A randomised phase II study of perioperative epirubicin, cisplatin and capecitabine (ECX) ± lapatinib for operable, HER-2 positive gastric, oesophagogastric junctional (OGJ) or lower oesophageal adenocarcinoma: Results from the UK MRC ST03 lapatinib feasibility study (ISRCTN 46020948)

Background

Perioperative ECX chemotherapy and surgery is a standard of care for operable oesophagogastric adenocarcinoma (Cunningham NEJM 2006). Anti-HER-2 therapy improves survival in HER-2 positive patients (pts) with advanced disease (Bang Lancet 2010). We assessed the safety and feasibility of adding the tyrosine kinase inhibitor lapatinib to perioperative ECX.

Methods

Eligible patients had histologically proven, HER-2 positive (IHC 3+ or IHC 2+ and DDISH HER-2:CEP17 ratio ≥2), operable, gastric/OGJ/lower oesophageal adenocarcinoma. A planned 40 pts were to be randomised 1:1 open label to standard ECX, 3 pre- and 3 post-operative cycles of epirubicin 50 mg/m² iv d1, cisplatin 60 mg/m² iv d1, capecitabine 1250mg/m²/d1-21, or to ECX + L (ECX plus lapatinib d1-21 in each cycle and for 6 maintenance doses). The first 10 ECX + L pts were treated with capecitabine 1000mg/m², lapatinib 1250mg/d; pre-operative toxicity was then reviewed according to pre-defined criteria to determine doses for subsequent patients. The primary objective is to establish a recommended dosing regimen for a phase III trial, under which the grade 3/4 diarrhoea rate should not exceed 20%. Sponsored and co-ordinated by MRC CTU at UCL, funded by Cancer Research UK (CRUK06/025, NCT00450203).

Results

Between February 2013 and May 2016 441 pts underwent central HER-2 testing of whom 63 (14%) were positive. 46 pts were randomised and 44 (24 ECX, 20 ECX + L) are included in this analysis (2 ECX + L did not begin treatment and were replaced). 2 of the first 10 ECX + L pts reported pre-operative grade 3 diarrhoea so no dose adjustment was made. Final pre-operative grade 3 diarrhoea rates were 0/24 ECX, 4/20 ECX + L, other toxicities were similar between the arms. 1/24 ECX, 3/20 ECX + L stopped pre-operative treatment early and 4/20 ECX + L had a lapatinib dose reduction. Post-operative complication rates were similar in each arm.

Conclusions

Administration of lapatinib at 1250mg/day in combination with ECX chemotherapy was feasible with some increase in toxicity which did not compromise operative management.

Clinical trial identification

ISRCTN: 46020948. EUDRACT: 2006-000811-12

Legal entity responsible for the study

Trial sponsored by the Medical Research Council Clinical Trials Unit at University College London.

Funding

Cancer Research UK; GlaxoSmithKline

Disclosure

E. Smyth: I have been on an advisory board for Five Prime Therapeutics. K. Sumpter: Advisory board - Roche (2006); Travel grant to educational meeting - world GI 2011 - Roche; Virtual meeting pass for ASCO 2014 – Roche. D. Cunningham: Corporate-sponsored research: Merck Serono; Celgene; Sanofi; MedImmune; Merrimack; Amgen Research Munich GmbH; Asia & Emerging Markets Innovative Medicine of AstraZeneca R&D. All other authors have declared no conflicts of interest.