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When it comes to small cell lung cancer (SCLC), there are a lot of highs and lows. For instance, it has a fairly low incidence rate, accounting for about , and it is predominantly confined to those with a history of tobacco use.

Compare that with non-SCLC, which has a U.S. of around 80% in smokers and up to 20% in non-smokers.

But SCLC is also a very "aggressive high-grade neuroendocrine carcinoma with a very poor prognosis," noted Anne C. Chiang, MD, PhD, and Xiao Wang, MD, both of Yale School of Medicine in New Haven, Connecticut, writing in the .

And treatments for SCLC -- the standard is chemotherapy with a platinum agent (cisplatin or carboplatin) and etoposide, along with add-on thoracic radiotherapy for limited-stage SCLC -- have been flat since the 1980s. On a "high" note, in the past half-dozen years, "there have been significant advances in SCLC treatment, with the use of immune checkpoint inhibitors (ICIs), targeted therapies, cellular therapies, and improved supportive care coming to the forefront," Chiang and Wang said.

One up-and-coming agent in SCLC is tarlatamab (Imdelltra), which gained FDA approval in 2024 for extensive-stage SCLC, in patients with disease progression on or after platinum-based chemotherapy.

The delta-like ligand 3 (DLL3) and CD3 bispecific T-cell engager (BiTE) represents one of the most promising changes to treatment paradigms on the horizon, and will be further explored in single-agent or combination trials not only in the relapsed setting, but also for limited stage or maintenance, Chiang and Wang stated. "Ongoing clinical trials, especially with DLL3-targeted therapies have shown exciting results, although it remains to be seen whether these will show benefit in randomized trials."

The accelerated approval for the agent came about because of findings from the phase II trial, which "reported remarkable clinical outcomes," Chiang and Wang noted -- specifically a 40% overall response rate (ORR), 9.7-month median duration of response (DOR), and 9-month overall survival (OS) rate.

In a trials update, Afshin Dowlati, MD, of Case Western Reserve University in Cleveland, and co-authors discussed how tarlatamab fared in terms of its sustained benefit, and intracranial activity, in patients in the phase II study. Below are highlights from the team's report.

Which patients are in the DeLLphi-300 population, and who makes up the follow-up group?

Dowlati et al: Tarlatamab was evaluated in patients with previously treated SCLC. Patients with asymptomatic, treated, stable brain metastases were eligible. This extended follow-up, with data cutoff 14.5 months beyond the initial report, focuses on 152 patients treated with clinically relevant doses of tarlatamab (≥10 mg administered once every 2 weeks, once every 3 weeks, or once on day 1 and once on day 8 of a 21-day cycle), including 72 patients from the initial report [n=107] and 80 patients not included in the initial report.

The primary end point was safety. CNS tumor sum of diameters was assessed per modified Response Assessment in NeuroOncology Brain Metastases (mRANO-BM) criteria; all CNS tumors were considered nontarget lesions given previous treatment.

At baseline, 25.0% of patients had brain metastases. DLL3 expression was detected in 93.8%, with an evaluable baseline tumor sample. The median follow-up was 12.1 months.

What were some of the main findings?

Dowlati et al: The incidence of immune effector cell–associated neurotoxicity syndrome [ICANS] and associated neurologic events was similar in patients with or without baseline brain metastases (any grade 10.5% any grade vs 12.3%), primarily occurring in patients treated with tarlatamab >10 mg dose administered once every 2 weeks, once every 3 weeks, or once on day 1 and once on day 8 of a 21-day cycle (94.4%), similar to a . The ORR was 25.0%, median DOR was 11.2 months, and median OS was 17.5 months.

Considering treatment-related adverse events (TRAEs) with ≥20% incidence, pyrexia and nausea resolved quickly. There were no late-onset occurrences of CRS [cytokine release syndrome] or ICANS and associated neurologic events.

Of 28 patients evaluable for mRANO-BM analyses, 16 had a baseline CNS [central nervous system] lesion ≥10 mm. Intracranial disease control occurred in 87.5%, with a median duration of 7.4 months. CNS tumor shrinkage of ≥30% was observed in 62.5%.

All 16 patients had brain radiotherapy before study initiation -- 37.5% who completed radiotherapy ≥50 days before tarlatamab initiation had ≥30% CNS tumor shrinkage. In addition, for a subset of patients, the nadir in CNS tumor shrinkage occurred long after previous radiotherapy. Concordance was seen between systemic disease control and brain metastasis shrinkage.

What's the main take-home message?

Dowlati et al: Tarlatamab demonstrated sustained clinical benefit in patients with previously treated SCLC, including long DOR, unprecedented OS, and a subset of patients with sustained disease control with time on treatment ≥52 weeks.

This study's longer follow-up revealed limited late-onset TRAEs and relatively rapid time to resolution for some of the most common TRAEs and CRS along with ICANS. Further study on intracranial efficacy of tarlatamab is needed, including on the mechanisms underlying potential CNS activity.

Read the review here.