DeLLphi-304: Tarlatamab bests SoC chemo as 2L treatment for SCLC

Tarlatamab was associated with significant improvements in overall survival (OS), progression-free survival (PFS) and patient-reported outcomes (PROs) vs standard-of-care (SoC) chemotherapy in patients with small-cell lung cancer (SCLC) undergoing second-line (2L) therapy, according to the primary analysis of the phase III DeLLphi-304 study presented at ASCO 2025.

Tarlatamab is a half-life–extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3), which is selectively expressed in SCLC tumours and has minimal normal tissue expression. As tarlatamab directs cytotoxic T cells to DLL3-expressing SCLC cells, it results in tumour lysis. [Clin Cancer Res 2021;27:1526-1537]

Tarlatamab has demonstrated clinical benefit and safety in previously treated SCLC in phase I and II trials. [N Engl J Med 2023;389:2063-2075; J Thorac Oncol 2024;19:S30-S31] The phase III DeLLphi-304 trial assesses whether tarlatamab (n=254; median age, 64 years; male, 72 percent; Asian, 38 percent) is more effective than chemotherapy (n=255; median age, 66 years; male, 66 percent; Asian, 42 percent) in the treatment of patients with SCLC whose disease progressed or recurred following one line of platinum-based chemotherapy. The chemotherapy options on the trial are topotecan, lurbinectedin or amrubicin, based on local availability. The primary endpoint is OS, while PFS and PROs are the key secondary endpoints. [N Engl J Med 2025;393:349-361]

“Key inclusion criteria include progression after one line of platinum-based chemotherapy with or without the addition of PD-1– or PD-L1–directed immunotherapy. Prior anti–PD-[L]1 therapy was used in 71 percent of patients. Of all patients, 44 percent had chemotherapy-resistant disease, defined as a chemotherapy-free interval after completion of first-line chemotherapy of <90 days,” reported presenter Dr Charles Rudin of Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, US. “Importantly, asymptomatic brain metastases were allowed, and those patients were encouraged to participate in the trial regardless of prior therapy.” [ASCO 2025, abstract LBA8008]

Tarlatamab reduced risk of death by 40 percent

The first interim analysis was carried out at a median follow-up of 11.2 months, at which time the median OS was 3.6 months with tarlatamab vs 8.3 months with chemotherapy (hazard ratio [HR], 0.60; 95 percent confidence interval [CI], 0.47–0.77; p<0.001). The OS rate at 12 months was 53 percent in the tarlatamab group vs 37 percent in the group treated with chemotherapy.

“The survival benefit was seen across all of the prespecified patient subgroups, including the chemotherapy-resistant subset [HR, 0.60; 95 percent CI, 0.43–0.84] and patients with brain metastases at baseline [HR, 0.45; 95 percent CI, 0.31–0.65],” highlighted Rudin.

At a median follow-up of 11.0 months, PFS was also significantly longer with tarlatamab vs chemotherapy (HR, 0.71; 95 percent CI, 0.59–0.86; p=0.002). “The median PFS was only modestly improved from 3.7 months with chemotherapy to 4.2 months with tarlatamab,” commented Rudin. “But you can see that while the [PFS] curves were almost superimposable for the first few months, they started to clearly separate at 6 months, and the gap continues to widen over time.”

Tarlatamab was associated with more frequent and durable responses than chemotherapy. The objective response rates were 35 and 20 percent, respectively. The median duration of response (DoR) was 6.9 months with tarlatamab and 5.5 months with chemotherapy. “But the median doesn’t really tell the story,” remarked Rudin. “Like the PFS curves, the DoR curves remained similar over the first 5–6 months, but then a clear separation occurred, which continued to widen over time, suggesting a durable benefit in the tarlatamab arm.”

Furthermore, at the time of the present data cutoff, ongoing response was noted in 47 percent of patients on tarlamatamb vs 5 percent of patients on chemotherapy.

Patient-reported outcomes

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The change from baseline after 18 weeks in symptoms of chest pain, cough and dyspnoea were measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the supplementary symptom scores for Lung Cancer (QLQ-LC13).

“Although the benefit in terms of chest pain was not statistically significant, all of the PRO measures trended in favour of the tarlatamab vs chemotherapy arm,” reported Rudin.

The least squares (LS) mean improvement in dyspnoea from baseline was 1.94 with tarlatamab and -7.20 with chemotherapy, resulting in a LS mean difference of -9.14 (95 percent CI, -12.64 to -5.64; p<0.001). The proportion of patients who experienced improvement in their cough after 18 weeks from baseline was 16.1 percent in the tarlatamab arm and 9.0 percent in the chemotherapy arm (odds ratio, 2.04; 95 percent CI, 1.17–3.55; p=0.012).

Chest pain improved in 8.7 percent of patients treated with tarlatamab vs 3.5 percent of patients treated with chemotherapy after 18 weeks from baseline, but the difference did not meet statistical significance.

Fewer high-grade AEs with tarlatamab

“Tarlatamab had a more favourable safety profile relative to chemotherapy,” stated Rudin. “Grade ≥3 treatment-related adverse events [TRAEs] [62 vs 27 percent] as well as TRAEs leading to dose interruption and/or reduction [55 vs 19 percent] or discontinuation [6 vs 3 percent] occurred in twice or more than twice as many patients treated with chemotherapy vs tarlatamab.” 

“The cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS] are toxicities of concern for patients receiving T cell engagers,” said Rudin. “They occur almost exclusively during the first two infusions of tarlatamab in week 1 or 2.”

Treatment-emergent CRS occurred in 56 percent of patients on tarlatamab, but 98 percent of those cases were of grade 1 or 2 in severity. “ICANS events were reported in 6 percent of patients and were exclusively of grade 1 or 2. However, one patient had fatal neurologic decline, which was attributed to ICANS. It occurred in the context of hypoxaemia, hypotension, fever, and a very recent history of recurrent pneumonia,” added Rudin.

Haematologic toxicities, such as anaemia and neutropenia, including those of grade ≥3, were more common with chemotherapy.

A new paradigm?

“2L chemotherapy options for SCLC patients provide modest benefit, with OS estimates in the range of 7–9 months, and are associated with substantial haematologic toxicities,” said Rudin. [J Clin Oncol 2014;32:4012-4018; Lancet Oncol 2020;21:645-654; J Clin Oncol 2006;24:5441-5447]

“I think, taken together, the efficacy and safety data clearly support tarlatamab as a preferable therapy for patients in the 2L setting for SCLC. [In addition,] beyond redefining the SoC for these patients, this study also establishes a new paradigm for the use of bispecific T cell engager immunotherapies in our patients with lung cancer,” he concluded.