P01.071 Genomic profiling identifies tubulin mutations that may predict response to depatuxizumab mafodotin in patients with glioblastoma

Abstract

Depatuxizumab mafodotin (depatux-m) is an antibody-drug conjugate (ADC) composed of an EGFR-targeted antibody conjugated to a microtubule inhibitor warhead, monomethyl auristatin F. In a Phase 1 study in glioblastoma (GBM), selection for EGFR amplification (amp) enriched for patients (pts) likely to respond. We sought to identify other determinants of sensitivity. We identified an index case with prolonged disease control but unexpectedly without EGFR amp. Whole exome sequencing (WES) of pre-treatment archival tissue identified a point mutation in TUBA3C (tubulin alpha 3c) which mechanistically affects sensitivity to the microtubule-directed warhead of depatux-m, as opposed to the EGFR-targeted antibody. WES analysis, with a focus on the tubulin gene family, was expanded to 48 pts with sufficient archival tissue. In vitro synthetic lethality experiments were performed to confirm the hypothesized importance of tubulin mutations on depatux-m sensitivity. WES revealed some tubulin genes were differentially mutated in depatux-m responders (n = 8) vs non-responders (n = 24), all with EGFR amp. TPPP2, TTLL11, TTLL6, TTLL7, TUBA3C, TUBA3D, TUBAL3, and TUBGCP4 mutations (1–2 per tumor) were observed preferentially in responders; gene knockdown enhanced response in vitro, consistent with mechanistic relevance to warhead sensitivity. TTLL2, TTLL4, TUBB2A, TUBB2B, TUBG1, TUBGCP2, TUBGCP5, TBCC, and TBCE mutations (1–3 per tumor) were observed exclusively in non-responders. Response to ADCs depends not only on the presence of the target antigen but also on sensitivity to the conjugated toxin. We identified tubulin gene family mutations correlating with response to the microtubule inhibitor warhead of the ADC depatux-m. While verification of this observation in an independent cohort is required, other experiments to elucidate the mechanism are ongoing. Further data will be presented. A proposed investigator-initiated trial encompassing tubulin mutations as an eligibility criterion is in development. These data related to warhead sensitivity of depatux-m may serve as a guide to support rational drug combination therapy in GBM.