Acquired resistance in NSCLC with EGFR mutation treated with TKI's: Single center experience and treatment outcome

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Background: Acquired resistance in NSCLC with activating EGFR mutations has been defined by Jackman et al. The molecular mechanisms have been studied in small series of patients: in about 50% of cases, T790 M mutation confers acquired resistance, in 25% c-Met amplification. Other as of yet unknown mechanisms might also play a role. Here we present the acquired resistance mechanisms in a cohort of 16 patients (out of 33 pts.) with activating EGFR mutations treated with TKI and identified at our center. Treatment methods and outcome are also described. Methods: 161 consecutive patients (s. abstract Halbfass et al.) were molecularly studied for EGFR mutations in exons 18 – 21. EGFR mutation analysis was performed by Sanger Sequencing or by hybridization based COBAS methodology after microdissection of tumor tissue to ascertain a high percentage of tumor tissue. c-Met IHC was performed automatized by standard procedure (BondMax, Menarini). ALK rearrangement was studied using a break apart FISH-Probe (Abbott). Remission was measured by RECIST 1.1 criteria. Results: Of 161 patients tested, 35 had an EGFR mutation, of which 4 had primary resistance mutations (T790 M 1 case, Exon 20 insertions 2 cases). Of these 30 pts., 20 had acquired resistance and 16 were rebiopsied. Of the 16 rebiopsied pts, 8/14 had T790 M, 8/12 had overexpression of c-Met (2+,3+) in IHC, 1/9 patients had an acquired ALK translocation. Therapy in the acquired resistance situation was afatinib, chemotherapy, afatinib + cetuximab and crizotinib. The DCR rate of afatinib in T790 M + patients was higher than in T790 M WT patients. PFS and OS data will be presented at the meeting. Conclusion: The understanding of resistance mechanisms in acquired TKI resistance is of academic interest and might be important for subsequent treatment options. Therefore, rebiopsy at progress while on TKI therapy should be discussed with patients. As targeted treatment options are available for c-Met, ALK as well as T790 M, resistance mechanisms potentially may guide therapeutic strategies in EGFR mutated patients with acquired resistance.