Asco 2022 – the spirit of Rova-T struggles to live on

When Abbvie’s Rova-T crashed and burned many might have assumed that DLL3 blockade was finished as an oncology drug mechanism. Not so: through an Asco poster covering its T-cell engager HPN328, Harpoon Therapeutics today continued a tenuous bid to join Amgen and Boehringer Ingelheim among a small group of companies working clinically on this mechanism of action.

Still, Harpoon’s data are very early, and there is little to celebrate just yet: there is just one confirmed partial response, and hopes that a second might be confirmed have fallen on stony ground. With the group 85% below its IPO price, and 90% off its peak a year ago, investors clearly need more data to be convinced.

Some will take heart in the lack of severe cytokine release or neurotoxicity of any sort, facts that do at least allow HPN328 to be dosed higher in future. And, at least in SCLC, which had been the intended use for Rova-T, the data point in the right direction: among 18 patients with various tumours, four of the six SCLC subjects given high HPN328 doses showed a decrease in the sum of their target lesions.

But at a December cutoff Harpoon had reported a second, unconfirmed, partial response, which is now classified as stable disease. A further patient, also with SCLC, with partial response at their target lesion is classified a progressive disease after new asymptomatic brain metastases were identified, the waterfall plot in today’s poster reveals.

Not alone

Rova-T was canned after failing in phase 3 for SCLC, suggesting that the $5.8bn Abbvie had spent in 2016 to buy its originator, Stemcentrx, was money down the drain.

Still, some see the problem with Rova-T as having been not the target but the design of Stemcentrx’s project, an antibody-drug conjugate. Indeed, Harpoon is not the only company pursuing this target.

Boehringer Ingelheim and Amgen each have clinical-stage T-cell engagers targeting DLL3, and the latter’s tarlatamab had SCLC data at last year’s Asco showing a 20% confirmed overall remission rate. This seemed impressive given that the 64 patients in question had not been preselected for DLL3 expression, and that this was still at the dose-escalation stage.

A phase 1 study of Amgen’s AMG 119, a Car-T therapy against DLL3, was suspended last year after enrolling just six subjects. A phase 2 tarlatamab trial, in SCLC patients progressed after at least one platinum regimen and one other therapy line, began in December.