Ash 2022 preview – Brukinsa has the edge over Calquence

When Astrazeneca’s Calquence challenged Imbruvica’s most important setting of chronic lymphoblastic leukaemia it became the BTK inhibitor that others had to beat. Yesterday an Ash late-breaker suggested that Beigene’s Brukinsa had done precisely this – at least on a cross-trial basis.

Beigene’s Alpine trial features among six just unveiled Ash late-breaking abstracts, and shows the extent to which Brukinsa has beaten Imbruvica head to head. Nevertheless, Beigene shares fell 9%, possibly on concerns over whether the PFS benefit would hold up longer term; or maybe Beigene investors just saw this as a clearing event for a stock that had climbed 55% since October 11.

That surge had been triggered when Beigene first toplined Alpine, a trial in relapsed/refractory CLL. Momentum continued when six days ago the EU approved Brukinsa in first-line and r/r CLL, on the basis of the Sequoia and Alpine trials respectively; median PFS and some other safety data from Alpine remained under wraps, however, and have only emerged in the Ash abstract.

The stage is set for a fierce battle between the three US-approved BTK inhibitors. So far only Johnson & Johnson’s Imbruvica and Calquence carry CLL on their labels, but the FDA is to decide on Beigene’s Brukinsa filing by January 20. The Ash abstract suggests that approval is a no-brainer.

In Alpine Brukinsa cut risk of progression by 35% versus Imbruvica, meeting a threshold for superiority with a p value of 0.0024. In Astra’s corresponding Elevate-RR study Calquence only managed to show non-inferiority versus Imbruvica, with identical median PFS values; as of an August cutoff Brukinsa has yet to reach median PFS for in Alpine, but its 24-month PFS rate of 80% beats Calquence’s 70% in Elevate-RR.

Another key win for Brukinsa is a strong PFS advantage over Imbruvica in CLL patients with the intractable 17p deletion mutation; here Calquence had shown no advantage versus the J&J drug.

If there is a concern about the Alpine data it is that the PFS benefit might not hold up with longer-term follow-up. The PFS curves show a fair amount of censoring before the medians, but this does not appear to be disproportionate in one cohort versus the other. No OS data are given in the abstract.

It was OS that impressed in Astra’s Elevate-RR study: though this was non-significant Calquence patients were 18% less likely to die than those on Imbruvica. This might have been thanks to Calquence’s better safety profile versus Imbruvica, which is associated with toxicities such as atrial fibrillation.

However, here too Brukinsa has an edge. Its 5% atrial fibrillation rate in Alpine beat Imbruvica’s 13%, and is better on a cross-trial basis than Calquence’s 9%. In Elevate-RR Calquence was no better than Imbruvica on severe atrial fibrillation (though the patient numbers were low), and information on this metric in Alpine will be keenly awaited at Ash.

As for how the BTK market plays out, much will clearly depend on the three companies’ pricing strategies. Sellside consensus compiled by Evaluate Pharma suggests that Calquence will nearly catch up with Imbruvica’s $5.5bn sales in 2028, but that Brukinsa will lag this, with a 2028 revenue forecast of just $2.5bn.

Beigene will clearly want to turn the tables, and the Ash data support such hopes.

The Ash conference is due to take on December 10-13 in New Orleans, Louisiana.