382P The potential utility of end-binding protein 1 (EB1) as response-predictive biomarker for lisavanbulin: Final results from a phase I study of lisavanbulin (BAL101553) in adult patients with recurrent glioblastoma (GBM)

Abstract

Stereotaxic biopsy was performed in 17 pts (71%); 9 (53%) had grade II diffuse astrocytoma, and 3 (18%) pilocytic astrocytoma; glioblastoma (GBM) was found in 1 patient at diagnosis and in another at a late recurrence of a glial proliferation. Pons and bulb were the main sites of the tumor (N¼10/10). Among the 21 treated pts, all underwent radiotherapy (RT); 7 received sequential radiotherapy and chemotherapy (RT+CT). Median OS was 45.2 months and 5-y OS was 48.7% (95% CI 24.5-69.2%). No statistically significant association was found between OS and age, tmt modality, or MRI contrast enhancement. ECOG-PS 3-4 was identified as negative PF; although no statistically significant, there was a numerical difference of outcomes regarding histological grade (Table ).

Assessment of lisavanbulin (BAL101553) as an anti-lymphoma agent

“…The microtubule-associated protein EB1 has been indicated as a potential biomarker of sensitivity to avanbulin and lisavanbulin, especially in the context of glioblastoma, in which a small number of cases express high protein levels, and these could be the case that most benefit from treatment with the MTA [18][19][20] . In our DLBCL series, we did not observe a clear correlation between EB1 expression and avanbulin anti-tumor activity, but only a trend for higher sensitivity in high EB1 expressor cell lines.…”

“…Moreover, since the avanbulin tubulin binding site differs from both vinca alkaloids and MMAE and it does not appear to be a MDR1 substrate 5,7,9,12,14 , lisavanbulin might be an alternative strategy also in patients that have developed resistance to these agents via tubulin mutations or MDR1 overexpression. A matter of concern for treating these patients is the potential overlapping toxicities, especially peripheral neuropathies, common to all MTAs 5,8,16–18 , which might represent a limiting factor for using lisavanbulin in individuals already exposed to vincristine, vinblastine or antibody drug conjugates containing a MTA as payload.…”

“…Based on the reported possible association between EB1 and sensitivity to avanbulin [18][19][20] , we evaluated RNA expression in lymphoma cell lines, with no differences between GCB and ABC DLBCL (Supplementary Figure 4). All lymphoma cell lines expressed a high level of EB1.…”

“…Avanbulin is active in various preclinical models of solid tumors, including in cells resistant to drugs that bind to either the taxane or the vinca alkaloid site on tubulin or that are substrates of the multidrug resistance pump MDR1 [10][11][12][13][14] . Its highly soluble prodrug, lisavanbulin (BAL101553), 15 has entered the initial clinical evaluation with early signs of clinical activity in patients with advanced solid tumors and with recurrent glioblastoma [16][17][18] . Clinical and laboratory data suggest that the anti-tumor activity of avanbulin and of its prodrug lisavanbulin is higher in tumors with strong expression of end-binding protein 1 (EB1) [18][19][20] , a microtubule-associated protein, important for the regulation of microtubule dynamics 21 .…”

“…Its highly soluble prodrug, lisavanbulin (BAL101553), 15 has entered the initial clinical evaluation with early signs of clinical activity in patients with advanced solid tumors and with recurrent glioblastoma [16][17][18] . Clinical and laboratory data suggest that the anti-tumor activity of avanbulin and of its prodrug lisavanbulin is higher in tumors with strong expression of end-binding protein 1 (EB1) [18][19][20] , a microtubule-associated protein, important for the regulation of microtubule dynamics 21 .…”