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Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial Florian Lordick, Yoon-Koo Kang, Hyun-Cheol Chung, Pamela Salman, Sang Cheul Oh, György Bodoky, Galina Kurteva, Constantin Volovat, Vladimir M Moiseyenko, Vera Gorbunova, Joon Oh Park, Akira Sawaki, Ilhan Celik, Heiko Götte, Helena Melezínková, Markus Moehler, on behalf of the Arbeitsgemeinschaft Internistische Onkologie (AIO) and EXPAND Investigators*
Summary Lancet Oncol 2013; 14: 490–99 Published Online April 15, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70102-5 See Comment page 440 *Members listed in the appendix University Cancer Center Leipzig, University of Leipzig, Leipzig, Germany (Prof F Lordick MD); Asan Medical Center, Division Oncology Department, Seoul, Korea (Prof Y-K Kang MD); Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea (Prof H-C Chung MD); Fundación Arturo López Pérez, Santiago, Chile (P Salman MD); Department of Oncology, Korea University Guro Hospital, Seoul, South Korea (Prof S C Oh MD); Department of Oncology, St László Hospital, Budapest, Hungary (Prof G Bodoky MD); Specialized Hospital for Active Treatment, Center of Oncology, Sofia, Bulgaria (G Kurteva MD); Centrul de Oncologie Medicala, Iasi, Romania (C Volovat MD); N N Petrov Research Institute of Oncology, St Petersburg, Russia (Prof V M Moiseyenko MD); Russian Cancer Centre, Moscow, Russia (Prof V Gorbunova MD); Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (J O Park MD); Aichi Cancer Center Hospital, Nagoya, Japan (A Sawaki MD); Merck KGaA, Darmstadt, Germany (Prof I Celik MD, H Götte PhD, H Melezínková MD); and University Medical Center of the Johannes Gutenberg University Mainz, First Department of Internal Medicine, Mainz, Germany (Prof M Moehler MD)
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Background Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. Methods In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio) chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m² (on days 1–14) and intravenous cisplatin 80 mg/m² (on day 1), with or without weekly cetuximab (400 mg/m² initial infusion on day 1 followed by 250 mg/m² per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. Findings Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4·4 months (95% CI 4·2–5·5) compared with 5·6 months (5·1–5·7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1·09, 95% CI 0·92–1·29; p=0·32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3–4 adverse events, including grade 3–4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3–4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3–4 skin reactions and acne-like rash was substantially higher in the cetuximabcontaining regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. Interpretation Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. Funding Merck KGaA.
Introduction In 2008, gastric cancer was the second most common cause of death related to cancer worldwide (9·7%).1 Although the overall incidence of gastric cancer is decreasing, the incidence of gastro-oesophageal junction tumours, which have an especially poor prognosis, is increasing. Complete surgical resection of early disease offers a chance for cure, although most patients (80–90%) in high-income non-Asian countries present with either advanced disease or develop a recurrence within 5 years of undergoing curative resection.2 Treatment with combination chemotherapy improves outcomes compared with single-drug chemotherapy or no chemotherapy in patients with advanced gastric cancer.3 With no international standard at present,
first-line chemotherapy regimens commonly used in treatment include a platinum compound (typically cisplatin) in combination with either infusional fluorouracil or an oral fluoropyrimidine (typically capecitabine) or S-1, which is a preferred treatment in Asia.4–6 Despite the development of new chemotherapy regimens, the 5-year survival of patients in this setting is less than 10%, and therefore a high and unmet need exists for efficacious treatment.2 Introduction of biological drugs into treatment strategies has shown promise in this setting. Trastuzumab, a HER2 antibody, in combination with first-line cisplatin and fluoropyrimidine-based chemotherapy significantly improved overall survival in patients with HER2-overexpressing tumours compared with those receiving www.thelancet.com/oncology Vol 14 May 2013
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chemotherapy alone.7 EGFR, part of the family of receptor tyrosine kinases including HER2, is expressed in gastric and oesophageal tumours and is associated with poor prognosis.8,9 Addition of cetuximab (an EGFR antibody) to standard first-line chemotherapy regimens improved clinical outcome in patients with KRAS wild-type metastatic colorectal cancer,10,11 recurrent or metastatic squamous-cell carcinoma of the head and neck,12 and advanced non-small-cell lung cancer.13 Moreover, manageable and expected safety profiles with substantial activity (objective response rates of 41–65%) were reported in phase 2 studies of cetuximab plus various first-line chemotherapy regimens in patients with advanced gastric cancer.14–17 In the randomised international Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) study, we aimed to assess efficacy and safety of addition of cetuximab to first-line capecitabine-cisplatin chemotherapy in patients with unresectable advanced or metastatic gastric adenocarcinoma.
or C; chronic diarrhoea or short bowel syndrome; pregnancy or lactation; legal incapacity or limited legal capacity; and contraindications to study treatment. The study was done according to the principles of the Declaration of Helsinki and the International Conference on Harmonisation on Good Clinical Practice and was approved by local or national ethics committees or institutional review boards. All patients provided written informed consent. A separate data and safety monitoring board, with three independent members in Switzerland, Singapore, and Germany, reviewed study data.
In this open-label study, patients were randomly assigned (1:1) to receive capecitabine-cisplatin with or without cetuximab. Randomisation was done centrally with an interactive voice response system. We used a stratified, permuted, block randomisation procedure (variable block size) with the following strata: disease stage (M0 vs M1),
Study design and participants
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See Online for appendix
Randomisation and masking
Methods In this open-label, randomised, controlled, phase 3 study, we enrolled adults (aged ≥18 years) with histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction with locally advanced unresectable (M0) or metastatic (M1) disease. Patients were enrolled at 164 sites (teaching hospitals and clinics) in 25 countries worldwide (appendix). Other inclusion criteria were availability of tumour material for EGFR expression assessment; at least one radiographically documented measurable lesion (≥2 cm in at least one dimension by conventional techniques or ≥1 cm by spiral CT) in a previously non-irradiated area according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1);18 an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 with adequate organ function; no previous chemotherapy for metastatic or locally advanced unresectable gastric or gastrooesophageal junction cancer; adjuvant chemotherapy completed at least 1 year before randomisation and not more than 300 mg/m² cisplatin administered; no previous treatment with drugs targeting EGFR-related or VEGFR-related signalling pathways; and no clinically relevant coronary artery disease, congestive heart failure, cardiomyopathy, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia. Exclusion criteria were known brain metastasis or leptomeningeal disease; other malignant disease in the previous 5 years, apart from basal-cell cancer of the skin or pre-invasive cancer of the cervix uteri; radiotherapy (apart from limited volume radiotherapy for pain relief), major surgery, or any investigational drug within 30 days before the start of study treatment; concurrent chronic systemic immune or hormone therapy; active hepatitis B
Correspondence to: Prof Florian Lordick, University Clinic Leipzig, University Cancer Center Leipzig (UCCL), 04301 Leipzig, Germany fl
[email protected]
Sex, male
Capecitabinecisplatin plus cetuximab group (n=455)
Capecitabinecisplatin group (n=449)
339 (75%)
334 (74%)
Age, years Median (range, IQR) ≥65
60 (23–84, 51–66)
59 (18–81, 53–66)
139 (31%)
141 (31%)
0
237 (52%)
228 (51%)
1
218 (48%)
220 (49%)
White
242 (53%)
248 (55%)
Asian
173 (38%)
166 (37%)
Other
40 (9%)
35 (8%)
376 (83%)
371 (83%)
71 (16%)
73 (16%)
8 (2%)
5 (1%)
ECOG performance status
Ethnic group
Primary site Stomach Gastro-oesophageal junction Unknown Histological type (Lauren) Intestinal
162 (36%)
149 (33%)
Diffuse
76 (17%)
94 (21%)
Mixed
24 (5%)
26 (6%)
193 (42%)
180 (40%)
113 (25%)
116 (26%)
Unknown Peritoneal metastasis Disease status* Locally advanced
16 (4%)
12 (3%)
439 (96%)
436 (97%)
Previous oesophagectomy or gastrectomy*
92 (20%)
90 (20%)
Previous (neo)adjuvant chemo(radio)therapy*
28 (6%)
27 (6%)
Metastatic
Data are n (%), unless otherwise stated. *Stratification factors.
Table 1: Baseline characteristics
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previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no).
Procedures We treated patients with 3-week cycles of chemotherapy (oral capecitabine 1000 mg/m² twice daily from the evening of day 1 until the morning of day 15 plus intravenous cisplatin 80 mg/m² on day 1) with or without once-weekly cetuximab (400 mg/m² at the first infusion then 250 mg/m² every week), dependent on randomisation assignment. Treatment was continued until radiographically documented tumour progression, unacceptable toxicity, or withdrawal of consent by the patient. In the experimental group (capecitabine and cisplatin plus cetuximab), patients who discontinued chemotherapy could continue on cetuximab monotherapy and those who discontinued cetuximab could continue chemotherapy, until progressive disease, unacceptable toxicity, or withdrawal of consent. Dose reductions were specified in the protocol: 2-week therapy delay for toxic effects was allowed for all study drugs; for grade 3 skin reactions 1191 patients screened
297 ineligible* 229 violated inclusion or exclusion criteria 18 withdrew consent 2 adverse events 1 death 1 lost to follow-up 1 symptomatic deterioration 44 other† 1 reason missing 287 discontinued
904 randomly allocated treatment (intention-to-treat population)
455 allocated capecitabine-cisplatin plus cetuximab
449 allocated capecitabine-cisplatin
9 did not receive ≥1 dose and were excluded from the safety analysis
13 did not receive ≥1 dose and were excluded from the safety analysis
447 discontinued treatment 247 disease progression 74 adverse events 24 deaths 41 withdrawal of consent 31 symptomatic deterioration 4 non-compliance 2 lost to follow-up 24 other
444 discontinued treatment 223 disease progression 75 adverse events 24 deaths 51 withdrawal of consent 22 symptomatic deterioration 10 non-compliance 1 lost to follow-up 38 other
455 included in the intention-to-treat analyses 446 included in the safety analyses
449 included in the intention-to-treat analyses 436 included in the safety analyses
Figure 1: Trial profile *Ten of 297 ineligible patients were randomised to treatment. †Most patients in this category were ineligible because recruitment was put on hold.
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cetuximab dose reductions to 200 mg/m² were permitted, with further reduction to 150 mg/m² for repeated grade 3 skin reactions; capecitabine dose reduction of up to 50% of the starting dose was allowed depending on severity and frequency of adverse drug reactions; cisplatin dose reduction to 25% of the starting dose was allowed for specific haematological toxic effects. We assessed response according to RECIST guidelines. We confirmed complete or partial responses at least 4 weeks after the initial response measurement. We did radiological imaging of the chest and abdomen at baseline and every 6 weeks from the date of randomisation until progressive disease occurrence. Date of progression and best overall response were assessed by masked review at an independent review committee (IRC) The IRC consisted of external experts from Germany, contracted by Perceptive Informatics. An oncologist at the IRC reviewed clinical documentation of progressive disease. We assessed safety in all patients who received at least one dose of any study treatment. We coded adverse events according to the Medical Dictionary for Regulatory Activities (MedDRA; version 14.1). We graded severity with the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE; version 3). We defined special adverse event categories of interest and composite categories of preferred terms according to MedDRA version 14.1; definitions of each special adverse event category are provided in the appendix. We determined tumour HER2 status according to a scoring system for gastric cancer,19 which included immunohistochemistry with a Dako HercepTest kit (Glostrup, Denmark) and fluorescence in-situ hybridisation (FISH) with a Dako HER2 FISH pharmDx kit. We retrospectively assessed tumour EGFR expression analysis by immunohistochemistry with a Dako EGFR pharmDx kit (Glostrup, Denmark). We used immunohistochemistry data to generate an EGFR immunohistochemistry score on a continuous scale of 0–300 as described previously (appendix).20
Statistical analysis Our main objective was to test the null hypothesis that IRC-adjudicated PFS—the primary endpoint—was equal between the experimental and capecitabine-cisplatin alone (control) groups. The primary analysis was done in the intention-to-treat population of all patients randomly allocated a study treatment. We used a stratified, twosided log-rank test to compare the treatment groups, accounting for the randomisation strata. We required 631 PFS events to ensure 80% power for rejection of the null hypothesis of equal treatment effects at a two-sided significance level of 5%, assuming a hazard ratio (HR) of 0·80 and 1:1 randomisation. We planned to enrol 870 patients to be randomised during an accrual period of 27 months and expected 631 PFS events after an additional 7 months of follow-up, assuming a median PFS time of 5·6 months with capecitabine-cisplatin alone.16 www.thelancet.com/oncology Vol 14 May 2013
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Secondary objectives included assessment of overall survival, best overall tumour response (adjudicated by IRC), and safety. We compared secondary efficacy endpoints between the treatment groups with two-sided stratified tests, with stratification factors as for the primary endpoint. We compared best overall response between the treatment groups with a stratified Cochran-MantelHaenszel test. We defined PFS as the time from randomisation to either first observation of progressive disease or occurrence of death due to any cause within 60 days of the last tumour assessment or randomisation. Censoring rules for PFS are provided in the appendix. Overall survival was defined as the time from randomisation to death. To adjust for multiplicity, we applied a ranking of efficacy endpoints according to clinical relevance: PFS, followed by overall survival, followed by best overall response. With this hierarchical ordering, all p values can be tested at the 5% level. A hypothesis can only be rejected at the 5% level if the hypotheses with higher rank are rejected. Because of the hierarchical ordering, the familywise error rate is protected without formal adjustment of the p values for multiplicity. Ignoring the ranked hypotheses, at least 631 deaths were necessary to detect an HR of 0·8 with 80% power in terms of overall survival. Review of PFS projection data during the study suggested that the required number of IRC-confirmed PFS events (631 events) for the primary analysis might not be reached because patients went off study without radiologically confirmed progression. However, 631 deaths were likely to be reached. In response, we modified the timing of statistical analyses in a protocol amendment (from Oct 31, 2011) by fixing the cutoff date for statistical analyses to allow the PFS analysis to be done with fewer events, accepting some loss in power. Therefore final PFS and survival analyses were done in parallel on data obtained from the clinical cutoff date, determined when 631 PFS events were reported by the IRC, or March 31, 2012, which ever occurred first. We correlated tumour HER2 status (a predefined subgroup), EGFR immunohistochemistry score, and the presence of first-cycle grade 1–4 acne-like rash (exploratory landmark analysis,11 not prespecified in the protocol) with outcomes. We planned to generate a scatter plot showing PFS and overall survival time for each patient plotted against EGFR immunohistochemistry score. We assessed associations between clinical outcome and EGFR immunohistochemistry score with a subpopulation treatment-effect pattern-plot method.20,21 Statistical analyses were done with SAS version 9.1.3 or later and R version 2.14.1. This study is registered with EudraCT, number 2007-004219-75.
Role of the funding source The sponsor was responsible for data management and statistical analysis. The EXPAND clinical study was designed by Merck KGaA in collaboration with the www.thelancet.com/oncology Vol 14 May 2013
coordinating investigator (FL), the Arbeitsgemeinschaft Internistische Onkologie, and an international expert advisory panel (funded by Merck KGaA). This analysis and data interpretation was done by the sponsor in cooperation with the authors. The drafting of the manuscript was commissioned by the sponsor. All authors had full access to all study data and FL had the final responsibility for the decision to submit for publication.
Results Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients (table 1, figure 1). Recruitment was temporarily suspended in July 6, 2009, after 380 patients had been allocated treatment, because of an imbalance in cardiac events detected by the data and safety monitoring board. The study was restarted in Dec 11, 2009 after implementation of a cardiac monitoring programme (appendix). Baseline characteristics were generally well balanced (table 1). Only 16 (4%) of 455 patients in the experimental group and 12 (3%) of 449 patients in the control group had locally advanced unresectable disease, as assessed locally by the investigator.
Capecitabine-cisplatin plus cetuximab group (n=446)
Capecitabine-cisplatin group (n=436)
Cetuximab Duration of treatment, months Cumulative dose, mg/m²
3·4 (1·6–5·6) 3403 (1660–5654)
·· ··
Initial dose (400 mg/m²) Dose intensity, mg/m² per week
400 (397–401)
··
Relative dose intensity 80–
