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Publication Detail
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
  • Publication Type:
    Journal article
  • Authors:
    Propper DJ, Gao F, Saunders MP, Sarker D, Hartley JA, Spanswick VJ, Lowe HL, Hackett LD, Ng TT, Barber PR, Weitsman GE, Pearce S, White L, Lopes A, Forsyth S, Hochhauser D
  • Publisher:
    Springer Science and Business Media LLC
  • Publication date:
    09/11/2022
  • Journal:
    British Journal of Cancer
  • Medium:
    Print-Electronic
  • Status:
    Accepted
  • Country:
    England
  • Print ISSN:
    0007-0920
  • PII:
    10.1038/s41416-022-02015-x
  • Language:
    English
  • Keywords:
    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.
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