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Investors appear to be resetting their expectations for Puma Biotechnologys experimental HER2-positive breast cancer treatment neratinib. An abstract released last week - ahead of this years ASCO annual meeting (May 29 - June 2) - indicates that neratinibs 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 Pumas shares to decline by around 20 percent.
As discussed here, Pumas 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 neratinibs 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 FirstWords new Therapy Trends report.
A key point of debate around the commercial opportunity for neratinib is tied to Roches ongoing study of Herceptin and Perjeta in the adjuvant setting (in the APHINITY study) as a means of potentially enhancing Herceptins efficacy profile, which KOLs indicate has a high chance of success. Auerbach has played down the significance of the APHINITY study as neratinibs potential use in the extended adjuvant indication (i.e. after 12 months Herceptin or Herceptin/Perjeta therapy) represents a distinct setting.
Roches 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.
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
- Based on updated efficacy data from the ExteNET study and factoring in that 40 percent of patients in the trial suffered serious diarrhoea, what impact would you expect neratinib to have in the clinical setting for the treatment of extended adjuvant patients?
- Assuming that the absolute difference in DFS between the neratinib and control arms was 4 percent or higher (based on reassessment of HER2 positivity), what impact would you expect neratinib to have in the clinical setting for the treatment of extended adjuvant patients?
- If the combination of Herceptin and Perjeta is shown to improve DFS (primary endpoint) and overall survival (secondary endpoint) versus Herceptin alone in the ongoing APHINITY study, would you expect this to also limit use of neratinib in the extended adjuvant setting?
- What is your opinion towards this statementif approved, neratinib will likely end up in the metastatic setting as a salvage therapy?
- Based on the entrenchment of Herceptin, your experience of using Kadcyla and top-line data from the MARIANNE study (when Kadcyla plus Perjeta was not shown to be superior to Herceptin plus Perjeta in first-line patients), what are your expectations for Kadcyla in the adjuvant setting (currently being trialled versus Herceptin in the KATHERINE study)?
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