Epkinly fails its first confirmatory test

The growing pains of anti-CD20 T-cell engagers in early lines of lymphoma treatment are becoming hard to ignore, and Genmab is now squarely in the spotlight.

The company confirmed on Friday that Epcore-DLBCL-1, its potentially confirmatory phase 3 study of Epkinly in previously treated diffuse large B-cell lymphoma, missed its primary endpoint of overall survival, something that could put in jeopardy the accelerated approval that this drug received in 2023 in the third line.

Epcore-DLBCL-1

The study tested the AbbVie-partnered T-cell engager in patients given at least one prior line of treatment, with nearly three quarters of them treated with two or more prior lines. Genmab has yet to release full efficacy data, which could be presented at ASCO or EHA, but is trying to frame the miss as a product of timing.

The company pointed to two major headwinds: the Covid pandemic, given that the trial opened in January 2021, and treatment landscape changes, which could refer to Car-T entering the second-line market.

Still, the trial’s long and winding path suggests that the problems could run deeper. Epcore-DLBCL-1 was originally slated to read out in 2023, only for Genmab to amend the protocol that year to expand the sample size from 480 to a planned 552 patients.

After that, the company repeatedly pushed back timelines, most recently to the end of 2026. Strangely, in the end only 483 patients were enrolled, and the trial has been toplined earlier than the most recent timeline suggested.

Genmab has reported a 0.96 hazard ratio for OS, with wide confidence intervals (upper bound 1.20), indicating no difference at all for Epkinly versus Rituxan-gemox or Rituxan-bendamustine. It did play up a purported PFS benefit, with reduction in risk of progression or death of 26%, but this was a secondary endpoint, so is likely irrelevant given the failure to hit the primary metric of OS.

Until the full survival curves are presented at a medical meeting, and more is disclosed on details such as patients' subsequent therapies, it's impossible to suggest precise reasons for the failure.

Columvi's precedent

A key question now is whether Genmab will be able to retain Epkinly’s accelerated approval. The FDA requires confirmatory evidence, and a negative OS readout in a pivotal study is not a good start for the regulatory agency.

There is, however, a roadmap Genmab will be hoping that regulators follow. Roche managed to keep Columvi on the market after that drug's Starglo second-line study DLBCL showed an overall survival benefit driven by Asian patients, even as Western populations failed to demonstrate the same effect, with hazard ratios suggesting a detriment for Columvi versus Rituxan plus chemo.

Ultimately, Columvi's accelerated approval was saved thanks to another potentially confirmatory phase 3 trial being under way, namely Skyglo, in first-line DLBCL. And Genmab’s fallback could similarly lie in Epkinly's broader phase 3 programme. 

The Danish company is running Epcore-DLBCL-4, a second-line study combining Epkinly with Revlimid, which could still give confirmatory support. In a notable shift, Genmab now says it expects data from this study later this year, having previously guided to readout in 2028.

Beyond that, a first-line phase 3 trial, Epcore-DLBCL-2, remains on track, with data expected in 2026.

Potentially confirmatory phase 3 trials of Epkinly in DLBCL

Source: OncologyPipeline.