Dr Efraim Idelevich MD, PhD Gastro-intestinal Oncology Unit Phase II study of Erbitux, CisPlatin, Epirubicin, Leucovorin with UFT (E-PELUF) as neoadjuvant treatment in patients with gastric cancer Dr Efraim Idelevich MD, PhD Gastro-intestinal Oncology Unit Institute of Oncology Kaplan Medical Center

Neoadjuvant CT of Gastric & EG Junction Cancer Positive Trials: MAGIC French FNLCC/FFCD trial MRC/OEO2 (British study) Negative Trials: INT 0113 (US study) Dutch trial ERTC trial

Idelevich E, et al. Acta Oncol 2007; 46(3): 324-329 Phase II study of cisPlatin, Epirubicin, LV and UFT (PELUF) as first-line chemotherapy in metastatic gastric cancer Idelevich E, et al. Acta Oncol 2007; 46(3): 324-329

PELUF regimen for Metastatic Gastric Cancer (MGC) Cisplatin 60 mg/m2 and epirubicin 50 mg/m2 iv UFT 300 mg/m2/d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning) 1-week rest period Day 1 8 15 21 28 All patients received ondansetron and dexamethasone for prevention of emesis before administration of cisplatin and epirubicin Cycles repeated every 4 weeks until disease progression, unacceptable toxicity, or patient refusal of further treatment Idelevich E, et al. Acta Oncol 2007; 46(3):324-329

PELUF in MGC: Efficacy Response n=39 Complete response, n (%) Partial response, n (%) Overall response, % [95% CI] Stable disease, n (%) Progressive disease, n (%) TTP (months) MOS (months) 1-year survival rate, % [95% CI] 2 (5) 13 (33) 38 [24-52] 16 (41) 8 (21) 6.5 9.5 36 [21-51] Idelevich E, et al. Acta Oncol 2007;46:324-329

PELUF in MGC: Tolerability Cycles with adverse events n (%) (n=196) Patients with adverse events n (%) (n=39) Adverse event Grade 3 Grade 4 Leukopenia Neutropenia Anemia Thrombocytopenia Diarrhea Nausea/vomiting Mucositis 31 (16%) 27 (14%) 3 (1.5%) 2 (1%) 12 (6%) 15 (8%) 7 (4%) 6 (3%) 0 (0) 6 (15%) 4 (10%) 2 (5%) 1 (3%) 3 (8%) 0 (0) No hand–foot syndrome was reported Idelevich E, et al. Acta Oncol 2007;46(3): 324-329

review The role of UFT in advanced Gastric Cancer Aykan N, Idelevich E Annals of Oncology, Volum 19, 6, June 2008, 1045-1052

MGC: New-generation combinations Regimen Response rate Median OS (months) Adverse events (grade 3/4 >10%) FOLFIRI + Erbitux1 Cetuximab 400 mg/m2 d1 then 250 mg/m2 weekly Irinotecan 180 mg/m2 d1 LV 1000 mg/m2 d1,2 5-FU 400 mg/m2 bolus + 600 mg/m2 CI d1,2 q2w ORR 44% CR 12% TTP 8 mo OS 16 mo (expected) Neutropenia 42% Acne-like rash 21% PELUF + Erbitux may achieve similar results Pinto C, et al. Ann Oncol 2007;18:510–517

MGC: New-generation combinations Regimen Response rate Median OS (months) Adverse events (grade 3/4 >10%) Cispaltin+Docetaxel + Erbitux1 Cetuximab 400 mg/m2 d1 then 250 mg/m2 weekly Cisplatin 75 mg/m2 d1 Docetaxel 75 mg/m2 d1 q3w ORR 41% TTP 5 mo OS 9 mo Neutropenia 44.4% Acne-like rash 21% No toxic death was observed 72 pts PELUF + Erbitux may achieve similar results Pinto C, et al. Br J Cancer 2009;101(8):1261-1268

Mutation detection of K-ras in MGC Of the 52 cancers, K-ras mutations were found in 5 (9.6%).1 The presence of K-ras mutation were found in 13.3% (32pts).2 K-ras mutation were found in 11% of examined specimens.3 Liu ZM et al. Mutation detection of KRAS by high-resolution melting analysis in Chinese with gastric cancer. Laboratory Center, Dalian Medical University, 116027, PR China Park SR et al. Predictive factors for the efficacy of cetuximab plus chemotherpay as salvage therapy in metastatic gastric cancer patients. Center for Gastric Cancer, Research Institute and Hospital, National cancer Center, Republic of Korea Idelevich E. unpublished data, GI Oncology Unit, Institute of Oncology, Kaplan Medical Center

Three cycles repeated every 4 weeks, followed by gastrectomy. E-PELUF regimen (Phase II study). Neoadjuvant CT with CisPlatin, Epirubicin, oral UFT & Leucovorin and Erbitux for resectable gastric and EGJ Cancer Cisplatin 60 mg/m2 and Epirubicin 50 mg/m2 iv, Erbitux 500 mg/m2 UFT 300 mg/m2/d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning) 1-week rest period Day 1 8 15 21 28 Day 1 Erbitux Day15 Erbitux Three cycles repeated every 4 weeks, followed by gastrectomy. Primary study objective: R0 resection rate, following neoadjuvant chemotherapy (PELUF-E) regimen in combination with Erbitux. Secondary study objectives: Safety profile, Overall Survival, Disease Free Interval, Overall Response Rate, Comparison results of this treatment with historical control group of pts, which did not receive neoadjuvant chemotherapy.

E-PELUF : Patient characteristics Value No. of evaluable patients Median age, years (range) Male / female, n (%) ECOG performance status, n (%) 1 Weight loss n (%) 0-5 kg > 5-10 kg > 10 kg Clinical staging, n (%) T3 N0 T2 N1 T3 N1 K-RAS status n (%) Wild Mutated B-RAF status n (%) HER2 status n (%) Positive (+3) Negative 29 64.7 (45–80) 20 (69%) / 9 (31%) 6 (20%) 23 (80%) 5 (17%) 22 (76%) 2 (7%) 1 (3%) 26 (90%) 16 (89%) 2 (11%) 1(6%) 17 (94%) Clinical staging assessments included endoscopy&biopsy, endoscopic ultrasonography (EUS), computed tomography scan of chest&abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET) Clinical stat C

Objective response Response No. of patients (%) (n=29) Complete response Partial response Stable disease Progressive disease 1(4%) 12 (41%) 11 (38%) 5 (17%) Tumor response was assessed after the 3d treatment cycle. Assessments included endoscopy, endoscopic ultrasonography, computed tomography scan of chest and abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET).

Patients with adverse events NCI-CTCAE grade% (n=29) Tolerability Patients with adverse events NCI-CTCAE grade% (n=29) Adverse event Grade 3 Grade 4 Skin rash Neutropenia Anemia Thrombocytopenia Diarrhea Nausea Vomiting Mucositis Hypomagnesemia Perforation 20 14 4 3 7 10 6 One treatment related death observed due to grade 5 neutropenia

Surgery Twenty eight patients underwent surgery. 17 with partial gastrectomy, 8 patients total gastrectomy, three patients with intra-abdominal metastases, recognized at time of surgical exploration, did not undergo resection. Twenty (80%) had an R0 and 5 (20%) had an R1 resection. Postoperative complications occurred in 11 patients (46%). These included wound infection and anastomotic leakage. No patients died during the postoperative period.

Postoperative treatment All 25 “resected” patients received adjuvant therapy: 20 chemotherapy, 5 chemoradiotherapy. Five patients (17%) had metastatic disease (MD). Staging of these 5 (17%) patients were identified as T3N1M0 disease before starting neoadjuvant chemotherapy. Intra-abdominal metastases were diagnosed at time of surgery in 3 patients. In two cases pathological examination identified T3N3(M1) and T3N1M2 diseases. All these 5 patients received palliative chemotherapy.

Pre- and post-treatment stagea Pre-treatmentb Post-treatmentc n (%) T3 N0 M0 T2 N1 M0 T3 N1 M0 T0 N0 M0 T(any)N3 T(any)N(any)M1 2 (7) 1 (3) 26 (90) - 4 (14) 3 (11) 15 (54) 1(4) 1 (4) 4 (13) aStage grouping according to the International Union Against Cancer, 5th edition bStaged by endoscopic ultrasonography, CT scan, (PET FDG) scan cStaged by pathological examination

Survival & Pattern of Disease Recurrence After a median follow-up of 24 months 20 patients (69%) were alive. 9 of whom showed no disease recurrence. No local recurrence (LR) observed in group of patients who underwent R0 resection,1 patient of R1 resection group suffers from LR and systemic metastases,10 patients from metastatic disease. Median overall survival was not reached yet.

Summary & Conclusions The study is still ongoing. Data presented support the role of oral fluoropyrimidines as logical replacement for 5-FU in the treatment of gastric cancer. The biological agents are at the doorstep. The preliminary results of the study show that addition of erbitux to PELUF combination in patients with K-ras wild type gastric cancer has the promising activity.