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  • Lorenzo Fornaro, MD Unit of Medical Oncology 2

    Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori

    Pisa- Italy

    Highlights STOMACH CANCER

    UPDATES and NEWS from the Gastrointestinal

    Cancers Symposium in San Francisco

    Roma, 10-11 Febbraio 2017

  • Agenda

    Palliation of gastric outlet obstruction: surgery or not?

    Pretreated metastatic GC: confirmations (good or not)

    Immunotherapy: a seismic shift in metastatic GC?

    Conclusions

  • Agenda

    Palliation of gastric outlet obstruction: surgery or not?

    Pretreated metastatic GC: confirmations (good or not)

    Immunotherapy: a seismic shift in metastatic GC?

    Conclusions

  • Palliative surgery in patients with GOO

    Fujitani K et al. ASCO GI 2017 (abstr. 6)

    Incurable advanced GC with GOO

    Surgical palliation (total gastrectomy, distal gastrectomy, gastrojejunostomy) [endoscopic stent not allowed]

    Clinical assessment (baseline, 2 weeks, 1 month, 3 months)

    Primary endpoint: Changes in QoL (EuroQol-5D, EORTC QLQ-STO22) Secondary endpoints: Improvement of oral intake (GOOSS) Safety Postoperative OS

  • QoL and GOO: Results

    Fujitani K et al. ASCO GI 2017 (abstr. 6)

  • REGATTA trial

    Fujitani K et al. Lancet Oncol 2016

  • Surgery for all patients with GOO?

    Improvements in systemic therapy

    1st-line CT improves OS and QoL (RR: 35%-40%)

    Early nutritional support

    Endoscopic stent: lower risks and costs, immediate recovery

    No data about long-term outcome

    Selection of patients with better outcome?

    No data about CT regimens

    Is CT-first reasonable after careful prognostic evaluation?

  • Palliative surgery for all patients with mGC?

    Fornaro L et al. (submitted)

  • Palliative surgery for all patients with mGC?

    Fornaro L et al. (submitted)

  • Agenda

    Palliation of gastric outlet obstruction: surgery or not?

    Pretreated metastatic GC: confirmations (good or not)

    Immunotherapy: a seismic shift in metastatic GC?

    Conclusions

  • Ramucirumab efficacy according to age

    Muro K et al. ASCO GI 2017 (abstr. 3)

  • Ramucirumab according to age

    Muro K et al. ASCO GI 2017 (abstr. 3)

  • Ramucirumab safety according to age

    Muro K et al. ASCO GI 2017 (abstr. 3)

  • Ramucirumab safety by age: AESI Gr3

    Muro K et al. ASCO GI 2017 (abstr. 3)

    45 years >45 -

  • Second-line CT: Age not an issue

    Fanotto V et al. Gastric Cancer 2016

    Multivariate analysis ECOG PS LDH level Neu/lympho ratio First-line PFS

  • Still looking for biomarkers

    Fuchs CS et al. Br J Cancer 2016

    No association with efficacy for: VEGFR-2 expression, HER2 status, circulating VEGF-C, VEGF-D, VEGFR-1 and VEGFR-3

    High VEGFR2 group Low VEGFR2 group

  • Agenda

    Palliation of gastric outlet obstruction: surgery or not?

    Pretreated metastatic GC: confirmations (good or not)

    Immunotherapy: a seismic shift in metastatic GC?

    Conclusions

  • ATTRACTION-2

    Kang YK et al. ASCO GI 2017 (abstr. 2)

    Statistics:

    OS from 4 to 6.15 months (HR 0.65)

    power 90%, alpha (1-sided) 2.5%

    Interim analysis: re-assessed sample size from 261 to 328 OS events

  • Phase III nivolumab vs. placebo in 3rd-line

    Kang YK et al. ASCO GI 2017 (abstr. 2)

  • Nivolumab vs. placebo (3rd-line)

    Kang YK et al. ASCO GI 2017 (abstr. 2)

  • Nivolumab vs. placebo (3rd-line)

    Kang YK et al. ASCO GI 2017 (abstr. 2)

  • Nivolumab vs. placebo (3rd-line)

    Kang YK et al. ASCO GI 2017 (abstr. 2)

  • Nivolumab vs. placebo (3rd-line): Safety

    Kang YK et al. ASCO GI 2017 (abstr. 2)

  • Where are we in 3rd-line?

    Li J et al. J Clin Oncol 2016

    Median: 6.5 vs. 4.7 months HR 0.709, 95%CI 0.537-0.937

    Median: 5.8 vs. 4.5 months

    Pavlakis N et al. J Clin Oncol 2016

  • Where are we in 3rd-line?

    Median: 6.5 vs. 4.7 months HR 0.709, 95%CI 0.537-0.937

    Median: 5.8 vs. 4.5 months

    Pavlakis N et al. J Clin Oncol 2016 Vivaldi C et al. Transl Gastroenterol Hepatol (in press)

    Li J et al. J Clin Oncol 2016 Fornaro L et al. J Clin Oncol 2016

  • Phase Ib KEYNOTE-012

    Muro K et al. Lancet Oncol 2016

    Pembrolizumab

    Pembrolizumab 10 mg/kg IV

    q2w

    39 patients (57% 3 lines of CT) ECOG PS 0-1

    Measurable disease RECIST v.1.1

    PD-L1 expression in 1% tumor cells

  • Phase I/II CheckMate-032

    Janjigian YY et al. ASCO Ann Meeting 2016 (abs 4010)

    160 patients EC, GEJC, GC Progressed on CT

    Irrespective of PD-L1 status

    Nivolumab 3 mg/kg Nivolumab 1 mg/kg Ipilimumab 3 mg/kg

    Nivolumab 3 mg/kg Ipilimumab 1 mg/kg

    ORR 14% 26% 10%

    OS rate

    6-month 49% 54% 43%

    12-months 36% 34% NA

    G3-4 AEs 17% 45% 27%

    G3-4 serious AEs 5% 35% 15%

    Stop tx due to tox 5% 22% 12%

  • Selection criteria for immunotherapy?

    Tumor location in the stomach

    GEJ vs. gastric body

    TCGA molecular subgroups

    MSI and EBV

    Target expression

    PD-L1+

  • Selection criteria for immunotherapy?

    Tumor location in the stomach

    GEJ vs. gastric body

    TCGA molecular subgroups

    MSI and EBV

    Target expression

    PD-L1+

    Not mutually exclusive

    Regional differences

    Tumor vs. host factors

    Single biomarker unlikely

  • Selection for immunotherapy: Clinics not enough

    Kang YK et al. ASCO GI 2017 (abstr. 2)

  • Dulak AM et al, Cancer Res 2012

    Upper vs. lower GI tumors

  • Cancer Genome Atlas Research Network, Nature 2014

    9%

    22%

    20% 50%

    Gastric cancer: TCGA molecular subgroups

  • Subgroups, MSI, PD-L1/2 and immunotherapy

    Cancer Genome Atlas Research Network, Nature 2014; Le DT et al. N Engl J Med 2015

  • Subgroups, MSI, PD-L1/2 and immunotherapy

    Cancer Genome Atlas Research Network, Nature 2014; Le DT et al. N Engl J Med 2015

  • Chung HC et al, ASCO Ann Meeting 2016 (abstr 4009)

    PD-L1 expression as biomarker?

    Avelumab PFS according to PD-L1 status

  • Cristescu R et al, Nature Med 2015

    Molecular subgroups: East vs. West

  • Immunotherapy in GC: Ongoing trials

    Agent Peri-operative First-line Second-line Third-line

    Ipilimumab (anti-CTLA-4)

    Ph 3 649/648 Nivo+Ipi vs. CT

    Ph 2 Ipi vs. SOC

    Nivolumab (anti-PD-1)

    Phase 3 577 adj. Nivo vs. Placebo

    Ph 3 649/648 Nivo+Ipi vs. CT

    Ph 3 473 Nivo vs. Taxanes

    Ph 2 4538-07 Nivo

    Pembrolizumab (anti-PD-1)

    Ph 3 KEYNOTE062 Pembro vs. Pembro CF vs. CF

    Ph 3 KEYNOTE181 Pembro vs. SOC Ph 3 KEYNOTE061 Pembro vs. Paclitaxel

    Ph 2 KEYNOTE180 Pembro

    Durvalumab (anti-PD-L1)

    Ph 2 maintenance Dur vs. Cape vs. Trast. vs. Observation

    Ph 1b/2 Dur vs. Treme vs. Dur + Treme

    Ph 1b and 2 Dur + Treme

    Atezolizumab (anti-PD-L1)

    Ph2 peri-oper. FOLFOX/FLOT +/- Atezo

    Ph 1 Atezo + Beva +/- CT (HER2-neg.)

    Ph 1 Atezo + Beva +/- CT (HER2-neg.)

    Avelumab (anti-PD-L1)

    Ph 3 JAVELIN 100 Ave vs. CT (maint.)

    Ph 3 JAVELIN 300 Ave vs. SOC

    SOC: standard of care

  • Agenda

    Palliation of gastric outlet obstruction: surgery or not?

    Pretreated metastatic GC: confirmations (good or not)

    Immunotherapy: a seismic shift in metastatic GC?

    Conclusions

  • Conclusions

    Role of palliative surgery in mGC still debated

    Patient first (not symptom)

    Better systemic therapy available: relevance of timing

    Ramucirumab is effective regardless of age

    Established option in 2nd-line

    1st-line trial ongoing

    Immunotherapy may open new ways in metastatic disease

    PD-L1 and MSI: predictive role?

    Monotherapy vs. combinations?

    Setting: upfront CT vs. maintenance vs. pretreated?

  • Thank you!

    lorenzo.fornaro@gmail.com