Late-stage ovarian cancer projects have, unfortunately, seen far more noteworthy setbacks than stand-out successes in the past few years. So it is perhaps unsurprising that the mid-stage pipeline contains relatively few novel projects with data on the horizon.
Those that are attracting attention include AstraZeneca’s first-in-class WEE1 inhibitor MK-1775 and the most advanced immuno-oncology asset in this cancer type, VentiRx’s motolimod, over which Celgene has already staked a claim. With so few successes here, these projects and others under way will be closely watched for signs of progress (see table below).
This analysis only includes projects for which data are awaited, excluding Oxigene’s fosbretabulin, formerly known as Zybrestat, on which detailed phase II data were released last week. The NCI-sponsored study tested the vascular disrupting agent in combination with Avastin, significantly prolonging progression-free survival by 2.5 months in patients with recurrent disease, and by a more notable 3.3 months in those with platinum-resistant disease.
Roche’s blockbuster antibody received its first US approval in ovarian cancer last week, in platinum-resistant patients, a narrow label that could complicate plans to take the combination any further in wider patient populations. And while data from patients are still being collected, any improvement in overall survival has yet to be detected – after 33 events from the 107 patients no difference between the two arms was seen.
Zybrestat is not alone in failing to demonstrate an impact on overall survival. Not one closely watched targeted agent has managed to show an extension of the lives of ovarian cancer patients in recent large studies, despite statistically extending PFS (Therapeutic focus – Survival benefit still eludes ovarian cancer trials, November 12, 2014).
The most recent example of this is Amgen’s trebananib; other phase III disappointments of the past few years include nintedanib, Boehringer Ingelheim’s triple angiokinase inhibitor, and GlaxoSmithKline’s multi-kinase inhibitor pazopanib, branded Votrient.
Ultimately it was the overall profiles of these agents – tolerability and a lack of meaningful impact on either overall or progression-free survival – that meant regulatory approvals were never sought, and trebaninib looks likely to go the same way. And course there are also numerous examples of agents that made it into phase III but failed to show any benefit – Eisai’s anti-folate receptor alpha antibody farletuzumab for example.
|Ones to watch in phase II: selected development projects awaiting results|
|Product||Pharma class||Company||Overall status||Trial ID||Primary completion|
|NGR-hTNF||CD13 APN inhibitor||MolMed||Recruiting (124)||NCT01358071||Dec 2013|
|Oregovomab||Anti-CA125 MAb||Quest Pharmatech||Active, not recruiting (80)||NCT01616303||Jun 2014|
|INCB24360||IDO inhibitor||Incyte||Active, not recruiting (110)||NCT01685255||Oct 2014|
|MK-1775||WEE1 inhibitor||AstraZeneca||Active, not recruiting (120)||NCT01357161||Feb 2015|
|Not yet recruiting (177)||NCT02272790||Apr 2016|
|DCVAC/OvCa||Autologous dendritic cell immunotherapy||Sotio||Recruiting (90)||NCT02107937||Dec 2014|
|Recruiting (60)||NCT02107378||Apr 2015|
|Recruiting (60)||NCT02107950||Mar 2015|
|Fang vaccine||Autologous cancer vaccine||Gradalis||Recruiting (14)||NCT01867086||Sep 2014|
|Recruiting (50)||NCT01309230||Jan 2015|
|PankoMAb-GEX||Anti-MUC1 MAb||Glycotope||Recruiting (210)||NCT01899599||Sep 2016|
|DNIB0600A||Anti-NaPi2b antibody drug conjugate||Roche||Recruiting (92)||NCT01991210||Jan 2016|
|Motolimod||TLR8 agonist||VentiRx||Active, not recruiting (290)||NCT01666444||Mar 2016|
|Pimasertib + SAR245409||MEK 1/2 / PI3K/MTOR inhibitor||Merck KGaA/Sanofi||Recruiting (110)||NCT01936363||May 2016|
|TroVax||Anti-5T4 cancer vaccine||Oxford BioMedica||Recruiting (100)||NCT01556841||May 2016|
Results could emerge any time now from a phase II study of Incyte's IDO inhibitor INCB24360, which was studied in 110 patients in complete remission after first-line chemotherapy. However with a number of deals subsequently put in place to test the project in combination with immuno-oncology assets, it is debatable whether this trial, started back in 2012, will reflect any future development strategy. It could provide a glimpse into potential, however.
MolMed was expected to report results from the 124-patient trial of NGR-hTNF in platinum-resistant patients in the second quarter of this year. This is a combination of a tumour-homing peptide with human tumour necrosis factor; a prior 37-patient single-arm study was stopped early for efficacy.
Next year should see results from MK-1775, a WEE1 inhibitor. AstraZeneca took over development from Merck & Co last year, paying $50m up front. Data from a 120-patient, Merck-run study could emerge mid-year, testing patients with the P53 gene mutation. In an R&D update this week AstraZeneca said it planned to start a phase II combination study with Lynparza early next year, while a decision on whether to push into phase III will also be taken at some point in 2015.
Later in 2015 could also see results from Quest PharmaTech’s trial of oregovomab, an anti-CA125 antibody that works by stimulating the immune system; recruitment completed in July. The future of the financially distressed company appears to be the biggest risk to this study, however.
Results from the two autologous immunotherapies are likely to be further away.
Sotio, a private Czech-based biotech, is seeking to recruit more than 200 patients over three European trials of its immunotherapy DCVAC, having won US orphan drug designation in 2013. The company describes the project as an active cellular immunotherapy created from the dendritic cells of individual patients – very reminiscent of the now bankrupt Dendreon’s premise.
Gradalis, a private Texan biotech, is also working on a personalised immunotherapy, although this is described as a cancer vaccine that is created from a portion of a patient’s tumour after surgical removal.
One of the largest phase II studies in this analysis is being run by Germany’s Glycotope, which raised €55m ($69m) in a substantial private financing earlier this year. It is recruiting patients into a large maintenance study of its MUC1 targeting antibody, PankoMAb-GEX.
However VentiRxis conducting the biggest phase II trial, a 290-patient study that completed recruitment earlier this year, assessing motolimod in patients with recurrent or pesistent disease. The company has boldly chosen overall survival as the primary endpoint, hence the wait for a readout.
Motolimod is a TLR8 agonist that directly activates multiple components of the innate immune system, and appears to be the most advanced immuno-oncology asset being tested in ovarian cancer. Celgene has an option to buy the company pending certain clinical milestones in this and another study in head and neck cancer.
The swift progress seen elsewhere with immuno-oncology projects means the phase II ovarian cancer pipeline could easily see new additions emerge in the coming months. Considering the swift progress seen in other tumour types, the hope has to be that this approach can have a similar impact.