimens 21-day cycles ECX ECX 3 cycles ECX + Bevacizumab ECX + Bevacizumab 3 cycles ECX - Epirubicin 50mg/m 2 IV on day 1 - Cisplatin 60mg/m 2 IV on day 1 - Capecitabine 1250mg/m 2 PO daily Surgery 5-6 week break 6-10 week break Surgery ECX + Bevacizumab -Bevacizumab 7.5mg/kg IV on day 1 added to each ECX cycle ECX 3 cycles ECX + Bevacizumab 3 cycles Maintenance Bevacizumab 6 doses

26 ST03 MAGIC-Bevacizumab OVERALL SURVIVAL n 472 deaths (233 ECX, 239 ECX+B) have been observed N ECX ECX+B n Median follow-up is 33 months in both arms Time from randomisation (months) ECX ECX+B Median OS Overall survival ECX ECX+ B months months Hazard Ratio (95% CI) ( to 1.279) Log-rank p-value year overall survival (95% CI) ECX ECX+B 48.9% (43.6% to 53.8%) 47.6% (42.3% to 52.7%)

27 FLOT4 Study Design Gastric cancer or adenocarcinoma of the gastroesophageal junction type I-III Medically and technically operable stages T2-4, every N, M0 or every T, N+, M0 S T R A T I F I C A R T I O N R n=714 4xFLOT - OP - 4xFLOT FLOT: docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, every two weeks 3xECF(X) - OP - 3xECF(X) ECF(X): Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided into two doses d1-d21), every three weeks Primary endpoint Phase II (n=300): rate of complete pathological remission (pcr) Primary endpoint for phase III (n=714): OS, HR 0.76, power 80%, two sided p<0.05

28 Pathological Remission with ECF/ECX vs. FLOT Central Evaluation, ITT group* Pathological regression ECF/ECX n(%) N=137 FLOT n(%) N=128 P-Value (2-sided) Complete (pcr) 8 5, ,6.015 Subtotal (psr) 23 16, ,1 pcr+psr 31 22, ,7.015 Partial (ppr) 28 20, ,0 Minor (pmr) 44 32, ,2 No response (pnr) 8 5,8 4 3,1 Not resectable 26 19,0 9 7,0 *primary Endpoint phase II STO3 (ITT) 5.4%

29 Schema

30 Treatment for advanced gastric cancer: What is standard of care? ESMO guidelines Inoperable or metastatic Surgery Re-assess Palliative chemotherapy Best supportive care if unfit for treatment HER-2 negative Platinum+ fluorpyrimidinebased doublet or triplet regimen HER-2 positive Trastuzumab + CF/CX Consider clinical trials of novel agents 2 nd line chemo Clinical trials if adequate PS Waddell T, et al. Ann Oncol 2013;24(Suppl 6): By permission of the European Society of Medical Oncology

31 n Based upon superiority trials: n 5-FU n Cisplatin n Docetaxel n Trastuzumab Treatment for metastatic/unresectable gastric cancer: Active agents in first line n Based upon non-inferiority trials n Oxaliplatin n Capecitabine n S1 n Irinotecan Cervantes A, et al. Cancer Treat Rev 2012; 39:60-67

32 Have we made any progress in the treatment of advanced gastric cancer? Transtuzumab + CDDP+ FU or Cape months EOX 5 5-FU + LV + Oxaliplatin (FLO) 4 Capecitabine + Cisplatin (XP) months 10.7 months 10.5 months Docetaxel +Cisplatin + 5-FU months 5-FU monotherapy 1 7 months Best supportive care 1 4 months MEDIAN OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER 1. Wagner A, et al. JCO van Cutsem E, et al. J Clin Oncol 2006;24: Kang YK et al, Ann Oncol 2009; 20: Al Batran SE, et al. J Clin Oncol 2008;26: Cunningham D, et al. N Engl J Med 2008;358: Bang YJ, et al. Lancet 2010;376: EOX: Epirubicin/Oxaliplatin/Capecitabine.

33 FFCD-GERCOR-FNCLCC Phase III Study. FOLFIRI vs ECF in advanced gastric cancer Stratification: n Measurable or not n PS WHO 0-1 or 2 n Adj (R)CT or not n Linitis or not n Cardial or gastric n Center R A: ECX until progression; then FOLFIRI 2d line B: FOLFIRI until progression; then ECX 2d line ECX: D1 = Epirubicin 50 mg/m² (15 min.), Cisplatin 60 mg/m² (1 h); D2 to 15: Capecitabine 1 g/m² x 2/d. D1 = D21. Cumulated dose of Epirubicin < 900 mg/m² (max 18 cures) FOLFIRI: D1 = Irinotecan 180 mg/m² (90 min) + LV 400 mg/m² (2h), 5FU b 400 mg/m², 5FU c.i mg/m² (46h). D1 = D14 n n Objective I: 1 st line Time-to-Treatment Failure (TTF) Objectives II: n PFS, OS, (TTF 2 nd line) n Toxicity n Response rate, QoL* Time between randomisation and: 1/ progression Or 2/ TT discontinuation Or 3/ death Guimbaud R, et al. J Clin Oncol 2014;32:

34 n FFCD-GERCOR-FNCLCC Phase III Study. FOLFIRI vs ECF in advanced gastric cancer Objective II: Response Rate (RR), PFS and OS ECF N=209 FOLFIRI n=207 p value TTF (months) 4.2 5, RR 1 st 39.2% RR 2 nd 10.1% PFS (months) Median range OS (months) Median range % 13.7% n.s Guimbaud R, et al. J Clin Oncol 2014;32:

35 Phase II Study of modified DCF vs DCF plus G-CSF in advanced gastric cancer Stratification: n Measurable or not n Gastric vs GEJ n Center R A: modified DCF B: standard DCF plus G-CSF n n Objective : 6 months-pfs Objectives II: n RR, OS, Toxicity Shah MA, et al. J Clin Oncol 2015;33:

36 Shah MA, et al. J Clin Oncol 2015;33: Phase II Study of modified DCF vs DCF plus G-CSF in advanced gastric cancer

37 Shah MA, et al. J Clin Oncol 2015;33: Phase II Study of modified DCF vs DCF plus G-CSF in advanced gastric cancer

38 Docetaxel + Oxaliplatin + 5FU-LV/Capecitabine TE vs TEF vs TEX Van Cutsem E, et al. Ann Oncol 2015;26:

39 Docetaxel + Oxaliplatin + 5FU-LV/Capecitabine TE vs TEF vs TEX Treatment Patients nr RR % 95% CI PFS months 95% CI OS months 95% CI TE 79 23,1 14,3-34,0 4,50 3,68-5,32 8,97 7,79-10,9 TEX 86 25,6 16,6-36,6 5,55 4,30-6,37 11,30 8,08-14,0 TEF ,9-57,5 7,66 6,97-9,40 14,59 11,7-21,8 Van Cutsem E, et al. Ann Oncol 2015;26:

40 Targeted therapies in first-line treatment for advanced gastric cancer: Summary of Phase III Trials Trial Chemotherapy Biological ToGA 1 AVAGAST 2 EXPAND 3 REAL-3 4 RILOMET-1 5 Cisplatin+5-FU/ capecitabine Cisplatin+ capecitabine Cisplatin+ capecitabine Oxaliplatin+ epirubicin + capecitabine Cisplatin+ epirubiicin+ capecitabine HR OS P value Increase in median survival Trastuzumab months Bevacizumab months Cetuximab months Panitumumab months Rilotumumab Stopped in futility analysis METGASTRIC 6 FOLFOX6 Onartuzumab months 1. Bang YJ, et al. Lancet 2010;376: Van Cutsem E, J Clin Oncol 2012;30 (17): Lordick F, Lancet Oncol 2013;14: Waddell T, Lancet Oncol 2013;14: Cunigham ASCO Shah M. J Clin Oncol 2015;33(15)

41 Targeted therapies against HER2 in advanced gastric cancer: Summary of Phase III Trials on lapatinib TRIAL Chemotherapy backbone Line of therapy number HR OS P value Response rate Increase in median survival ToGA 1 Cisplatin+5-FU/ capecitabine First % vs 37% p= months LOGiC 2 Oxaliplatin/ capecitabine First % vs 39% p= months TyTAN 3 Paclitaxel Second % vs 9% p= months 1. Bang YJ, et al. Lancet 2010;376: Hecht JR, et al. j Clin Oncol 2016; 34: Satoh N, et al. J Clin Oncol 2014; 32:

42 Trial author Gastric cancer: Second line chemotherapy. Trials comparing BSC versus active treatment Year Patients random (n) Treatment Response rate (%) HR OS P value Gain in median survival Thuss-Patience, et al :1 Irinotecan NR SD 58% months Kang, et al :1 Irinotecan Docetaxel NR months Ford, et al :1 Docetaxel NR months 1. Thuss-Patience PC, et al. Eur J Cancer 2011;47: Kang JH, et al. J Clin Oncol 2012;30: Ford HE, et al. Lancet Oncol 2014;15:78 86.

43 Ford HE, et al. Lancet Oncol 2014;15: Gastric cancer second line chemotherapy: Docetaxel vs BSC (COUGAR-02 Trial) is improving survival

44 Gastric cancer: Second line chemotherapy trials comparing BSC versus active treatment 1. Thuss-Patience PC, et al. Eur J Cancer 2011;47: Kang JH, et al. J Clin Oncol 2012;30: Ford HE, et al. Lancet Oncol 2014;15: Otshu A. et al. J Clin Oncol 2013;31: Fuchs CS, et al. Lancet 2014;383: Trial author Year Patients random (n) Treatment HR OS P value Gain in median survival Thuss-Patience, et al Kang, et al Ford, et al Otshu, et al Fuchs, et al : : : : :1 Irinotecan months Irinotecan Docetaxel months Docetaxel months Everolimus months Ramucirumab months

45 Gastric cancer: Second line chemotherapy trials comparing BSC versus active treatment 1. Thuss-Patience PC, et al. Eur J Cancer 2011;47: Kang JH, et al. J Clin Oncol 2012;30: Ford HE, et al. Lancet Oncol 2014;15: Otshu A. et al. J Clin Oncol 2013;31: Fuchs CS, et al. Lancet 2014;383: Trial author Year Patients random (n) Treatment HR OS P value Gain in median survival Thuss-Patience, et al Kang, et al Ford, et al Otshu, et al Fuchs, et al : : : : :1 Irinotecan months Irinotecan Docetaxel months Docetaxel months Everolimus months Ramucirumab months

46 Gastric cancer: Second line and third line trials comparing BSC versus active treatment 1. Thuss-Patience PC, et al. Eur J Cancer 2011;47: Kang JH, et al. J Clin Oncol 2012;30: Ford HE, et al. Lancet Oncol 2014;15: Otshu A. et al. J Clin Oncol 2013;31: Fuchs CS, et al. Lancet 2014;383: Li J, et al. J Clin Oncol 2016; ahead of print. Trial author Year Patients random (n) Treatment HR OS P value Gain in median survival Thuss-Patience, et al Kang, et al Ford, et al Otshu, et al Fuchs, et al Li, et al : : : : : :1 Irinotecan months Irinotecan Docetaxel months Docetaxel months Everolimus months Ramucirumab months Apatinib months

47 Gastric cancer second line treatment: Ramucirumab vs BSC (REGARD Trial) is improving survival Reprinted from Fuchs CS, et al. Lancet Oncol 2014;383:31 39 (2005) with permission from Elsevier

48 Gastric cancer: Second line chemotherapy trials comparing two active treatments Trial author Year Patients (n) Hironaka, et al Wilke et al Treatment Irinotecan vs paclitaxel Paclitaxel+/- ramucirumab HR OS P value Gain in median survival 0.9 months for irinotecam months 1. Hironaka S, et al. J Clin Oncol 2013;31: Wilke H, et al. Lancet Oncol 2014;15:

49 Gastric cancer second line treatment: Addition of ramucirumab to paclitaxel improves overall survival (Rainbow Trial) Wilke HJ, et al. Lancet Oncol 2014;15: (2005) with permission from Elsevier

50 Phase II Study of weekly Paclitaxel +/- Olaparib for second line in advanced gastric cancer Stratification: n ATM Low A: weekly Paclitaxel R B: weekly Paclitaxel plus Olaparib 100 mg bid n Primary end point: PFS n Co-Primary end point: PFS in ATM Low n Secondary end points: OS, OS in ATM Low, Toxicity Bang JY, et al. J Clin Oncol 2015;33:

51 Bang JY, et al. J Clin Oncol 2015;33: Phase II Study of weekly Paclitaxel +/- Olaparib for second line in advanced gastric cancer

52 Bang JY, et al. J Clin Oncol 2015;33: Phase II Study of weekly Paclitaxel +/- Olaparib for second line in advanced gastric cancer

53 Pembrolizumab induces responses in chemorefractory gastric cancer Central review N = 36 a Investigator review N = 39 ORR, % (95% CI) 22.2 (10.1, 39.2) 33.3 (19.1, 50.2) Best overall response, n (%) Complete response b 0 0 Partial response b 8 (22.2) 13 (33.3) Stable disease 5 (13.9) 5 (12.8) Progressive disease 19 (52.8) 21 (53.8) No assessment c 1 (2.8) Not determined d 3 (8.3). Muro K, et al. ASCO GI 2015; Abstract nr.03

54 Classification of gastric adenocarcinoma: Pathology n Intestinal versus diffuse subtypes Lauren P. et al. Acta Pathol Microbiol Scand 1965;64:31 49

55 Classification of Gastric Adenocarcinoma: Pathology n Papillary carcinomas n Tubular carcinomas n Mucinous carcinomas n Poorly cohesive carcinomas WHO Classification of Tumours of the Digestive System 4th Ed.2010 (International Agency for Cancer Research)

56 Comprehensive Molecular Characterization of Gastric omprehensive Adenocarcinoma: Molecular Characterization Molecular platforms of Gastric denocarcinoma: Molecular platforms n Array-based somatic copy number analysis n Whole exome sequencing n Array-based DNA methylation profiling n Messenger RNA sequencing n microrna sequencing n Reverse Phase Protein Array (RPPA) The Cancer Genome Atlas Research Network. Nature 2014; 513:

57 Comprehensive Molecular Characterization of Gastric Adenocarcinoma: Molecular platforms The Cancer Genome Atlas Research Network. Nature 2014; 513:

58 50% 9% 20% 22% The Cancer Genome Atlas Research Network. Nature 2014; 513:

59 Comprehensive Molecular Characterization of Gastric Adenocarcinoma: PI3KCA mutations by subtype The Cancer Genome Atlas Research Network. Nature 2014; 513:

60 Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes Cristescu R, et al. Nat Med 2015; 513:

61 Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes Cristescu R, et al. Nat Med 2015; 513:

62 Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes Cristescu R, et al. Nat Med 2015; 513:

63 Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes Cristescu R, et al. Nat Med 2015; 513:

64 Advanced Oesophago-Gastric cancer: Take-home messages I n Her2 status to be determined in all patients with advanced disease n Trastuzumab to be added if HER2 positive (+++) n Platinum-based chemotherapy as first option, with FOLFIRI as an alternative n Second line chemotherapy also prolongs survival in good PS patients n Ramucirumab as single agent prolongs survival versus BSC n Ramucirumab in combination with paclitaxel improves outcomes over paclitaxel

65 Advanced Oesophago-Gastric cancer: Take-home message II n Most targeted therapies failed in molecularly unselected trials n Immunotherapy (Pembrolizumab) under development with interesting data to be confirmed n Better selection of patients needed in clinical trials n Validation of molecular classification in trials n International cooperation