ATNT-02DETERMINANTS OF RESPONSES AND RESISTANCE TO ABT-414: RESULTS OF NEXT-GENERATION SEQUENCING

BACKGROUND: ABT-414 is an EGFR-targeted antibody conjugated to the toxic antimicrotubule agent monomethylauristatin F. In an ongoing phase I study (abstract by Gan et al), all confirmed responses as determined by RANO criteria have been restricted to patients whose tumors harbor EGFR amplification. Genomic analysis was performed to explore mechanisms associated with innate sensitivity and acquired resistance. METHODS: Whole exome sequencing (WES) of diagnostic tumor samples from relapsed glioblastoma patients treated with ABT-414 + temozolomide (TMZ) or ABT-414 alone was performed. WES data were correlated with EGFR amplification and EGFRvIII as determined by FISH and RT-PCR, respectively. To explore acquired resistance, tissue was collected prior to starting ABT-414/TMZ from a patient who had a complete response and again postrelapse. WES and RNAseq of collected tissue were performed to identify mutations and associated transcriptional changes occurring at relapse. RESULTS: WES has been completed for 13 patients (14 samples) and is ongoing for 11 additional samples. Of the 9 samples determined to be EGFR amplified by FISH, 8 were amplified by WES. All 5 samples determined to be EGFRvIII positive by RT-PCR were positive by WES. In the patient with serial tumor collection, EGFR amplification and EGFRvIII expression was not significantly altered postprogression. Mutations in 25 genes were detected only in the postrelapse biopsy including in TOP2A and TOPORS, both of which are reported to be associated with chemotherapeutic resistance. RNAseq demonstrated a 1.7-fold upregulation of TUBGCP4 at the time of relapse. Given the involvement of TUBGCP4 in tubulin biology, this may potentially influence sensitivity to ABT-414's microtubule toxin. CONCLUSIONS: To date, EGFR amplification is necessary but not sufficient for response to ABT-414. Genomic profiling of longitudinally collected tissue may suggest factors involved in treatment sensitivity and acquired resistance. Ongoing mutation analysis in additional samples will be presented.