In patients with small cell lung cancer, second-line treatment with the bispecific T-cell engager tarlatamab-dlle (which targets the delta-like ligand 3 [DLL3]) vs standard-of-care chemotherapy appeared to significantly improve overall survival, progression-free survival, and patient-reported outcomes, with a favorable safety and tolerability profile. These results from the primary analysis of the global phase III DeLLphi-304 trial were presented during the 2025 ASCO Annual Meeting and simultaneously published in TheNew England Journal of Medicine.^1,2

“Together, we think the efficacy and safety shown in this trial support tarlatamab as defining a new standard of care for patients with previously treated small cell lung cancer….”

— CHARLES M. RUDIN, MD, PhD

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“Together, we think the efficacy and safety shown in this trial support tarlatamab as defining a new standard of care for patients with previously treated small cell lung cancer,” said Charles M. Rudin, MD, PhD, Deputy Director of the Cancer Center, Co-Director of the Druckenmiller Center for Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York.

Study Details

A total of 509 patients who experienced disease progression during or after first-line platinum-based chemotherapy, with or without PD-(L)1 inhibition, were randomly assigned in a 1:1 ratio to receive tarlatamab (n = 254) or chemotherapy (n = 255). They were stratified by prior exposure to anti–PD-(L)1 therapy, chemotherapy-free interval, brain metastases, and intended chemotherapy.

Baseline characteristics appeared to be well balanced between the arms. A total of 71% of patients had prior exposure to anti–PD-(L)1 therapy. A chemotherapy-free interval of up to 90 days was observed in approximately 44% of patients. Nearly 45% of the population had baseline brain and/or liver metastases. Of the patients with available tissue samples for analysis, about 94% demonstrated measurable DLL3 levels.

Efficacy Results

The DeLLphi-304 trial met its primary endpoint, showing a prolonged estimated median duration of overall survival with tarlatamab vs chemotherapy (13.6 vs 8.3 months; hazard ratio [HR] = 0.60; P < .001). The estimated 1-year rates were 53% and 37%, respectively.

“The median follow-up here is only 11.2 months [with tarlatamab], so it will be interesting to continue to follow these [Kaplan-Meier] curves out,” Dr. Rudin commented. “[The] tarlatamab curve…is essentially superimposable on what we saw in the phase II DeLLphi-301 trial, and the chemotherapy curve is also behaving as expected….” He furthermore noted that the survival benefit with tarlatamab was consistent across prespecified patient subgroups, including those with chemoresistant disease (HR = 0.60) and baseline brain metastases (HR = 0.45).

Dr. Rudin reported a significant but “modest” improvement in median progression-free survival with tarlatamab vs chemotherapy (4.2 vs 3.7 months; HR = 0.71; P = .002). “Again, these data are immature,” he remarked, but tarlatamab appeared to result in a fivefold increase in the estimated 1-year progression-free survival rate (20% vs 4%).

Treatment with tarlatamab vs chemotherapy was found to be associated with more frequent (35% vs 20%) and durable (median, 6.9 vs 5.5 months; estimated 12-month rate: 41% vs 13%) objective responses. A total of 47% and 15% of responders are still receiving tarlatamab and chemotherapy, respectively; thus, according to Dr. Rudin, “we will need to see how these curves mature out.”

Safety Results

“This trial [assessed] patient-reported outcomes [after 18 weeks], and there was significant improvement in both dyspnea and cough—symptoms that are common in our lung cancer population,” Dr. Rudin remarked. “The benefit in terms of chest pain was not statistically significant, but all measures of patient-reported outcomes in this study trended in favor of tarlatamab vs chemotherapy.”

According to the objective safety data, with tarlatamab, the rates of treatment-related adverse events of grade 3 or higher (27% vs 62%) and treatment-related adverse events leading to dose interruption and/or reduction (19% vs 55%) and treatment discontinuation (3% vs 6%) were less than half of those observed with chemotherapy.

“Cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome are toxicities that are of concern for patients who are receiving T-cell engagers,” stated Dr. Rudin. They were documented in 56% and 6% of those treated with tarlatamab, respectively. Most of these treatment-emergent events appeared to be grade 1 or 2, with cytokine-release syndrome found to occur almost exclusively during the first two infusions.

“Late in this clinical trial, we reduced the required monitoring from inpatient hospitalization for 48 hours to outpatient management for 6 to 8 hours, [and] this was not associated with any substantial adverse events,” Dr. Rudin commented. “There will be more data regarding the shorter monitoring of this drug in subsequent trials.”

In addition to cytokine-release syndrome, treatment-emergent dysgeusia—another known class effect of T-cell engagers—was more frequently observed with tarlatamab than with chemotherapy. According to Dr. Rudin, treatment-emergent hematologic toxicities were more often documented with chemotherapy, as expected.

“Beyond redefining the standard of care,” Dr. Rudin concluded, “this study also establishes a new paradigm for the use of bispecific T-cell engager immunotherapies in our patients with lung cancer.” 

DISCLOSURE: Dr. Rudin has served as a consultant or advisor to AbbVie, Amgen, AstraZeneca, Auron Therapeutics, Daiichi Sankyo/UCB Japan, DISCO, Earli, Genentech/Roche, Jazz Pharmaceuticals, and Merck; has received research funding from Daiichi Sankyo, Merck, and Roche/Genentech; and has received royalties related to licensing of anti-DLL3 antibodies. For full disclosures of the other study authors, visit coi.asco.org.

REFERENCES

1. Rudin CM, Mountzios GS, Sun L, et al: Tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer: Primary analysis of ph3 DeLLphi-304. 2025 ASCO Annual Meeting. Abstract LBA8008. Presented June 2, 2025.

2. Mountzios G, Sun L, Cho BC, et al: Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med 393:349-361, 2025.

EXPERT POINT OF VIEW

“The standard of care for extensive-stage small cell lung cancer is evolving,” commented invited discussant of the DeLLphi-304 trial, Catherine Belle Meador, MD, PhD, Attending Physician at the Massachusetts General Hospital Center for Thoracic Cancers and Instructor of Medicine at Harvard Medical School, Boston. During her presentation, she discussed the clinical implications of the second-line use of tarlatamab-dlle vs chemotherapy, highlighting its potential to shift the current treatment paradigm.

Catherine Belle Meador, MD, PhD

The second-line treatment landscape includes both cytotoxic chemotherapies (ie, topotecan and lurbinectedin) and the bispecific T-cell engager tarlatamab. However, before these data were presented at the 2025 ASCO Annual Meeting, “we did not have hard data to decide between [these approaches],” she remarked.

Given the approximate 5-month overall survival benefit with tarlatamab vs chemotherapy, Dr. Meador stated: “This is a remarkable result and should be considered immediately practice-changing. There was a low effective crossover rate of 5.8%, and this is likely due to low global commercial availability of tarlatamab during the trial accrual period. However, there is significant censoring here, so I would expect [this] rate to increase as patients continue to progress. It will be interesting to see, as the data mature, whether a tail on the curve [emerges]—similar to what has been seen with PD-L1 inhibitors.”

‘Unique Management Considerations’

Although tarlatamab demonstrated an improved toxicity profile compared with chemotherapy, according to Dr. Meador, it does present “some unique management considerations.” Because of the prevalence of cytokine-release syndrome, she added, during the first two infusions, patients require more intense monitoring on the first and eighth days of the first cycle.

Dr. Meador continued: “As we work to provide [tarlatamab] to more and more patients…, we should work further to optimize our administration and our monitoring strategies to achieve equitable access.” She emphasized the importance of establishing better predictive biomarkers to pinpoint patients at risk for higher-grade cytokine-release syndrome, allowing targeted monitoring. In addition, Dr. Meador suggested adapting established hematology monitoring protocols and exploring alternative care settings (eg, home hospital and outpatient monitoring) during the cytokine-release syndrome risk window.

Tarlatamab is currently being evaluated in the first-line setting for extensive-stage small cell lung cancer, as well as for the treatment of limited-stage disease; it is also being tested in combination with B7-H3 antibody-drug conjugates. Dr. Meador furthermore noted that “there are multiple [other] DLL3-targeted therapies in the pipeline that we will learn over time how to incorporate into our treatment sequence,” with the trispecific T-cell engager alveltamig representing a “promising” option. 

DISCLOSURE: Dr. Meador has served as a consultant or advisor to Genentech; and has received research funding from Novartis.