Tarlatamab for ES-SCLC

Prof Dr Luis Paz-Ares, a medical oncologist at the 12 de Octubre University Hospital in Madrid, summarises his presentation from the session ‘New drugs in oncology: incorporation into practice’. He starts with a comprehensive overview of recent advances in the treatment of SCLC, focusing on the clinical development and impact of tarlatamab, a novel bispecific T-cell engager. SCLC remains a particularly aggressive malignancy, characterised by rapid progression, high metastatic potential, and poor long-term survival outcomes. Despite initial responses to standard first-line treatments, typically a combination of chemotherapy and PD-1/PD-L1 inhibitors, disease relapse is almost universal, and long-term survivorship is rare. Given these limitations, there is an urgent need for innovative therapeutic strategies capable of overcoming mechanisms of immune evasion intrinsic to this disease.

One such mechanism involves the frequent downregulation of MHC class I molecules and disruption of antigen presentation pathways in SCLC, limiting the efficacy of conventional immune checkpoint blockade. T-cell engagers represent a rational approach to bypass these defects by directly recruiting and activating T-cells against tumour cells through non-MHC-dependent mechanisms. Tarlatamab, in particular, has been engineered to simultaneously bind CD3 on T-cells and DLL3 on SCLC cells. DLL3 is an aberrantly expressed surface protein found in the vast majority of SCLC tumours, with minimal expression in normal tissues, making it an attractive and selective therapeutic target.

Clinical development of tarlatamab has progressed through early-phase trials in patients with relapsed SCLC, consistently demonstrating promising efficacy. Response rates in these studies have ranged from 35% to 40%, with median PFS between 4.5 and 5 months. Notably, mature follow-up from phase 1 studies revealed a median OS exceeding 18 months in some cohorts, a significant improvement for this historically treatment-refractory disease. At ASCO, Dr Charles Rudin presented results from a pivotal phase 3 randomised trial comparing tarlatamab to standard second-line chemotherapy. The study confirmed a clear survival benefit, with tarlatamab extending median OS from 8 to 13 months and achieving a hazard ratio of 0.6, firmly establishing its clinical value in this setting.

Regarding safety, tarlatamab was generally well tolerated, with a manageable toxicity profile. The primary adverse events of concern were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS was observed in approximately 50% to 60% of patients, predominantly of mild (grade 1) or moderate (grade 2) severity, while grade 3 events were rare, occurring in only 0% to 5% of patients depending on the study, and approximately 1% in the phase 3 trial. ICANS occurred less frequently, with an incidence of 8% to 10%, typically mild and self-limiting. Crucially, these adverse events were most common during the initial infusions. The implementation of mitigation strategies, including step-dosing protocols (initiating with a 1 mg dose before escalating to 10 mg) and prophylactic administration of dexamethasone, significantly reduced the incidence and severity of these toxicities. 

Initially, hospitalisation for monitoring during the first 24 to 48 hours post-infusion was standard practice. However, subsequent experience has indicated that, in carefully selected patients—those living near treatment centers and with continuous caregiver support—ambulatory administration with post-infusion observation and daily follow-up can be safely implemented without compromising patient outcomes. These adaptations have improved the feasibility of tarlatamab in routine clinical practice.