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
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?
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 safety by age: AESI Gr≥3
Muro K et al. ASCO GI 2017 (abstr. 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
• 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
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
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
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?