Matuzumab plus epirubicin, cisplatin and capecitabine (ECX ...

original article

Annals of Oncology 21: 2213–2219, 2010 doi:10.1093/annonc/mdq247 Published online 23 May 2010

Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study S. Rao1, N. Starling1, D. Cunningham1*, K. Sumpter2, D. Gilligan3, T. Ruhstaller4, M. Valladares-Ayerbes5, H. Wilke6, C. Archer7, R. Kurek8, C. Beadman8 & J. Oates1 1 Gastrointestinal Unit, Royal Marsden Hospital, London and Surrey, UK; 2Oncology Department, Newcastle General Hospital, Newcastle, UK; 3Oncology Department, Addenbrooke’s NHS Trust, Cambridge, UK; 4Department of Haematology and Oncology, St Gallen, Switzerland; 5Department of Medical Oncology, Complejo Hospitalario Juan Canalejo, A Corun˜a, Spain; 6Oncology Department, Kliniken Essen-Mitte, Essen, Germany; 7Oncology Department, St Mary’s Hospital, Portsmouth, UK; 8Gastrointestinal Oncology, Merck Serono, Darmstadt, Germany

Received 4 December 2009; revised 19 March 2010; accepted 22 March 2010

epirubicin, cisplatin and capecitabine (ECX) chemotherapy in untreated advanced oesophago-gastric (OG) cancer. The aim was to evaluate the efficacy of matuzumab plus ECX versus ECX alone. Patients and methods: In this multicentre, randomised open-label phase II study, 72 patients with metastatic OG cancer were randomly assigned to either 800 mg matuzumab weekly plus epirubicin 50 mg/m2, cisplatin 60 mg/m2 on day 1 and capecitabine 1250 mg/m2 daily in a 21-day cycle (ECX) or the same ECX regimen alone. The primary end point was objective response. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life, safety and tolerability. Results: Following random assignment, 35 patients (median age 59 years) received ECX/matuzumab and 36 patients (median age 64 years) ECX. The addition of matuzumab to ECX did not improve objective response: 31% for ECX/ matuzumab [95% confidence interval (CI) 17–49] compared with 58% for the ECX arm (95% CI 41–74) P = 0.994 (one sided). There was no significant difference in median PFS: 4.8 months (95% CI 2.9–8.1) for ECX/matuzumab versus 7.1 months (95% CI 4.4–8.5) for ECX, or in median OS: 9.4 months (95% CI 7.5–16.2), compared with 12.2 months (95% CI 9.8–13.8 months). Grade 3/4 treatment-related toxicity was observed in 27 and 25 patients in the ECX/matuzumab and ECX groups, respectively. Conclusion: Matuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer. Therefore, ECX/matuzumab should not be examined further in phase III trials. Key words: advanced, anti-EGFR, chemotherapy, oesophago-gastric cancer, randomised, treatment

introduction Oesophageal and gastric cancer remain a significant health burden and are the second and sixth most common causes of cancer deaths globally [1]. For advanced disease, combination chemotherapy has demonstrated a survival benefit compared with best supportive care [2, 3]. There is no universally accepted standard regimen for chemotherapy-naive advanced oesophago-gastric (OG) cancer. At the time of designing this study, epirubicin, cisplatin and 5-fluorouracil (5FU) (ECF) was *Correspondence to: Prof. D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-661-3156; Fax: +44-208-643-9414; E-mail: [email protected]

a reference regimen in Europe on the basis of two phase III studies and a meta-analysis [4–6]. Furthermore, the interim results from the phase III REAL-2 study [a four-arm study evaluating the substitution of capecitabine for 5FU and oxaliplatin for cisplatin: ECF, EOF, ECX and EOX (E, epirubicin; C, cisplatin; F, 5FU; X, capecitabine; O, oxaliplatin)] had demonstrated acceptable safety profile and encouraging antitumour activity for capecitabine 1250 mg/m2 daily combined with epirubicin and cisplatin (ECX) [7]. The substitution of capecitabine for continuously infused 5FU obviates the need for central venous catheters and their associated complications and is preferable for patients provided efficacy is not compromised [8–10]. Recently, the

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original article

Background: Clinical data showed promising antitumour activity with feasible tolerability for matuzumab plus

original article results from the final analysis of the REAL-2 study reported non-inferiority for capecitabine versus 5FU and oxaliplatin versus cisplatin in terms of overall survival (OS) with acceptable toxicity for all treatment arms. The median OS for the ECX and ECF arms was 9.9.months, with similar toxicity, aside from increased frequency of hand and foot syndrome for ECX [11]. Other cytotoxic combination regimens have been evaluated in phase III studies. The V325 study demonstrated a survival benefit for docetaxel, cisplatin and 5FU (TCF) versus cisplatin and 5FU (median OS 9.2 versus 8.6 months), although TCF was associated with >80% grade 3 and 4 neutropenia [12]. While irinotecan has demonstrated activity in this setting, a randomised study of 333 patients with advanced gastric or oesophago-gastric junction (OGJ) cancer failed to demonstrate a survival benefit for irinotecan combined with 5FU compared with cisplatin/5FU [13]. Thus, further progress is required and newer active regimens are needed to improve the outlook for advanced OG cancer. Epidermal growth factor receptor (EGFR) activation leads to a cascade of signal transduction pathways involved in cell proliferation, angiogenesis, metastasis and invasion [14–17]. EGFR overexpression in 30% and up to 90% of gastric and oesophageal cancers [18–21], respectively, and its association with poorer survival formed the rationale for the combination of matuzumab (a humanised anti-EGFR monoclonal antibody) with ECX chemotherapy in a phase I study which has been previously reported [22]. This demonstrated encouraging activity, acceptable toxicity and inhibition of the EGFR signalling in skin biopsies at the maximum tolerated dose (MTD) of matuzumab 800 mg weekly combined with fixed dose ECX. Therefore, this multicentre randomised phase II study was designed to determine whether the addition of matuzumab 800 mg weekly to the ECX chemotherapy regimen increases efficacy. The primary end point was objective response, as assessed by an independent review committee (IRC). Other planned analyses included progression-free survival (PFS), OS, safety and quality of life (QOL).

patients and methods Patients Patients with histopathologically confirmed metastatic gastric adenocarcinoma or adenocarcinoma of the lower third of the oesophagus who had not received prior chemotherapy for advanced disease underwent screening for intratumoural EGFR expression after initial written informed consent. Only patients with EGFR-positive tumours were enrolled into the study. Other eligibility requirements included radiologically measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0/1, minimum age of 18 years, normal cardiac function (left ventricular ejection fraction within the institutional normal range), a minimum 12-month interval from completion of any neoadjuvant or adjuvant chemotherapy, a minimum 4-week interval from completion of radiotherapy and adequate liver, bone marrow and renal function as defined by alanine aminotransferase/aspartate aminotransferase no greater than 5· the upper limit of normal (ULN), bilirubin 1500 mm3, platelets >100 000/ll, haemoglobin >10 g/dl and serum creatinine 2 Missing Site of metastasis, % Peritoneal Non-peritoneal

ECX, N = 36

69 31

75 25

59 29–79

64 36–76

37 63

33 67

40 60

44 56

100

100

23 46 31 0

25 64 8 3

29 71

25 75

ECX, epirubicin, cisplatin and capecitabine; ECOG, Eastern Cooperative Oncology Group; GOJ, gastric oesophageal junction.

results From August 2005 to November 2006, a total of 72 patients were entered in a randomised trial: 36 were randomly assigned to ECX/matuzumab and 36 to ECX at 22 centres in the UK and Europe. One patient was withdrawn from the study directly after randomisation due to a poor GFR 11 months, possibly reflecting the use of salvage chemotherapy in >40% of patients. EGFR overexpression and the associated correlation with poorer prognosis provided a strong rationale for the use of anti-EGFR therapy combined with chemotherapy in advanced

Figure 1. Kaplan–Meier plot for progression-free survival–independent review committee assessment. Group A: epirubicin, cisplatin and capecitabine. Group B: epirubicin, cisplatin and capecitabine/matuzumab.

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Volume 21 | No. 11 | November 2010

original article

Annals of Oncology

Figure 2. Kaplan–Meier plot for overall survival. Group A: epirubicin, cisplatin and capecitabine. Group B: epirubicin, cisplatin and capecitabine/ matuzumab.

Table 3. Most common grade 3/4 treatment-related adverse events in ITT population Adverse event, n (%) Neutropenia Anaemia Thrombocytopaenia Febrile neutropenia Fatigue/lethargy Nausea Vomiting Diarrhoea Dehydration Palmar plantar erythrodysaesthesia Pulmonary embolism Infection Hypokalaemia Hyperkalaemia Myocardial infarction Dypsnoea Headache Peripheral sensory neuropathy Syncope Skin disordersa Death within 30 daysc

ECX/matuzumab, N = 35 13 2 0 1 7 4 1 2 3 2 3 1 2 1 1 1 1 0

(37) (6) (3) (20) (11) (3) (6) (9) (6) (9) (3) (6) (3) (3) (3) (3)

2 (6) 23b (66) 2 (6)

a

Any grade. Only one grade 3 skin toxicity related to matuzumab. c Death within 30 days after the last study drug administration. ECX, epirubicin, cisplatin and capecitabine. b


ECX, N = 36 12 2 1 2 5 1 1 2 1 3

(33) (6) (3) (6) (14) (3) (3) (6) (3) (8)

1 2 1 1 2 1 1 2

(3) (6) (3) (3) (6) (3) (3) (6)

0 11 (31) 3 (8)

OG cancer [18–21]. Our previous phase I study demonstrated that the MTD of 800 mg matuzumab weekly combined with standard ECX was associated with acceptable toxicity, encouraging antitumour activity and inhibition of EGFR downstream signalling, which led to this study design [22]. One possible explanation for the negative findings in this study was that the optimum biological dose of matuzumab may not have been reached. The MTD for single agent matuzumab is 1600 mg weekly [23] and the established MTD for matuzumab combined with ECX was 800 mg weekly, with dose-limiting toxicity (DLT) of grade 3 lethargy at higher dose levels [22]. Pharmacodynamic data from our phase I study of ECX plus matuzumab demonstrated EGFR abrogation in skin biopsies at all dose levels of matuzumab evaluated with no dose–response relationship [22]. Thus, it is possible that the optimal biological dose of matuzumab when combined with ECX is > 800 mg weekly but this is not feasible to safely administer due to DLT. This is an important consideration when designing end points for future early-phase trials incorporating biologically targeted cytostatic agents where the maximum biologic effect may occur outside the range of the MTD, unlike cytotoxic drugs [24]. Furthermore, skin biopsies may not be an appropriate surrogate for tumour tissue when evaluating pharmacodynamic data and this needs to be examined further in early development studies of biological agents. The alternative explanation for our findings is that disease progression in these tumours was driven by EGFR-independent mechanisms. There were no significant differences in dose intensity between the two ECX regimens. There was no significant difference in QOL between the two groups. The incidence and pattern of toxicity for ECX alone were similar to that

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Annals of Oncology

Table 4. EORTC QLQ-C30 global health status scale, baseline score and best overall change Global health status score

Mean (standard deviation) Minimum; maximum

ECX/matuzumab Baseline, N = 30

Best overall change, N = 21

ECX Baseline, N = 33

Best overall change, N = 32

53.3 (27.3) 0; 100

0.0 (28.1) 233; 75

67.9 (22.4) 25; 100

210.0 (33.9) 283; 50

EORTC, European Organization for Research and Treatment of Cancer; QLQ-C30, quality of life questionnaire version 3.0; ECX, epirubicin, cisplatin and capecitabine.

reported previously [7, 11]. The addition of matuzumab to ECX resulted in a modest increase in the incidence of skin disorders, nausea, hypokalaemia and lethargy. Rash and other skin disorders are well recognised sequelae with the use of antiEGFR monoclonal antibodies [25, 26] and their incidence in this trial was comparable to previous study reports investigating combination chemotherapy regimens plus matuzumab [27, 28]. Hypokalaemia and hypomagnesaemia have been previously reported following the administration of cetuximab and panitumumab and a magnesium-wasting syndrome is postulated to be associated with lethargy [29–31]. Several single-arm phase II studies investigating combination chemotherapy with cetuximab in this setting have reported objective response rates ranging from 40% to 55% [32–34]. A median time to progression of 5.5 months and median OS of 9.9 months was reported for the combination of cetuximab with FOLFOX-6 in advanced gastric cancer [33]. A study of FOLFIRI plus cetuximab achieved an overall response of 44% and median time to progression of 8 months [35]. However, these findings appear comparable to those reported for ECX chemotherapy (overall response rate 46%, median PFS 6.7 months and median OS 9.9 months) and EOX chemotherapy (overall response rate 48%, median PFS 7.0 months and median OS 11.2 months) in the phase III REAL-2 study [11] and TCF chemotherapy (median time to progression 5.6 months, median OS 9.2 months) in the phase III V325 study [12]. A phase II study of erlotinib in advanced OG cancer demonstrated activity in OGJ tumours but no objective responses in gastric tumours [36]. Recently, the addition of trastuzumab to cisplatin/5FU in human epidermal growth factor receptor 2-positive gastric cancer demonstrated a significant survival benefit in a randomised phase III trial [37]. Despite recent advances, the median OS for advanced OG cancer with combination chemotherapy still only approaches 11 months. Thus, there is a need for novel treatment strategies and the clinical benefit of anti-EGFR therapies needs to be established in randomised phase II/III studies utilising optimal chemotherapy regimens as the reference comparator. However, on the basis of the results of this study, matuzumab does not warrant further evaluation in phase III studies in advanced OG cancer.

funding Merck KGaA. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre.

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acknowledgements We would like to thank patients and their families and all participating centres.

disclosure KS, Roche consultant, honoraria and educational activity support; MV-A, Merck Serono consultant, honoraria; RK and CB, employee Merck Serono; DC, consultant Merck; DG, advisor to Roche, honoraria. Research funding from Merck KGaA to MV-A and DC and from Roche to DC.

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