Tarlatamab Safety Varies Between Clinical and Real-World SCLC Trials

Tarlatamab showed encouraging clinical activity in a group of patients with heavily pretreated small cell lung cancer (SCLC), including those with untreated brain metastases, according to a real-world study published in Clinical Lung Cancer.¹

However, these patients also had higher rates of serious adverse events compared with those in clinical trials, especially cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), raising important safety considerations for the treatment in the real-world setting. As this bispecific T-cell engager becomes more widely available, researchers noted it will be increasingly important to maintain informed CRS and ICANS management algorithms and consider the role of prescribed opioids in low-grade ICANS.

“Our study highlights that administration of tarlatamab to a more diverse patient population requires careful patient selection for outpatient management,” the researchers wrote. “Specifically, patients with high-volume untreated brain metastases, who are at risk for higher grades of ICANS, may benefit from closer monitoring during treatment initiation.”

Tarlatamab demonstrated favorable antitumor activity in a small cohort in Virginia, but with higher rates of adverse events. | Image credit: didesign – stock.adobe.com

The retrospective, observational cohort study included 21 patients with SCLC and 1 with a delta-like ligand 3 (DLL-3)–positive carcinoid tumor, all of whom were treated with tarlatamab at the University of Virginia between May and October 2024.^1,2 Tarlatamab was approved to treat extensive-stage SCLC in May 2024.³ Now, a year later, this study demonstrates how these patients used and responded to the bispecific T-cell engager in the real world—particularly important as the DeLLphi-301 trial data supporting its approval did not include a control arm.

While smaller, this cohort was more diverse than that of the DeLLphi-301 trial, with higher percentages of brain (n = 9) and liver (n = 14) metastases.¹ Patients in the cohort were mostly female (59.1%) with a history of smoking (95.5%) and extensive-stage SCLC (85.7%), ranging in age from 41 to 80 years. This contrasts with the approval data focusing mainly on Asian and European men (vs North American women) and with only 2% of patients treated in the second-line setting compared with 31.8% in the new study. Additionally, 4 patients in this study had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or greater—indicating increasing levels of disability—making them ineligible for the DeLLphi-301 trial.

Researchers observed favorable antitumor activity with tarlatamab, with an objective response rate (ORR) of 42.9% at 6.7 months of follow-up and most patients responding to the treatment within 6 weeks of initiation. However, this was overshadowed by 72.7% of patients experiencing CRS and 40.9% experiencing ICANS after receiving the 10 mg tarlatamab infusion, compared with 51% and 8%, respectively, in the DeLLphi-301 study.

All patients who experienced CRS and ICANS did so within the first cycle of treatment, with similar times to onset as seen in DeLLphi-301, but with shorter durations. For CRS, this could be due to more patients receiving at least 1 dose of tocilizumab to manage CRS (27.3% vs 5%) compared with the past study. Meanwhile, the shorter duration of ICANS could be attributed to earlier and more frequent steroid use, researchers said. Of note, patients with untreated brain metastases had higher rates and grades of ICANS, with a grade 4 case causing one patient to discontinue treatment permanently, though all other cases were manageable with early intervention.

Only 5 patients remained on treatment at the time of analysis, with a median duration of 8 weeks and 3 cycles of infusions among the whole cohort. The main reasons for discontinuation were disease progression (n = 11), death (n = 3), and higher-grade immune-related adverse events (n = 2). This cohort also saw a shorter median progression-free survival at 2.7 months compared with 4.9 months in the DeLLphi-301 study.

“Differences in baseline performance status may have translated to higher rates of toxicity in our cohort, as we observed higher rates of fatigue, dysgeusia, and weight loss,” the researchers noted.

As this new study is limited by its retrospective design, small sample size, and short follow-up, further real-world research is necessary to better understand the drug’s safety outside of clinical trials.

“Special considerations are required for patients with untreated intracranial metastases due to the increased risk of severe immune cell-associated neurotoxicity syndrome,” the researchers concluded.

References

1. Bolte FJ, Dougherty SC, Danos AO, et al. Real-world outcomes of tarlatamab in small cell lung cancer, including patients with untreated brain metastases. Clin Lung Cancer. Published online March 26, 2025. doi:10.1016/j.cllc.2025.03.006
2. Cooper AJ, Rekhtman N, Baine MK, Thomas MC, Lynch AC, Gentzler RD. First report of response to tarlatamab in a patient with DLL3-positive pulmonary carcinoid: case report. JTO Clin Res Rep. 2024;5(12):100750. doi:10.1016/j.jtocrr.2024.100750
3. Joszt L. Tarlatamab receives accelerated approval for extensive-stage SCLC. AJMC^®. May 16, 2024. Accessed May 5, 2025. https://www.ajmc.com/view/tarlatamab-receives-accelerated-approval-for-extensive-stage-sclc