The combination of tarlatamab and standard anti-PD-L1 therapy as first-line maintenance therapy led to “unprecedented” survival gains among patients with extensive-stage small cell lung cancer (ES-SCLC) in the phase 1b DeLLphi-303 trial.

Patients receiving the combination had a median overall survival of more than 2 years than the historic benchmark of about 1 year, reported lead investigator Kelly Paulson, MD, PhD, Providence Swedish Cancer Institute, Seattle, in a presentation at the World Conference on Lung Cancer (WCLC) 2025.

The survival data are “truly exciting,” Paulson told attendees, noting that the combination therapy’s safety profile was manageable.

Study discussant Charles Rudin, MD, PhD, thoracic medical oncologist and deputy director, Memorial Sloan Kettering Cancer Center, New York City, agreed that the survival benefit was impressive. “We have not seen that before ever in our patients,” he said. “I know I’m supposed to be critical, but, you know, it’s a wow.”

Rudin cautioned, however, that the finding should also be seen in context: “Patients had to get through chemoimmunotherapy induction, still be alive, still be in response, or at least [have] stable disease, to be able to be enrolled in this trial,” he pointed out.

The results were simultaneously published in The Lancet Oncology.

ES-SCLC is an aggressive cancer with poor long-term prognosis. Most patients respond to first-line chemoimmunotherapy, followed by a PD-L1 inhibitor in the maintenance setting. However, relapse often occurs quickly, with trials reporting a median progression-free survival of about 5 months and a median overall survival of 1 year.

Tarlatamab is a bispecific T-cell engager immunotherapy that directs cytotoxic T cells to cancer cells expressing delta-like ligand 3. Previous studies have shown that tarlatamab as second-line treatment for patients with SCLC improves overall survival and has a better safety profile vs standard chemotherapy. Last year, the FDA granted accelerated approval to tarlatamab for the treatment of patients with ES-SCLC who progress on chemotherapy.

The phase 1b DeLLphi-303 trial tested the safety and efficacy of tarlatamab in the first-line maintenance setting in combination with a PD-L1 inhibitor (atezolizumab or durvalumab). The trial enrolled 88 patients with ES-SCLC who had completed four to six cycles of first-line platinum-etoposide chemotherapy and anti-PD-L1 therapy without disease progression.

Maintenance treatment — initiated within 8 weeks from the start of the last chemoimmunotherapy cycle and continued until disease progression — was intravenous atezolizumab (1680 mg every 4 weeks) or intravenous durvalumab (1500 mg every 4 weeks) plus intravenous tarlatamab (10 mg every 2 weeks). The median exposure to tarlatamab was 35 weeks (range, 0.1-119).

At a median follow-up from the start of maintenance of 18.4 months, the median overall survival was 25.3 months (95% CI, 20.3 to not estimable), with a median progression-free survival of 5.6 months (95% CI, 3.5-9.0). Both outcomes were similar whether patients received atezolizumab or durvalumab.

Overall, 21 patients (24%) had an objective response to maintenance therapy, as measured from a baseline scan after completion of chemoimmunotherapy. That included 19 patients with a partial response and two with a complete response; their median duration of response was 16.6 months.

Notably, said Paulson, the disease control rate was 60%, with 36% of patients having sustained disease control of at least 1 year.

The combination therapy’s safety profile of tarlatamab was consistent with that observed with tarlatamab monotherapy, according to Paulson — with no dose-limiting toxicity or treatment-related deaths and a low incidence of discontinuation (6%).

Cytokine-release syndrome was the most common treatment-related adverse event (56%), with most being grade 1 (43%) or grade 2 (11%); all events resolved with supportive care. Immune effector cell-associated neurotoxicity syndrome occurred in 6% of patients, with a median onset of 9 days after the first tarlatamab dose; again, all those events were resolved with supportive care.

Other treatment-related adverse events included dysgeusia (53%), fatigue (38%), and pyrexia (25%).

If these findings are confirmed in the ongoing randomized phase 3 DeLLphi-305 study, Paulson said, the tarlatamab/anti-PD-L1 combination could establish a new standard for first-line maintenance therapy in ES-SCLC.

The study was funded by Amgen Inc. Paulson reported receiving research funding to her institution from Amgen Inc., BMS, Merck, Iovance Biotherapeutics, and Immunocore; and consulting fees from BMS. Rudin did not provide disclosure information.