Merck and Daiichi Sankyo Face Setback as FDA Places Partial Hold on Antibody-Drug Conjugate Trial

Merck and Daiichi Sankyo's late-stage development program for their antibody-drug conjugate (ADC) ifinatamab deruxtecan has encountered a significant obstacle. The U.S. Food and Drug Administration (FDA) has imposed a partial clinical hold on the Phase III IDeate-Lung02 trial following reports of patient deaths attributed to interstitial lung disease (ILD), a known side effect of Daiichi Sankyo's DXd-based ADCs.

Trial Suspension and Safety Concerns

The IDeate-Lung02 trial, which has enrolled over 500 patients with relapsed small cell lung cancer (SCLC), was evaluating ifinatamab deruxtecan (I-DXd) against active chemotherapy comparators. The study's recruitment has been voluntarily halted by Daiichi Sankyo after detecting "a higher than anticipated incidence of grade 5 interstitial lung disease events," according to a joint statement from the companies.

While the exact number of fatalities has not been disclosed, the severity of the situation prompted immediate action. Patients currently enrolled in the trial will be allowed to continue treatment, but no new participants will be recruited during the hold period.

Implications for Drug Development and Regulatory Strategy

The partial clinical hold does not affect other studies in the I-DXd clinical development program, but it raises questions about the future of this particular ADC. Merck and Daiichi Sankyo are now working closely with the FDA and an independent data monitoring committee to review safety data and determine the next steps for the affected study.

This setback comes at a critical time for the partners, who were aiming for an accelerated approval of I-DXd for pretreated SCLC based on promising Phase II results. In September, the companies reported a 48.2% objective response rate in the Phase II IDeate-Lung01 trial, which they believed could support an accelerated approval pathway.

Broader Context and Industry Impact

The collaboration between Merck and Daiichi Sankyo on DXd-based ADCs, initiated in October 2023 with a $5.5 billion deal, has faced previous challenges. Earlier this year, the partners withdrew their biologics license application for another ADC, patritumab deruxtecan (HER3-DXd), in non-small cell lung cancer due to efficacy concerns and regulatory discussions.

Despite these setbacks, the potential of ADCs in oncology remains significant. AstraZeneca, another major player in the field, has successfully partnered with Daiichi Sankyo, securing approvals for two ADCs: Enhertu in late 2019 and Datroway in January 2025.

As the pharmaceutical industry closely watches the developments surrounding I-DXd, the outcome of this safety review could have far-reaching implications for the development of ADCs and their regulatory pathways. The balance between efficacy and safety in treating aggressive cancers like SCLC remains a critical challenge for drug developers and regulators alike.