Patritumab deruxtecan BLA for patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer is voluntarily withdrawn- Daiichi Sankyo and Merck Inc

The Biologics License Application (BLA) seeking accelerated approval in the U.S. for Daiichi Sankyo and Merck & Co. Inc'’s patritumab deruxtecan (HER3-DXd) based on the HERTHENA-Lung01 phase II 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non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies has been voluntarily withdrawn. The decision to withdraw the BLA is based on topline overall survival (OS) results from the confirmatory HERTHENA-Lung02 phase III trial where OS did not meet statistical significance as well as discussions with the FDA 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.

Results from the HERTHENA-Lung02 phase III 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 (#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.

HERTHENA-Lung01 (NCT04619004)  is a global, multicenter, open-label, two-arm phase II 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 I 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. 
 

HERTHENA-Lung02 (NCT05338970) is a global, multicenter, open-label, phase III 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. 

"EGFR-mutated non-small cell lung cancer has proven to be difficult-to-treat in the second-line metastatic setting and beyond,” said Dr.  Ken Takeshita, 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 patients with EGFR-mutated non-small cell lung cancer in the second and later line settings,” said Dr.  Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories. “We would like to thank the patients, their families and investigators for their participation in this study.”

See citation- Yu H, Goto Y et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. J Clin Oncol 2023, 41: 5363  doi: 10.1200/JCO.23.01476. PMID: 37689979