Tarlatamab, PD-L1 Inhibitor Combo Shows Promise in 1L Maintenance for ES-SCLC

Findings from a phase 1b study of tarlatamab combined with a programmed cell death ligand 1 (PD-L1) inhibitor has delivered encouraging survival results for patients with extensive-stage small cell lung cancer (ES-SCLC), one of the most aggressive forms of lung cancer.¹

The results, published in Lancet Oncology, suggest that pairing the bispecific T-cell engager (BiTE) tarlatamab (Imdelltra; Amgen) with atezolizumab (Tecentriq; Genentech) or durvalumab (Infinzi; AstraZeneca) could reshape the treatment landscape for this hard-to-treat disease.

The results, write the researchers, highlight how bispecific T-cell engagers may complement checkpoint inhibitors by bypassing tumor immune evasion mechanisms. Unlike PD-L1 inhibitors, which rely on tumor antigen presentation, tarlatamab directly redirects T-cells to attack DLL3-expressing cells, potentially overcoming resistance pathways in SCLC. Still, the group cautioned that these results, while promising, come from a small, non-randomized study.

ES-SCLC accounts for the majority of small-cell lung cancer diagnoses and is characterized by rapid progression and poor survival outcomes. While most patients initially respond to platinum–etoposide chemotherapy combined with a PD-L1 inhibitor, relapses typically occur within months.

“Given real-world data supporting that only approximately 40% of patients with ES-SCLC proceed to second-line therapy, there is a crucial need to improve upon the outcomes seen with standard of care first-line therapy,” described the researchers.

The phase 1b DeLLphi-303 trial enrolled 88 patients across 13 countries who had completed 4 to 6 cycles of chemo-immunotherapy without disease progression. Patients then received tarlatamab every 2 weeks alongside either atezolizumab or durvalumab, both PD-L1 inhibitors used in frontline SCLC. The primary goal was to assess safety and determine the recommended dose; efficacy was evaluated as a secondary endpoint.

Earlier studies in relapsed disease showed tarlatamab could extend survival with a manageable safety profile, leading researchers to test it earlier in treatment. The BiTE is currently approved under accelerated approval for second line and later ES-SCLC, based on data from the phase 2 DeLLphi-301 trial.²

Amgen has already launched the DeLLphi-305 randomized phase 3 trial, evaluating tarlatamab with durvalumab against current standard care. If confirmed, this regimen could become a new first-line standard.

In DeLLphi-303, all patients experienced at least 1 treatment-emergent side effect. The most common serious side effects included cytokine release syndrome (24%), fever, pneumonia, and neurotoxicity. Importantly, no treatment-related deaths were reported, and side effects were generally manageable with supportive care. Most cytokine release cases were mild to moderate and resolved within days.

“Given the predictable timing and largely low-grade profile of cytokine release syndrome, the inpatient monitoring period after tarlatamab infusion was reduced as the trial progressed,” wrote the researchers. “Adoption of a shortened monitoring period in an outpatient setting in the DeLLphi-300 and DeLLphi- 304 trials was effective for detection and management of cytokine release syndrome.”

Hyponatremia, anemia, and neutropenia were the most frequent grade 3–4 laboratory toxicities. Only 6% of patients discontinued therapy due to side effects, underscoring the regimen’s tolerability.

After median follow-up of 18.4 months, with more than one-fifth of participants remaining on therapy at data cut-off, median overall survival (OS) was 25.3 months, surpassing the historic 12 to 13 months typically achieved with standard first-line therapy. Data from the IMpower133 study of atezolizumab showed a median OS of 12.5 months.

At 12 months in DeLLphi-303, overall survival was 82%, and at 18 months was 75%.

Median progression-free survival was 5.6 months, and 34% of patients were progression-free at 1 year. While PFS results were more modest than OS, nearly one-third of patients achieved sustained disease control for over a year, a striking result in a disease where long-term responders are rare, explained the researchers.

Objective response was observed in 24% of patients, including 2 complete responses, with responses lasting a median of 16.6 months.

References

1. Paulson KG, Lau SCM, Ahn M-J, et al. Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study. Lancet Oncol. Published online September 8, 2025. doi: 10.1016/S1470-2045(25)00480-2

2. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. News release. Last updated May 16, 2024. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer