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S. La Monica

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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): S. La Monica

      • Abstract

      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.

      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.

      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.

      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”

      AstraZeneca partially supported

      All authors have declared no conflicts of interest.