ifinatamab deruxtecan (DS-7300)

P1/2, N=170, Not yet recruiting, Merck Sharp & Dohme LLC

Novel agents such as tarlatamab (DLL3-targeting) and ifinatamab deruxtecan (B7-H3-targeting) have shown encouraging efficacy in early-phase trials, though predictive markers remain elusive. A multi-dimensional approach combining tissue, blood, and immune profiling is essential to advance precision oncology in SCLC and improve patient selection for emerging therapies.

P2, N=187, Active, not recruiting, Daiichi Sankyo | Trial completion date: Nov 2025 --> Dec 2026

P3, N=540, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

I-DXd 12 mg/kg Q3W showed promising efficacy in patients with previously treated ES-SCLC. The observed safety profile was consistent with previous reports, with no new safety signals identified.

P1/2, N=250, Recruiting, Daiichi Sankyo | Trial completion date: Mar 2027 --> Oct 2029 | Trial primary completion date: Dec 2025 --> Apr 2027

Patients with small cell lung cancer (SCLC) have poor prognosis and limited treatment options beyond first-line therapy. Secondary endpoints include ORR by investigator; progression-free survival, duration of response, disease control rate, and time to response, all by BICR and investigator; patient-reported outcomes; and safety. IDeate-Lung02 will ascertain whether I-DXd treatment after only one prior line of systemic treatment improves outcomes for patients with relapsed SCLC compared with topotecan, amrubicin, or lurbinectedin.Clinical Trial Registration: NCT06203210.

For decades, outcomes stagnated: most patients present with extensive-stage disease, screening rarely detects early tumors, surgery is seldom feasible, and platinum-etoposide remained the first-line standard with median overall survival (OS) 80% of SCLC, enables T-cell-redirecting therapy: the bispecific T-cell engager tarlatamab improved OS to 13.6 vs 8.3 months over standard second-line chemotherapy, with manageable cytokine release syndrome and occasional ICANS. B7 homolog 3 (B7-H3, CD276), uniformly expressed across SCLC subtypes and linked to poor prognosis, is another compelling target: the antibody-drug conjugate ifinatamab deruxtecan achieved a 54.8% response rate and meaningful survival in heavily pretreated patients, earning FDA Breakthrough designation. Together, DLL3- and B7-H3-directed therapies (with additional ADCs against Trop-2 and SEZ6 in development) are redefining second-line and later care. Key next steps include optimizing sequencing/combination strategies, managing BiTE-specific toxicities, and developing predictive biomarkers. After decades of futility, SCLC is transitioning from uniform chemotherapy to a precision-medicine paradigm with cautious optimism.

P2, N=96, Recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Sep 2030 --> Mar 2032

Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 (dual PSMA/STEAP1-targeted), and DXC008 (dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, the B7-H3-targeted ADC ifinatamab deruxtecan has initiated an international multicenter phase Ⅲ clinical trial (NCT06925737) for mCRPC in May 2025. This review summarizes recent advances in ADCs targeting key antigens in mCRPC (including PSMA, B7-H3, STEAP1, TROP2, SLC44A4, and others) and explores combination strategies, offering insights to inform the clinical management of this highly lethal disease.

P1/2, N=228, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting | Trial completion date: Feb 2031 --> Jan 2032 | Trial primary completion date: Feb 2031 --> Jan 2032

P1/2, N=242, Recruiting, Merck Sharp & Dohme LLC | N=138 --> 242