The phase Ib DeLLphi-303 trial has reported overall survival data for a novel maintenance regimen in extensive-stage small cell lung cancer following first-line chemoimmunotherapy. Patients treated with the bispecific T-cell engager tarlatamab-dlle plus a PD-L1 inhibitor had a median overall survival of 25.3 months and a 12-month overall survival rate of 82%, a survival time labeled “unprecedented” by lead author Kelly G. Paulson, MD, PhD, of the Providence-Swedish Cancer Institute in Seattle.
“These results are truly exciting and compare very favorably to the 10 to 15 months in prior reported studies,” Dr. Paulson said during her presentation at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer.1 The findings were concurrently published in The Lancet Oncology.2
“A 2-year plus median survival is really striking,” said Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, the study’s invited discussant. “We have not seen that before, ever, in our patients with extensive-stage small cell lung cancer.”
Background and Study Details
As Dr. Paulson noted, current practice guidelines recommend continuation of maintenance anti–PD-L1 (eg, atezolizumab or durvalumab) following first-line chemoimmunotherapy. With current regimens, the overall survival from the start of maintenance has ranged from 10 to 15 months in published studies. “DeLLphi-303 seeks to add a second agent, tarlatamab, in addition to an anti–PD-L1 inhibitor, to see if we can further improve outcomes,” she said.
Tarlatamab, a delta-like ligand 3 (DLL3)-targeting bispecific T-cell engager, activates the T-cell receptor through the CD3 binding domain. It has been approved by the U.S. Food and Drug Administration in the second-line or later setting for extensive-stage small cell lung cancer.
Dr. Paulson presented extended follow-up data from the global phase Ib DeLLphi-303 trial of 88 previously untreated patients. Patients had received four to six cycles of first-line platinum/etoposide plus an anti–PD-L1 agent. Those without disease progression or other exclusions were enrolled and treated with tarlatamab (10 mg intravenously every 2 weeks after an initial 1-mg dose) and either atezolizumab or durvalumab. Median exposure to tarlatamab was 35 weeks.
In the study population, about 70% were White, and 67% were male. Almost all patients had a history of smoking, and 88% had received prior anti–PD-L1 treatment.
Overall Survival Data
“Here is the exciting part,” announced Dr. Paulson. “The overall survival we saw by adding tarlatamab to a PD-L1 inhibitor in the maintenance setting was impressive.” After a median follow-up of 18.4 months, the median overall survival was 25.3 months, the 12-month overall survival rate was 82%, and the 18-month overall survival rate was 75%, she reported.
Dr. Paulson contrasted this encouraging survival with data from other landmark studies. In the maintenance setting, median overall survival with atezolizumab was 12.5 months in the IMpower133 trial3 and 13.2 months with atezolizumab and the alkylating agent lurbinectedin in the IMforte trial.4
In the current analysis of the DeLLphi-303 trial, median progression-free survival was 5.6 months, with 34% of patients remaining progression-free at 12 months. The objective response rate was 24%, and the disease control rate was 60%; the median duration of response was 16.6 months.
In their article in The Lancet Oncology,2 Dr. Paulson and colleagues pointed out that the objective response and disease control rates were notable, given the baseline scans were obtained after completion of standard-of-care first-line chemoimmunotherapy. “Thus, responses in this context represented an additional tumor response beyond that observed after platinum/etoposide chemotherapy plus a PD-L1 inhibitor,” they wrote.
More than half the patients who experienced disease progression remained on tarlatamab “and obtained a continued benefit,” she said, reporting that 36% maintained disease control for at least 1 year. Some patients received adjunctive treatment, such as radiation therapy, to help control disease progression. Tumor shrinkage after induction was seen in many patients, often producing sustained disease control, Dr. Paulson remarked.
Safety Profile
“With longer follow-up, tarlatamab with a PD-L1 inhibitor as first-line maintenance therapy had a manageable safety profile, with no dose-limiting toxicities, no fatal treatment-related adverse events, and low frequency of treatment discontinuation due to tarlatamab-related adverse events. Immune-related adverse events, excluding cytokine-release syndrome and associated neurologic events, were rare (1%). The incidence of treatment-emergent adverse events decreased over time, which supports the treatment’s long-term tolerability,” Dr. Paulson said.
Cytokine-release syndrome was reported in 56% of patients, with most events (43%) grade 1 or grade 2 (11%) and all resolving. Immune effector cell–associated neurotoxicity syndrome occurred in 6%, all with an early onset (< 3 months), grade 1 or 2, and resolving with supportive care. The most common grade 3 or 4 adverse events were hyponatremia (10%), anemia (8%), and neutropenia (7%). Serious adverse events occurred in 57% of patients, with the most common being cytokine-release syndrome (24%). No deaths from treatment-related adverse events were reported.
A Changing Paradigm?
“This is changing the paradigm of how we think about small cell lung cancer,” Dr. Paulson said. Instead of switching therapies once disease progression occurs, she said, “we are looking at managing the disease like we do other immunotherapy-sensitive solid tumors and thinking about using combination approaches to keep patients on immunotherapy for as long as possible.”
The randomized phase III DeLLphi-305 study will evaluate this regimen vs standard-of-care therapy in the first-line treatment setting of extensive-stage small cell lung cancer.
Expert Point of View
Dr. Rudin, the Sylvia Hassenfeld Professor and Chief of Thoracic Oncology at Memorial Sloan Kettering Cancer Center, New York, believes the addition of a bispecific T-cell engager such as tarlatamab-dlle may be a rational approach to improving maintenance therapy for small cell lung cancer, noting that it is already a new standard of care for recurrent disease.
“Suppression of antigen presentation is a primary cause of immunotherapy failure in small cell lung cancer, and tarlatamab bypasses this,” he pointed out. Because of tarlatamab’s mechanism of action, he added, its combination with a PD-L1 inhibitor would be at least additive and potentially synergistic. By recruiting T cells into “an immune desert,” tarlatamab is “lighting the fire with local inflammation.”
Cautious Optimism
In DeLLphi-303, the effect of this combination as maintenance therapy led to a survival outcome that was incredibly beneficial, Dr. Rudin said. “I know I’m supposed to be critical, but it’s a ‘wow.’ The curves look better than I thought they would.”
Dr. Rudin continued: “However, you have to take that with a little bit of a grain of salt. Because to be enrolled, patients had to survive chemoimmunotherapy induction and still be in response or at least have stable disease. You can expect these curves to come down a little in the next study.”
Additional considerations are whether this regimen should be used earlier in the treatment course and in limited-stage small cell lung cancer. “Clearly, I think it should be tested in that context,” he said. “But the bottom line is, I’m very impressed.”
DISCLOSURE: Dr. Paulson has received institutional research funding from Amgen, Bristol Myers Squibb, Merck, Iovance Biotherapeutics, and Immunocore; and has served as a consultant to Bristol Myers Squibb. Dr. Rudin reported no conflicts of interest.
REFERENCES
1. Paulson KG, Lau SC, Ahn MJ, et al: Safety and survival update of tarlatamab with anti–PD-L1 as first-line maintenance after chemo-immunotherapy for extensive-stage small cell lung cancer: DeLLphi-303 ph1b trial. 2025 World Conference on Lung Cancer. Abstract OA13.01. Presented September 8, 2025.
2. Paulson KG, Lau SCM, Ahn MJ, et al: Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): A multicentre, non-randomised, phase 1b study. Lancet Oncol. September 8, 2025 (early release online).
3. Horn L, Mansfield AS, Szczęsna A, et al: First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379:2220-2229, 2018.
4. Paz-Ares LG, Borghaei H, Liu S, et al: Lurbinectedin + atezolizumab as first-line maintenance treatment in patients with extensive-stage small cell lung cancer: Primary results of the phase 3 IMforte trial. 2025 ASCO Annual Meeting. Abstract 8006. Presented June 2, 2025.
