Tarlatamab Shows Promise in Treating Extensive-Stage SCLC

A combination of tarlatamab with first-line chemoimmunotherapy has demonstrated encouraging efficacy and a manageable safety profile in patients suffering from extensive-stage small cell lung cancer (ES-SCLC). These findings stem from the cohort results of the phase 1b DeLLphi-303 study (NCT05361395), which were presented at the 2025 ESMO Congress and published in The Lancet Oncology.

At a median follow-up of 13.8 months, the results indicated an objective response rate (ORR) of 71%, comprising a complete response rate of 5% and a partial response rate of 66%. Additionally, 11% of patients experienced stable disease, while 8% had progressive disease. The median duration of response was 11.0 months, with a disease control rate of 82% and a median duration of disease control lasting 10.7 months. Notably, 39% of patients sustained disease control for at least a year.

Martin Wermke, MD, the lead author and director of the Trial Management/Early Clinical Trial Unit at the German Cancer Research Center, highlighted the significance of these findings. He noted that 49% of patients maintained ongoing responses at the time of data cutoff, indicating a promising trajectory as data continues to mature.

In terms of safety, the treatment regimen was well tolerated. Patients underwent a median treatment duration of 46 weeks, during which three dose-limiting toxicities were observed. All patients experienced treatment-related adverse events (TRAEs), with 43% categorized as grade 3 and 35% as grade 4. Tragically, one patient died due to a TRAE attributed to sepsis from the chemotherapy component. Wermke emphasized that the addition of tarlatamab produced a safety profile consistent with the individual agents involved.

“I hope I could convince you that the combination of another frontline chemoimmunotherapy that targets PD-L1 in the maintenance setting is safe and has a manageable toxicity profile,” Wermke stated during his oral presentation. “There is no indication of additive or synergistic toxicity.”

Currently, the standard treatment for patients with ES-SCLC involves chemoimmunotherapy followed by maintenance therapy using PD-1/PD-L1 inhibitors. Tarlatamab is classified as a bispecific T-cell engager and has previously been explored in the second-line setting as a standalone treatment in the phase 3 DeLLphi-304 trial (NCT05740566).

The phase 1b DeLLphi-303 study focused on patients who had received one cycle of chemoimmunotherapy consisting of platinum-etoposide along with an anti-PD-L1 inhibitor, regardless of their therapy response. Inclusion criteria mandated measurable disease per modified RECIST 1.1 guidelines and an ECOG performance status of 0 or 1. Patients with treated and asymptomatic brain metastases were also eligible.

During the first three cycles, participants received tarlatamab at 20 mg intravenously every three weeks, combined with platinum-etoposide and a PD-L1 inhibitor, either atezolizumab (Tecentriq) or durvalumab (Imfinzi). From cycle four onward, the same regimen continued as part of the frontline maintenance phase.

The study’s coprimary endpoints included dose-limiting toxicities, treatment-emergent adverse events, and TRAEs. Secondary endpoints focused on ORR, duration of response, disease control, progression-free survival (PFS), and overall survival (OS).

Regarding baseline characteristics, the median age of participants was 63.0 years, with 67% being male. The demographic composition was predominantly White (74%), followed by Asian (16%), Other (9%), and Black (1%). At diagnosis, 77% had extensive-stage disease, and 55% presented with an ECOG performance status of 1.

The findings further revealed a median PFS of 10.3 months, with a Kaplan-Meier estimate indicating a 12-month PFS rate of 43.1%. Although the median OS is not yet estimable, the Kaplan-Meier estimate for the 12-month OS rate was recorded at 80.6%.

Investigators also monitored treatment-emergent cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) across cycles, with most cases occurring during the first cycle. These events were primarily mild, resolving without fatalities. The median time to onset for CRS was 13.3 hours, while ICANS occurred at a median of 5 days post-treatment.

Wermke concluded that the data collected from this study supports the need for further investigation of this treatment regimen, which is set to be explored in the upcoming phase 3 DeLLphi-312 study (NCT07005128).

Disclosures included honoraria and consulting roles for various pharmaceutical companies, reflecting Wermke’s extensive involvement in the field.