DLL3 (Delta Like Canonical Notch Ligand 3)

While immunotherapy has improved outcomes, most patients ultimately relapse. Integrating molecular subtyping, optimizing multimodality care, and accelerating clinical trial enrollment are key to further progress in SCLC.

Overall, durable clinical benefit in SCLC will likely require temporally sequenced, biomarker driven combination strategies that anticipate and constrain tumor plasticity. Integrating lineage-directed targeting, epigenetic modulation, immune engagement, and metabolic intervention may enable more effective and sustained disease control in this highly adaptive cancer.

Meaningful progress in the coming years will depend on multicenter collaboration, standardization of molecular and histologic assessment, and clinical trials that link biologic grading with treatment outcomes. Establishing a unified framework that connects pathology, genomics, and patient response will help translate scientific advances into improved survival and quality of life for individuals living with MTC.

P3, N=390, Not yet recruiting, Boehringer Ingelheim | Trial completion date: May 2030 --> Dec 2029

P2/3, N=105, Not yet recruiting, Boehringer Ingelheim International GmbH, Boehringer Ingelheim Espana S.A.

P2/3, N=74, Not yet recruiting, Boehringer Ingelheim International GmbH, Boehringer Ingelheim Espana S.A.

A modified dosing and monitoring protocol may improve the safety of tarlatamab in patients with MTC while maintaining efficacy. Further research is needed to evaluate the role of tarlatamab in MTC.

The most significant improvement was achieved by substituting Val4 with rigid 1-aminocyclopropanecarboxylic acid, which produced the lead peptide B5 with a K D of 12.3 nM. These results validate our rational design strategy and identify peptide B5 as a promising candidate for the future development of DLL3-targeted theranostic agents.

Affordability constraints are more stringent in China than in the United States. These findings inform value-based pricing, reimbursement negotiations, and equitable access strategies.

P2, N=87, Recruiting, Grupo Espanol de Tumores Neuroendocrinos

Emerging therapies, such as antibody-drug conjugates targeting B7-H3/DLL3 (I-Dxd, ZL-1310) and bispecific antibody tarlatamab, have demonstrated intracranial response rates of 62.5%-71%. Future directions involve developing new drugs with high blood-brain barrier penetration, such as radioligand therapy, conducting prospective studies to optimize HA and SRS applications, establishing high-quality RWE databases to support personalized treatments, exploring molecular subtypes (SCLC-A/N/P/I) and leveraging AI technologies to advance precision radiotherapy. SCLC management needs to be patient-centered, integrating precise treatment of brain metastases, QoL improvement, and the application of RWE to achieve a balance between survival benefits and QoL.

MLAs consistently express B7-H3, TROP2, and CLDN6, identifying them as highly promising therapeutic targets for ADC-based therapies, but this may require biomarker informed eligibility screening. DLL3 is unlikely to be a useful therapeutic target in this aggressive histotype. These findings expand the biomarker landscape in MLA and provide a rationale for clinical investigation of ADCs in this setting.