Therapy focus: no giving up on brain cancer

Glioblastoma is one of the hardest tumour types to treat, and the failure last week of a gene therapy being developed by Vascular Biogenics served as yet another reminder of the difficulty.

But the fact is that with risk comes opportunity, and a search of EvaluatePharma reveals a huge mid-stage industry pipeline of assets targeting this disease. Indeed, at least five are still in phase III development (see table below). While all are risky, advanced biologicals, especially those targeting immune system checkpoints, should be watched with interest.

The most advanced checkpoint therapy in glioblastoma is Bristol-Myers Squibb’s Opdivo. This is in two phase III studies – Checkmate-498 and Checkmate-548 – in which it is being tested either versus Merck & Co’s Temodar or on top of this drug, respectively, in newly diagnosed patients.

These represent Bristol’s immediate shots on goal after last year’s failure of Checkmate-143, which pitted Opdivo with or without Yervoy versus Roche’s Avastin in second-line subjects. Temodar is a front-line chemotherapy in glioblastoma, and patients who progress after receiving it can be given Avastin; the Roche drug has separately failed in the first-line setting.

Global failure

The fact that there has been no real advance in treating glioblastoma since Temodar’s first-line approval back in 1999 shows just how tough this cancer is, and failures are frequently shrugged off.

No such luck for Vascular Biogenics, whose phase III Globe trial added the group’s VB-111 gene therapy on top of second-line Avastin. Last week’s revelation that Globe had failed to extend patients’ overall survival sent the company’s stock down 60%. The crash was partly because VB-111 was Vascular’s lead asset, but also because it had actually extended OS and PFS in phase II.

Replicating promising mid-stage data in phase III is a particular problem in glioblastoma. Patients can be poorly characterised, meaning that treatment cohorts have differing baseline characteristics, and since many mid-stage trials rely on historical controls the picture that emerges can be misleading.

Meanwhile, the controversial Northwest Biotherapeutics had clinical hold on a pivotal glioblastoma study of its DCVax-L dendritic cell vaccine lifted in February 2017, and without reaching the planned recruitment target nevertheless proceeded to trial readout. A year later – 16 years since the phase III trial was first posted on Clinicaltrials.gov – results have still not been announced.

Other immune system strategies in advanced glioblastoma trials include Green Cross Cell’s activated T lymphocyte therapy Immuncell-LC, and Cell-Medicine’s cancer vaccine AFTVac. The former was reported to have extended overall survival in first-line patients versus Temodar, and though this did not hit statistical significance the project remains a focus for the South Korean group.

Meanwhile, investors following the fortunes of US companies will note two late-stage assets in development at Abbvie and Celgene – the antibody-drug conjugate depatuxizumab mafodotin and the proteasome inhibitor marizomib – though Celgene's focus is multiple myeloma, and marizomib’s phase III glioblastoma trial is being sponsored by the academic group EORTC.

Depatuxizumab could yield data in 2020 from its first-line pivotal study, in which it is also being added on top of Temodar, but which is taking an interesting biomarker-based approach, focusing on subjects with EGFR amplification.

Selected phase III industry assets targeting glioblastoma multiforme
Project Pharmacology Company Trial ID Notes
Opdivo +/- Yervoy Anti-PD-1 Mab +/- anti-CTLA 4 MAb Bristol-Myers Squibb/Ono NCT02617589, NCT02667587 Checkmate-498 vs Temodar, Checkmate-548 on top of Temodar, both 1st line; data 2019
Depatuxizumab mafodotin Anti-EGFR MAb-monomethyl auristatin F conjugate Abbvie/Seattle Genetics NCT02573324 1st line, on top of Temodar, in patients with EGFR amplification
Marizomib Proteasome inhibitor Celgene/Triphase Accelerator NCT03345095 1st line, on top of Temodar, trial to begin April 2018 
DCVax-L Cancer vaccine Northwest Biotherapeutics NCT00045968 Hold lifted Feb 2017, with trial proceeding to readout; still no data
Immuncell-LC Immunostimulant Green Cross Cell NCT00807027 1st-line trial on top of Temodar completed; numerical, but not stat sig, extension of survival
AFTVac Cancer vaccine Cell-Medicine (none) Private Japanese company
JP001 (siroquine) Undisclosed Johnpro Biotech NCT03008148 1st-line trial on top of Temodar due to start Jan 2017, but not yet recruiting
Transcrocetinate sodium Vitamin A analogue Diffusion Pharmaceuticals (none) Private US company
Vocimagene amiretrorepvec + flucytosine Gene therapy & pyrimidine analogue  Tocagen NCT02414165 On top of Temodar or Avastin; data 2019
VB-111 (ofranergene obadenovec) Anti-angiogenic gene therapy Vascular Biogenics NCT02511405 Failed in 2nd-line Avastin combo study
OT-101/AP 12009 (trabedersen) TGF beta 2 antisense Oncotelic/Autotelic NCT00761280 Trial (Sapphire) terminated early; last reported phase I/II data at AACR 2017
Source: EvaluatePharma and Clinicaltrials.gov.

The intractable nature of glioblastoma and the many failures that, before VB-111, included even well-designed trials like that of Celldex’s Rintega, will weigh heavy with investors.

But the extent of the industry pipeline shows just how much promise any advance on Temodar or Avastin would represent. Earlier in development than the projects listed above are such important assets as Lilly’s Lartruvo, Merck’s Keytruda, Astrazeneca’s Imfinzi, and Gilead’s CAR-T therapy targeting EGFRvIII.

And the extent of Vascular Biogenics’ fall last week will suggest how much expectation is invested in some of the upcoming readouts.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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