MANAGEMENTOF METASTATIC OR ADVANCED GASTRIC CANCER : FIRST LINE OPTIONS

Time to Make A Decision: Critical Considerations for 1st Line Therapy

Mohamed Abdulla M.D.

Prof. of Clinical Oncology

Cairo University

Ritz Carlton Hotel, Cairo28/09/2017

Speaker Disclosures:

Member of Advisory Board, Consultant, and Speaker for:

• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen Cilag, Sanofi, MSD, Merck Serono, Novartis, Pfizer, Eli Lilly, Mundipharma.

Basic Facts:

• Decreasing incidence over past decades.• 3rd Leading Cause of Cancer Related Death (2012).• 80% at presentation: advanced, metastatic or recurrent median survival < 1 year. 10 – Year OAS (all stages) 20%.

• Shift from distal to proximal lesions (GEJ) & among whites.

• Surgical resection is the cornerstone in curative management loco-regional failures (40 – 65%).

• East versus West.

Landry et al. Patterns of failure following curative resection of gastric cancer. Int J Ra- diat Oncol Biol Phys 1990;191:1357-62. Jemal etal. Cancer Statistics, 2010. CA Cancer J Clin 2010. Ferlay et al, GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide. IARC CancerBase, accessed 16/12/14. International Agency for Research on Cancer.

Stomach Cancer (C16): 2010-2011One-, Five- and Ten-Year Net Survival (%), Adults Aged 15-99, England & Wales

1-Year Survival (%)

5-Year Survival (%)

10-Year Survival (%)

Men

Net Survival 43.9 19.5 15.3

95% LCL 43.6 18.3 13.3

95% UCL 44.2 20.7 17.3

Women

Net Survival 38.0 17.9 14.6

95% LCL 37.5 16.2 12.0

95% UCL 38.6 19.6 17.4

Adults

Net Survival 41.8 18.9 15.0

95% LCL 41.6 18.0 13.5

95% UCL 42.1 19.9 16.7

Five- and Ten-year survival has been predicted for patients diagnosed in 2010-2011 (using an excess hazard statistical model) 95% LCL and 95% UCL are the 95% lower and upper confidence limits

Please include the citation provided in our Frequently Asked Questions when reproducing this chart: http://info.cancerresearchuk.org/cancerstats/faqs/#HowPrepared by Cancer Research UKOriginal data sources:Survival estimates were provided on request by the Cancer Research UK Cancer Survival Group at the London School of Hygiene and Tropical Medicine. http://www.lshtm.ac.uk/eph/ncde/cancersurvival/

Goals of Systemic Treatment Enhancing Quality of Life

Prolong Survival Parameters

Symptom Palliation

Problems with Gastric Cancer:

Early:

• Indigestion

• Nausea & vomiting

• Dysphagia

• Postprandial fullness

• Loss of appetite

• Hematemesis

• Loss of Weight

Late:

• Peritoneal affection

• Obstruction

• Bleeding

• Evident nutritional deficiency

Poor Performance & Comorbidities

Uptodate.com Accessed 17/08/2017

Changes in Practice Trends:

• HR (OAS) = 0.49.• Survival Advantage = 4.3 to 11 months.• Total Survival with maintained High Quality of Life (69% - 47% P < .05)

Wagner et al. J Clin Oncol 24:2903-2909. 2006Cochrane Data Base Syst Reviews. 2010

Single Agent ActivityOlder Agents

Newer Agents

Uptodate.com Accessed 17/08/2017

Single versus Combined Agents:

Wagner et al. J Clin Oncol 24:2903-2909. 2006Wagner et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010; CD004064.

• Fluoropyremidines & Platinum.• Fluoropyremidines

Monotherapy Combination is not Feasible.

Combination Chemotherapy:1st Line AGC

5-Fu Cisplatin

Capecitabine

Oxaliplatin+

AnthracyclinesDocetaxel/Irinotecan

• Basic Benchmark Duplet.• Substitutions = Variations on Same Melody.• Triplets REAL 2 Study.

5-Fu – Cisplatin =Capecitabine – Cisplatin =5-Fu – Oxaliplatin =Capecitabine – Oxaliplatin

Wagner et al. Cochrane Database Syst Rev 2010; CD004064. Kang et al, Ann Oncol 2009; 20:666-73. Cunningham et al, N Engl J Med 2008; 358:36-46. Okines et al, Ann Oncol 2009; 20:1529-34

1002 AGC Patients

263 = ECF

250 = ECX

245 = EOF

244 = EOXNon - Inferiority

HR = .86

HR = .92

HR = .80P = 0.02

Cunningham et al, N Engl J Med 2008; 358:36-46.

Combination Chemotherapy:1st Line AGC: REAL2 STUDY

Network Meta-analysis:

ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)

ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)

Network Meta-analysis:Treatment versus BSC

ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)

Network Meta-analysis:Treatment versus FU

ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)

Network Meta-analysis:Different Regimens: OAS

ter Veer et al. JNCI J Natl Cancer Inst (2016) 108(10)

Network Meta-analysis:Different Regimens: PFS

Pathogenesis of Gastric Cancer:

Tan & Yeoh. Gastroenterology 2015;149:1153–1162

Trastuzumab Mode of Action:

R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362

Lancet 376:687, 2010

Presented By Jaffer Ajani at 2016 ASCO Annual Meeting

TOGA Trial: Updated Results

R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362

TOGA Trial: Updated Results

R.A. Pazo Cid, A. Antón / Critical Reviews in Oncology/Hematology 85 (2013) 350–362

Refining The Role of Trastuzumab

Updated TOGA OS

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

Trastuzumab beyond progression

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

GASTHER 1

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

Phase IIIB trastuzumab post marketing in AGC trial design (HELOISE)

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

Uptodate.com Accessed 17/08/2017

Do we need a 2nd Line Therapy in Gastric Cancer?

Two pivotal RCTs establishing second- or subsequent-line therapy for gastric cancer

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

Overall survival with second-line chemotherapy in advanced oesophago-gastric cancer: <br />meta-analysis of patient-level data

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

Disease Overview:Angiogenesis:

Hallmark of Malignancy:

Proliferation Invasion Metastases

Treatment FailureApoptosis Resistance

VEGF +

+

TK+

m-TOR

Angiogenic Factors:

Tyrosine Kinase Receptors

VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2

VEGFs

VEGF - A VEGF - B VEGF - C VEGF - D PlGF

Angiogenesis in Gastric Cancer:

Yasuhiko Kitadai. Journal of Oncology Volume 2010, Article ID 468725, 8 pages

Take Home Message:

• No international consensus for the optimal regimen.

• Triplets versus Duplets: Higher response rate & modest survival improvement but with higher toxicity.

• IV and Oral FP are equivalent.

• Platinum Analogues: No superiority over each other.

• Anti-Her 2neu therapy had expanded the therapeutic platform of gastric cancer

• Anti-angiogenic therapy is an emerging keyplayer

• Still we have an unmet need.