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

Abstract

Background Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). Methods Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. Results Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. Conclusions The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. Trial registration number ClinicalTrials.gov number: NCT01862003.

HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs

“…In orthotopic IBC models, the combination of paclitaxel and AZD8931 proved to be more successful in slowing tumor growth than either drug alone [ 135 ] . In phase I/II research, high-dose pulsed AZD8931 combined with irinotecan/5-FU chemotherapy had acceptable toxicity in metastatic colorectal cancer (CRC) [ 136 ] . Oxaliplatin + capecitabine plus AZD8931 had a tolerable safety profile in oesophagogastric cancer [ 137 ] .…”

FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC

“…Due to the limitations of chemotherapy, the 5-year overall survival (OS) of chemotherapy alone is just 10.8% for mCRC [3]. Combination therapy might be a promising way to improve the efficacy of anti-tumor agents and have acceptable toxicity [4]. Thus, there is an urgent need for us to unveil the underlying mechanisms of mCRC and develop novel treatment strategies for mCRC.…”