TARLATAMAB-DLLE

Tarlatamab, a DLL3-targeted bispecific T-cell engager, has emerged as a second-line therapy for extensive-stage small cell lung cancer (ES-SCLC) following progression on platinum-based chemoimmunotherapy. While clinical trials have demonstrated promising efficacy, real-world data on safety remain limited.

This retrospective study included 40 patients with SCLC or high-grade neuroendocrine carcinoma treated with tarlatamab at Moffitt Cancer Center between May 2024 and February 2025. Clinical, laboratory, and treatment-related variables including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reviewed. Predictive models for these toxicities were developed using Firth logistic regression based on data from 30 patients who did not receive prophylactic tocilizumab.

The median age was 66.5 years; 55% were male, and 87.5% had an ECOG performance status of 0 to 1. Among patients who did not receive prophylactic tocilizumab (N = 30), 53.3% developed CRS and 23.3% developed ICANS after Cycle 1 Day 1, with 10% experiencing grade ≥ 3 severity for each. Three patients discontinued treatment due to severe CRS/ICANS, with 2 deaths and 1 transition to hospice. Among those who received prophylactic tocilizumab (N = 10), 1 patient developed grade 2 CRS and none developed ICANS. Elevated LDH and liver metastasis were independent predictors of CRS; LDH was also predictive of grade ≥ 2 CRS. Diabetes and cardiovascular disease were independently associated with ICANS.

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.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive malignancy, accounting for approximately 3% of all primary lung malignancies. Due to its rarity, the treatment paradigm for LCNEC is primarily derived from retrospective data from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). This review synthesizes current evidence and discusses emerging treatment strategies. For medically fit patients with resectable disease, surgical resection, in particular lobectomy, should be offered, while stereotactic body radiation therapy can be reserved for medically inoperable patients. Adjuvant chemotherapy is suggested for most resected tumors, with SCLC regimens (eg, etoposide-cisplatin) associated with better outcomes; however, very early-stage tumors (stage IA) warrant individualized decision-making. There is currently no evidence supporting the use of adjuvant immunotherapy in LCNEC. The role of adjuvant radiotherapy, neoadjuvant therapy and prophylactic cranial irradiation in LCNEC remains undefined. For unresectable, locally advanced disease, concurrent chemoradiation with etoposide-cisplatin followed by consolidation durvalumab is recommended, although the optimal dose-fractionation and the duration of consolidation immunotherapy remain to be investigated. In metastatic disease, etoposide-platinum chemotherapy remains the first-line treatment, while targeted therapy can be considered if tumors harbor actionable genomic alterations. The potential benefit of immunotherapy is currently under investigation. While several second-line treatment options have been reported with modest efficacy, local ablative treatment has shown promise in oligometastatic LCNEC. Among the most promising emerging treatment strategies are DLL3-targeting therapies, buoyed by the recent success of tarlatamab in SCLC. The evolving role of molecular profiling in prognostication and treatment decision-making is also examined.