Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

Abstract

Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. 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). M e t h o d s : AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin þ 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 þ Xelox at RP2D or Xelox only for two

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

“…In the FOCUS4-D study of metastatic colorectal cancer, patients with tumours that were stable or responding to cytotoxic chemotherapy received single agent AZD8931 40 mg bd continuously, and there was no PFS benefit of AZD8931 compared with placebo [8]. Despite using doses that were between 4 and 8 times higher than those previously used, the toxicity attributed to AZD8931 in this study was lower than that reported in studies using more prolonged dosing schedules and was in general well-tolerated [8,35]. Thus, high-dose pulse scheduling in combination with standard doses of cytotoxic chemotherapy appears feasible.…”

A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead

“…[2] Although the majority of studies investigating the potential of HER2 inhibition for curativelytreated GEA showed promising results [16][17][18]21,24], some studies show no evident effect of the addition of HER2 targeting therapy. [20,22,25] This includes a large randomized study with 203 patients demonstrating no benefit of the addition of trastuzumab to six weeks of nCRT. [25] This is in contrast to breast cancer, in which the addition of single-agent trastuzumab was able to improve DFS in HER2 positive tumors.…”

“…The study demonstrated an acceptable safety profile with the addition of the compound, although preliminary efficacy suggested no additional activity compared to chemotherapy only. [22] Single HER2 targeting with checkpoint inhibitors…”

HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives

“…TKIs have been extensively studied in advanced/metastatic HER2-positive G/GEJ adenocarcinoma. The phase II DEBIOC trial of sapitinib in combination with chemotherapy demonstrated antitumor activity in the neoadjuvant treatment of patients with HER2-positive resectable GEA [97]. A phase II trial of dacomitinib monotherapy showed efficacy and safety in patients with HER2-positive GC who had received prior treatment [98].…”