P1/2, N=232, Active, not recruiting, Harpoon Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Recruiting --> Active, not recruiting

Our findings suggest that flare reaction occurs within days of initiating tarlatamab, possibly attributable to acute immune activation, as reported in BiTE therapies. Awareness of this possibility may help avoid premature discontinuation of effective treatment.

Given lack of standard-of-care treatments for patients with actionable oncogenic alteration NSCLC transformed to SCLC, this remains a challenge and unmet need for treating these patients. Here, we present a case of a patient with ALK-rearranged NSCLC with transformation to SCLC, who has progressed on several lines of therapies and successfully treated with tarlatamab to elicit and maintain clinical benefit, including intracranial response.

The pervasive absence of HER2, folate receptor alpha, DLL3, TROP-2, and nectin-4 expression in SCSTs suggests ADCs targeting these antigens may be of limited clinical benefit. The design of clinical trials investigating the use of tissue factor-targeting ADCs for the treatment of adult GCTs warrants future consideration.

DLL3 has emerged as the most clinically relevant target to date, with the bispecific TCE tarlatamab demonstrating meaningful and durable response, manageable cytokine-release toxicity, and ultimately achieving accelerated FDA approval for previously treated extensive-stage SCLC... Collectively, these emerging immunotherapies illustrate a shift toward antigen-specific targeting in a disease historically defined by limited therapeutic innovation. Continued optimization of antigen selection, payload and linker engineering, and biomarker-driven trial design will be critical for translating early promise into durable clinical benefit and reshaping the treatment landscape for SCLC.

Tarlatamab is associated with higher CRS and ICANS rates in real-world settings than observed in trials. Prophylactic tocilizumab may mitigate these toxicities in high-risk patients and should be considered for incorporation into treatment protocols.

Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression, but persistence of other targetable neuro-endocrine epitopes; in other patients, DLL3 is retained on CTCs, but accompanied by systemic markers of T cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance.

P1/2, N=120, Not yet recruiting, National Cancer Institute (NCI)

P1/2, N=138, Recruiting, Molecular Partners AG | Not yet recruiting --> Recruiting | Trial completion date: Sep 2030 --> Sep 2032

P3, N=420, Recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd | Not yet recruiting --> Recruiting

P1/2, N=350, Recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd | Not yet recruiting --> Recruiting

P1/2, N=54, Recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Sep 2025 --> Sep 2026