The human epidermal growth factor receptor (HER) family plays a crucial role in tumorigenesis and progression. Among them, EGFR (HER1) and HER2, as classic therapeutic targets, have been widely used in clinical practice. Although research on HER3 (ERBB3) started relatively late, its biological significance has gradually gained attention. HER3 is abnormally expressed in various malignant tumors. According to clinical data, HER3 overexpression can be detected in approximately 83% of non-small cell lung cancer (NSCLC) and 30%-50% of breast cancer tissues. Mechanistic studies have shown that HER3 can mediate tumor cell resistance to various treatment methods by activating signaling pathways such as PI3K/AKT, MAPK, and JAK/STAT, including targeted drugs like tamoxifen, cetuximab, trastuzumab, EGFR inhibitors such as gefitinib and osimertinib, and even chemotherapeutic drugs like docetaxel. Therefore, HER3 has become an important potential target for overcoming tumor resistance.
Patritumab Deruxtecan (U3-1402) is an HER3-targeted antibody-drug conjugate (ADC) developed by Daiichi Sankyo. Its design is based on the core advantage of ADC drugs: delivering cytotoxic payloads precisely to tumor cells with high expression of targets through the targeting of monoclonal antibodies, achieving "precision chemotherapy". U3-1402 consists of three parts: an anti-HER3 monoclonal antibody (Patritumab), a cleavable linker, and the topoisomerase I inhibitor DXd (deruxtecan). It is worth noting that DXd is also the cytotoxic payload of the HER2-targeted ADC drug DS-8201 (T-DXd), which has characteristics such as high activity, membrane permeability, and a bystander effect, and can effectively kill target cells and tumor cells in the surrounding microenvironment. Currently, U3-1402 has been granted breakthrough therapy designation by the US FDA for patients with metastatic or locally advanced EGFR-positive NSCLC who have progressed after treatment with third-generation EGFR inhibitors and platinum-based chemotherapy, highlighting its potential in the treatment of refractory tumors.
U31402-A-U102 is a multicenter phase I clinical trial, including dose escalation and dose expansion phases, aiming to evaluate the safety and efficacy of U3-1402 in patients with EGFR-mutant resistant NSCLC. The dose escalation phase included patients with locally advanced or metastatic EGFR-mutant NSCLC who had progressed after EGFR inhibitor treatment to explore the maximum tolerated dose (MTD) and recommended dose (RD) of the drug. Based on previous results, the dose expansion phase adopted 5.6 mg/kg as the recommended dose, and patients were divided into 4 cohorts:
Cohort 1: Patients with EGFR-mutant adenocarcinoma who had previously received EGFR inhibitors and platinum-based chemotherapy;
Cohort 2: Patients with non-squamous or squamous NSCLC (without classic mutations such as EGFR Ex19del and L858R) who had previously received platinum-based chemotherapy and immunotherapy;
Cohort 3: Patients with EGFR-mutant NSCLC of any histological type (excluding small cell or mixed cell types), randomly assigned to the 5.6 mg/kg group (3a) and the dose escalation group (3b) at a ratio of 1:1;
Cohort 4: To evaluate the bioavailability difference between the investigational U3-1402 and the commercially available preparation.
The primary endpoint of the study was the objective response rate (ORR) assessed by the Blinded Independent Central Review (BICR). Secondary endpoints included ORR assessed by investigators, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. As of the data cutoff date, a total of 264 patients were enrolled globally, of which 102 received the recommended dose of 5.6 mg/kg, and 78 were patients who had progressed after treatment with third-generation EGFR inhibitors (such as osimertinib) and platinum-based chemotherapy, forming the core analysis population.
Pooled analysis showed that among the 102 patients treated with 5.6 mg/kg U3-1402, the median follow-up time was 23 months (range 11.8-36.0 months). The ORR assessed by BICR reached 40.2%, the DCR was 78.4%, the median DOR was 7.6 months, the median PFS was 6.4 months, and the median OS was 15.8 months. Subgroup analysis showed that among the 78 patients who had received third-generation EGFR inhibitors and platinum-based chemotherapy, the efficacy data were more significant: the ORR was 41.0%, the median PFS was 6.4 months, and the median OS reached 16.2 months, suggesting that U3-1402 still has clinical activity in refractory patients who failed multiple lines of treatment.
It is worth noting that for patients with a history of central nervous system (CNS) metastasis (previously treated with radiotherapy or untreated), U3-1402 still showed certain intracranial activity, with an ORR of 36.4%, which was not statistically different from that of patients without CNS metastasis (44.7%), suggesting that it may cross the blood-brain barrier and provide a solution to the clinical problem of brain metastasis. In addition, the study found no significant correlation between efficacy and HER3 expression level, indicating that U3-1402 may not require strict screening of patients with high HER3 expression, expanding the range of potential benefit patients.
Safety analysis showed that 76.5% of patients experienced grade 3 or higher treatment-emergent adverse events (TEAE), and 56.9% were treatment-related adverse events (TRAE), mainly including hematological toxicity (thrombocytopenia 26%, neutropenia 21%, anemia 9%) and non-hematological toxicity (fatigue 10%, nausea 7%, hypokalemia 7%). It is worth noting that interstitial lung disease (ILD), as a characteristic adverse reaction of DXd-based ADCs, had an incidence of 7.8% (8/102) in this study, including 2 cases of grade 1, 3 cases of grade 2, 1 case of grade 3, and 2 cases of grade 5 (death), suggesting that close monitoring of pulmonary symptoms and timely intervention are required in clinical application to reduce the risk of fatality.
U31402-A-J101 is an ongoing phase I/II clinical trial focusing on patients with HER3-positive, HER2-negative locally advanced or metastatic breast cancer, aiming to explore the optimal dose and efficacy of U3-1402. The study is divided into three phases: dose escalation, dose exploration, and dose expansion. The dose expansion phase uses 4.8 mg/kg or 6.4 mg/kg, including patients with hormone receptor-positive (HR+)/HER2- and triple-negative breast cancer (TNBC). The primary endpoint is ORR, and secondary endpoints include DOR, PFS, OS, and safety.
Subgroup analysis showed that among HR+/HER2-/HER3-positive patients, the ORR of the HER2 low-expression (IHC 1+ or IHC 2+/ISH-) subgroup (n=58) was 36.2%, the median DOR was 7.2 months, the median PFS was 5.8 months, and the median OS was 13.7 months; the ORR of the HER2 0 expression subgroup (n=39) was 28.2%, the median DOR was 7.0 months, the median PFS was 8.2 months, and the median OS was 14.6 months. Among TNBC patients, the ORR of the HER2 low-expression subgroup (n=29) was 20.7%, the median DOR was 4.1 months, the median PFS was 4.4 months, and the median OS was 12.7 months; the ORR of the HER2 0 expression subgroup (n=19) was 26.3%, the median DOR was 8.4 months, the median PFS was 8.4 months, and the median OS was 16.6 months. The above results indicate that U3-1402 has certain efficacy in HER3-positive, HER2-negative breast cancer, and shows more durable remission (median DOR 8.4 months) in TNBC with HER2 0 expression, providing a new therapeutic idea for this type of refractory tumor.
Safety data showed that the incidence of grade 3 or higher TRAE was 69.7% in 142 Japanese patients, mainly including hematological toxicity; the incidence of grade 3 or higher TRAE in American patients was 52.5%, and the overall safety profile was consistent with that of the NSCLC study. It is worth noting that there are racial differences in the incidence of ILD: the incidence of treatment-related ILD in Japanese patients was 8.5% (12/142), including 1 case of grade 5 event; no ILD was observed in American patients, suggesting that East Asian populations may be more sensitive to DXd-related pulmonary toxicity, which is similar to the clinical characteristics of DS-8201, and enhanced monitoring is required in Asian patients.
Patritumab Deruxtecan (U3-1402), as an HER3-targeted ADC drug, has shown significant anti-tumor activity in EGFR-mutant resistant NSCLC and HER3-positive, HER2-negative breast cancer, especially providing a new option for patients who failed multiple lines of treatment. Its unique drug design (HER3 monoclonal antibody + DXd) endows it with the dual advantages of precise delivery and potent killing, but the risk of DXd-related ILD (especially in East Asian populations) remains a major challenge in clinical application. Future studies need to further explore: 1) the combination strategy of U3-1402 with other treatments (such as immune checkpoint inhibitors); 2) whether the response of patients who have previously received DS-8201 treatment to U3-1402 is affected by cross-resistance; 3) the optimal detection method and cutoff value of HER3 expression level to optimize patient screening. With the deepening of research, U3-1402 is expected to become an important therapeutic means for HER3-driven tumors, promoting the development of precision oncology.
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