DLL3 Targeting Therapy Prospects

Delta-like ligand 3 (DLL3) has recently gained attention as a promising target for cancer therapy, specifically in neuroendocrine malignancies such as small cell lung cancer (SCLC). This protein is typically absent in most healthy tissues but is found in high levels in certain cancers, making it an attractive focus for treatment strategies. Targeting DLL3 could offer a more precise approach to cancer therapy, especially for neuroendocrine cancer patients who have limited treatment options. DLL3 is involved in the regulation of the Notch signaling pathways, crucial for cell differentiation. In normal cells, DLL3 expression is tightly controlled. However, in cancerous cells, its abnormal expression is linked to tumor initiation and progression. Its presence in up to 80% of SCLC tumors, while being minimally expressed in normal adult tissues, underscores its potential as a therapeutic target.

Pharmaceutical companies are exploring various modalities to target DLL3. Among the most advanced in clinical research are bispecific antibodies, particularly T cell engagers. These bispecific T cell engagers work by connecting cancer cells to immune cells, facilitating a targeted attack on the cancer cells while minimizing damage to healthy tissues. This method leverages the body's immune system to specifically target and kill DLL3-expressing tumor cells.

One notable development in this area is Amgen's creation of Tarlatamab, which utilizes the company's proprietary BiTE (bispecific T-cell engager) technology. In the phase 2 DeLLphi-301 trial, which evaluated multiple efficacy parameters such as objective response rate, duration of response, disease control rate, progression-free survival, and overall survival, Tarlatamab demonstrated promising results. The trial, which included participants with advanced-stage SCLC who had undergone at least two prior treatments including platinum-doublet chemotherapy, reported an objective response rate of 40% and a disease control rate of 63%.

Encouraged by these results, Amgen submitted a biologics license application (BLA) to the US FDA for the use of Tarlatamab in treating advanced SCLC. The FDA granted Priority Review status to this application in December 2023, setting a Prescription Drug User Fee Action date of June 12, 2024. This designation indicates the potential importance and urgency of the treatment.

Other approaches to DLL3-targeted therapies include cell therapies and antibody-drug conjugates. For instance, Tianjin Medical University Cancer Institute and Hospital has developed a DLL3-CAR-NK cell therapy, while Legend Biotech is working on LB2102, a DLL3-CAR-T cell therapy. Additionally, earlier studies with Rovalpituzumab Tesirine, an antibody-drug conjugate, have shown the anticancer effects of targeting DLL3, paving the way for further development in this area.

While most DLL3-targeted therapies are still in the early stages of development, Tarlatamab has shown significant promise, evidenced by its multiple designations and the encouraging results from clinical trials. DLL3-targeted treatments hold substantial potential for advancing cancer therapy, offering hope for improved outcomes where conventional treatments have failed. With ongoing research and clinical trials, DLL3-targeted therapies could significantly enhance survival rates for patients with neuroendocrine cancers.