Positive results of Nerlynx’s Nala trial in third-line Her2-positive breast cancer have provided Puma Biotechnology with a handy distraction. Investors have so far had to contend with the company’s plummeting valuation and the drug’s underwhelming performance in its approved indication of extended adjuvant breast cancer treatment.
How relevant the Nala data are in the real world is a separate question, however. The lack of an overall survival benefit versus Novartis’s Tykerb – itself a somewhat irrelevant player in the metastatic third-line setting – do not bode well for Nerlynx, even if it does secure this additional use on its label.
Still, US approval is not out of the question. Nala had been run under a special protocol assessment, implying that the FDA supported its analysis plan, under which a win on either the PFS or the OS co-primary endpoint would have deemed the result positive.
In the event Nala’s statistical analysis showed a strong win on PFS: the p value of 0.0059 cleared the multiplicity-adjusted significance barrier of 0.01. OS, however, came in with a clearly non-significant p of 0.21.
Until the absolute numbers are revealed at a scientific meeting the real benefit remains unclear. According to Stifel analysts Nerlynx has shown a 64% response rate and 40-week median PFS in previous third-line breast cancer clinical trials.
In the specific setting of Nala patients had to have failed at least two lines of therapy, meaning that they will likely have progressed on the first-line standards of care of Herceptin and/or Perjeta, and second-line Kadcyla. An unspecified number had also failed a third line of therapy, Puma said.
|Her2-positive metastatic breast cancer treatment|
|Setting||Current option(s)||Additional clinical trials|
|1st line||Herceptin +/- taxane||Tykerb failed to improve PFS (MA.31 trial)|
|1st line||Herceptin + Perjeta +/- taxane||Nerlynx failed to improve PFS (NEfERT-T)|
|1st line||Kadcyla failed to improve OS (Marianne)|
|2nd line||Kadcyla||Possible Tykerb + Herceptin PFS benefit (EGF104900)|
|3rd line||Tykerb + Xeloda||Nerlynx + Xeloda extended PFS, not OS (Nala)|
|3rd line||Herceptin (off label) + chemo|
|Source: product labels, Asco.|
One problem is the use of Tykerb as comparator. This Novartis drug is the formal third-line standard, but Herceptin is often used off label. Tykerb last year sold only around $100m, less than a third of its 2012 peak.
Puma stressed that Herceptin was not brain penetrating, and thus could not hit brain metastases, an attribute that it has long maintained is a key advantage of Nerlynx. The company also pointed out that metastatic breast cancer drugs including Ibrance, Afinitor and Femara had been approved on the strength of PFS alone.
But it is not immediately clear why, even if Nerlynx is approvable on the Nala data, a doctor should prescribe it if it does not extend a patient’s life. Thus even Tykerb’s paltry revenue figures might be out of reach for Puma; earlier this year Leerink forecast peak sales of $300m for Nerlynx in third-line breast cancer.
The drug was launched for extended adjuvant use in July 2017, and its first four quarters on the market have resulted in sales of $113m. Sellside consensus for 2024 revenue, meanwhile, has fallen from $1.5bn in April to $697m currently, according to EvaluatePharma.
A year ago Leerink had suggested that in light of Nerlynx’s notorious toxicity of diarrhoea the market was assuming just 15% penetration of the extended adjuvant setting and no third-line metastatic use. Since then Seattle Genetics has bought Puma’s rival Cascadian Therapeutics, and Puma stock has fallen 80%.
Even though the shares climbed 5% this morning, the Nala data alone look unlikely to reverse this trajectory.