AbbVie broadens its telisotuzumab conjugate push

AbbVie already looked like it was moving away from its approved cMet-targeting ADC Emrelis in favour of a next-generation project, telisotuzumab adizutecan, and a new listing on clinicaltrials.gov reinforces this view.

The latest study, M25-713, will test teliso-A in second-line EGFR-mutant non-small cell lung cancer, adding to a first-line phase 2/3 that was first posted in June and began in August. Neither trial appears to require cMet overexpression – which is notable because Emrelis is only approved in patients at the high end of this spectrum.

Still, the Luminosity trial, which backed Emrelis’s approval, primarily tested EGFR-wild type patients instead of those with EGFR-mutated cancer – although the drug’s labelled indication makes no mention of EGFR status.

Teliso-A vs Emrelis

Both teliso-A and Emrelis are based on the MAb telisotuzumab, but the former has a topoisomerase 1 inhibitor payload, while the latter uses MMAE (vedotin). Emrelis’s FDA accelerated approval in May, for pretreated NSCLC, stipulated that patients must have high cMet expression, defined as ≥50% of tumour cells with strong (IHC 3+) staining.

AbbVie estimates that around 25% of EGFR wild-type, non-squamous NSCLC cancers have cMet overexpression, but only around half of these patients are said to have high expression of this protein.

It seems that the company has ambitions to go beyond this niche. The new study, slated to start in November, will enrol around 430 NSCLC patients with EGFR exon 19 deletions or exon 21 L858R mutations who have progressed on a third-generation EGFR inhibitor such as AstraZeneca’s Tagrisso. There is no mention in the clinicaltrials.gov listing of cMet status.

The phase 2 portion of the trial will test two different doses of teliso-A. In the phase 3 part patients will receive the chosen dose of teliso-A, versus investigator’s choice of standard of care; this isn’t specified but could include chemo or Johnson & Johnson’s Rybrevant plus chemo.

The primary endpoint of the phase 3 portion is progression-free survival.

Benchmarks

In Mariposa-2, Rybrevant plus chemo led to a median PFS of 6.3 months and an ORR of 53%, versus 4.2 months and 29% respectively for chemo alone.

A clue about teliso-A’s potential activity could come from a phase 1 basket trial presented at this year’s ASCO meeting. In 41 third-line or later EGFRm non-squamous NSCLC patients ORR was 63%, and this was maintained at 60% in 20 patients with cMet expression of <25% with IHC 3+.

Still, this was an early, uncontrolled study, and activity could drop off in a more rigorous trial.

AbbVie previously abandoned plans to test Emrelis in post-Tagrisso patients; however, this pivotal trial, known as M22-142, had been due to evaluate an Emrelis/Tagrisso combo.

The company is now combining teliso-A with Tagrisso in its phase 2/3 first-line study. That trial requires patients to undergo cMet expression analysis, but there’s no entry requirement for any level of cMet. It also includes a dose-finding portion.

AbbVie is also pursuing colorectal cancer, with the phase 3 Andrometa-CRC trial enrolling patients with ≥10% cMet expression with IHC 3+.

Key studies of AbbVie's cMet-targeting ADCs

Source: OncologyPipeline.