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


95% LCL 37.5 16.2 12.0

95% UCL 38.6 19.6 17.4

Adults


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


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)


Network Meta-analysis:Treatment versus BSC


Network Meta-analysis:Treatment versus FU


Network Meta-analysis:Different Regimens: OAS


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

Refining The Role of Trastuzumab

Updated TOGA OS

Presented By Ian Chau at 2017 Gastrointestinal Cancers Symposium

Trastuzumab beyond progression


GASTHER 1


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


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

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


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


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.

MANAGEMENTOF METASTATIC OR ADVANCED GASTRIC CANCER : FIRST LINE OPTIONS

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