On May 29, 2025 Daiichi Sankyo (TSE: 4568) and Merck’s (NYSE: MRK), known as MSD outside of the United States and Canada, reported that the Biologics License Application (BLA) seeking accelerated approval in the U.S. for patritumab deruxtecan (HER3-DXd), based on the HERTHENA-Lung01 Phase 2 trial for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies, has been voluntarily withdrawn (Press release, Merck & Co, MAY 29, 2025, View Source [SID1234653490]).
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The decision to withdraw the BLA is based on topline overall survival (OS) results from the confirmatory HERTHENA-Lung02 Phase 3 trial where OS did not meet statistical significance, as well as discussions with the U.S. Food and Drug Administration. The decision is unrelated to the Complete Response Letter that was received in June 2024 and outlined findings pertaining to an inspection of a third-party manufacturing facility.
Patritumab deruxtecan is a specifically engineered HER3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and Merck
Results from the HERTHENA-Lung02 Phase 3 trial, including previously reported statistically significant progression-free survival (PFS) along with topline OS results, will be presented during an oral presentation (#8506) at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (#ASCO25) Annual Meeting on Sunday, June 1, 2025.
HERTHENA-Lung02 is evaluating patritumab deruxtecan monotherapy versus doublet chemotherapy, consisting of platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy, in patients with EGFR-mutated (exon 19 deletion or L858R mutated) advanced NSCLC after disease progression with a third generation EGFR tyrosine kinase inhibitor (TKI) treatment. Patients achieving tumor response will continue to receive patritumab deruxtecan or chemotherapy until disease progression, per investigator assessment.
"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, R&D, 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. We remain confident in the broad development program of this HER3 directed antibody drug conjugate, which currently includes multiple clinical trials across 15 types of cancer."
"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, head of global clinical development and chief medical officer, Merck Research Laboratories. "We would like to thank the patients, their families, and investigators for their participation in this study."
The safety profile seen in HERTHENA-Lung02 was consistent with that observed for patritumab deruxtecan in previous lung cancer clinical trials, with no new safety signals identified.
About HERTHENA-Lung01
HERTHENA-Lung01 is a global, multicenter, open-label, two-arm Phase 2 trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy. Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an uptitration regimen (n=50). The uptitration arm was discontinued as the dose of 5.6 mg/kg of patritumab deruxtecan was selected following a risk-benefit analysis conducted from a separate Phase 1 trial assessing the doses in a similar patient population.
The primary endpoint of HERTHENA-Lung01 was objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary endpoints included duration of response, PFS, disease control rate, and time to response – all assessed by both BICR and investigator assessment – as well as investigator-assessed ORR, OS, safety and tolerability. The ORR data and additional results for key secondary endpoints of HERTHENA-Lung01 were published in the Journal of Clinical Oncology in September 2023.
HERTHENA-Lung01 enrolled 277 patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.
About HERTHENA-Lung02
HERTHENA-Lung02 is a global, multicenter, open-label, Phase 3 trial evaluating the efficacy and safety of patritumab deruxtecan (5.6 mg/kg every three weeks) monotherapy versus four cycles of doublet chemotherapy) pemetrexed and platinum chemotherapy) in patients with metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) after failure of third-generation (e.g., osimertinib, lazertinib, aumolertinib, alflutinib) EGFR TKI therapy. Patients in the chemotherapy arm without disease progression after four cycles of pemetrexed and platinum chemotherapy are able to continue treatment with maintenance pemetrexed with no restriction on the number of cycles.
The primary endpoint of HERTHENA-Lung02 is PFS as assessed by BICR. Secondary endpoints included OS, ORR, duration of response, clinical benefit rate, time to response, disease control rate, and safety. Patients enrolled in the study underwent brain imaging to allow for assessment of intracranial endpoints, including intracranial PFS as assessed by BICR.
HERTHENA-Lung02 enrolled 586 patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.
About EGFR-Mutated Non-Small Cell Lung Cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022. Lung cancer is the most common cancer and the leading cause of cancer-related deaths worldwide.9 NSCLC accounts for about 87% of all lung cancers1. Approximately 10% to 15% of patients with NSCLC in the U.S. and Europe, and 30% to 40% of patients in Asia have an EGFR mutation.3,4
NSCLC is diagnosed at an advanced stage in up to 70% of patients.2 For patients with tumors that have an EGFR mutation, the established first-line treatment in the metastatic setting includes EGFR-directed therapy with or without platinum-based chemotherapy.While these therapies have improved outcomes, most patients eventually experience disease progression and receive subsequent therapies.5,6,7,8
About HER3
HER3 is a member of the HER family of receptor tyrosine kinases.11 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment.12 HER3 is associated with poor treatment outcomes, including shorter relapse-free survival and significantly reduced survival.13,14 There is currently no HER3 directed therapy approved for the treatment of any cancer.
About Patritumab Deruxtecan
Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
About the Patritumab Deruxtecan Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of patritumab deruxtecan across cancers. Trials in combination with other anticancer treatments are also underway.