A reprieve for Blenrep?

Judging by the outcome of GSK’s Dreamm-7 study this morning no drug should ever be written off entirely. The apparent success of this second-line multiple myeloma trial, featuring the group’s anti-BCMA antibody-drug conjugate Blenrep, ranks as one of 2023’s biggest surprises.

Blenrep, which has been pulled from the US in late-line multiple myeloma, is said in Dreamm-7 to have beaten Johnson & Johnson/Genmab’s juggernaut Darzalex – on progression-free as well as overall survival – and GSK plans to take the data to health authorities. Enthusiasm will, however, be tempered by the ominous words: “Safety and tolerability ... was consistent with [Blenrep’s] known profile.”

This profile will have to be weighed carefully by any regulatory agency now asked to review Dreamm-7. Blenrep is notoriously toxic, its US label citing vision loss in 53% of patients, with 28% at grade 3 or 4, and including a boxed warning recommending ophthalmic examinations throughout a patient’s treatment.

Withdrawn

That label is no longer relevant, of course, as GSK has withdrawn Blenrep after an FDA request. In the EU the CHMP refused to renew Blenrep’s marketing authorisation in September, suggesting that withdrawal was imminent, though GSK requested a re-examination of this opinion.

Still, though toxicity clearly weighs heavy with Blenrep, a key difference regarding the withdrawal of Blenrep’s approved use is that the confirmatory Dreamm-3 trial failed to beat Pomalyst plus dexamethasone in terms of either PFS or OS, yielding hazard ratios above 1.00 in both cases.

In contrast, GSK said this morning that Dreamm-7 did succeed on both measures. The study has been stopped after an interim analysis showed that adding Blenrep on top of Velcade and dexamethasone extended PFS versus Darzalex, Velcade and dexamethasone, and yielded a “strong and clinically meaningful OS trend, with nominal p value <0.0005”.

Darzalex is an established standard of care for relapsed/refractory multiple myeloma, and is building a presence as part of a front-line combo too. The latter setting has been boosted by strong PFS data from the Perseus trial, due to be presented at a late-breaker during next month’s ASH conference, so Blenrep beating Darzalex is no mean feat.

A separate phase 3 trial called Dreamm-8 tests Blenrep in another second-line setting, as part of a Pomalyst/dexamethasone combo, being pitted head to head against Velcade, Pomalyst and dexamethasone. GSK recently delayed Dreamm-8 readout by over a year, citing a lower than expected event rate.

Strangely, the company back then also said Dreamm-7 would be delayed, for the same reason, to the first half of 2024. Such delays rarely spell a positive outcome, so the fact Dreamm-7 has after all read out positively – and wasn’t delayed by as long as feared – comes as a double surprise.

Selected Blenrep trials in multiple myeloma

Source: prescribing information & OncologyPipeline.

As ApexOnco went to press GSK hadn’t responded to a query about the next regulatory steps. It’s likely that a new filing will now have to be made, though in the EU perhaps Dreamm-7 can be used as supporting evidence to overturn the CHMP’s move to withdraw – bearing in mind Blenrep’s toxicity and the fact full Dreamm-7 data are still under wraps.

Though no other BCMA-targeting drugs are approved second-line, J&J/Legend’s Car-T therapy Carvykti might get this setting on its label, as the FDA is to rule on a filing based on the Cartitude-4 trial by April 2024. J&J’s anti-BCMA T-cell engager Tecvayli is approved for fifth-line multiple myeloma, and its second-line Majestec-3 study could read out next year.

It’s also worth bearing in mind Dreamm-10, a front-line Blenrep study that GSK had planned to initiate two years ago, but whose start went on hold pending data from Dreamm-7 and 8. Though toxicity continues to loom large, today’s readout is a vote in favour of getting Dreamm-10 under way.