Pfizer has not won its 100-1 bet on palbociclib, but still could win its 10-1 wager. The pharma giant disclosed that it had failed to get a win on overall survival in an interim analysis of the Paloma-1 first-line breast cancer trial, a revelation that will probably keep it from filing for approval on phase II data.
The project is not dead, though – not by a long shot: the progression-free survival (PFS) benefit when administered with letrozole looks decisive over letrozole alone. Still, hope for a filing in the coming weeks had risen so high that the news was enough to take shares of the mighty Pfizer down 3% to $31.32 in mid-morning trading, wiping away $6bn in market capitalisation.
Best ever not good enough
This PFS benefit, should it be confirmed in phase III, ought to make palbociclib approvable. The data, outlined yesterday at the American Association for Cancer Research meeting in San Diego, showed PFS of 20.2 months – double letrozole’s 10.1 months, and a significant improvement at p=0.0004. The 10.1 months' difference was, however, a drop from the PFS benefit of 18 months found at an interim analysis.
ISI Group analyst Mark Schoenebaum said this deterioration was disappointing, helping push the selloff this morning. But he noted that the finding was suggestive of a very beneficial drug: “It’s still the best that has ever been seen in this breast cancer population.”
As for an overall survival (OS) finding, a more reasoned review should have revealed a significant difference here to be an unlikely outcome in this scenario. This population, oestrogen receptor-positive and human epidermal growth factor-2-negative patients, typically lives three to four years after diagnosis.
Out of 165 patients in Paloma-1, only 15 had died at the interim OS analysis date, meaning that showing an overall survival benefit was “mathematically insurmountable”, Mr Schoenebaum said. “This should have been the base-case street expectation.”
Today's selloff was a sign that expectations had got well ahead of reality, an increasingly common event in today’s pharma and biotech market. The idea was that an OS advantage would lead to a launch as early as 2015 based on the FDA’s assignment of breakthrough therapy status, as JP Morgan analysts forecast (Event – Paloma faith essential to palbo bull case, March 25, 2014). This would have put Pfizer more than a year ahead in the cyclin-dependent kinase (CDK) 4 & 6 inhibitor space, where Novartis’s LEE011 is a strong contender.
Pfizer has not tipped its hands on filing plans, saying it is discussing the path forward with the FDA and other regulators. One additional concern beyond less than compelling OS results is potential cardiac events; regulators might want to see more safety data before giving an OK.
Mr Schoenebaum has not dismissed the possibility of a phase II filing, but adds that if phase II is not sufficient Pfizer might not have to wait for pivotal data. However, a final Paloma-1 OS analysis will have to turn out well, and interim phase III results will have to look good for a pre-pivotal filing to go ahead. The worst-case scenario would be the need to wait for complete phase III data, which would close the gap between palbo and LEE011.
Palbo’s perceived potential began to grow once Amgen showed itself willing to pay $10.4bn for its originator, Onyx Pharmaceuticals, in August, but it could now be viewed as a victim of unrealistic expectations. Palbo has not been shown to be a failure at all, but looking a little less distinguished has turned out to be damaging enough.