Abstract
BackgroundAZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). MethodsAZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. ResultsDuring escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). ConclusionXelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791).
Highlights
In the UK, gastric and oesophageal cancers account for approximately 16,000 cases per annum with mortality approaching 13,000 cases per annum [1]
Twenty-four patients were recruited to the escalation phase between June 2012 and October 2014 in three Experimental Cancer Medicine Centre (ECMC) UK centres (Oxford, Leicester and Belfast)
Thirty patients were randomised to the expansion phase between March 2015 and May 2016 in five ECMC UK centres (Oxford, Leicester, Belfast, Bristol and Leeds) and follow-up ended in November 2017
Summary
In the UK, gastric and oesophageal cancers account for approximately 16,000 cases per annum with mortality approaching 13,000 cases per annum [1]. The UK national oesophagogastric cancer (OGC) audit (2018) determined that only 38.6% of patients were treated with curative intent, with a 5-year overall survival (OS) of 15% for oesophageal and 19% for gastric cancers [4]. Trastuzumab has demonstrated activity in patients with advanced human epidermal growth factor receptor-2 (EGFR) (HER2/erbB2) positive OGC [12,13], and results from neoadjuvant studies using this in addition to chemotherapy are awaited [14,15]. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 þ chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC).
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