FDA Grants Full Approval to Tarlatamab for Extensive-Stage Small Cell Lung Cancer

The FDA has granted traditional approval to tarlatamab-dlle (Imdelltra) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or following platinum-based chemotherapy.1

The regulatory decision is supported by data from the phase 3 DeLLphi-304 study (NCT05740566) in which tarlatamab led to a median overall survival (OS) of 13.6 months (95% CI, 11.1-not evaluable) vs 8.3 months (95% CI, 7.0-10.2) with standard-of-care (SOC) chemotherapy, translating to a 40% reduction in the risk of death (HR, 0.60; 95% CI, 0.47-0.77; P < .001).2,3

Tarlatamab also led to a 28% reduction in the risk of disease progression or death vs SOC; the median progression-free survival in the respective arms was 4.2 months (95% CI, 3.0-4.4) and 3.2 months (95% CI, 2.9-4.2; HR, 0.72; 95% CI, 0.59-0.88; P < .001).

In May 2024, the FDA granted accelerated approval to tarlatamab for this indication.4 The decision was based on findings from the phase 2 DeLLphi-301 trial (NCT05060016), in which tarlatamab elicited an objective response rate (ORR) of 40% (95% CI, 31%-51%) with a median duration of response of 9.7 months (range, 2.7-20.7+).

When initially approved, OncLive® spoke with Taofeek Owonikoko, MD, PhD, who is the executive director of the University of Maryland Marlene and Stewart Greenebaum Cancer Center and chief of service of the University of Maryland Medical Center, about the significance of the decision:5

What is the design of the DeLLphi-304 trial?

The open-label, randomized, controlled study included patients with histologically or cytologically confirmed SCLC who experienced disease progression after a frontline platinum-based regimen plus or minus an immune checkpoint inhibitor.2,3 Patients were at least 18 years of age and had an ECOG performance status no higher than 1. Those with asymptomatic, previously treated, or untreated brain metastases were permitted.

Patients were randomly assigned 1:1 to receive tarlatamab or chemotherapy comprising lurbinectedin (Zepzelca; n = 47), topotecan (n = 185), or amrubicin (n = 23). They were stratified based on previous treatment with a PD-(L)1 inhibitor (yes vs no), chemotherapy-free interval (<90 days vs ≥90 days to <180 days vs ≥180 days), presence of brain metastases (yes vs no), and intended chemotherapy (topotecan/amrubicin vs lurbinectedin).

The trial’s primary end point was OS, and secondary end points included PFS and patient-reported outcomes (PROs). Investigators also assessed objective response rate (ORR), duration of response (DOR), disease control rate, and safety.

The median patient age was 64 years (range, 20-86) in the tarlatamab arm vs 66 years (range, 26-84) in the chemotherapy arm. Most patients in both arms were male (72%; 66%), were White (60%; 55%), and were current or former smokers (91%; 88%). More than half of patients in both arms had an ECOG performance status of 1 (67%; 68%), received prior anti–PD-(L)1 therapy (71%; 71%), and had prior exposure to radiotherapy (63%; 63%). A chemotherapy-free interval of less than 90 days was most common in both arms (43%; 45%), followed by at least 90 days and less than 180 days (33%; 31%), and at least 180 days (24%; 25%).

Brain metastases were present in 44% of those in the tarlatamab arm vs 45% of patients in the chemotherapy arm. The rates of patients with liver metastases were 33% and 37% in the respective arms. Among evaluable patients, 95% in the tarlatamab arm (n = 217) and 93% in the chemotherapy arm (n = 214) were positive for DLL3 expression.

What else was learned about the efficacy of tarlatamab in this population?

Tarlatamab elicited an ORR of 35% (95% CI, 29%-41%) vs 20% (95% CI, 16%-26%) with chemotherapy. In the tarlatamab arm, the rates of complete response, partial response, stable disease, and progressive disease were 1%, 34%, 33%, and 22%, respectively; in the chemotherapy arm, these rates were 0%, 20%, 44%, and 20%, respectively. Ten percent and 16% of patients in the tarlatamab and chemotherapy arms, respectively, were not evaluable for response.

The median DOR was 6.9 months with tarlatamab arm vs 5.5 months with chemotherapy. The respective 6- and 12-month DOR rates were 56% and 41% for tarlatamab vs 29% and 13% with chemotherapy. The median time to response was 1.5 months vs 1.4 months in the respective arms. At data cutoff, response was ongoing in 47% of patients in the investigative arm vs 15% of the control arm.

Regarding PROs, the mean improvement in dyspnea score from baseline to week 18 was 1.94 in the tarlatamab arm vs –7.20 in the chemotherapy arm (difference, –9.14; 95% CI, –12.64 to –5.64; P < .001). At week 18, cough score improvements were reported in 16.1% of patients in the tarlatamab group vs 9.0% of patients in the control group (odds ratio [OR], 2.04; 95% CI, 1.17-3.55; P = .012). Improvements in chest pain at week 18 were reported in 8.7% and 3.5% of patients, respectively (OR, 1.84; 95% CI, 0.89-3.81; P = .100); differences in chest pain improvement did not reach statistical significance.

What was the safety profile of tarlatamab in patients with ES-SCLC?

Any-grade treatment-emergent adverse effects (TEAEs) were reported in 99% of patients who received tarlatamab vs all patients given chemotherapy. Any-grade treatment-related AEs (TRAEs) occurred in 93% and 91% of patients, respectively.

Grade 3 TRAEs were experienced by 27% of those in the tarlatamab arm vs 62% of those in the chemotherapy arm. Serious TRAEs occurred in 28% and 31% of patients. TRAEs led to dose interruption and/or reduction in 19% of patients treated with tarlatamab compared with 55% of patients who received chemotherapy. TRAEs resulted in treatment discontinuation for 3% and 6% of patients, respectively. One patient (0.4%) who received tarlatamab experienced a grade 5 TRAE vs 4 patients (2%) who were given chemotherapy.

In the tarlatamab arm, treatment-emergent cytokine release syndrome (CRS) was observed during the first 2 treatment cycles for 60% of patients who were monitored for 48 hours (n = 209); cases were grade 1 (45%), grade 2 (13%), and grade 3 (1%). Nineteen percent of patients were reported to have serious CRS, and CRS led to treatment discontinuation for 0.5% of patients. The median time to intervention was 27 hours from the last tarlatamab dose.

In patients who were monitored for CRS for a minimum of 6 to 8 hours during the first 2 cycles of tarlatamab (n = 43), CRS was reported in 37% of patients at grade 1 (28%) and in 9% of patients at grade 2. Seven percent of CRS instances in this group were serious, although none led to treatment discontinuation. The median time to intervention was 17 hours.

TEAEs like CRS, dysgeusia, pyrexia, and decreased appetite were more common with tarlatamab; those in the chemotherapy arm experienced increased incidence of anemia, neutropenia, thrombocytopenia, and decreased platelet counts compared with tarlatamab. The rates of grade 3 or higher TEAEs like anemia, neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, decreased platelet count, decreased neutrophil count, fatigue, pneumonia, and hyponatremia were all higher with chemotherapy compared with tarlatamab.

References

1. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. November 19, 2025. Accessed November 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
2. Rudin C, Mountzios G, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008
3. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. Published online June 2, 2025. doi:10.1056/NEJMoa2502099
4. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed November 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
5. Owonikoko TK. Dr Owonikoko on the impact of the FDA approval of tarlatamab in ES-SCLC. OncLive.com. June 28, 2024. Accessed November 19, 2025. https://www.onclive.com/view/dr-owonikoko-on-the-impact-of-the-fda-approval-of-tarlatamab-in-es-sclc