Daiichi Sankyo Submits Second Clinical Trial Application in China for HER3-Targeted ADC U3-1402

On April 20, the CDE website showed that Daiichi Sankyo's HER3 ADC new drug U3-1402 submitted a new clinical trial application. The drug was first applied for clinical trials in China in May 2021, and a Phase II clinical trial for EGFR-mutated NSCLC was initiated in November 2021.

U3-1402 Project Details

Source: Insight Database Mini Program (http://db.dxy.cn/v5/home/)

HER3 is a member of the HER receptor tyrosine kinase family and is expressed in various types of cancer. Its overexpression can be observed in colorectal cancer, gastric cancer, squamous cell carcinoma of the head and neck, breast cancer, lung cancer, etc. The overexpression of HER3 is associated with the metastasis of NSCLC cancer cells and reduced patient survival rates, making it a promising new treatment for advanced and metastatic NSCLC.

U3-1402 is an antibody-drug conjugate under research by Daiichi Sankyo. Its antibody component is the HER3 monoclonal antibody patritumab (U3-1287), covalently linked through a linker to the topoisomerase I inhibitor exatecan (MAAA-1181a), with each antibody linked to eight exatecan molecules. By binding to HER3 on the surface of cancer cells, U3-1402 is internalized into the cell where exatecan is released, thereby exerting cytotoxic effects and killing cancer cells.

The antibody part of the drug, Patritumab, is a HER3-targeting monoclonal antibody co-developed by U3pharma and Amgen. In 2008, Daiichi Sankyo acquired U3pharma and obtained the rights to its in-development Patritumab and related intellectual property. In 2016, due to unsatisfactory clinical data, Daiichi Sankyo halted the development of Patritumab for the treatment of NSCLC. However, the emergence of ADC technology gave new life to this monoclonal antibody, and Daiichi Sankyo developed it into an ADC drug, resulting in U3-1402.

Currently, U3-1402 has progressed to Phase 2 clinical trials outside of China, with 8 sets of data already presented at various major medical conferences. At the 2021 ASCO meeting, Daiichi Sankyo provided an update on the latest data from the Phase 1 clinical trial (NCT03260491).

U3-1402 Project Details

Source: Insight Database Global New Drug Module (http://db.dxy.cn/v5/home/)

As of September 24, 2020, a total of 57 NSCLC patients were enrolled in this phase 1 clinical trial. All these patients had previously received EGFR-TKI treatment, 86% osimertinib, 91% platinum-based chemotherapy, and 40% immunotherapy, with a median number of treatment lines being 4. This included 27 cases of brain metastasis.

The results showed that the objective response rate (ORR) assessed by BICR was 39%, the disease control rate (DCR) was 72%, the median duration of response (mDoR) was 6.9 months, and the median progression-free survival (mPFS) was 8.2 months. Notably, the efficacy data of 44 patients previously treated with osimertinib and platinum-based chemotherapy (the OSI group in the figure) were similar to those of other patients.

Source: 2021 ASCO

Partial tumor responses to U3-1402 were observed across various mechanisms of EGFR-TKI resistance, including EGFR C797S mutations, MET amplification, HER2 mutations, and BRAF fusions. In patients with resistance mechanisms within the EGFR pathway, the ORR reached 47%; in those with resistance via non-EGFR/MET pathways (including KRAS, BRAF, ALK, etc.), the ORR was 45%. Additionally, U3-1402 demonstrated activity in patients with brain metastases, showing an ORR of 32%, a DCR of 80%, and an mPFS of 8.2 months, which is comparable to its efficacy in patients without brain metastases.

Source: 2021 ASCO

Notably, Daiichi-Sankyo pointed out that HER3 expression remains stable and is unaffected by the number of TKI treatment lines or duration. Therefore, U3-1402 is effective against various resistance mechanisms, potentially benefiting a broader patient population. Moreover, there were cases of relief regardless of high or low HER3 expression.

Based on the positive data from the Phase 1 clinical trial, Daiichi Sankyo has initiated the pivotal Phase 2 clinical HERTHENA-Lung01 study, which is expected to be completed in 2022. Beyond NSCLC, U3-1402 is also being developed for colorectal cancer (CRC) and breast cancer indications, as detailed in the figure below:

Source: Daiichi Sankyo Official Website

Currently, there are few companies in China targeting the HER3 point. Apart from Daiichi Sankyo, Baili Pharmaceutical has relatively more HER3 projects. The company simultaneously has an EGFR/HER3 bispecific antibody SI-B001 and an EGFR/HER3 bispecific ADC BL-B01D1. The former is at the highest phase II development stage. Recently, a phase II/III clinical trial for EGFR-mutated NSCLC was just initiated in combination with Osimertinib. The latter is still in phase I development.

Note: The original text has been abridged.