Lung toxicity deaths halt ifinatamab

Interstitial lung disease continues to dog antibody-drug conjugates that use a deruxtecan warhead, with the latest high-profile casualty being Daiichi Sankyo/Merck & Co’s ifinatamab deruxtecan. The B7-H3-targeting ADC’s pivotal Ideate-Lung02 study has been put on global hold, ApexOnco has learned.

The precise reason is that “a higher than anticipated incidence of grade 5 interstitial lung disease (ILD) events have been reported”, according to the EU clinical trials registry. This could spell more bad news for Merck, which licensed ifinata-dxd from Daiichi in 2023 as part of a monster ADC deal worth $5.5bn up front.

It follows the collapse of a US filing for another jointly owned ADC, patritumab deruxtecan, when its confirmatory study bust on overall survival and revealed treatment-related deaths, including some from ILD. Terms of the 2023 tie-up were split out by project: $1.5bn up front plus $500m in immediate R&D funding was accounted for by patri-dxd, with Merck paying the same amounts again for ifinata-dxd.

News of the hold first emerged on the EU clinical trials registry, which cited “temporary halts” in 10 EU countries including France, the Netherlands and Germany. Enrolment in the Czech Republic, Greece and Austria is still listed as “authorised, recruitment pending”.

However, asked for clarification Daiichi told ApexOnco: “The study is currently on global hold.” Merck didn’t respond to a request for comment, and it’s not immediately clear why the fact Ideate-Lung02 has been put on global clinical hold hasn’t been announced to the markets.

The study, in post-platinum small-cell lung cancer, is one of three pivotal trials of ifinata-dxd. The other two, Ideate-Prostate01 and Ideate-Esophageal01, are both recruiting and haven’t been halted, according to the US and EU trial registries.

Ideate-Lung02 was begun largely on the strength of phase 2 data, which at World Lung in 2024 revealed hints that toxicities had been problematic at a high dose. While there were no deaths from ILD, one case of ILD, graded 2, caused treatment discontinuation.

Astra too

ILD is a problem not only for Merck, but for also for AstraZeneca, which has rights to two key Daiichi-originated ADCs: Enhertu and Datroway.

While approval of the former has revolutionised breast cancer treatment, and redefined the meaning of HER2 positivity, it has come with a boxed warning of ILD and pneumonitis in the drug’s US prescribing information. Datroway finally limped over the US regulatory finish line this year with a warning – albeit not boxed – over ILD/pneumonitis.

The emergence of ILD, and the way such events were being graded, had dogged Datroway’s development, though the key problem for regulators was the drug’s repeated failure to show an overall survival benefit.

And the ILD problem isn’t about to go away: it has emerged, also on the EU trials registry, that one of Datroway’s 13 phase 3 studies, Tropion-Lung15, has also been temporarily halted in all seven of its EU member states. The reason isn’t deaths specifically, but an “increase in overall cases of high-grade ILD reported to date”.

Tropion-Lung15 tests Datroway monotherapy or combination with Tagrisso, versus chemo, in post-Tagrisso, EGFR-mutated NSCLC. Like Ideate-Lung02, its clinicaltrials.gov entry was changed in September from “recruiting” to “active, not recruiting”.

All eyes will now turn to the Daiichi/Merck deal’s third hope, the anti-CDH6 ADC raludotatug deruxtecan. Limited data revealed so far are highly impressive, but ILD has also been noted.

The five Daiichi ADCs licensed to AstraZeneca and Merck & Co

Source: OncologyPipeline.