Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX)in 1st line metastatic gastric cancer.

Final results from a multicenter phase II studyof the AIO upper GI study group.

F. Lordick1, S. Lorenzen1, S. Hegewisch-Becker2, G. Folprecht3,E. Wöll4, T. Decker5, E. Endlicher6, N. Röthling7, F. Fend1, C. Peschel1

1 Klinikum rechts der Isar, Technische Universität München, Munich, Germany2 Onkologische Schwerpunktpraxis Eppendorf, Hamburg, Germany 3 Universitätsklinikum Carl Gustav Carus, Dresden, Germany 4 Krankenhaus St. Vinzenz, Zams, Austria 5 Onkologische Schwerpunktpraxis Ravensburg, Germany 6 Klinikum der Universität Regensburg, Germany 7 Center for Clinical Studies, Munich, Germany

Phase II according to Simon‘s two stage optimal designNull hypothesis: 30% response; alternative hypothesis: 50%Inclusion of 15 patients in stage 1.If > 6 responders in stage 1, continuation of accrualto a minimum of 46 patients (= 0.05; 1-=0.80).

Endpoints:- Response rate (according to RECIST)Secondary:- Toxicity (according to NCI.AE reporting system, version 3.0)- Time to progression (time from inclusion to tumor progression)- Overall survival (time from inclusion to death of any cause)

7 active study sitesEnrollment of 52 patients from 04/2005 - 03/2006

Study design

Histologically proven adenocarcinoma of the stomach or esophago gastric junction ECOG performance status 0-2 Metastatic disease Measurable disease No prior malignancy (except in situ carcinoma of the cervix, basal or squamous cell carcinoma of the skin) No prior chemotherapy for metastatic disease. Perioperative CTx allowed, if stopped > 6 months prior to inclusion into this trial No CNS metastases No peripheral neuropathy > grade 2 No serious concomitant illness and organ dysfunction Written informed consent Age > 18 years

Main eligibility criteria

Infusion days: 1, 8, 15, 22; qd 36

*Cetuximab 400 mg/m2 at first infusion followed by 250 mg/m2

Cetuximab was given also on day 29 of each cycle

Treatment regimen

LVLV200 mg/m200 mg/m22

LVLV200 mg/m200 mg/m22

OxaliplatinOxaliplatin50 mg/m50 mg/m22

OxaliplatinOxaliplatin50 mg/m50 mg/m22

5-FU 2,000 mg/m5-FU 2,000 mg/m22 via 24-h via 24-h IInfusionnfusion5-FU 2,000 mg/m5-FU 2,000 mg/m22 via 24-h via 24-h IInfusionnfusionCetuximabCetuximab

250250 mg/m mg/m2 2 **CetuximabCetuximab

250250 mg/m mg/m2 2 **

- 2 0 2 2426 hours

Patients‘ characteristics (I)

Age median 63 years (38-80)

Gender female 13 pts.male 39 pts.

ECOG-PS* 0 19 pts.1 25 pts.2 8 pts.

* ECOG-PS indicates Performance Status according to the Eastern Cooperative Oncology Group

Primary tumor localizationEsophago-gastric junction 25 pts. (48%)Stomach 27 pts. (52%)

StageMetastatic 52 pts. (100%)

Prior therapySurgery 26 pts. (50%)Chemotherapy (adjuvant/neoadjuvant) 12 pts. (23%)Radiation (adjuvant) 3 pts. (6%)

Patients‘ characteristics (II)

Sites of disease

Site N (%)

Primary tumor 26 (50%)

Lymph nodes 45 (86%)

Liver 23 (46%)

Peritoneum 16 (31%)

Lung 9 (17%)

Bone 4 (8%)

Other sites 5 (10%)

Median number of sites/patient: 3 (range 1-5)

60-day-mortality rate: 9.6% (5 pts.)*

Tumor-related: 3 pts (5.8%)All three pts. died from rapid tumor progression:2 in extracerebral sites and 1 in the CNS

Treatment-related: 2 pts (3.8%) 1 pt. died from septic shock (febrile neutropenia and diarrhea) 1 pt. died 2 weeks after he had suffered an allergic shock and aspiration during the first cetuximab infusion followed by pneumonia. He had been premedicated with an anti-histamine and dexamethasone

*The 60-day mortality rate in the previously published phase II study evaluating FUFOX without cetuximab in metastatic gastric cancer was 4.2% (Lordick et al., Brit J Cancer 2005; 93: 190-194).

Safety

Patients completed median 2 cycles (cy) of chemotherapy (range 0-8)

The median duration of study treatment was 10 weeks (range 0-42)

Feasibility

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Adverse events °1/2 (NCI.AE) ( > 5% of 51 evaluable pts.)

Grade 1 (n) Grade 2 (n) Grade 1/2 (%)

Anemia 32 10 42 (82%)

Neutropenia 17 6 23 (45%)

Thrombocytopenia 13 2 15 (29%)

Diarrhea 13 13 26 (51%)

Nausea 21 7 28 (54%)

Emesis 10 5 15 (29%)

Sensory neuropathy 17 16 33 (65%)

Fatigue/Asthenia 14 16 30 (59%)

Alopecia 7 2 9 (18%)

Hand-foot syndrome 8 8 16 (31%)

Skin rash 15 18 33 (65%)

Adverse events grade °3/4 (NCI.AE)

Grade 3 (n) Grade 4 (n) Grade 3/4 (%)

Anemia 0 0 0 (0%)

Neutropenia 2 1 3 (6%)

Febrile neutropenia 0 1 1 (2%)

Thrombocytopenia 0 1 1 (2%)

Diarrhea 14 3 17 (33%)

Nausea 3 0 3 (6%)

Emesis 0 0 0 (0%)

Sensory neuropathy 2 0 2 (4%)

Fatigue/Asthenia 5 0 5 (10%)

Hand-foot syndrome 3 0 3 (6%)

Skin rash 12 0 12 (24%)

Discontinuation of study treatment

Reasons for stopping study treatment

Progression 17 pts (33%)Good response (investigators recommendation) 13 pts (25%)Toxicity / adverse event 8 pts (15%)Patient‘s decision 6 pts (11%)Early death 5 pts (10%)Resection (with no further postop. treatment) 2 pts (4%)Deterioration of general condition 1 pt (2%)

Only 33% received treatment until disease progression as indicatedin the study protocol. Early treatment discontinuation was decided dueto a variety of other reasons.

Best response (RECIST; centrally reviewed)(evaluable in 46 patients)

Complete response (CR) 4 8.7Partial reponse (PR) 26 56.5Stable disease (SD) 8 17.4Progressive disease (PD) 8 17.4

Overall response rate (ORR) 30 65.2

n %

Response

95% CI [49.8–78.6]

Confirmed responses (RECIST) 18 39.1

Disease stabilization rate 38 74.595% CI [60.5–85.7]

Time to tumor progression (TTP)

24181260

months

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TTP

Median 7.6 months95% CI 5.0-10.1 months

Mean 8.5 monthsSD +/- 1.0 months

Overall survival (OS)

24181260

months

100

80

60

40

20

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Su

rviv

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%]

OS

Median 9.5 months95% CI 7.9-11.1 months

Mean 10.6 monthsSD +/- 1.0 months

EGFR Immunohistochemistry (ICH)

Central testing for EGFR is available in 42 patientsDefinition for positivity: detection of EGFR in >1% of the tumor cells; with faint,moderate or intense staining intensity.

Positive staining for EGFR 25 pts. 59.5%

Outcome according to EGFR-IHC detectable non-detectableOverall response (ORR) 54.2% 76.5%Disease stabilization (SD+PR+CR) 79.2% 82.4%Time to progression (TTP) 7.0 mon 9.4 monOverall survival (OS) 8.1 mon 9.9 mon

Secondary treatments

Secondary tumor resections 3 pts (6%)(primary tumor with or without metastases)

Second-line chemotherapy 13 pts (25%) - Taxanes (single agent or combination 3 pts - Irinotecan (singe agent or comination) 7 pts - Alternative Platin-fluoropyrimidine combination 3 pts

Secondary radiation 0 pts (0%)

These phase II results indicate that in metastatic

gastric cancer Cetuximab plus FUFOX 1st-line

Is a feasible regimen leading to expected toxicities Has a promising activity:

The ORR (65.2%) is higher than expected as expressed

by the alternative study hypothesis which was set to 50% Is associated with a very promising time to progression:

The TTP of 7.6 months compares favorable to TTP‘s

obtained with conventional chemotherapy regimens Is active independent of the detectability of EGFR by IHC

Discussion (I)

The overall survival of 9.5 months is not superior

compared to what has been achieved with other

regimens. It has to be taken into account that:

Patient selection was on the unfavourable side with

- altered performance status in 63%

- liver involvement in 46% and peritoneal disease in 31%

- high tumor burden (median number of involved sites 3)

- prior adjuvant or neoadjuvant chemotherapy in 23% Only every fourth patient received 2nd line chemotherapy

Discussion (II)

Conclusion

Cetuximab plus a platin-fluoropyrimidine combination

deserves further investigation in phase III