Interstitial lung disease (ILD) has forced a global clinical hold on the Ideate-Lung02 trial of ifinatamab deruxtecan, the B7-H3–targeting antibody-drug conjugate (ADC) licensed to Merck from Daiichi Sankyo, according to entries on the EU clinical trials registry. The registry cited a “higher than anticipated incidence of grade 5 interstitial lung disease (ILD) events” as the reason for the temporary halts.
The hold affects multiple EU countries, with the registry listing temporary halts in 10 states including France, the Netherlands and Germany. Enrollment in the Czech Republic, Greece and Austria remains authorised but recruitment is pending. Daiichi said the study is “currently on global hold.” Merck said the FDA’s hold followed a voluntary pause initiated by Daiichi and stressed that other studies were not affected.
Ifinatamab deruxtecan was licensed to Merck in 2023 as part of a multi-project deal with Daiichi that involved significant upfront payments. Ideate-Lung02, which targets post-platinum small-cell lung cancer, is one of three pivotal trials for ifinatamab; Ideate-Prostate01 and Ideate-Esophageal01 are listed as recruiting on US and EU registries.
The Ideate-Lung02 program advanced largely on phase 2 data. At World Lung 2024 investigators reported toxicity signals at higher doses, including one grade 2 ILD that led to treatment discontinuation, though no ILD deaths were reported in that dataset.
The development setback follows other deruxtecan-related safety and efficacy issues. Merck and Daiichi’s jointly owned patritumab deruxtecan saw its US filing collapse after a confirmatory trial failed to show an overall survival benefit and identified treatment-related deaths, including ILD cases.
ILD has also affected AstraZeneca’s ADCs originating from Daiichi. Enhertu (trastuzumab deruxtecan) carries a boxed warning for ILD and pneumonitis and has transformed HER2-positive cancer treatment despite the risk. Datroway (datopotamab deruxtecan) received US approval this year with an ILD/pneumonitis warning; its development was complicated by how ILD events were graded and by repeated failures to demonstrate overall survival benefits.
One Datroway phase 3 trial, Tropion-Lung15, has been temporarily halted in all seven EU member states where it was running because of “an increase in overall cases of high-grade ILD reported to date.” Tropion-Lung15 compares Datroway alone or with Tagrisso against chemotherapy in post-Tagrisso, EGFR-mutated non–small-cell lung cancer; its clinicaltrials.gov status was changed in September from “recruiting” to “active, not recruiting.”
Another ADC from the Daiichi/Merck collaboration, raludotatug deruxtecan (anti-CDH6), has shown promising early efficacy but has also been associated with ILD in limited data. The phase 3 component of Rejoice-Ovarian01 includes a 4.8 mg/kg dose that was linked to one grade 3 ILD event in phase 2.
Summary of Daiichi-originated ADCs licensed to AstraZeneca and Merck:
Enhertu (HER2) — licensed to AstraZeneca; major transformative approvals in multiple cancers; boxed warning for ILD and pneumonitis.
Datroway (TROP2) — licensed to AstraZeneca; approved for pretreated EGFR-mutant NSCLC and certain breast cancers with ILD/pneumonitis warning; Tropion-Lung15 paused in the EU due to increased high-grade ILD cases.
Patritumab deruxtecan (HER3) — licensed to Merck; US filing withdrawn after confirmatory study failed to show OS benefit and reported increased toxicities, including ILD deaths.
Ifinatamab deruxtecan (B7-H3) — licensed to Merck; Ideate-Lung02 on global hold for higher-than-expected grade 5 ILD events.
Raludotatug deruxtecan (CDH6) — licensed to Merck; limited data promising but ILD observed; phase 3 ongoing.
This story has been updated.
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