83P - Evaluation of response-predictive biomarkers for lisavanbulin: A phase II study in patients with recurrent glioblastoma

Background

Lisavanbulin (BAL101553, prodrug of BAL27862) destabilizes microtubules, promoting tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic small molecule shown in rodents to penetrate the brain, with antitumor activity in orthotopic glioblastoma (GBM) models. In the phase I part of this study, 2 of 20 patients with recurrent GBM or high-grade glioma showed long-lasting objective responses and strong end-binding protein 1 (EB1) expression in GBM tissue by IHC. EB1, a protein located on the plus-ends of microtubules, is involved in microtubule function. GBM mouse models suggested EB1 is a predictive marker of response to lisavanbulin.

Methods

The objective of the phase 2 study was to investigate prospectively the response-predictive value of EB1, and to identify RNA-based response signatures. A Simon’s Two-Stage design was used with an objective response rate (ORR) ≥ 2/9 required in Stage 1 to enable a final ORR ≥ 6/19. A prescreening program identified patients with EB1-positive archival GBM tissue. Patients with recurrent and measurable disease per RANO receiving treatment for ≥ 6 weeks were evaluable. All patients received 25 mg oral lisavanbulin once daily. RNA-seq was performed on archival GBM tissues.

Results

13 sites in 4 countries participated in this study. Samples from 64 of 629 patients (10.2%) were EB1-positive, and 18 patients received lisavanbulin. Of the 9 patients with measurable disease evaluable for response in Stage 1, there was 1 PR (RANO −58%) and a second patient with a 44% reduction of the target lesion (SD). These patients, and two others with non-measurable disease are ongoing for >10 months. Despite sustained activity in these patients, formal stage transition criteria were not met within the predefined evaluation period, and the study was closed. While IHC testing for EB1 did not show sufficient enrichment for response, RNA-seq analyses identified a 5-gene response signature.

Conclusions

This phase 2a study supports previous study results that lisavanbulin is associated with durable responses and clinical benefit in a subset of patients with GBM. RNA-seq analyses of GBM samples suggest further evaluation of the lisavanbulin predictive response signature.

Clinical trial identification

NCT02490800.

Editorial acknowledgement

Legal entity responsible for the study

Basilea Pharmaceutica International Ltd, Allschwil.

Funding

Basilea Pharmaceutica International Ltd, Allschwil.

Disclosure

J.S. Lopez: Financial Interests, Personal, Advisory Board: Roche Genentech, Basilea, Ellipses Pharma, Cureteq, Pierre Faber; Financial Interests, Institutional, Research Grant: Roche Genentech, Basilea, Astex. S. Häfliger: Financial Interests, Institutional, Advisory Board, 21.01.2021: Novartis; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Advisory Board: Takeda; Financial Interests, Institutional, Expert Testimony: Roche. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Fabre, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as Member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as Member of IDMC: GSK. P.M. Clement: Financial Interests, Institutional, Invited Speaker: Bristol-Myers Squibb, Astra Zeneca, Orbus; Financial Interests, Institutional, Advisory Board: MSD, AbbVie, Bayer, Rakuten, Merck, Vifor, Leo Pharma, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Astra Zeneca; Financial Interests, Institutional, Invited Speaker: Rakuten; Financial Interests, Personal, Invited Speaker: Basilea; Non-Financial Interests, Personal, Advisory Role: KCE; Non-Financial Interests, Personal, Advisory Role on reimbursement of pharmaceutical specialties in Belgium (Substitute Member): CTG; Non-Financial Interests, Personal, Member: ASCO, EHNS, BANO, SNO, EANO, EORTC, EURACAN, AACR, BSMO; Non-Financial Interests, Personal, Leadership Role: VWHHT; Other, Personal, Other, Advisory Role ad hoc with payment to my institution: EMA. H. Läubli: Financial Interests, Institutional, Expert Testimony: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Palleon Pharmaceuticals, GlycoEra; Financial Interests, Institutional, Invited Speaker: Novartis. P. Roth: Financial Interests, Personal, Expert Testimony: Roche, Merck; Financial Interests, Personal, Advisory Board: BMS, Virometix, QED, Debiopharm; Financial Interests, Personal, Invited Speaker: Novocure; Financial Interests, Institutional, Funding: Novocure; Financial Interests, Institutional, Invited Speaker: MSD. T. Evans: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Clovis, Eisai, Medivir, MSD, Nucana, Roche/Genentech. B. Wunderlich: Financial Interests, Personal, Full or part-time Employment: Discovery Life Sciences Biomarker Services GmbH. K.D. Beebe: Financial Interests, Personal, Officer: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics. J. Eisner: Financial Interests, Personal, Full or part-time Employment, Clinical And Translational Development: GeneCentric Therapeutics. M. Engelhardt, H.A. Lane: Financial Interests, Personal, Full or part-time Employment: Basilea Pharmaceutica International Ltd; Financial Interests, Personal, Stocks/Shares: Basilea Pharmaceutica International Ltd. P. Hau: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, GlaxoSmithKline, Merck, Sharp & Dome, Novocure; Financial Interests, Personal, Invited Speaker: Lilly, Medac. T. Hundsberger: Financial Interests, Personal, Advisory Board: Amicus, Sanofi Genzyme, Bayer AG, Novocure. J. Steinbach: Financial Interests, Personal, Advisory Board: Roche, Boehringer Ingelheim, Seagen, Novocure. All other authors have declared no conflicts of interest.