FDA Places Clinical Hold on Merck-Daiichi Sankyo ADC After Fatal Lung Toxicity Events
Key Insights
The FDA has placed a partial clinical hold on ifinatamab deruxtecan's Phase III IDeate-Lung02 trial after detecting a higher than anticipated incidence of fatal interstitial lung disease (search) events.
The study enrolled over 500 patients with relapsed small cell lung cancer (search), comparing the B7-H3 (search)-targeting ADC against standard chemotherapy options including topotecan and amrubicin.
This represents the latest safety setback for Daiichi Sankyo's deruxtecan-based ADC platform, which has consistently shown interstitial lung disease (search) as a class-wide toxicity across multiple approved and investigational agents.
The FDA has placed a partial clinical hold on Merck (search) and Daiichi Sankyo's antibody-drug conjugate ifinatamab deruxtecan after detecting "a higher than anticipated incidence of grade 5 interstitial lung disease (search) (ILD) events" in the Phase III IDeate-Lung02 trial. The action follows a voluntary recruitment halt initiated by Daiichi Sankyo after the companies identified an elevated number of fatal lung toxicity cases.
Trial Details and Patient Population
The IDeate-Lung02 study has enrolled more than 500 patients with relapsed small cell lung cancer (search), randomizing participants to receive either ifinatamab deruxtecan or active chemotherapy comparators including topotecan, amrubicin, and lurbinectedin. The B7-H3 (search)-targeting ADC had previously demonstrated promising efficacy signals, showing a 48.2% confirmed objective response rate in the same trial that is now under regulatory scrutiny.
According to a joint statement from the companies, the clinical hold "does not impact other studies in the I-DXd clinical development program." The partners are collaborating with the FDA and an independent data monitoring board to analyze the mortality events and determine appropriate next steps for the affected study.
Broader Safety Pattern for Deruxtecan Platform
The safety concerns extend beyond ifinatamab deruxtecan to other ADCs in Daiichi Sankyo's deruxtecan platform. As Jefferies analysts noted, "ILD is a potentially fatal side effect known to be associated with all of Daiichi's DX ADCs." Despite these toxicity concerns, the platform has achieved regulatory success with approved agents Enhertu and Datroway, both carrying warnings for interstitial lung disease (search) and pneumonitis (search).
The EU clinical trials registry reveals that another deruxtecan-based ADC, Datroway, has also faced recent regulatory action. The Tropion-Lung15 study testing Datroway in EGFR (search)-mutated non-small cell lung cancer (search) has been temporarily halted across seven EU member states due to "an increase in overall cases of high-grade ILD reported to date."
Impact on Merck-Daiichi Partnership
The clinical hold represents another setback for the $5.5 billion collaboration between Merck (search) and Daiichi Sankyo announced in October 2023. The partnership covers three deruxtecan-based ADCs, with Merck paying $1.5 billion upfront plus $500 million in immediate R&D funding specifically for ifinatamab deruxtecan development.
The companies previously encountered regulatory challenges with another jointly owned ADC, patritumab deruxtecan, when the FDA declined approval for locally advanced or metastatic non-small cell lung cancer (search) in June 2024. That rejection was attributed to third-party manufacturing issues rather than safety or efficacy concerns.
Ongoing Development Programs
Despite the IDeate-Lung02 hold, ifinatamab deruxtecan continues advancing in other indications. Two additional pivotal trials, IDeate-Prostate01 and IDeate-Esophageal01, remain active and recruiting patients according to clinical trial registries.
The partnership's third ADC, raludotatug deruxtecan targeting CDH6 (search), has shown "highly impressive" early data but has also reported interstitial lung disease (search) events, including one grade 3 ILD case at the 4.8 mg/kg dose level in the Phase II portion of the Rejoice-Ovarian01 trial.