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Efficacy of sequential treatment with first, second and third generation EGFR inhibitors and role of Hedgehog pathway in the acquisition of resistance in in vivo NSCLC models

Date

10 Oct 2016

Session

Poster display

Presenters

Carminia Maria Della Corte

Citation

Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362

Authors

C.M. Della Corte1, F. Papaccio1, G. Viscardi1, G. Esposito1, M. Fasano1, M.D. Castellone2, A. Parascandolo2, F. De Vita3, M. Orditura3, F. Ciardiello3, F. Morgillo3

Author affiliations

  • 1 Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
  • 2 Dipartimento Di Medicina Molecolare E Biotecnologie Mediche, Azienda Ospedaliera Universitaria Policlinico Federico II-AOU Federico II, 80131 - Napoli/IT
  • 3 Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 81130 - Napoli/IT
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Resources

Abstract 3314

Background

The management of EGFR mutant NSCLC has witnessed the development of first, second and third generation tyrosine kinase inhibitors (TKIs) reaching a substantial improvement in disease outcome. However, data on the optimal sequence of these therapies is needed.

Methods

An in vivo model of acquired resistance has been obtained by treating nude mice xenografted with the human EGFR mutant (del ex19) NSCLC cell line, HCC827, with a sequence of first, second and third generation EGFR-TKI. Mice were randomized to erlotinib or gefitinib in first line treatment; resistant tumors were re-implanted in mice and randomized to afatinib +/- cetuximab. Each first and second-generation EGFR-TKI resistant tumor was again re-implanted and randomized to osimertinib or standard chemotherapy with cisplatinum-pemetrexed.

Results

In the first line treatment, an initial dose-dependent decrease in tumor volume with subsequent development of acquired resistance was evidenced in the majority of tumors with a response rate (RR) of 60%. In the second step, while afatinib treatment resulted in a RR of 85%, mostly represented by partial responses, the combination of afatinib plus cetuximab displayed a RR of 100% (85% complete responses). In the third step, although none of resistant tumors was T790M + , treatment with osimertinib resulted in a RR of 71% (including one complete response lasted more than 10 weeks). Chemotherapy caused predominantly stable diseases lasted less than 5 weeks. Protein and gene expression analysis on protein extracts from tumors with acquired resistance showed a progressively increasing activation of the Hedgehog pathway as compared to untreated controls in the majority of samples, with higher protein level of SMO and Gli1.

Conclusions

Osimertinib is effective after failure of first and second generation EGFR-TKIs, independently from the T790M presence. These experiments confirm the role of Hedgehog pathway as important mediator of resistance to EGFR inhibition.

Clinical trial identification

Legal entity responsible for the study

Second University of Naples

Funding

AstraZeneca

Disclosure

All authors have declared no conflicts of interest.

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