Tarlatamab Shows Promising Efficacy in Extensive-Stage SCLC

Patients with extensive-stage small cell lung cancer (ES-SCLC) have shown encouraging responses to a novel treatment combining tarlatamab with first-line chemoimmunotherapy and PD-L1-directed maintenance therapy. This finding emerged from the phase 1b DeLLphi-303 study, which was presented at the 2025 ESMO Congress and published in The Lancet Oncology. At a median follow-up of 13.8 months, the objective response rate (ORR) reached an impressive 71%.

The study revealed a complete response rate of 5% and a partial response rate of 66%, with an additional 11% of patients experiencing stable disease. Despite 8% of patients showing progression, the overall disease control rate stood at 82%. Lead investigator Martin Wermke, MD, emphasized the significance of these results, stating that 39% of patients maintained disease control for at least 52 weeks.

Safety Profile and Treatment Regimen

Wermke, who is the director of Trial Management at the German Cancer Research Center, noted that the treatment exhibited a manageable safety profile. With a median treatment duration of 46 weeks, the study recorded three dose-limiting toxicities. Treatment-related adverse events (TRAEs) affected all patients, with 43% experiencing grade 3 and 35% grade 4 events. Tragically, one patient died from a TRAE linked to sepsis, attributed to the chemotherapy component.

The study also reported that 6% of patients discontinued treatment due to tarlatamab-related adverse events. Immune-related adverse events, excluding cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were noted in 2% of cases. Wermke expressed optimism regarding the combination therapy, asserting that it did not exhibit any additive or synergistic toxicity.

Study Design and Patient Demographics

The DeLLphi-303 study enrolled adult patients with ES-SCLC who had undergone one cycle of chemoimmunotherapy, which included platinum-etoposide and an anti-PD-L1 inhibitor. Patients were required to have measurable disease based on modified RECIST 1.1 criteria and an ECOG performance status of 0 or 1. The eligibility criteria allowed for those with treated and asymptomatic brain metastases.

In the initial treatment cycles, patients received tarlatamab, administered at 20 mg intravenously every three weeks alongside platinum-etoposide and a PD-L1 inhibitor, either atezolizumab or durvalumab. Following the initial cycles, treatment continued with tarlatamab alongside the PD-L1 inhibitors until disease progression was observed.

Baseline characteristics revealed that the median age of participants was 63 years, with 67% identifying as male. Most patients were White (74%), with 16% Asian and 1% Black. The majority of patients were former smokers, and a significant number had received prior PD-L1 inhibitors during standard treatment.

Further efficacy data highlighted a median progression-free survival (PFS) of 10.3 months, with a 12-month PFS rate estimated at 43.1%. The median overall survival (OS) remains to be fully assessed, but preliminary data suggest a 12-month OS rate of 80.6% with the tarlatamab regimen.

Investigators monitored treatment-emergent CRS and ICANS, which predominantly occurred during the first treatment cycle. Most events were classified as grades 1/2 and resolved without fatalities. The trial’s findings support the need for further investigation, with a phase 3 study, NCT07005128, set to explore this regimen’s efficacy in greater detail.

Ultimately, the results of the DeLLphi-303 study provide a promising outlook for patients with ES-SCLC, highlighting the potential of tarlatamab in enhancing treatment outcomes while maintaining a tolerable safety profile.