Download - Highlights STOMACH CANCER - aiom.it Agenda • Palliation of gastric outlet obstruction: surgery or not? • Pretreated metastatic GC: confirmations (good or not) • Immunotherapy:

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

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)

Agenda




• Conclusions

Ramucirumab efficacy according to age

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

Ramucirumab according to age


Ramucirumab safety according to age


Ramucirumab safety by age: AESI Gr≥3


≤45 years >45 - <70 years ≥70 years ≥75 years

Placebo vs. Ram Placebo vs. Ram Placebo vs. Ram Placebo vs. Ram

REGARD 12 vs. 27 68 vs. 165 35 vs. 44 13 vs. 21

Hypertension 0% vs. 3.7% 1.5% vs. 7.3% 5.7% vs. 11.4% 0% vs. 23.8%

RAINBOW 37 vs. 37 224 vs. 224 68 vs. 66 16 vs. 20

Neutropenia 5.4% vs. 24.3% 19.2% vs. 38.8% 25.0% vs. 56.1% 18.8% vs. 55.0%

Febrile neutropenia 0% vs. 0% 3.1% vs. 2.7% 1.5% vs. 6.1% 0% vs. 5.0%

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




• 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


Nivolumab vs. placebo (≥3rd-line)


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


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


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

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




• 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!

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