Tarlatamab May Offer New SOC for Relapsed ES-SCLC With Brain Metastases

The therapeutic landscape for extensive-stage small cell lung cancer (ES-SCLC) has long been challenging, with limited options for patients who progress after initial chemoimmunotherapy. Historically, subsequent treatment has relied on chemotherapies like topotecan or lurbinectedin (Zepzelcan).

In an interview with CancerNetwork®, Bingnan Zhang, MD, MBA, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, highlighted that tarlatamab represents a "brand-new mechanism of drug" as a bispecific T-cell engager, a highly innovative treatment and only the second of its class to be approved for solid tumors.¹

Tarlatamab has demonstrated superior efficacy, showing "superior progression-free survival [PFS] and overall survival [OS]" in patients with relapsed ES-SCLC. A particularly significant finding for this patient population is the drug's robust intracranial activity. Zhang noted that early observations from the phase 1 DeLLphi-300 trial (NCT05361395) showed tumor shrinkage in patients with treated brain metastases.²

Subsequent studies, including the phase 3 DeLLphi-304 trial (NCT05740566),specifically included a small subset of patients with untreated brain metastases, where the drug showed "great activity" and a lower HR compared with other groups.³ This is a critical development, as it allows clinicians to potentially defer or delay whole brain radiation, which is associated with long-term cognitive decline and other adverse effects. While its adoption has faced challenges due to unique adverse effects that require inpatient monitoring for the first 2 doses, according to Zhang, the superior benefit often outweighs these initial considerations.

Transcript:

SCLC treatment has been limited… to chemoimmunotherapy and a few different options for chemotherapy after relapse. Tarlatamab is a brand-new mechanism of [treatment]. It’s a bispecific T-cell engager. It’s the second approved bispecific engager in solid tumors. It is a very innovative type of treatment, and it has shown superior PFS and OS in patients with relapsed ES-SCLC. They are becoming used [more frequently].

The initial adoption is a bit challenging because of the unique [adverse] effects associated with these drugs, with the bispecifics, including cytokine release syndrome and neurotoxicity. That requires the first 2 doses to be administered mostly in the health care inpatient setting, because that requires 20- to 24-hour monitoring, post-dosing. However, because of the superior efficacy, and I will mention the intracranial efficacy as well, because it was initially noticed in the phase 1 [DeLLphi-300 trial] when patients treated for brain metastases had ongoing shrinkage after being on tarlatamab, and later trials included a small set of patients with untreated brain metastases and had shown benefit.

If you look at the phase 3 DeLLphi-304 data, when they included a small subset of patients with untreated brain metastases, their HR is lower, suggesting [great activity] in this population. We also have observed real-world patient data, when we started tarlatamab for patients with numerous untreated brain metastases who would otherwise require whole brain radiation to experience a rapid initial response, and those patients will have symptom improvement as well.

Thankfully, we can delay the brain radiation because the whole brain radiation has its own set of toxicities and long-term sequelae with cognitive decline. For many of those patients, we can safely defer radiation, but it’s always a multi-disciplinary discussion with our radiation oncologists as well to best sequence the medication and the timing of radiation.

References

1. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. News release. FDA. May 16, 2024. Accessed September 23, 2025. https://tinyurl.com/48k34rw5
2. Paz-Ares L, Champiat S, Lai WV, et al. Tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. J Clin Oncol. 2023;41(16):2893-2903. doi:10.1200/JCO.22.02823
3. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. 2025;393(4):349-361. doi:10.1056/NEJMoa2502099