Investors appear to be resetting their expectations for Puma Biotechnology's experimental HER2-positive breast cancer treatment neratinib. An abstract released last week – ahead of this year's ASCO annual meeting (May 29 – June 2) – indicates that neratinib's superiority versus placebo in 'extended adjuvant' patients (those treated with neratinib following 12 months of adjuvant therapy with Herceptin) is not as pronounced as expected (ViewPoints: As the ASCO abstract dump claims its biggest casualty, Puma Biotechnology CEO argues for a reprieve).
An absolute difference of 2.3 percent in favour of the neratinib arm – 93.9 percent of patients achieved invasive disease-free survival (DFS) at two years versus 91.6 percent of patients in the control arm – prompted Puma's shares to decline by around 20 percent.
As discussed here, Puma's disclosure nearly a year ago that neratinib had achieved a hazard ratio of 0.67 in the ExteNET study raised expectations significantly, both among investors and physicians polled by FirstWord, as well as among analysts who have frequently touted Puma as a likely large-cap acquisition target.
The new data suggest these expectations will need to be revised, particularly when the efficacy demonstrated by neratinib is considered alongside its side-effect profile and high rates of grade 3 diarrhoea.
Even prior to recent publication of the ASCO abstract, which has raised question marks over efficacy benefit in the extended adjuvant setting, key opinion leaders (KOLs) interviewed by FirstWord for a forthcoming report on the breast cancer landscape (for more details click HERE) cited neratinib's side-effect profile as a preclusion to widespread use. They instead suggest that if approval is secured, it is likely to be as a third- or fourth-line 'salvage therapy' used in the metastatic setting.
Puma CEO Alan Auerbach has suggested that the prognosis for neratinib should improve when further data is presented at ASCO. Only locally confirmed HER2 positivity was required for enrolment in the ExteNET study and around 80 percent of these patients were subsequently confirmed to be HER2 positive upon central testing. Thus the absolute difference in DFS between the neratinib and control arms should widen, argues Auerbach, with analysts at Leerink suggesting it could expand to around 4.5 percent. Furthermore, they argue that any further improvement of over 4 percent in disease-free survival with 1 year of neratinib over a 6 percent improvement from the current standard care of 1 year of Herceptin to be highly clinically significant.
A notable read across from the abstract is just how effective Herceptin is at treating HER2-positive breast cancer, argue analysts at Stifel; a view backed up by a chorus of KOL opinion in FirstWord's new Therapy Trends report.
A key point of debate around the commercial opportunity for neratinib is tied to Roche's ongoing study of Herceptin and Perjeta in the adjuvant setting (in the APHINITY study) as a means of potentially enhancing Herceptin's efficacy profile, which KOLs indicate has a high chance of success. Auerbach has played down the significance of the APHINITY study as neratinib's potential use in the 'extended adjuvant' indication (i.e. after 12 months Herceptin or Herceptin/Perjeta therapy) represents a distinct setting.
Roche's ability to enhance the treatment paradigm for adjuvant patients may also be shaped by results from the KATHERINE study, where Kadcyla is being assessed head-to-head versus Herceptin. KOLs are more sceptical towards a positive result from this trial, however, given publication of disappointing top-line data from the MARIANNE study in December.
Reasons to Purchase
To better ascertain the impact of new data for neratinib and ongoing studies being run by Roche in the adjuvant setting, we are asking US and EU5-based oncologists the following questions…