Tarlatamab Plus Anti–PD-L1 Therapy as Frontline Maintenance Shows Unprecedented OS in ES-SCLC

The addition of tarlatamab-dlle (Imdelltra) to anti–PD-L1 therapy as frontline maintenance following chemoimmunotherapy led to unprecedented overall survival (OS) outcomes with long-term tolerability in patients with extensive-stage small cell lung cancer (ES-SCLC), according to extended follow-up findings from the phase 1b DeLLphi-303 trial (NCT05361395).1,2

The data, which were presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC) and published in The Lancet Oncology, 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); a low frequency of TRAEs resulted in discontinuation (6%). 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) resulted in 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 60% of patients, 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). Moreover, the approach induced an overall objective response rate (ORR) of 24%, which included 2 complete responses (CRs) and 19 partial responses (PRs); the median duration of response (DOR) was 16.6 months (95% CI, 7.1-NE).

Specifically, when tarlatamab was paired with atezolizumab (n = 48), it led to a median OS of 25.3 months (95% CI, 20.3-NE) and a median PFS of 5.6 months (95% CI, 2.0-14.9). When tarlatamab was combined with durvalumab (n = 40), the median OS was NE (95% CI, 19.9-NE) and the median PFS was 5.3 months (95% CI, 3.5-11.2).

“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 Research Paved the Way for the Examination of Tarlatamab in DeLLphi-303?

After patients with ES-SCLC receive frontline chemoimmunotherapy, current clinical practice guidelines call for continuation of anti–PD-L1 therapy in the form of atezolizumab or durvalumab as maintenance treatment.1 It is known that beginning from first-line maintenance, the median OS achieved with single-agent anti–PD-L1 therapy or anti–PD-L1 therapy paired with lurbinectedin (Zepzelca) has ranged from 10.6 months to 13.2 months.

Tarlatamab received accelerated approval from the FDA in May 2024 for use in patients with ES-SCLC with disease progression on or following platinum-based chemotherapy.4 The regulatory decision was supported by data from the phase 2 DeLLphi-301 trial (NCT05060016), in which the DLL3-targeting bispecific T-cell engager immunotherapy induced an ORR of 40% (95% CI, 31%-51%) with a median DOR of 9.7 months (range, 2.7 to 20.7+).

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 up to 1 and who had not experienced disease progression following 4 to 6 cycles of frontline chemoimmunotherapy.1 Those with treated and asymptomatic brain metastases were able to enroll, but those with active autoimmune disease or disease that required immunosuppressive treatment were excluded.

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 included 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. The majority of 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%). The median sum of lesion diameters was 33.0 mm. 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 Did Prior Data from DeLLphi-303 Demonstrate?

Findings from the first report of the trial were shared during the 2024 IASLC WCLC.5 At a median follow-up of 10.0 months, tarlatamab plus anti–PD-L1 therapy as first-line maintenance led to a 9-month OS rate of 89%.1 Specifically, when tarlatamab was paired with durvalumab, it led to a disease control rate of 62.5% (95% CI, 45.8%-77.3%) with a median duration of disease control that was NE (95% CI, 3.9-NE). When paired with atezolizumab, the DCR was 62.5% (95% CI, 47.4%-76.0%) and the median duration of disease control was 7.2 months (95% CI, 5.6-NE).

Additionally, at a median time of 3.5 months from frontline chemoimmunotherapy to maintenance, when tarlatamab was paired with durvalumab, it led to a 9-month OS rate of 91.8% (95% CI, 76.6%-97.3%); the median PFS was 5.3 months (95% CI, 3.5-NE). When paired with atezolizumab, the 9-month OS rate was 86.7% (95% CI, 70.3%-94.4%), and the median PFS was 5.6 months (95% CI, 3.5-8.5).

“Tarlatamab has been a major breakthrough for patients with ES-SCLC, who have had limited options for the past 30 years, and these data are impressive as a potential first-line maintenance treatment as well,” Sally Lau, MD, oncologist and assistant professor of medicine, Perlmutter Cancer Center, NYU Grossman School of Medicine, stated in a past news release. “In particular, tarlatamab in combination with a PD-L1 inhibitor showed exciting safety and efficacy, which strongly supports continued evaluation in the ongoing phase 3 DeLLphi-305 trial.”

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

Safety findings from the current analysis indicated that in the overall population, the median duration of treatment with tarlatamab was 35 weeks (interquartile range [IQR], 8-75); with atezolizumab, it was 28 weeks (IQR, 10-69), and with durvalumab, it was 31 weeks (IQR, 5-82).1 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%). When broken down by time periods, in 0 to under 3 months (n = 88), CRS incidence was 56%, dysgeusia was 44%, fatigue was 31%, headache was 22%, decreased appetite was 23%, nausea was 25%, and pyrexia was 27%. In the time period of at least 3 months but under 12 months (n = 63), these respective rates were 5%, 24%, 21%, 18%, 13%, 8%, and 3%. In the time period of 12 months or longer (n = 36), these respective rates were 3%, 0%, 8%, 11%, 6%, 6%, and 0%.

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.

What Comes Next for Tarlatamab? What Is the DeLLphi-305 Study Examining?

The open-label, multicenter, randomized, phase 3 DeLLphi-305 study is currently recruiting patients with ES-SCLC who are at least 18 years of age who have completed 3 to 4 cycles of platinum etoposide chemotherapy with concurrent durvalumab as frontline treatment before enrollment.6 Key eligibility criteria include: an ECOG performance status no higher than 1, a minimum life expectancy of longer than 12 weeks, and acceptable organ function. Toxicities associated with previous anticancer therapies also must have resolved to grade 1 or below.

Those with symptomatic central nervous system metastases or leptomeningeal disease, a previous history of severe or life-threatening events from immune-mediated therapy, a history of other malignancy within the past 2 years, active or previous documented autoimmune or inflammatory disorders, myocardial infarction, or a history of arterial thrombosis, are excluded.

Those on the study will receive tarlatamab once every 2 weeks plus durvalumab once every 4 weeks or durvalumab alone.

The primary outcome measure is OS, and secondary outcome measures include PFS, ORR, DCR, DOR, time to progression, and safety, among others.

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://www.iaslc.org/iaslc-news/press-release/tarlatamab-anti-pd-l1-first-line-maintenance-after-chemo-immunotherapy-es
4. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed September 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
5. Amgen presents new data for first-in-class Imdelltra (tarlatamab-dlle) in small cell lung cancer at WCLC 2024. News release. Amgen. September 9, 2024. Accessed September 10, 2025. https://www.amgen.com/newsroom/press-releases/2024/09/amgen-presents-new-data-for-firstinclass-imdelltra-tarlatamabdlle-in-small-cell-lung-cancer-at-wclc-2024
6. Study comparing tarlatamab and durvalumab versus durvalumab alone in first-line extensive-stage small-cell lung cancer (ES-SCLC) following platinum, etoposide and durvalumab (DeLLphi-305). ClinicalTrials.gov. Updated September 12, 2025. Accessed September 10, 2025. https://clinicaltrials.gov/study/NCT06211036