HER3-Targeted ADC U3-1402 Shows 100% Disease Control Rate in Osimertinib-Resistant NSCLC, Files for IPO

Recently, the highly anticipated 2019 American Society of Clinical Oncology (ASCO) Annual Meeting has been underway, reporting several encouraging clinical results in cancer treatment. Among them, the most notable is U3-1402, a novel antibody-drug conjugate (ADC) developed by Daiichi Sankyo. This drug remains effective in patients with non-small cell lung cancer (NSCLC) who have developed resistance to osimertinib, achieving a disease control rate of 100%.

Figure 1. ADC drug U3-1402

As shown in Figure 1, U3-1402 is a novel antibody-drug conjugate (ADC). Antibody-drug conjugates (ADCs) represent an emerging class of innovative therapeutics that have gained prominence in recent years. These agents consist of an antibody linked to a cytotoxic drug via a linker moiety. The antibody component specifically recognizes and delivers the drug to the lesion site. Upon reaching the target tissue, the linker typically undergoes cleavage in the local pH environment, thereby releasing the therapeutic payload. This mechanism enables selective accumulation and efficacy at the disease site while minimizing damage to non-target cells, significantly reducing adverse effects. This approach is particularly effective in mitigating the toxicity associated with potent antineoplastic agents. Consequently, ADCs are a key focus in drug development under the current paradigm of "precision medicine."

Figure 2 Exatecan (DX-8951)

U3-1402, a novel antibody-drug conjugate (ADC) under Daiichi Sankyo, is composed of the HER3 antibody patritumab covalently linked to the topoisomerase inhibitor DX-8951 (exatecan, Figure 2). Looking back at the development journey of U3-1402, it represents a successful case where Daiichi Sankyo took an innovative approach to further develop the antibody drug patritumab.

In 2016, Daiichi Sankyo announced the termination of patritumab’s development for non-small cell lung cancer (NSCLC) after the clinical trials failed to meet their endpoints, showing no significant difference compared with the control group. Nevertheless, given patritumab’s undisputed ability to specifically target HER3, Daiichi Sankyo researchers pursued an alternative approach and successfully repurposed it for antibody-drug conjugate (ADC) development, leading to the creation of U3-1402.

Figure 3. U3-1402 demonstrates significant efficacy in overcoming EGFR-targeted therapy resistance in HER3-positive cases

Notably, the encouraging data presented at this year’s ASCO demonstrate that U3-1402 is not only effective in patients with HER3-positive EGFR inhibitor-resistant tumors, but also shows efficacy across other diverse resistance mechanisms, including C797S mutations, HER2 alterations, and CDK4-related pathways. Among the 16 patients enrolled in the clinical study, all exhibited tumor reduction, with a median reduction of 29%; the disease control rate (DCR) reached an impressive 100%.

Figure 4. U3-1402 is effective in patients with various resistance mechanisms

As is well known, patients with non-small cell lung cancer (NSCLC) typically develop drug resistance during the course of treatment. In recent years, EGFR-targeted therapies for NSCLC have undergone continuous updates and iterations, progressing from first- and second-generation to third-generation agents (such as osimertinib). However, clinical practice has revealed that even the third-generation EGFR-TKI osimertinib is not immune to the challenge of resistance, a dilemma that has long left healthcare professionals and patients with limited options. The promising clinical outcomes of U3-1402 undoubtedly offer significant hope for addressing this persistent challenge.

Furthermore, as a targeted therapeutic agent, U3-1402 is not only being developed for the treatment of non-small cell lung cancer (NSCLC). Current clinical trials indicate that it is also under development for other malignancies, including prostate cancer, breast cancer, and colorectal cancer, positioning it as an anticancer drug with significant market potential. It is hoped that U3-1402 will meet expectations in further clinical development, achieve successful market approval at an early date, and benefit a broad population of cancer patients. Additionally, there is anticipation for the successful development of more promising agents to address resistance to third-generation EGFR-TKIs.

References:

1. 2019ASCO；

2. An HER3-targeting antibody-drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC，2018；

3. https://clinicaltrials.gov/ct2/show/NCT03260491?term=U3-1402&rank=1；

4. https://clinicaltrials.gov/ct2/show/NCT02980341?term=U3-1402&rank=2.