Tarlatamab Shows Activity in SCLC With Brain Metastases in Real-World Cohort

Real-world data presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting suggest that tarlatamab (Imdelltra), a delta-like ligand 3 (DLL3)-directed bispecific T-cell engager (BiTE), demonstrates feasible administration, manageable toxicity, and clinically meaningful antitumor activity in patients with extensive-stage small cell lung cancer (ES-SCLC) who have brain metastases, a population historically underrepresented in clinical trials.¹

The single-center retrospective analysis from Sylvester Comprehensive Cancer Center at the University of Miami included 23 patients with ES-SCLC treated with tarlatamab between January 2024 and October 31, 2025. Among evaluable patients, the objective response rate (ORR) was 27.7%, and the disease control rate (DCR) was 44.4%. Median progression-free survival (PFS) was 139 days, and median overall survival (OS) was 323 days (95% CI, 31–614 days).

A Population Often Excluded From Trials

The cohort was notable for its clinical complexity. Sixty-one percent of patients were male, 61% identified as Hispanic, and 61% had brain metastases at the time of tarlatamab initiation. Forty-three percent had received 2 or more prior lines of therapy. The median age was 72 years.

This demographic profile stands in contrast to the populations enrolled in the pivotal trials that supported tarlatamab's regulatory approval. The phase 2 DeLLphi-301 trial (NCT05060016), which formed the basis for the FDA’s accelerated approval of tarlatamab in May 2024,² and the confirmatory phase 3 DeLLphi-304 trial (NCT05740566), which supported full approval in November 2025,³ both enrolled primarily non-Hispanic White patients with more limited CNS disease burdens. DeLLphi-304 demonstrated a median OS of 13.6 months with tarlatamab vs 8.3 months with investigator's choice chemotherapy, reducing the risk of death by 40%.

By contrast, the Sylvester cohort was predominantly Hispanic and carried a substantially higher burden of central nervous system (CNS) involvement.

Radiographic Response and Survival Outcomes

Radiographic response was assessable by RECIST criteria in 18 of the 23 patients. The remaining 5 were not evaluable: 2 died shortly after the first cycle, 2 were lost to follow-up, and 1 transitioned to hospice after the first cycle.

Among the 18 evaluable patients, 5 (27.7%) achieved a partial response and 3 (16.7%) had stable disease; no complete responses were observed. Ten patients (55.5%) experienced disease progression as their best overall response. Median time on treatment was 92 days, with a median of 4 cycles administered.

No variables were independently associated with PFS or OS on multivariable Cox proportional hazards regression analysis, which the authors note may reflect the relatively small sample size.

Safety Profile Consistent With Trial Data

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)—the characteristic immune-mediated toxicities associated with T-cell engager therapy—were observed but remained limited to grade 1 or 2 severity. No grade 3 or higher toxicities were reported in this cohort. These events occurred predominantly during cycle 1, consistent with the timing pattern observed in the DeLLphi-301 trial. Three patients discontinued treatment due to toxicity.

This toxicity profile supports the feasibility of administering tarlatamab in a real-world academic oncology setting, including in older patients with comorbidities and CNS disease who may not have met eligibility criteria for the phase 2 and phase 3 studies.

Implications for Clinical Practice

The findings add to a growing body of real-world evidence for tarlatamab, which received traditional FDA approval in November 2025 following the positive results of DeLLphi-304. That trial enrolled 509 patients randomized 1:1 to tarlatamab or standard-of-care chemotherapy (topotecan, lurbinectedin, or amrubicin) and demonstrated a statistically significant and clinically meaningful OS benefit.

The Sylvester cohort's ORR of 27.7% is numerically lower than the approximately 40% ORR observed at the 10-mg dose level in DeLLphi-301, a discrepancy that may reflect the more heavily pretreated, CNS-burdened nature of the real-world population. The median OS of 323 days (approximately 10.6 months) in this real-world cohort, while derived from a small sample with wide confidence intervals, is directionally consistent with outcomes reported in the pivotal trials.

The authors acknowledge the study's limitations: its retrospective design, single-center setting, and small sample size preclude definitive conclusions about efficacy in the CNS-disease subgroup. The wide confidence interval around the OS estimate reflects substantial uncertainty.

REFERENCES

1. Sucre S et al. Tarlatamab in small cell lung cancer with brain metastases: A real-world experience. J Clin Oncol. 44, 2026 (suppl 16; abstr 8108). doi:10.1200/JCO.2026.44.16_suppl.8108

2. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. News release. US FDA. May 16, 2024. Accessed June 11, 2026. https://tinyurl.com/bddwjpk2

3. FDA grants traditional approval to tarlatamab-dlle for extensive-stage small-cell lung cancer. FDA. November 19, 2025. Accessed June 11, 2026. https://tinyurl.com/ycy7hety