Merck & Co. and Daiichi Sankyo have withdrawn their U.S. regulatory application for patritumab deruxtecan, an experimental antibody-drug conjugate (ADC) for treating non-small cell lung cancer, after the therapy failed to demonstrate overall survival benefits in a pivotal Phase III trial.
The companies announced Thursday that they voluntarily pulled their Food and Drug Administration submission for the investigational therapy, also known as HER3-DXd, following disappointing topline results from the HERTHENA-Lung02 trial and subsequent discussions with the FDA.
Trial Results Fall Short of Survival Endpoint
The Phase III HERTHENA-Lung02 study enrolled nearly 280 patients with locally advanced or metastatic non-small cell lung cancer carrying mutations in the EGFR gene. While patritumab deruxtecan demonstrated a significant improvement in progression-free survival compared to doublet chemotherapy in September 2024, the drug failed to significantly improve overall survival—the gold standard for cancer drug approval.
"This outcome is a reminder of how challenging it can be to treat these patients with EGFR-mutated non-small cell lung cancer in the second and later line settings," said Eliav Barr, chief medical officer of Merck Research Laboratories, in the company statement.
Regulatory History and Manufacturing Issues
This withdrawal represents the second regulatory setback for patritumab deruxtecan. The FDA previously issued a Complete Response Letter in June 2024, rejecting the initial application due to issues with a third-party manufacturer. However, the companies emphasized that Thursday's voluntary withdrawal is unrelated to the prior rejection and stems specifically from the survival data findings.
The companies clarified that the earlier regulatory rejection did not flag problems with the ADC's efficacy and safety package, focusing instead on manufacturing concerns.
ADC Mechanism and Development Strategy
Patritumab deruxtecan is designed to target the HER3 protein, which is highly expressed in many different types of solid tumors. The ADC carries an exatecan derivative payload that, when released inside a cancer cell, can trigger cell death.
Ken Takeshita, Daiichi Sankyo's global head of R&D, indicated the companies are "conducting further biomarker analyses" to better identify lung cancer patients who might benefit from treatment. "We remain confident in the broad development of [our drug]," he added, noting ongoing trials across 15 types of cancer.
Impact on Multibillion-Dollar Partnership
The setback affects a collaboration that could potentially be worth as much as $22 billion. Merck formed the alliance with Daiichi Sankyo in 2023, a month after the Japanese company reported Phase 2 data that supported the accelerated approval application for patritumab deruxtecan.
This partnership was part of Merck's broader strategy to diversify its portfolio as its blockbuster cancer immunotherapy Keytruda faces patent expiration later this decade. Merck's share price has fallen nearly 40% over the last 12 months amid investor skepticism about the company's plans to offset future Keytruda revenue losses.
Broader ADC Development Challenges
The withdrawal follows a similar pattern seen with other Daiichi Sankyo ADC partnerships. In November 2024, datopotamab deruxtecan—a Daiichi Sankyo ADC partnered with AstraZeneca—also had its regulatory application withdrawn after its Phase III lung cancer trial "was not reviewed favorably by the FDA," according to Dale Shuster, head of global precision medicine at Daiichi Sankyo.
The companies plan to present study results from the HERTHENA-Lung02 trial at the American Society of Oncology Meeting on Sunday, potentially providing additional insights into the therapy's performance and future development strategy.
