Therapeutic focus – Much activity in glioblastoma but little hope for imminent improvements

The rollercoaster performance of ImmunoCellular Therapeutics’ share price in response to release of clinical data on its glioblastoma immunotherapy – first positive, then disappointing – points to the huge unmet need in this disease. This has been further underlined by the similar levels of investor excitement engendered last week by the five-year survival seen with Agenus’ cancer vaccine in the same disease.

But the great difficulty of making a difference in glioblastoma is highlighted by the high-profile failures in this space, of which ImmunoCellular’s ICT-107 may come to be the latest. Merck has been forced to abandon cilengitide and Avastin’s showing in the first-line setting has so far been less than breathtaking. There are now just three novel drugs being tested in phase III - including Avastin - and a review of the mid-stage pipeline reveals few prospects of new breakthoughs any time soon (see tables below).

Speculative

An analysis of active phase III glioblastoma trials testing novel therapeutic agents reveals that all are being tested in a first-line setting; the first to report will be a 300-patient study of Northwest Biotherapeutics’ DCVax-L.

However there are enormous question marks over this company and the product, not least the similarities between it and ImmunoCellular's ICT-107.

Investigators running a tiny phase I trial of ICT-107 in late November reported impressive survival rates in a couple of patients, but confirmatory phase II data this month illustrated just how unreliable a marker of success small studies can be. The 124-patient trial failed to hit its primary endpoint, with no benefit in overall survival detected, although progression-free survival, a secondary endpoint, was significantly extended, by two months compared to placebo. Shares in the company plunged 60% on the news (Celldex and ImmunoCellular fall and rise on hype and hope, November 26, 2013).

ImmunoCellular intends to continue to track overall survival in the study in case the final reading improves, but the signs are not promising. Northwest must hope it can defy this distressing precedent; it is by no means certain that dendritic cell vaccines such as ‘107 and DCVax-L can elicit a strong enough immune response to substantially improve survival. Additionally, it is widely accepted that cancer vaccines have to be administered over a long period of time to work, and the average glioblastoma patient survives just 14.6 months after diagnosis. Should any signal of efficacy be seen, combining these therapies with more potent drugs could well be a path forward for the future, if funding can be secured.

The other fairly speculative candidate in phase III is Celldex Therapeutics’ CDX-110 or rindopepimut, an immunotherapy previously being developed with Pfizer, but that was handed back in 2010. Two relatively large trials are ongoing, the phase III Act-IV study in newly diagnosed patients, and the phase IIb React trial, in recurrent glioblastoma. Early data from React released in November was hard to interpret but not particularly encouraging, and the jury certainly remains out on the prospects for the product.

Avastin has won conditional approval as a second line therapy in the US on the basis of objective response rates seen in a single arm study, but the company is attempting to confirm the drug's place in this disease with further studies. Two phase III trials are currently active; a first line study conducted under the auspices of the NIH ought to report soon, while a confirmatory second-line study was only started this year by the company.

Final data from the first-line AVAglio study reported at the the Society of Neuro-Oncology meeting in November showed that while Avastin extended progression-free survival by 4.4 months, it did not show a statistical improvement in overall survival.

Merck & Co’s Temodar, the main first-line therapy, was approved in 1999 on the strength of a 10-week improvement in overall survival when added to radiotherapy. It remains the only drug to show a significant effect on survival in newly-diagnosed glioblastoma in a rigorous phase III trial.

Tyrosine kinase inhibitors

Outside of phase III numerous agents are being trialed - Avastin is being widely tested elsewhere - but it is interesting to note that a large proportion of the substantial phase II studies EP Vantage has identified are investigator-sponsored studies (ISS), run by independent researchers. That the big pharma owners of these agents have elected to invest in other indications, leaving glioblastoma to the non-profits, is a telling sign of the difficulty in showing efficacy in this disease, as well as its relative scarcity and thus smaller commercial potential.

Investigators at hospitals and academic groups have selected many of the industry’s more potent small molecule tyrosine kinase inhibitors for their phase II trials. The table below highlights two of Pfizer’s TKIs, the pan-HER-targeting dacomitinib and VEGFr-inhibiting Inlyta, or axitinib, which is already marketed for renal cell carcinoma; both are the subject of two studies.

Also being put through fairly large trials by various independent groups are Novartis’s PI3K inhibitor buparlisib, or BKM120, which the pharma giant has in phase III in breast cancer; GlaxoSmithKline’s Tykerb, which targets EGFr and HER2 and is already approved in breast cancer, is also under investigation in glioblastoma.

Very few of the studies in the analysis, though, will be able to generate anything more than exploratory data. Most are open label and single arm – glioblastoma is a huge unmet need but more rigorous studies will have to follow if promising signals are seen.

Exceptions to this are the studies being run by the big pharma companies themselves. Roche’s onartuzumab ought to be the first of the new phase II drugs to report data – the company has confirmed to EP Vantage that recruitment in this trial has been completed and that results are expected in 2014. Importantly, these data will confirm whether the anti-c-Met MAb can add anything to Avastin in this disease, and will also give an insight into c-Met inhibition – also a tyrosine kinase, c-Met is implicated in variety of cancers – itself.

Lilly’s LY2157299, also called galunisertib, is a TGF-beta RI kinase inhibitor being tested in combination with chemotherapy and as a monotherapy; combination with chemotherapy forms the active control arm of the trial.

It is a fair bet that, if the studies of onartuzumab and LY2157299 show significant benefits in survival – no mean feat, after all – the companies will seek, and very possibly be granted – an accelerated path to approval.

But even if they succeed, these agents are still quite a way from the market. And proof that these supposedly potent and targeted agents can add anything to old-fashioned chemotherapy is still to be found.

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