Ash 2022 – talquetamab heads to the regulators

The FDA will soon rule on the approvability of the industry’s first anti-GPRC5D project, and Ash just saw the data the agency will be reviewing.

Johnson & Johnson is making a bid to own the late-stage multiple myeloma space, in which attention is falling increasingly on approaches beyond BCMA blockade. Yesterday the group filed talquetamab, and today an Ash update revealed the data it has taken to regulators.

A big question is how broad a label the FDA might give the project, a T-cell engager against the novel antigen GPRC5D. J&J’s two approved anti-BCMA treatments, the Car-T therapy Carvykti and the T-cell engager Tecvayli, both carry fifth-line labels, but talquetamab’s supporting Monumental-1 trial tested this project as early as fourth line.

A similar consideration is whether talquetamab will compete directly against BCMA-directed therapies, or whether it will be used, at least at first, only in those who relapse on the likes of Carvykti and Tecvayli. The former use sets a higher bar to approval than the latter, given a 98% remission rate, and 78% complete response rate, cited by Carvykti’s label.

Going SC

Monumental-1 tested talquetamab in both settings, and the Ash presentation added the study’s phase 2 portion for the first time, zeroing in on a total of 288 patients given one of two SC doses, 0.4mg weekly or 0.8mg every two weeks; the trial had earlier looked at IV dosing, but it is the SC project that was filed yesterday.

The headline number was a 74% overall response rate across the two doses, with 95 of the 212 remissions being deemed complete. Mount Sinai School of Medicine’s Dr Ajai Chari, presenting the data at an Ash press briefing this morning, called this result impressive given that until recently 30% ORR in this type of heavily pretreated multiple myeloma population had been considered positive.

Looking only at 51 patients in whom T-cell redirection therapy – in effect meaning bispecifics, ADCs or Car-T therapies targeting BCMA – had failed, the ORR was 63%, including a 24% rate of complete remissions.

Response rates in all phase 1/2 patients given SC doses (left), and in those after T-cell redirection therapy (right). Source: Ash & Dr Ajai Chari.

Dr Chari’s enthusiasm is understandable, but multiple myeloma treatment has moved quickly recently. This is exemplified by the near-100% response rates seen with Carvykti, and the 68% ORR cited on the label of J&J’s own anti-BCMA bispecific, the recently approved Tecvayli.

This comparison is important; if talquetamab were to be restricted to the white space of BCMA failures that would be one thing, but if – as today’s data suggest – it is to treat patients who have yet to be exposed to BCMA inhibition then it is anti-BCMA agents against which it must be compared. And on a cross-trial basis talquetamab’s efficacy looks not much better than Tecvayli's.

Safety advantage?

Still, Dr Chari claimed that there was an additional benefit: safety, and specifically a reduced risk of Covid infections, which he said remain a problem for severely immunocompromised haematological malignancy patients.

Monumental-1 was conducted during the Covid pandemic, including during a time before Covid vaccines were available, but the dataset at Ash details only two deaths due to Covid.

The study “was being accrued at a concurrent time to [those testing] the BCMA bispecifics, where there have been many deaths reported from Covid,” said Dr Chari. “If you measure Covid antibodies, patients on [talquetamab] are producing antibodies. That’s a really different signal than what we’ve seen before.”

So is this down to hitting a different target? “I think so,” he told the press briefing. “I think it’s partly because of the dirtiness of BCMA.”

Asked whether he saw talquetamab being used in BCMA-naive and BCMA-relapsed patients alike, he said yes. Soon it will be the FDA’s turn to decide on this matter.

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