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

David J Propper, Fangfei Gao, Mark P Saunders, Debashis Sarker, John A Hartley, Victoria J Spanswick, Helen L Lowe, Louise D Hackett, Tony T Ng, Paul R Barber, Gregory E Weitsman, Sarah Pearce, Laura White, Andre Lopes, Sharon Forsyth, Daniel Hochhauser, David J Propper, Fangfei Gao, Mark P Saunders, Debashis Sarker, John A Hartley, Victoria J Spanswick, Helen L Lowe, Louise D Hackett, Tony T Ng, Paul R Barber, Gregory E Weitsman, Sarah Pearce, Laura White, Andre Lopes, Sharon Forsyth, Daniel Hochhauser

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.

Conflict of interest statement

TTN is Chief Medical Officer of Nano Clinical Ltd. PRB has shares in, and is a consultant for, Nano Clinical Ltd. All other authors declare no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study flow chart for Phase I and phase II cohorts.
Fig. 2. Swimmer plot of 18 AZD8931-treated…
Fig. 2. Swimmer plot of 18 AZD8931-treated patients.
The swimmer plot depicts individual patient responses at 12 weeks, duration until disease progression, and duration until death or last follow-up.
Fig. 3. Kaplan-Meier for progression-free survival (PFS)…
Fig. 3. Kaplan-Meier for progression-free survival (PFS) and for overall survival (OS) among patients who received FOLFORI and AZD8931 160 mg bd.
PFS events were defined as disease progression or death, whichever occurred first. OS events include deaths from any cause. Number at risk are given under the plot.

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