Tarlatamab/Anti–PD-L1 Maintenance Shows Unprecedented ES-SCLC OS

Tarlatamab-dlle (Imdelltra) plus anti–PD-L1 therapy as first-line maintenance following chemoimmunotherapy yielded unprecedented overall survival (OS) outcomes with long-term tolerability and acceptable safety in patients with extensive-stage small cell lung cancer (ES-SCLC), according to extended follow-up data from the phase 1b DeLLphi-303 trial (NCT05361395).^1,2

The findings, which were presented during the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, showed that with a longer median follow-up of 18.4 months, the approach had a manageable toxicity profile with no dose-limiting toxicities (DLTs) or fatal treatment-related adverse effects (TRAEs). Moreover, a low frequency of TRAEs led to discontinuation (6%), and the incidence of treatment-emergent AEs (TEAEs) decreased over time, indicative of long-term tolerability.

Tarlatamab with anti–PD-L1 therapy as frontline maintenance (n = 88) led to a median OS of 25.3 months (95% CI, 20.3–not evaluable [NE]) and a median progression-free survival (PFS) of 5.6 months (95% CI, 3.5-9.0). For more than half of patients (60%), the approach led to disease control; 36% of these patients had sustained disease control for 52 weeks or longer. The median duration of disease control was 14.6 months (95% CI, 7.2–18.4). The overall objective response rate (ORR) was 24%, which comprised 2 complete responses and 19 partial responses; the median duration of response (DOR) was 16.6 months (95% CI, 7.1-NE).

“The combination of tarlatamab with anti–PD-L1 therapy as first-line maintenance demonstrates a manageable safety profile and unprecedented OS in this patient population,” Kelly G. Paulson, MD, of Providence-Swedish Cancer Institute, said.³ “These results support further evaluation of this combination in the active phase 3 DeLLphi-305 trial [NCT06211036] as a promising therapeutic strategy in first-line ES-SCLC.”

What Did the DeLLphi-303 Study Examine in ES-SCLC?

The nonrandomized trial enrolled patients with ES-SCLC who had an ECOG performance status of 0 or 1 and who had not experienced disease progression after 4 to 6 cycles of first-line chemoimmunotherapy.¹ Those with treated and asymptomatic brain metastases were allowed to enroll, but those with active autoimmune disease or disease that required immunosuppressive treatment were not.

Maintenance treatment commenced within 8 weeks of the start of the last cycle of first-line chemoimmunotherapy. Patients received either 10 mg of intravenous (IV) tarlatamab every 2 weeks (Q2W) plus 1680 mg of IV atezolizumab (Tecentriq) every 4 weeks (Q4W; n = 48) or 10 mg of IV tarlatamab Q2W paired with 1500 mg of IV durvalumab (Imfinzi) Q4W (n = 40). Of note, patients were allowed to switch to a different anti–PD-L1 agent than what they received as part of frontline chemoimmunotherapy.

The primary end points of the study were DLTs, TEAEs, and TRAEs, and secondary end points comprised PFS, OS, ORR, DOR, and disease control.

In the overall population that received tarlatamab plus anti–PD-L1 therapy, the median age was 64 years (range, 27–85), and 63% were male. Most patients were White (70%), had an ECOG performance status of 1 (59%), were former smokers (72%), and had extensive-stage disease at initial diagnosis (85%). Moreover, 88% of patients had prior exposure to anti–PD-L1 treatment, and 30% previously received radiotherapy. Brain and liver metastases were present in 25% and 36% of patients, respectively. The median time from start of frontline chemoimmunotherapy to first-line maintenance treatment was 3.6 months (range, 2.9–5.8).

What Was the Safety Profile of Tarlatamab Plus Anti–PD-L1 Maintenance Therapy in ES-SCLC?

In the overall population, the median duration of treatment with tarlatamab was 35 weeks (IQR, 8–75); with atezolizumab, it was 28 weeks (IQR, 10–69), and with durvalumab, it was 31 weeks (IQR, 5–82). All patients experienced all-grade TEAEs, and 98% experienced all-grade AEs related to tarlatamab; they were grade 3 or 4 in 27% of patients and serious in 38% of patients. They led to dose interruption or reduction for 23% of patients.

“Immune-related AEs, excluding cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS] and associated neurological events, were rare,” Paulson noted in the presentation.

TEAEs with an overall incidence of at least 25% included CRS (56%), dysgeusia (53%), fatigue (38%), headache (32%), decreased appetite (31%), nausea (31%), and pyrexia (28%). Most CRS events were grade 1 (43%) or 2 (11%), occurred after the first or second dose of tarlatamab in cycle 1, and all resolved. ICANS was observed in 6% of patients, with all of these cases occurring in under 3 months. All events were grade 1 or 2 and resolved with supportive care.

REFERENCES:

1. Paulson KG, Lau SCM, Ahn M-J, et al. Safety and survival update of tarlatamab and anti-PD-L1 as first-line maintenance after chemo-immunotherapy for extensive-stage small cell lung cancer: DeLLphi-303 ph1b trial. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA13.01.

2. 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-randomized, phase 1b study. Lancet Oncol. Published online September 8, 2025. doi:10.1016/S1470-2045(25)00480-2

3. Tarlatamab with anti-PD-L1 as first-line maintenance after chemo-immunotherapy for ES-SCLC demonstrates acceptable safety profile and unprecedented overall survival News release. International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer. September 8, 2025. Accessed September 10, 2025. https://tinyurl.com/yc4wcu82