Daiichi Sankyo and Merck have voluntarily withdrawn their Biologics License Application (BLA) seeking accelerated approval for patritumab deruxtecan (HER3-DXd) in the United States. The withdrawal follows disappointing topline overall survival results from the confirmatory HERTHENA-Lung02 Phase 3 trial, which failed to meet statistical significance for this critical endpoint.
The BLA was originally submitted for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who had previously received two or more systemic therapies. The application was based on data from the HERTHENA-Lung01 Phase 2 trial.
Phase 3 Trial Results Fall Short of Expectations
The HERTHENA-Lung02 Phase 3 trial evaluated patritumab deruxtecan monotherapy at 5.6 mg/kg every three weeks versus doublet chemotherapy consisting of platinum plus pemetrexed induction followed by pemetrexed maintenance in 586 patients across Asia, Europe, North America and Oceania. All patients had EGFR-mutated advanced NSCLC with exon 19 deletion or L858R mutations after disease progression on third-generation EGFR tyrosine kinase inhibitor treatment.
While the trial had previously demonstrated statistically significant progression-free survival (PFS), the primary endpoint, the overall survival data did not achieve statistical significance. The complete results, including both the previously reported PFS data and the topline overall survival findings, will be presented at the 2025 American Society of Clinical Oncology Annual Meeting on June 1, 2025.
"EGFR-mutated non-small cell lung cancer has proven to be difficult-to-treat in the second-line metastatic setting and beyond," said Ken Takeshita, MD, global head of R&D at Daiichi Sankyo. "While we are disappointed with the overall survival results of HERTHENA-Lung02, we are conducting further biomarker analyses to better identify patients that may benefit from patritumab deruxtecan to guide our continued development in lung cancer."
Safety Profile Remains Consistent
The safety profile observed in HERTHENA-Lung02 was consistent with previous lung cancer clinical trials of patritumab deruxtecan, with no new safety signals identified. This consistency provides some reassurance as the companies evaluate next steps for the development program.
Addressing Significant Unmet Medical Need
The withdrawal underscores the persistent challenges in treating EGFR-mutated NSCLC in later-line settings. Nearly 2.5 million lung cancer cases were diagnosed globally in 2022, with lung cancer representing the most common cancer and leading cause of cancer-related deaths worldwide. NSCLC accounts for approximately 87% of all lung cancers.
Approximately 10% to 15% of patients with NSCLC in the U.S. and Europe have an EGFR mutation, while this proportion rises to 30% to 40% in Asia. NSCLC is diagnosed at an advanced stage in up to 70% of patients, and while first-line EGFR-directed therapies have improved outcomes, most patients eventually experience disease progression requiring subsequent treatments.
"Lung cancer is one of the leading causes of cancer-related deaths worldwide and these results are 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, MD, senior vice president and head of global clinical development at Merck Research Laboratories.
HER3 as a Therapeutic Target
Patritumab deruxtecan targets HER3, a member of the HER family of receptor tyrosine kinases. Approximately 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment. HER3 expression is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival. Currently, no HER3-directed therapy is approved for treating any cancer.
The investigational antibody drug conjugate is designed using Daiichi Sankyo's proprietary DXd ADC Technology, consisting of a fully human anti-HER3 IgG1 monoclonal antibody attached to topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers.
Broader Development Program Continues
Despite this setback, both companies remain committed to the broader patritumab deruxtecan development program. The HER3-directed ADC is currently being evaluated across multiple clinical trials in 15 different cancer types. The companies plan to conduct additional biomarker analyses to better identify patient populations that may derive benefit from the treatment.
The withdrawal decision was unrelated to a Complete Response Letter received in June 2024, which outlined findings from an inspection of a third-party manufacturing facility. This regulatory action was based solely on the clinical efficacy data from the confirmatory Phase 3 trial and subsequent discussions with the FDA.
