It has been two years since Tocagen upsized its pivotal Toca-5 study, focusing its investment case squarely on the result, and since the trial involves recurrent brain cancer failure is much more likely than success. But the group’s chief executive, Marty Duvall, accepts that a third outcome is also a real possibility.
The trial could result in a smaller than expected survival benefit that misses statistical significance yet is clinically meaningful – a scenario that, if backed by supportive secondary endpoints, would be taken to regulators, he tells Vantage. Investors, who have sent Tocagen’s stock down 60% year to date, will know soon enough.
At issue is whether the 403-subject study is sufficiently powered to deliver its desired 4.5-month median overall survival benefit favouring Tocagen’s project, Toca 511 & Toca FC. In the setting of recurrent brain cancer a 4.5-month benefit is an aggressive goal.
Toca-5 is 85% powered to detect a 31.5% reduction in the risk of death at 257 events, expecting mOS of 14.3 months for Toca 511 & Toca FC versus 9.8 months for control. Mr Duvall accepts that this represents a big effect size, but says the assumptions are in line with what Tocagen had seen in phase I.
“In the case of a miss on the mOS endpoint with a trend on survival and positive secondary endpoints we’ll do everything we can to get this product over the regulatory line,” he states. Secondary endpoints include 12-month survival and durable response rate.
|Project||Toca 511 & Toca FC|
|% of mkt cap||821%|
|Event||Final readout of Toca-5 study|
The Tocagen project hinges on the view that 5-FU is an effective cancer chemotherapy that is plagued by haematological toxicities. To deliver high-dose 5-FU locally with improved safety the two-part project combines Toca 511, a retroviral replicating vector (RRV) coding for cytosine deaminase, injected locally, with Toca FC, a 5-FU prodrug, given orally.
RRVs are, like oncolytic viruses, believed to preferentially infect dividing cancer cells, but unlike oncolytic viruses they are non-lytic. Once the prodrug is dosed, the thinking goes, it is converted locally into 5-FU by the cysteine deaminase that Toca 511 has encoded.
If this sounds like rocket science Mr Duvall disagrees. “Neurosurgeons are fired up about this ‘additional tool’,” he says, insisting that injecting the retrovirus into the brain cavity is just an adjunct to normal surgery; Toca FC is then dosed orally every six weeks.
So has it got a chance? A big caveat is that a phase I effect tends to wane in the more rigorous pivotal setting, something that Celldex learned with Rintega.
A second question is how the control cohort will perform. Toca-5 enrolled subjects who had failed one or two lines of therapy; the control arm of Bristol-Myers Squibb’s Checkmate-143 study in recurrent subjects showed median OS of about 10 months.
Interim green light
A separate issue that has vexed the markets is the two interim analyses that Toca-5 passed. Neither was designed for a stop in the event of futility, largely to preserve statistical power and “provide the greatest possible opportunity to generate compelling data”.
However, the Tocagen bull case accordingly became an early study stop on knockout results; if Toca-5 was merely continued, which is what happened, futility could not be ruled out, and the stock sold off.
Toca-5 actually started out as a 187-patient study designed to yield final data in 2018, but the decision to upsize it was taken after Toca 511 & Toca FC got US breakthrough designation. “We saved two or three years’ development, but we took away a datapoint,” says Mr Duvall.
In the coming months he will find out whether this gamble was worth taking.