T-cell engagers enter new pivotal studies

Johnson & Johnson and Amgen, big pharma companies notable for work on T-cell engaging bispecific antibodies, are expanding their phase 3 efforts in this area. Two newly listed studies on the clinicaltrials.gov registry reveal pivotal tests that seek to take Talvey and tarlatamab into early stages of their respective cancer settings.

The Dellphi-305 trial will investigate tarlatamab in first-line SCLC maintenance, and is the third phase 3 that Amgen has started with this anti-DLL3 bispecific. And J&J is launching the third phase 3 test of its approved anti-GPRC5D bispecific, Talvey: Monumental-6 will complement the confirmatory Monumental-3 study already under way.

Talvey approval

Talvey received accelerated US approval last August for multiple myeloma patients who have received at least four prior therapies, on the back of the uncontrolled Monumental-1 trial. This showed 73-74% of treated patients going into response, depending on the dose tested, and included a 33-35% rate of complete remissions.

Monumental-3, a phase 3 trial in the relapsed-refractory setting, was already under way at the time of the approval, and might serve as Talvey’s confirmatory study. Now J&J is adding Monumental-6 to the phase 3 arsenal; this newly listed trial is to begin at the end of this month.

Though Monumental-3 and 6 both concern relapsed/refractory multiple myeloma their settings are slightly different. While patients in the former have to have previously received Revlimid and a proteasome inhibitor like Velcade, the latter is a combo of Talvey with Pomalyst or Tecvayli, and mandates prior Revlimid and an anti-CD38 MAb like Darzalex.

As such Monumental-6 is a nod to the changing multiple myeloma treatment landscape; J&J/Genmab’s Darzalex is cementing its first-line presence, while Tecvayli is J&J’s anti-BCMA T-cell engager, approved for late-line use in 2022. It’s also clear that J&J is working here to build a multiple myeloma powerhouse to rival Bristol Myers Squibb.

A separate phase 3 trial, Monumental-5, was to compare Talvey against GSK’s Blenrep, but has been withdrawn, presumably because Blenrep has been pulled form the market. Monumental-6 tests progression-free survival against Pomalyst combined with either Empliciti or Velcade, and ends in mid-2027.

Selected phase 3 trials

Note: *Tecvayli is J&J’s anti-BCMA T-cell engager, approved in Aug 2022 for ≥4L (incl prior proteasome, imid & CD38) multiple myeloma. Source: OncologyPipeline.

Meanwhile, Amgen’s tarlatamab is awaiting US approval for small-cell lung cancer, backed by the uncontrolled Dellphi-301 trial, with a 12 June FDA action date.

At last year’s ESMO Dellphi-301 yielded a 40% ORR in third-line SCLC patients given a 10mg dose, which curiously outperformed 100mg. Like in Talvey’s case, a potentially confirmatory phase 3 study is already under way: Dellphi-304 compares tarlatamab against Zepzelca in second-line SCLC. The separate Dellphi-306 study investigates the earlier setting of limited-stage SCLC.

The newly listed Dellphi-305 trial concerns the advanced setting of extensive-stage disease, but seeks to take tarlatamab into first-line maintenance. Patients here must still be in response to Imfinzi plus chemo (like Tecentriq plus chemo this is a first-line standard), and will receive tarlatamab plus Imfinzi.

The sole primary endpoint is overall survival versus Imfinzi alone, and primary completion is late 2027.

Expansion of tarlatamab’s phase 3 programme marks yet more confidence about DLL3, a target that took a big knock with the failure of AbbVie’s Rova-T. Interestingly, neither the setting in which Amgen is seeking to have tarlatamab approved, nor any of its pivotal trials, mandates that patients’ tumours must express DLL3.