A Calquence win seven years in the making

AstraZeneca’s Calquence looks to have succeeded where AbbVie’s Imbruvica failed, by potentially helping patients with untreated mantle cell lymphoma live longer. The Echo trial hit its progression-free survival endpoint, and a trend to a benefit on overall survival was seen, the company said. 

OS data are not yet mature and the trial will continue to measure this endpoint; the absolute benefit remains important to know here. Full disclosure of these data will be keenly awaited, although Astra would be forgiven for looking over its shoulder at what BeiGene’s Brukinsa might be brewing. 

Brukinsa, which is emerging as the best covalent BTK inhibitor in the much larger chronic lymphoblastic leukaemia setting, is also being tested in first-line MCL. The phase 3 Mangrove trial started in 2019, so if this study follows the same timelines as the similarly sized Echo that suggests a topline readout in around two years’ time. 

Still, important differences in trial design make Mangrove's outcome hard to call. In what looks like a big gamble BeiGene has dropped the chemotherapy component, bendamustine, from the active arm in its trial, combining Brukinsa with Rituxan alone. 

If a survival benefit emerges BeiGene will be able to offer these frequently frail and elderly MCL patients a much more tolerable option. Whether this can come without compromising efficacy remains to be seen. 

Another potential competitor is InnoCare, whose orelabrutinib is on the market in China; the company plans to file in late-stage MCL in the US later this year, and also has a first-line study under way.

Enough for regulators?

Either way, with Mangrove results some years away, Astra should have time to capitalise on Calquence’s win here. However, it's not inconceivable that regulators will want to see that OS benefit confirmed at a final analysis, before granting approval.

True, Echo succeeded on its primary endpoint, with Astra claiming a “statistically significant and clinically meaningful improvement” on PFS for Calquence plus bendamustine and Rituxan, versus bendamustine and Rituxan. But Imbruvica also hit the primary PFS endpoint in Shine, before going on to fail on OS. 

That miss, plus the failure of the Selene trial in follicular and marginal zone lymphomas, prompted the withdrawal of Imbruvica's MCL approvals, which had been granted on an accelerated basis. 

This makes it crucial for Echo's OS trend to improve into a real signal, or Astra could find itself repeating the past. 

First-line mantle cell lymphoma: a BTK battle

Note: R=Rituxan; B=bendamustine. Source: OncologyPipeline.