With Roche (OTCQX:RHHBY) today saying its Aphinity trial of Perjeta delivered a positive result biotech investors have seen a key binary event of 2017. True, nothing has been revealed about Perjeta’s numerical benefit, but for Puma’s (NYSE:PBYI) neratinib things could hardly have been expected to be worse.
The likely timeline now has full Aphinity data being released at Asco – perhaps at the meeting’s plenary session, given Aphinity’s potential to be practice changing in breast cancer treatment. Puma will cling to neratinib’s vanishing potential in a patient subgroup, but the US FDA should now have ammunition to deal neratinib a fatal blow after a post-Asco adcom.
Perjeta and neratinib were set on this collision course after neratinib was delayed by a tweak to the statistical analysis of its Extenet trial. Extenet and Aphinity both concern extended adjuvant treatment of Her2-positive breast cancer patients who have initially been given Roche’s Herceptin.
True, they have slightly different designs, though they both measure efficacy in terms of invasive disease-free survival (iDFS).
Aphinity gave patients Perjeta plus Herceptin for a year versus Herceptin alone; Extenet had neratinib being given alone after a year’s Herceptin, presumably on the grounds that the Hera trial had shown two years’ Herceptin to give no added benefit over one.
Either way, the positive hit in Aphinity could render neratinib irrelevant, since the benefit the Puma project has shown in Extenet is tiny and questionable owing to vast amounts of patients being censored (Event – Roche has Aphinity for Perjeta trial success, but not Puma, January 5, 2017).
Moreover, neratinib treatment has been associated with serious diarrhea, notwithstanding Puma’s attempts to mitigate this with Imodium. Roche investors today breathed a sigh of relief, sending the stock up 6%, while Puma crashed 20% in early trade.
Investors will now want to know just how strong a benefit Perjeta has shown in Aphinity. A theoretical risk is that given the trial’s size – nearly 5,000 patients – strong statistical significance is possible from a marginal numerical benefit.
However, Roche previously revealed that it was keen to get a positive result into Asco; the deadline for submitting late-breaking abstracts for the meeting is March 16. It is virtually inconceivable that Roche would hold back borderline data for submission as an Asco late-breaker.
UBS analysts put it more strongly, earlier stating that, based on various analytical models, “Statistical geekery tells us what the worst possible good result looks like; and it ain't bad ... statistical significance likely means clinical significance.”
Beyond Aphinity being potentially practice changing, its positive readout has important repercussions for Roche, which now has a good defence against Herceptin biosimilars. Payers could see Perjeta and Herceptin bundled together at an attractive price as preferable to negotiating separately with Roche and biosimilar makers.
Neratinib has an FDA action date of July 20, with an advisory panel expected to be convened before that. Importantly, this will come after the potential Asco presentation; true, Perjeta will not yet have the Aphinity data on its label, but a practice-changing trial would be difficult for the panel and FDA to ignore.
Puma’s last hope will be to cling to neratinib’s purported benefit in a post hoc subset of hormone receptor-positive patients, but whether reviewers buy this is anyone’s guess. Meanwhile, it has been hit by an EU knockback, with regulators there telling it to restrict neratinib’s filing to patients initiating treatment within a year of completing Herceptin.
More fireworks should be expected at the US adcom, particularly over uneven Extenet patient censoring and other data analyses; in its annual filing with the SEC, for instance, Puma revealed that only 60% of the patients in Extenet had been assessed for Her2 status – a major red flag since Her2-positive is the target population.
And then there is the diarrhea side effect – an even more serious problem if in Perjeta patients have an efficacious and relatively safer alternative. For Puma the proverbial just hit the fan.
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