Asco – Puma might have to rely on extended follow-up
Having already fallen heavily two weeks ago on the publication of the Asco abstract on its breast cancer project neratinib, the real question on Monday was how much more shares in Puma Biotechnology would drop with the presentation of full data from the much-anticipated ExteNET study. The answer was 13%.
Given the high proportion of patients who experience unpleasant side-effects on neratinib, doubts had already been expressed as to whether the benefit demonstrated in ExteNET was sufficient to justify its use in the extended-adjuvant breast cancer setting. Neratinib's mediocre performance now leaves Puma reliant on longer-term follow-up data to convince clinicians – and possibly even regulators – of its merits.
ExteNET showed a statistically significant increase in disease-free survival after one year of treatment in women who had already completed one year of Herceptin adjuvant therapy. Unfortunately, it also showed that 40% of these otherwise healthy women experienced grade 3 diarrhoea.
Puma has repeatedly stressed that no anti-diarrhoeal medication was allowed in the ExteNET study, and argued that in subsequent studies, where patients were given prophylactic high-dose loperamide, the incidence of grade 3 diarrhoea was reduced to around 17% of patients.
However, clinicians seem to consider that even this is high. The prevailing wisdom seems to be that based on its current profile neratinib would only be used in women considered at high risk of progression.
ExteNET met its goal of showing a significant improvement in disease-free survival (DFS) over placebo, but with a surprisingly small absolute difference (Asco preview – Puma leaves investors growling in disbelief, May 14, 2015). The study showed that 93.9% of patients on neratinib were disease-free at two years versus 91.6% on placebo, a difference of just 2.3 percentage points. This absolute difference varied from 1.4 to 2.9 points depending on how disease-free survival was defined.
Puma had primed investors to expect a larger difference if only centrally confirmed Her2-positive patients were considered, as Her2 testing at local sites is presumed to be less exact. This was indeed the case: the presentation revealed that the two-year DFS rate in this group was 94.7% for neratinib and 90.6% for placebo. This represents a significant 49% reduction of risk of invasive disease recurrence or death.
Another criticism, voiced by the breast cancer expert Dr Hal Burstein of Dana Farber Cancer Institute in an interview with EP Vantage, was that two years was too short to understand neratinib’s benefit properly. Dr Burstein suggests that Puma might need to generate longer-term follow-up data to convince clinicians to use the product.
The company is collecting data that will allow comparison on DFS at five years, but there is a complicating factor in that Wyeth, neratinib’s initial owner and the ExteNET trial’s original sponsor, discontinued follow-up some years ago when the study was thought unlikely to render a positive result.
Going back after the fact is likely to be fraught with difficulties as key data on exactly when progression occurred – and in what form – might be missing. There is also a risk that the statistically significant difference in DFS seen at two years could disappear with longer follow-up.
Investors are also concerned that Roche’s ongoing Aphinity trial, which combines chemotherapy with Herceptin and Perjeta, could improve DFS to a greater degree than that seen with the current chemotherapy plus Herceptin regimen. This would leave little room for neratinib to show an additive benefit.
Puma intends to file neratinib for approval in early 2016, but long-term follow-up data may only become available the following year. In the meantime, Puma’s campaign to win back investor support – an analyst event at Asco – did not seem to work. Shares are down another 14% in early trading today.