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P. Petronini



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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      155P - Antitumoral efficacy of dual blockade of EGFR signaling by osimertinib in combination with selumetinib or cetuximab in activated EGFR human NSCLC tumor models (ID 536)

      12:30 - 13:00  |  Author(s): P. Petronini

      • Abstract

      Background:
      Osimertinib is the gold standard for activated-EGFR-NSCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by the addition of the monoclonal antibody, cetuximab, or the MEK1/2-inhibitor, selumetinib, to osimertinibin EGFR-mutated-NSCLC in vivo models.

      Methods:
      We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827(E746-A759del/T790M-), H1975(L858R/T790M+) and PC9-T790M (E746-A759del /T790M+) xenografts, in second line after the developing of resistance to osimertinib and in first line, and we explored mechanisms of resistance to these treatments.

      Results:
      The addition of selumetinib or cetuximab to osimertinib in second line reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50–80%, and a median PFS (mPFS) of first plus second line of therapy of 28 weeks. The early use of combinations in first line increased the RR to 90%, with amPFSnot reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0,005) as compared to osimertinib, that achieved in first line a mPFS of 17–18 weeks. Moreover, on ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found hedgehog pathway activation and we demonstrated that triple combination with a Smo inhibitor plus osimertinib.

      Conclusions:
      We demonstrated that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated-NSCLC and that Hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments.

      Clinical trial identification:


      Legal entity responsible for the study:
      University of Campania “L. Vanvitelli”

      Funding:
      AstraZeneca partially supported

      Disclosure:
      All authors have declared no conflicts of interest.