Alicia Frances Clare Okines

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

Summary Background EGFR overexpression occurs in 27–55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. Methods In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1–21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. Findings Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6–13·0) compared with 8·8 months (7·7–9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07–1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3–4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]). Interpretation Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. Funding Amgen, UK National Institute for Health Research Biomedical Research Centre.

Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up A. Okines, M. Verheij, W. Allum, D. Cunningham & A. Cervantes On behalf of the ESMO Guidelines Working Group* GI Clinical Trials Unit, Royal Marsden Hospital, Sutton, UK; Department of Radiation Oncology and Division of Cellular Biochemistry, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Surgery, Royal Marsden Hospital, London; Department of Medicine, Royal Marsden Hospital, Sutton, UK; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain

Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer

BACKGROUND The REAL-2 and ML17032 trials demonstrated that the oral fluoropyrimidine, capecitabine, is noninferior to 5-fluorouracil (5-FU) for overall survival (OS) and progression-free survival (PFS), respectively, in advanced oesophago-gastric cancer. METHODS Individual patient data were collected on all patients randomised within the trials (n = 1318). Kaplan-Meier survival curves were generated and the log-rank test was used to compare OS and PFS between patients receiving 5-FU combinations and capecitabine combinations. Stepwise multivariate Cox regression analysis was used to calculate corrected hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and PFS. Logistic regression was used for objective response rate. Forest plots with tests of heterogeneity were generated. RESULTS OS was superior in the 654 patients treated with capecitabine combinations compared with the 664 patients treated with 5-FU combinations; HR 0.87 (95% CI 0.77-0.98, P = 0.02). Poor performance status, age <60 and metastatic disease were independent predictors of poor survival. There was no significant difference in PFS between treatment groups on multivariate analysis. Assessable patients treated with capecitabine combinations were significantly more likely to have an objective response to treatment than those treated with 5-FU combinations; odds ratio 1.38 (95% CI 1.10-1.73, P = 0.006). CONCLUSION OS is superior in patients treated with capecitabine combinations compared with 5-FU combinations in advanced oesophago-gastric cancer.

Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial

Background:Complete resection of metastases can result in cure for selected patients with metastatic colorectal cancer.Methods:First BEAT evaluated the safety of bevacizumab with first-line chemotherapy in 1914 patients. Prospectively collected data from 225 patients who underwent curative-intent surgery were analysed, including an exploratory comparison of resection rate in patients treated with different regimens. NO16966 compared efficacy of oxaliplatin-based chemotherapy plus bevacizumab or placebo in 1400 patients. A retrospective analysis of resection rate was undertaken.Results:In First BEAT, 225 out of 1914 patients (11.8%) underwent curative-intent surgery at median 64 days (range 42–100) after the last dose of bevacizumab. R0 resection was achieved in 173 out of 225 patients (76.9%). There were no surgery-related deaths and serious post-operative complications were uncommon, with grade 3/4 bleeding and wound-healing events reported in 0.4% and 1.8%, respectively. Resection rates were highest in patients receiving oxaliplatin-based combination chemotherapy (P=0.002), possibly confounded by patient selection. In NO16966, 44 out of 699 patients treated with bevacizumab (6.3%) and 34 out of 701 patients treated with placebo (4.9%) underwent R0 metastasectomy (P=0.24).Conclusions:The rate of serious post-operative complications in First BEAT was comparable to historical controls without bevacizumab. In NO16966, there were no statistically significant differences in resection rates or overall survival in patients treated with bevacizumab vs placebo.

Epirubicin, Oxaliplatin, and Capecitabine With or Without Panitumumab for Advanced Esophagogastric Cancer: Dose-Finding Study for the Prospective Multicenter, Randomized, Phase II/III REAL-3 Trial

PURPOSE Epirubicin, oxaliplatin, and capecitabine (EOC) is a standard treatment in advanced esophagogastric cancer. Panitumumab (P) is a fully human, immunoglobulin G2 monoclonal antibody targeting epidermal growth factor receptor. Randomized Trial of EOC +/- Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer (REAL-3) will evaluate whether the addition of P to EOC improves survival in patients with advanced esophagogastric adenocarcinoma and undifferentiated carcinoma. PATIENTS AND METHODS The original design of REAL-3 added P 9 mg/kg to the standard dose of EOC (dose level [DL] + 1). Due to toxicity, a dose de-escalation was made to EOC + P DL-1 (epirubicin 50 mg/m(2), oxaliplatin130 mg/m(2), capecitabine 1,000 mg/m(2)/d + P 9 mg/kg every 3 weeks). After additional toxicity was observed, the study was amended to include two additional EOC + P dose levels. Using a 3 + 3 design, dose-limiting toxicities (DLTs) were assessed weekly during cycle 1. Patients were randomly assigned 1:1 to EOC +/- P. RESULTS Between July 2008 and October 2009, 29 patients were randomly selected for standard-dose EOC (n = 13) or EOC + P (n = 16). Five patients were treated at DL + 1, with grade 3 diarrhea in four of five patients by cycle 4. At DL-1, one patient had grade 3 diarrhea and grade 5 infection. Three patients were treated at DL-3, and then six were treated at DL-2, without DLTs. CONCLUSION The recommended dose for EOC + P is epirubicin 50 mg/m(2), oxaliplatin 100 mg/m(2), capecitabine 1,000 mg/m(2)/d, and P 9 mg/kg every 3 weeks. This dose has been selected for the ongoing phase II/III REAL-3 study.

Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial

BACKGROUND Perioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6-0.93)]. HER2 amplification is reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer. PATIENTS AND METHODS Diagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in tissue microarrays. The prognostic and predictive impact of HER2 status was investigated. RESULTS Concordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14-3.77); HER2 negative HR 0.58 (0.41-0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies. CONCLUSIONS HER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma.

A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3)

LBA4000 Background: EGFR overexpression occurs in 27-50% of esophagogastric adenocarcinomas (OGA), and correlates with poor prognosis. The REAL3 trial evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. METHODS Patients with untreated, metastatic or locally advanced OGA were randomised to EOC (E 50mg/m2, O 130mg/m2, C 1250mg/m2/day) or mEOC+P (E 50mg/m2, O 100mg/m2, C 1000mg/m2/day, P 9mg/kg). Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST after 4 and 8 cycles. Following IDMC review in October 2011 trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. RESULTS 553 patients were recruited (EOC 275, mEOC+P 278), with median follow-up 5.0 and 5.2 months respectively. Median OS was 11.3 months with EOC compared to 8.8 months with mEOC+P (HR 1.37: 95% CI 1.07-1.76, p=0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22: 95% CI 0.98-1.52, p=0.068), with RR being 42% compared to 46% (odds ratio 1.16: 95% CI 0.81-1.57, p=0.467). mEOC+P was associated with ↑ G3/4 diarrhoea (17% vs 11%), skin rash (14% vs 1%) and thrombotic events (12% vs 7%), but ↓ haem toxicity (>G3 neutropenia 14% vs 31%). In the mEOC+P arm, OS was significantly improved in patients with G1-3 rash (77%, n=209) on treatment compared to those without (23%, n=63); median OS 10.2 vs 4.3 months (p<0.001), with similar significant improvements seen in RR and PFS. Biomarker analysis in the first 200 patients has not identified other predictive markers associated with P therapy. Multivariate analysis for OS in these patients demonstrated a negatively prognostic role for KRAS mutation (HR 2.1: 95% CI 1.10-4.05, p=0.025) and PIK3CA mutation (HR 3.2: 95% CI 1.01-10.40, p=0.048). CONCLUSIONS Addition of P to EOC chemotherapy was associated with worsening of OS in an unselected advanced OGA population. This may be in part due to lowered doses of O and C in the mEOC+P regimen. Outcomes in patients treated with P varied by grade of skin toxicity.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report

BACKGROUND Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials

BACKGROUND REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

A phase II trial of preoperative chemotherapy with epirubicin, cisplatin and capecitabine for patients with localised gastro-oesophageal junctional adenocarcinoma.

Preoperative cisplatin/fluorouracil is used for the treatment of localised oesophageal carcinoma. This phase II study aimed to assess the efficacy and safety of administering preoperative epirubicin/cisplatin/capecitabine (ECX). Patients with stage II or III oesophageal/gastro-oesophageal junctional adenocarcinoma from one institution received 4 cycles of ECX (epirubicin 50 mg m−2 day 1, cisplatin 60 mg m−2 day 1, capecitabine 625 mg m−2 b.i.d. daily) followed by surgery. The primary end point was the pathological complete response (pCR) rate based on a Simon two-stage design. Secondary end points included overall and progression-free survival (OS/PFS). Thirty-four patients were recruited: median age 60 years (range 41–81), 91% male, 97% PS 0/1, 80% T3, 68% N1. Thirty-one patients completed four ECX cycles. Grade 3/4 toxicities ⩾5% included neutropenia (62%), hand–foot syndrome (15%) and nausea/vomiting (9%). Thirteen out of 28 (46%) evaluable patients responded to chemotherapy by EUS (⩾30% reduction in maximal tumour thickness). Twenty-six out of 34 (76%) patients underwent resection (R0=73%, R1=27%). Post-operatively, two patients died within 60 days of surgery. The pCR rate was 5.9% (95% CI 0–14%) in the intent-to-treat population. According to the statistical design, this prompted early study termination. However, with a median follow-up of 34 months the median OS and 1- and 2-year survival rates were 17 months, 67 and 39% respectively. Median PFS was 13 months. Of the 14 relapsed patients, 10 presented with distant metastases. Preoperative ECX is feasible and well tolerated. Although associated with a low pCR rate, survival with ECX was comparable with published studies suggesting that pCR may not correlate with satisfactory outcome from preoperative chemotherapy for localised oesophageal adenocarcinoma.