DLL3 (Delta Like Canonical Notch Ligand 3)

P1/2, N=80, Not yet recruiting, Novartis Pharmaceuticals

Unlike TGN1412, however, VHH38 exhibits a lateral paratope orientation that likely spatially hinder the cross-linking of CD28 molecules on the same T cell, probiding a structural basis for its co-stimulatory activity rather than superagonistic activity. In summary, through an integrated process of affinity screening, functional agonism ranking, and therapeutic efficacy evaluation, we have identified a panel of co-stimulatory anti-CD28 VHHs with strong potential as functional modules in Tri-TCEs for cancer immunotherapy.

CRS and ICANS emerge primarily during the first two cycles of treatment, have low to moderate severity and are generally manageable with general supportive measures and specialized immunosuppressive treatment including corticosteroids and monoclonal antibodies like tocilizumab. Tarlatamab appears to be a promising choice for relapsed SCLC, based on the results of the Phase III DeLLphi-304 trial, which demonstrated a clinically and statistically meaningful improvement in overall survival (OS) with its use compared to approved second-line chemotherapy (ChT) options. Having been recently granted FDA approval for use in patients with SCLC who progressed on or after platinum-based ChT, tarlatamab is currently being evaluated in multiple settings of SCLC, including first-line and maintenance treatment.

P2, N=75, Not yet recruiting, Technische Universität Dresden

P1, N=55, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Recruiting | Initiation date: Nov 2025 --> Mar 2026

P2, N=204, Recruiting, Boehringer Ingelheim | N=109 --> 204

P1, N=138, Recruiting, Shanghai Henlius Biotech | Not yet recruiting --> Recruiting

Platinum-etoposide has long been the standard first-line therapy, and the recent incorporation of immune checkpoint inhibitors (ICIs) such as atezolizumab (IMpower133) and durvalumab (CASPIAN, ADRIATIC) has modestly improved survival, including a new role for durvalumab as a consolidation therapy in limited-stage SCLC...Emerging approaches include DLL3-directed bispecific T-cell engagers (BiTEs), such as tarlatamab and obrixtamig, which have shown promising efficacy in relapsed disease, and next-generation antibody-drug conjugates (ADCs) targeting DLL3, B7-H3, TROP2, and SEZ6...Future therapeutic efforts will require biomarker-driven strategies that incorporate molecular subtyping (ASCL1, NEUROD1, POU2F3, and YAP1) and immune profiling to facilitate precise treatment selection. Combining ICIs, BiTEs, ADCs, and cellular or radioligand therapies in rational, evidence-based regimens represents a promising avenue to improve outcomes in this historically intractable disease.

P1, N=45, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Jun 2026 --> Dec 2026

As a result of this SCLC-like to LCNEC-like evolution, YAP1-positive cells lack several clinically relevant SCLC surface targets (i.e., DLL3, SEZ6), but are enriched for others (i.e., B7-H3, TROP2). We propose a model where YAP1 expressing cells emerge with SCLC treatment resistance and characterize a tenacious subpopulation capable of diverging from the treatment naïve lineage and adopting features to evade therapeutic response.

P=N/A, N=30, Chinese Academy of Medical Sciences Cancer Hospital; National Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Me

P2, N=120, Shandong Cancer Hospital; Suzhou Shengdiya Biomedical Co., LTD