Publications
Partners
Minneapolis - AstraZeneca has a track record of bringing drugs back from the dead. But in the case of the latest setback on a key cancer study, the odds are stacked against the company.
The drugmaker is adamant it has a shot at success after its next-generation treatment failed to slow lung cancer growth more than chemotherapy, a blow that could have killed the trial known as Mystic.
“The most important result is still to come,” CEO Pascal Soriot told reporters July 27.
Almost everybody else is betting against him. The shares slumped 15% the day the initial results were announced. Citigroup analyst Andrew Baum gives Mystic a less than 30% chance. And Sam Fazeli, an analyst at Bloomberg Intelligence in London, said investors should evaluate AstraZeneca based on other metrics and consider any positive results from the study icing on the cake.
“People should assume the trial - not the drug - isn’t going to be a success,” Fazeli said. “Given what happened, the most sensible thing is to assess the company based on everything else.”
Overall survival
Understanding why puts the spotlight on a shift in the way oncology drugs are tested and approved since the arrival of breakthrough medicines offered more options, sometimes in various combinations.
Proving that one single therapy can prolong life - for decades the standard path to approval - has become harder with patients on multiple treatments. Many drugmakers have raised questions about the difficulty of the target.
Not AstraZeneca. The Cambridge, England-based company is pinning its hopes on being able to show that the cocktail of two drugs it’s testing in Mystic can help patients live longer. That’s thanks to an unusual change it recently made to the study, adding overall survival to the primary goals.
There’s no better sign of the daunting challenge ahead for AstraZeneca than the US Food and Drug Administration’s shift in its approach. The regulator has retreated from the gold standard of requiring trials that show that a drug prolong survival before granting approval, a major evolution that was laid out in a recent blog post by Rick Pazdur, director of the FDA’s Oncology Center of Excellence.
“Achieving an improvement in overall survival may not always be possible,’’ Pazdur wrote June 1 on the FDA’s website.
The agency now takes a more encompassing, patient-centric view, speeding to market cancer treatments that achieved alternative targets that can be linked to a better life, if not longer. Those goals include progression-free survival, meaning the tumor stopped growing: That’s the endpoint Mystic missed.
The stock advanced 0.5% to £45.55 as of 09:52 trading on Monday. Astra had soared about 24% earlier this year, briefly climbing past the £55 a share that Pfizer had offered three years ago before being rebuffed.
A key stumbling block to overall survival is what’s known as crossover. Decades ago, when options were scarcer, patients enrolled in a clinical trial would stay with their assigned treatment.
Now, if cancer progresses, doctors typically try another drug when that option is available. The crossover medicine will likely obscure the patient’s survival results.
Crossover drugs
In Mystic, for example, patients got either AstraZeneca’s treatment - a combination of two immuno-therapies, a breakthrough type of drugs that activate the body’s own defense system to attack cancer - or chemotherapy.
Patients who worsened after chemotherapy received another drug approved for lung cancer. (AstraZeneca hasn’t provided detailed information on how much crossover there was). To show an improvement in overall survival, the AstraZeneca cocktail would have to keep patients alive longer than chemotherapy plus the other drug.
“I’m not trying to minimize the importance of overall survival,” Pazdur said in a June interview. “But one has to take a look at the fact that many times overall survival cannot be demonstrated because of crossover.’’
Other companies are tackling the issue. Mystic’s failure left Merck & Co’s Keytruda, plus chemotherapy, as the only approved immuno-oncology drug to treat lung cancer as first-line therapy, at least for now. Merck is now testing Keytruda, which got approved after hitting its progression-free survival target, hoping to show the treatment can also prolong lives.
“It becomes increasingly difficult over time to show overall survival differences,’’ said Roger Perlmutter, Merck’s head of research and development. “Patients who fail a chemotherapy regimen will likely be crossed over.’’
Track record
AstraZeneca executives told analysts that crossovers could eventually help. That’s because of the way trials are structured. Mystic patients whose cancer progressed after getting the experimental cocktail will receive chemotherapy, an approved drug for lung cancer. The length of the lives of those patients would be credited to the combination group in measuring overall survival.
Immuno-therapies, while very effective for some patients, can also take longer to kick in because they don’t attack the tumor directly, AstraZeneca executives said. Roche Holding AG’s Tecentriq, for instance, failed to hit the primary endpoint of overall survival at 12 months in second-line bladder cancer, but showed meaningful improvement longer-term.
The final Mystic results won’t be known until next year, and AstraZeneca CEO Soriot asked for patience. Based on AstraZeneca’s history, he shouldn’t be counted out.
After widespread use of its lung cancer Iressa was halted in the US in 2005 because it failed to show enough benefits, AstraZeneca persevered and identified a new market of patients with a certain mutation that got dramatically better. Soriot himself revived an ovarian cancer drug when he joined in 2012, and the once-scrapped treatment got US approval three years later.
“We have experienced results with Mystic which are not what we were expecting, for sure, but it’s only a matter of time,” he told analysts.
For now, Mystic has been mostly written off. That is, unless AstraZeneca can prove everybody wrong again.
SUBSCRIBE FOR FREE UPDATE: Get Fin24's top morning business news and opinions in your inbox.
Read Fin24's top stories trending on Twitter: Fin24’s top stories
