On May 29, 2025, Merck & Co. and Daiichi Sankyo announced the voluntary withdrawal of the Biologics License Application (BLA) for patritumab deruxtecan (HER3-DXd). The application sought accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adults with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who had previously received two or more systemic therapies.
The original submission was based on results from the HERTHENA-Lung01 phase 2 trial, which demonstrated an objective response rate (ORR) of 29.8% in 225 pretreated patients with advanced EGFR-mutant NSCLC. However, in June 2024, the FDA issued a complete response letter (CRL) due to inspection-related issues at a third-party manufacturing facility, delaying potential approval.
The decision to withdraw the application was further influenced by topline overall survival (OS) results from the HERTHENA-Lung02 phase 3 trial, which are being presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. According to the companies, the study failed to meet the primary OS endpoint with statistical significance. Discussions with the FDA also contributed to the decision.
Related Article: Three ADCs Expected To Be Approved In 2024-2025
HERTHENA-Lung02 Trial Overview
The HERTHENA-Lung02 (NCT05338970) is a phase 3, randomized, open-label trial designed to evaluate the efficacy of HER3-DXd compared to platinum-based chemotherapy (PBC) in patients with EGFR exon 19 deletion or L858R-mutated NSCLC who had progressed after treatment with third-generation EGFR TKIs.
A total of 586 patients were enrolled and randomized 1:1 to receive either HER3-DXd or PBC. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR), with overall survival (OS) as a key secondary endpoint. [1]
Efficacy and Safety Results
Progression-Free Survival (PFS): HER3-DXd showed a statistically significant improvement over PBC, with a median PFS of 5.8 months vs. 5.4 months (hazard ratio [HR] = 0.77). However, the absolute benefit was only 0.4 months.
Overall Survival (OS): The trial did not demonstrate a statistically significant OS benefit, failing to meet the key secondary endpoint.
Figure 1. HER3-DXd Significantly Reduced the Risk of Disease Progression (by BICR per RECIST) or Death vs PBC [1]
Safety Profile
Treatment discontinuation due to treatment-emergent adverse events (TEAEs) occurred in 11% of patients (33 cases) in the HER3-DXd group and 10% (27 cases) in the PBC group.
Notably, 14 patients (5%) in the HER3-DXd arm experienced interstitial lung disease (ILD) deemed related to the drug, including two fatal ILD cases.
About HER3
The epidermal growth factor receptor (EGFR) family is a subclass of receptor tyrosine kinase (RTK) proteins and consists of 4 members, EGFR (also known as ERBB1 or HER1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4).
Unlike other members, HER3 has little or no intrinsic tyrosine kinase activity, meaning it cannot activate signaling pathways on its own. Instead, it functions by forming heterodimers with other EGFR family receptors, especially HER2, to trigger downstream signaling that promotes cell survival and proliferation. HER3 is frequently overexpressed in various cancers, including breast, lung, and ovarian cancers, and plays a critical role in tumor progression and resistance to targeted therapies. [2]
Although HER3 was first identified more than 30 years ago in 1989, only one HER3-targeted therapy—Zenocutuzumab—has been approved for market use.
HER2/HER3 Bispecific Antibody Therapy - Zenocutuzumab
On December 4, 2024, Merus announced that the FDA had approved Zenocutuzumab (Bizengri), a bispecific antibody targeting HER2 and HER3, for the treatment of NRG1 fusion–positive pancreatic cancer and NSCLC. This approval represents a milestone achievement, marking the first time the previously "undruggable" HER3 target has been successfully addressed through a bispecific antibody approach. [3]
Zenocutuzumab is designed to simultaneously bind the extracellular domains of HER2 and HER3 expressed on the surface of tumor cells. It blocks HER2/HER3 dimerization and prevents neuregulin-1 (NRG1) from activating HER3, thereby inhibiting downstream signaling through the PI3K–AKT–mTOR pathway, which is critical to tumor cell proliferation and survival. In addition, Zenocutuzumab exerts its antitumor effect by inducing antibody-dependent cellular cytotoxicity (ADCC), enhancing immune-mediated tumor cell killing.
The approval was supported by data from the eNRGy trial, a multicenter, open-label, phase I/II study evaluating Zenocutuzumab in patients with advanced, unresectable, or metastatic NRG1 fusion–positive pancreatic ductal adenocarcinoma (PDAC) and NSCLC. In the PDAC cohort (n=30), the drug achieved an overall response rate (ORR) of 40%, with response durations ranging from 3.7 to 16.6 months. In the NSCLC cohort (n=64), the ORR was 33%, with a median duration of response of 7.4 months.
HER3-targeted ADCs
BL-B01D1 (iza-bren)
Developed by SystImmune in collaboration with Bristol Myers Squibb (BMS), BL-B01D1 (iza-bren) is a first-in-class bispecific antibody–drug conjugate (ADC) that simultaneously targets EGFR and HER3. At the 2025 ASCO Annual Meeting, two clinical studies of BL-B01D1 in NSCLC and small cell lung cancer (SCLC) were presented as oral reports, highlighting the drug’s growing clinical promise.
Structurally, iza-bren incorporates a bispecific EGFR × HER3 antibody (SI-B001), a cleavable tetrapeptide linker, and a potent topoisomerase I inhibitor payload (Ed-04, a camptothecin derivative). With a high drug-to-antibody ratio (DAR) of up to 8, iza-bren demonstrates superior antitumor activity compared to ADCs targeting either EGFR or HER3 alone. Prior phase I data showed that iza-bren had a favorable safety profile and encouraging efficacy in patients with EGFR wild-type NSCLC, EGFR-mutant NSCLC, and nasopharyngeal carcinoma.
Newly presented results further confirmed that BL-B01D1 exhibits robust antitumor activity and survival benefits in NSCLC patients harboring non-classical EGFR mutations or other oncogenic driver alterations, especially those with EGFR exon 20 insertions. In this subgroup, the drug achieved an objective response rate (ORR) of 69.2% and a median progression-free survival (PFS) of 10.5 months, underscoring its potential to overcome resistance in genetically defined NSCLC populations.
BL-B01D1 also showed notable efficacy in pretreated SCLC patients, particularly among those who had received only one prior line of treatment with PD-(L)1 inhibitors plus platinum-based chemotherapy. In this setting, the confirmed ORR reached 75.0%. A phase III trial (NCT06500026) is currently underway to evaluate BL-B01D1 in SCLC patients following first-line immunochemotherapy.
DB-1310
DB-1310 is an investigational ADC being developed by DualityBio for the treatment of multiple advanced solid tumors, including NSCLC, metastatic castration-resistant prostate cancer (mCRPC), head and neck squamous cell carcinoma (HNSCC), and breast cancer. It is composed of a humanized anti-HER3 IgG1 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor (P1021) via a cleavable maleimide tetrapeptide-based linker.
At the 2025 ASCO Annual Meeting, preliminary results from ongoing clinical studies of DB-1310 generated considerable attention. As of January 17, 2025, a total of 123 patients had been enrolled and treated with DB-1310 monotherapy in the Phase I clinical trial. Among the 42 efficacy-evaluable patients with EGFR-mutant NSCLC, 92.9% had previously been treated with a third-generation EGFR tyrosine kinase inhibitor (TKI), and 92.9% had received platinum-based chemotherapy. The unconfirmed objective response rate (ORR) was 25.5% (95% CI: 17.63–34.65) across all tumor types and 35.7% (95% CI: 21.55–51.97) in the EGFR-mutant NSCLC subgroup. Median progression-free survival (PFS) was 5.4 months overall and 7.0 months in patients with EGFR-mutant NSCLC. [6]
Conclusion
New drug development has always been a high-risk endeavor. While Daiichi Sankyo achieved tremendous success with its HER2-targeted ADC, DS-8201 (Enhertu), this does not guarantee similar outcomes when targeting HER3.
The recent approval of the HER2/HER3 bispecific antibody Zenocutuzumab underscores a key insight: HER3 may be a challenging standalone target for therapeutic intervention. The setbacks faced by HER3-targeted ADCs suggest that monotherapies focused solely on HER3 are unlikely to produce meaningful clinical outcomes. Instead, HER3-targeted strategies may be better realized through bispecific antibodies, bispecific ADCs, or rational combination therapies that can overcome its inherent limitations.
References:
[1] Tony S. K. Mok et al. Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study.. JCO 43, 8506-8506(2025). DOI:10.1200/JCO.2025.43.16_suppl.8506
[2] Haikala, H. M., & Jänne, P. A. (2021). Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(13), 3528–3539. https://doi.org/10.1158/1078-0432.CCR-20-4465
[3] https://ir.merus.nl/news-releases/news-release-details/merus-announces-fda-approval-bizengrir-zenocutuzumab-zbco-nrg1
[4] https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.3002 Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic small cell lung cancer (SCLC).
[5] https://www.asco.org/abstracts-presentations/ABSTRACT489588 Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with driver genomic alterations (GA) outside of classic EGFR mutations.
[6] Aaron Lisberg et al. DB-1310, a HER3-targeted ADC, in pts with advanced solid tumors: Preliminary results from the phase 1/2a trial.. JCO 43, 3000-3000(2025). DOI:10.1200/JCO.2025.43.16_suppl.3000
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