60PD - Inhibition of pEGFR in paired tumour biopsies from TKI treatment-naïve EGFR mutant NSCLC patients treated with gefitinib (EGFR inhibitor) or gefiti...

Date 14 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Targeting EGFR and ALK driven tumours
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Cancer Immunology and Immunotherapy
Translational Research
Presenter Tammie Yeh
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors T. Yeh1, V. Jacobs2, H. Angell3, J. Geradts3, J. Hou4, J. Karakunnel5, C. Barrett6
  • 1Oncology Imed Translational Sciences, AstraZeneca, 02451 - Waltham/US
  • 2Oncology Imed Translational Sciences, AstraZeneca, Macclesfield/GB
  • 3Oncology Imed Translational Sciences, AstraZeneca, Cambridge/GB
  • 4Gmd Oncology, AstraZeneca, Shanghai/CN
  • 5Oncology Clinical Development, MedImmune, Gaithersburg/US
  • 6Oncology Imed Translational Sciences, AstraZeneca, Waltham/US

Abstract

Background

Gefitinib (IRESSA™) has been approved as early as 2002 for the treatment of advanced NSCLC patients in over 90 countries. However, during the historical development of gefitinib, paired lung biopsies were challenging to collect and the evaluation of phosphorylated EGFR (pEGFR) inhibition in tumour samples was therefore extremely limited. We recently had an opportunity to revisit and evaluate pEGFR inhibition in the context of a gefitinib+durvalumab combination trial (NCT02088112) where pre- and post-treatment biopsies were collected in TKI-naïve patients with tumours harbouring EGFR mutations (i.e. L858R/Del19) in the dose expansion part of the study.

Methods

There were two arms in the dose expansion. Patients in Arm 1 were treated immediately with gefitinib+durvalumab; patients in Arm 2 were treated with gefitinib alone for 28 days (d) before starting the combination. For Arm 1, biopsies were collected at pre-treatment and at 10 d after combination treatment. For Arm 2, biopsies were collected at pre-treatment, 10 d after gefitinib alone and 10 d after combination (i.e. d 38). Biopsies were analysed for pEGFR/Y1173 by IHC and manually scored for membrane and cytoplasmic staining.

Results

There were 20 patients in dose expansion, 10 patients/arm. However, a number of the post-treatment biopsies contained little or no tumour cells, resulting in the final analysis of 3 tumour pairs for Arm 1 (combination) and 8 tumour pairs for Arm 2 (gefitinib run-in). Although baseline pEGFR levels were lower than expected, the majority (6/8) of the paired samples from Arm 2 and all (3/3) of the paired samples from Arm 1 showed pEGFR inhibition after 10 d of treatment, suggesting not only pEGFR inhibition by gefitinib but no antagonism by durvalumab with regard to gefitinib's mechanism of action.

Conclusions

Paired tumour biopsies from gefitinib- and gefitinib+durvalumab-treated patients suggested inhibition of pEGFR after 10 d of treatment, consistent with the observation of rapid tumour reductions in these patients. Analysis of immune biomarkers is ongoing (e.g. PD-L1) and will also be presented.

Clinical trial identification

NCT02088112

Legal entity responsible for the study

AstraZeneca and MedImmune

Funding

Sponsored by MedImmune, the global biologics R&D arm of AstraZeneca

Disclosure

T. Yeh: Employee of AstraZeneca. V. Jacobs, H. Angell, J. Geradts, J. Hou, C. Barrett: Employee of AstraZeneca and holds share in AstraZeneca. J. Karakunnel: Employee of MedImmune and holds share in MedImmune