Highlights STOMACH CANCER

Transcription

1 UPDATES and NEWS from the Gastrointestinal Cancers Symposium in San Francisco Roma, Febbraio 2017 Highlights STOMACH CANCER Lorenzo Fornaro, MD Unit of Medical Oncology 2 Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori Pisa- Italy

2 Agenda Palliation of gastric outlet obstruction: surgery or not? Pretreated metastatic GC: confirmations (good or not) Immunotherapy: a seismic shift in metastatic GC? Conclusions

3 Agenda Palliation of gastric outlet obstruction: surgery or not? Pretreated metastatic GC: confirmations (good or not) Immunotherapy: a seismic shift in metastatic GC? Conclusions

4 Palliative surgery in patients with GOO 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: Secondary endpoints: Changes in QoL (EuroQol-5D, EORTC QLQ-STO22) Improvement of oral intake (GOOSS) Safety Postoperative OS Fujitani K et al. ASCO GI 2017 (abstr. 6)

5 QoL and GOO: Results Fujitani K et al. ASCO GI 2017 (abstr. 6)

6 REGATTA trial Fujitani K et al. Lancet Oncol 2016

7 Surgery for all patients with GOO? Improvements in systemic therapy 1 st -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?

8 Palliative surgery for all patients with mgc? Fornaro L et al. (submitted)

9 Palliative surgery for all patients with mgc? Fornaro L et al. (submitted)

10 Agenda Palliation of gastric outlet obstruction: surgery or not? Pretreated metastatic GC: confirmations (good or not) Immunotherapy: a seismic shift in metastatic GC? Conclusions

11 Ramucirumab efficacy according to age Muro K et al. ASCO GI 2017 (abstr. 3)

12 Ramucirumab according to age Muro K et al. ASCO GI 2017 (abstr. 3)

13 Ramucirumab safety according to age Muro K et al. ASCO GI 2017 (abstr. 3)

14 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 vs vs vs. 21 Hypertension 0% vs. 3.7% 1.5% vs. 7.3% 5.7% vs. 11.4% 0% vs. 23.8% RAINBOW 37 vs vs vs 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% Muro K et al. ASCO GI 2017 (abstr. 3)

15 Second-line CT: Age not an issue Multivariate analysis ECOG PS LDH level Neu/lympho ratio First-line PFS Fanotto V et al. Gastric Cancer 2016

16 Still looking for biomarkers High VEGFR2 group Low VEGFR2 group No association with efficacy for: VEGFR-2 expression, HER2 status, circulating VEGF-C, VEGF-D, VEGFR-1 and VEGFR-3 Fuchs CS et al. Br J Cancer 2016

17 Agenda Palliation of gastric outlet obstruction: surgery or not? Pretreated metastatic GC: confirmations (good or not) Immunotherapy: a seismic shift in metastatic GC? Conclusions

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

19 Phase III nivolumab vs. placebo in 3 rd -line Kang YK et al. ASCO GI 2017 (abstr. 2)

20 Nivolumab vs. placebo ( 3 rd -line) Kang YK et al. ASCO GI 2017 (abstr. 2)

21 Nivolumab vs. placebo ( 3 rd -line) Kang YK et al. ASCO GI 2017 (abstr. 2)

22 Nivolumab vs. placebo ( 3 rd -line) Kang YK et al. ASCO GI 2017 (abstr. 2)

23 Nivolumab vs. placebo ( 3 rd -line): Safety Kang YK et al. ASCO GI 2017 (abstr. 2)

24 Where are we in 3 rd -line? Median: 6.5 vs. 4.7 months HR 0.709, 95%CI Median: 5.8 vs. 4.5 months Pavlakis N et al. J Clin Oncol 2016 Li J et al. J Clin Oncol 2016

25 Where are we in 3 rd -line? Median: 6.5 vs. 4.7 months HR 0.709, 95%CI Median: 5.8 vs. 4.5 months Pavlakis N et al. J Clin Oncol 2016 Vivaldi C et al. Transl Gastroenterol Hepatol (in Li J et al. J Clin Oncol 2016 Fornaro L et al. J Clin Oncol 2016

26 Phase Ib KEYNOTE patients ( 57% 3 lines of CT) ECOG PS 0-1 Measurable disease RECIST v.1.1 PD-L1 expression in 1% tumor cells Pembrolizumab Pembrolizumab 10 mg/kg IV q2w Muro K et al. Lancet Oncol 2016

27 Phase I/II CheckMate 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% Janjigian YY et al. ASCO Ann Meeting 2016 (abs 4010)

28 Selection criteria for immunotherapy? Tumor location in the stomach GEJ vs. gastric body TCGA molecular subgroups MSI and EBV Target expression PD-L1+

29 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

30 Selection for immunotherapy: Clinics not enough Kang YK et al. ASCO GI 2017 (abstr. 2)

31 Upper vs. lower GI tumors Dulak AM et al, Cancer Res 2012

32 Gastric cancer: TCGA molecular subgroups 9% 22% 20% 50% Cancer Genome Atlas Research Network, Nature 2014

33 Subgroups, MSI, PD-L1/2 and immunotherapy Cancer Genome Atlas Research Network, Nature 2014; Le DT et al. N Engl J Med 2015

34 Subgroups, MSI, PD-L1/2 and immunotherapy Cancer Genome Atlas Research Network, Nature 2014; Le DT et al. N Engl J Med 2015

35 PD-L1 expression as biomarker? Avelumab PFS according to PD-L1 status Chung HC et al, ASCO Ann Meeting 2016 (abstr 4009)

36 Molecular subgroups: East vs. West Cristescu R et al, Nature Med 2015

37 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 adj. Nivo vs. Placebo Ph 3 649/648 Nivo+Ipi vs. CT Ph Nivo vs. Taxanes Ph 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

38 Agenda Palliation of gastric outlet obstruction: surgery or not? Pretreated metastatic GC: confirmations (good or not) Immunotherapy: a seismic shift in metastatic GC? Conclusions

39 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 2 nd -line 1 st -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?

40 Thank you!