Phase II study of Erbitux, CisPlatin, Epirubicin, Leucovorin with UFT (E-PELUF) as neoadjuvant

treatment in patients with gastric cancer

Dr Efraim Idelevich MD, PhDGastro-intestinal Oncology Unit

Institute of OncologyKaplan 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

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)

Day 1 8 15 21 28

1-week rest period

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)

Idelevich E, et al. Acta Oncol 2007; 46(3):324-329

All patients received ondansetron and dexamethasonefor prevention of emesis before administration ofcisplatin and epirubicin

Cycles repeated every 4 weeks until disease progression, unacceptable toxicity, or patient refusal of further treatment

PELUF in MGC: Efficacy

Idelevich E, et al. Acta Oncol 2007;46:324-329

Responsen=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]

PELUF in MGC: Tolerability

Adverse event Grade 3 Grade 4 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%)

6 (3%)

2 (1%)

0 (0)

0 (0)

0 (0)

0 (0)

6 (15%)

4 (10%)

2 (5%)

1 (3%)

3 (8%)

3 (8%)

2 (5%)

4 (10%)

4 (10%)

1 (3%)

0 (0)

0 (0)

0 (0)

0 (0)

Idelevich E, et al. Acta Oncol 2007;46(3): 324-329

Cycles with adverse events

n (%) (n=196)

Patients with adverse events

n (%) (n=39)

No hand–foot syndrome was reported

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

RegimenResponse

rateMedian 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%

1. Pinto C, et al. Ann Oncol 2007;18:510–517

PELUF + Erbitux may achieve similar results

MGC: New-generation combinations

RegimenResponse

rateMedian 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

1. Pinto C, et al. Br J Cancer 2009;101(8):1261-1268

PELUF + Erbitux may achieve similar results

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

1. 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

2. 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

3. Idelevich E. unpublished data, GI Oncology Unit, Institute of Oncology, Kaplan Medical Center

E-PELUF regimen (Phase II study). Neoadjuvant CT with CisPlatin, Epirubicin, oral UFT & Leucovorin and Erbitux for resectable gastric and EGJ Cancer

Day 1 8 15 21 28Day 1 Erbitux Day15 Erbitux

1-week rest period

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)

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

Characteristic Value

No. of evaluable patients Median age, years (range)Male / female, n (%)ECOG performance status, n (%)

01

Weight loss n (%) 0-5 kg > 5-10 kg > 10 kgClinical staging, n (%) T3 N0 T2 N1 T3 N1K-RAS status n (%)WildMutatedB-RAF status n (%)WildMutatedHER2 status n (%)Positive (+3)Negative

2964.7 (45–80)

20 (69%) / 9 (31%)

6 (20%)23 (80%)

5 (17%)

22 (76%) 2 (7%)

2 (7%) 1 (3%)

26 (90%)

16 (89%) 2 (11%)

16 (89%) 2 (11%)

1(6%) 17 (94%)

CClinical statClinical staging assessments included endoscopy&biopsy, endoscopic ultrasonography (EUS), computed tomography scan of chest&abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET)

Objective response

ResponseNo. 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).

Tolerability

Adverse event Grade 3 Grade 4

Skin rash

Neutropenia

Anemia

Thrombocytopenia

Diarrhea

Nausea

Vomiting

Mucositis

Hypomagnesemia

Perforation

20

14

4

3

7

14

7

7

10

0

0

6

3

0

3

0

0

0

0

3

Patients with adverse events NCI-CTCAE grade% (n=29)

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

n (%) 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)

-

0

0

4 (14)

3 (11)

15 (54)

1(4)

1 (4)

4 (13)

StagePre-treatmentb Post-treatmentc

aStage grouping according to the International Union Against Cancer, 5 th 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.