The best first-line approach to be used in T790M+ NSCLCs has to be defined. Our aim is to test in T790M+ preclinical models the efficacy of second and third generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), as single agents or in combination with cetuximab or MEK-inhibitors (MEK-i).
Nude mice xenografted with the human NSCLC H1975 cell line, harboring both the EGFR activating (L858R) and resistant (T790M) mutations, were randomized to receive afatinib or osimertinib. Basing on previous literature data revealing synergism between afatinib and cetuximab and between osimertinib and the MEK-i selumetinib, other four arms of treatments with combination of afatinib/osimertinib with cetuximab or selumetinib have been included.
Treatment with afatinib resulted in 40% complete responses with a rapid acquisition of resistance whereas 100% complete response were reported in mice treated with osimertinib. In only 1 responding mice treated with osimertinib, tumor started to regrowth within 14 weeks. All mice treated with afatinib/osimertinib plus cetuximab or selumetinib experienced complete responses that have been lasting 16+ weeks. Preliminary results from gene analysis revealed appearance of SMO gene mutation (V404M) in one tumor resistant to afatinib and in the tumor resistant to osimertinib, with a concomitant activation of the Hedgehog pathway.
T790M+ tumors represent a subgroup of EGFR mutated NSCLC with innate resistance to first generation EGFR-TKIs. Our in vivo model of resistance demonstrated the superiority of osimertinib with respect to afatinib in this setting and a strong efficacy of experimental combinations (with cetuximab and MEK-I) as first line therapy. Moreover, we found that Hedgehog pathway is involved in mediating resistance to second- and third- generation EGFR-TKIs, suggesting new potential strategies of combination with Hedgehog inhibitors to prevent the occurrence of resistance in T790M + tumors.
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Second University of Naples
All authors have declared no conflicts of interest.