Asco – Little fanfare for GemVax and Merck KGaA setbacks

It might at times have seemed as though the Asco meeting saw nothing but success stories, but it did have its share of study failures too, many of which were disclosed with little fanfare at sessions kept under wraps until Monday morning.

Two such setbacks concerned KAEL-GemVax’s cancer vaccine GV1001 and Merck KGaA’s cilengitide. Given the two therapies’ highly risk-prone focus areas – pancreatic cancer and glioblastoma respectively – the failures probably did not come as huge surprises, but they were nevertheless significant for both companies involved.

Littered with setbacks

Not only is the field of pancreatic cancer littered with the corpses of failed candidates, but GV1001 is a cancer vaccine – a treatment approach that was full of early-stage promise yet delivered numerous failures in the clinic. For the privately owned KAEL-GemVax the readout came over six years after the 1,062-patient phase III Telovac trial had been initiated.

GV1001, a telomerase peptide that stimulates an immune response against telomerase, an enzyme over-expressed on tumours, had already changed hands several times. Its originator, Pharmexa, was bought by Affitech after a first study failed, and Affitech sold rights to KAEL-GemVax (GemVax cancer vaccine trial enters final stages, May 10, 2011).

Telovac recruited patients with advanced pancreatic cancer, and randomised them to three groups, given: gemcitabine plus capecitabine; gemcitabine plus capecitabine for eight weeks followed by GV10001; and gemcitabine, capecitabine and GV1001 given concurrently.

The trial did clear three safety audits, but anyone hoping that this presaged a positive outcome was in for a shock. Median overall survival – the primary endpoint – for the three arms was 7.89, 6.94 and 8.36 months respectively.

Because of multiple rounds of data analysis the criterion for statistical significance in an individual arm was set at p<0.0175 rather than the usual 0.05. The p value for median OS in arm two versus arm one was 0.0466, and arm three versus arm one was 0.6378. In terms of overall response arm two actually did worse that arm one, a finding that hit significance with a p value of 0.001.

At least KAEL-GemVac can take some comfort in the fact that its financial exposure in Telovac was limited. The trial had been funded largely by Cancer Research UK, and Royal Liverpool University Hospital is listed on clinicaltrials.gov as its sponsor.

Some hope for the vaccine still remains. A phase I pancreatic cancer study sponsored by Providence Health & Services, a non-profit organisation, is ongoing, while a 600-patient NSCLC study – this one does have KAEL-GemVax as sponsor – was to have started a year ago but has yet to begin recruitment.

Another disappointment

Merck KGaA’s cilengitide also remains in some early-stage trials, but the failure of the phase III Centric study came as a big blow when it was first disclosed in February. The German company has found late-stage pipeline success increasingly hard to come by (Merck KGaA pipeline struggles to produce growth, September 20, 2012).

On Monday the failure was quantified. Cilengitide, an integrin inhibitor, failed to prolong either overall or progression-free survival when added on top of temozolomide and radiotherapy in 545 patients with newly diagnosed glioblastoma with a methylated MGMT gene promoter.

Median OS was 26.3 months in both arms, while median PFS was numerically increased in the cilengitide arm – 13.5 months versus 10.7 months in patients on temozolomide and radiotherapy alone – but this was not statistically significant (p=0.48).

“There is no single subgroup on the forest plot that suggests activity,” said the lead investigator, Dr Roger Stupp, of the Centre Hospitalier Universitaire Vaudois. Because there were no safety issues in Centric an increase in toxicity could not be used as an explanation for the total lack of efficacy, he added.

Analysts had put little store by success in Centric, forecasting 2018 cilengitide sales of only $60m, according to EvaluatePharma’s consensus data. Other glioblastoma projects in late-stage development include Celldex Therapeutics' cancer vaccine rindopepimut, which is in a 440-patient phase III trial. Bio run-up momentum in Celldex is gaining traction, and the company’s stock is up 91% year to date.

Earlier cilengitide studies had suggested improved activity in tumours with methylated MGMT promoters, hence the logic of Centric. One ongoing study is Core, a phase II trial in tumours with unmethylated MGMT promoters, but cilengitide nevertheless looks mortally wounded.

The lack of toxicity does, however, point to one outside chance of a way forward, as summed up by the UCLA’s Dr Timothy Cloughesy: “There is now a huge opportunity to dose [cilengitide] up to a biological effect.”

To contact the writer of this story email Jacob Plieth in Chicago at [email protected] or follow @JacobEPVantage on Twitter