New therapeutic options are desperately needed for patients with small cell lung cancer (SCLC) whose disease has progressed or who have experienced disease recurrence after first-line therapy with a platinum-based chemotherapy, as current second-line standard-of-care (SOC) chemotherapy options for these patients result in modest overall survival (OS) benefit at best.
Fortunately, the novel agent tarlatamab, based on efficacy and safety data from the DeLLphi-304 trial presented by Charles M. Rudin, MD, PhD, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, has emerged as the new standard of care for these patients. This trial represents the first time a novel therapeutic agent has yielded improved OS compared with chemotherapy in this setting.
“Tarlatamab was associated with a 40% reduction in the risk of death compared with chemotherapy,” said Dr. Rudin, Chief of Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center. “Tarlatamab was also associated with a lower rate of high-grade adverse events (AEs) and AEs leading to treatment discontinuation, dose reduction, or interruption.”
Dr. Rudin presented the first planned interim analysis of the open-label, randomized, global, phase III DeLLphi-304 trial, which included patients with disease progression after one line of chemotherapy with or without the addition of a PD-1/PD-L1 inhibitor. Patients with asymptomatic brain metastases were encouraged to participate regardless of prior therapy.
In the last three hours during the SCLC session, we have witnessed more progress in this disease than we have observed in the past 30 years.
Corey J. Langer, MD, FACP, ILCN Editor
The primary endpoint was OS; key secondary endpoints were progression-free survival (PFS) and patient-reported outcomes. Additional secondary endpoints included safety, duration of response, objective response, and disease control rates.
Patients were well balanced between arms, with a median age of 64 years for tarlatamab and 66 years for chemotherapy. Patients were mostly white males; all patients had an ECOG performance status of 0 or 1. In both arms, 71% of patients had received a prior PD-1/PD-L1 inhibitor; 44% had chemotherapy-resistant disease in the tarlatamab arm (vs. 45% in the chemotherapy arm), as defined as a chemotherapy-free interval after completion of first-line chemotherapy of less than 90 days.
As noted, approximately 17.5% of total patients had brain metastases diagnosed at or before study enrollment. The vast majority of patients (95% and 93%, respectively) had detectable DLL3 expression.
A total of 509 patients were randomly assigned 1:1 to tarlatamab (n = 254) or to topetecan, lurbinectedin, or amrubicin, (n = 255) based on local regulatory approvals and availability. The median follow-up was 11.2 months.
Estimated median OS with tarlatamab was 13.6 months compared with 8.3 months for chemotherapy (hazard ratio [HR], 0.60 [95% CI: 0.47, 0.77]; p < 0.001). The median PFS was 4.2 versus 3.2 months (HR, 0.72 [95% CI: 0.59, 0.88]; p < 0.001), respectively. The survival benefit with tarlatamab was seen across all subgroups, including those patients with chemotherapy-resistant disease and those with brain metastases.
“The shape of the (progression-free survival) curve (for tarlatamab) is almost superimposable for the first few months, but then (there is) a clear separation at about 6 months, which continues to widen over time,” Dr. Rudin said. “Again, these data are immature, but we can estimate that the 1-year PFS on tarlatamab is about 20%, which is five times what we can see for chemotherapy at 4%.”
Patient-reported outcomes showed statistically significant improvement for tarlatamab regarding dyspnea and cough but not for chest pain, although all measures trended toward improvement for the tarlatamab arm, according to Dr. Rudin. Overall objective response was 35% versus 20%, and the median duration of response in those patients with confirmed response was 6.9 versus 5.5 months for tarlatamab versus chemotherapy.
Tarlatamab, a bispecific T-cell engager, induces tumor lysis by directing cytotoxic T cells to cancer cells that express DLL3. Other agents in this class have shown cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) to be common acute toxicities, both of which can lead to dose modifications, interruption, discontinuation, and even death.
Safety data for tarlatamab, however, showed that the incidence of grade 3 or higher treatment-related adverse events (TRAEs) was more than double for chemotherapy (62% vs. 27% for tarlatamab). In addition, 55% of the 244 patients who received chemotherapy underwent dose modification or interruption, and an additional 6% discontinued their therapy compared with 19% and 3%, respectively, of patients on tarlatamab.
Specific to CRS, 56% of the 252 patients who received tarlatamab experienced any-grade CRS, but only 1% of those experienced grade 3 CRS. The vast majority of these reactions occurred during the first two infusions. The incidence of ICANS occurred in 6% of patients on tarlatamab, and these were almost exclusively grade 1 or 2.
“Taking the efficacy and safety data together, these data clearly support tarlatamab as a preferable therapy in the second-line setting for patients with small cell lung cancer. Beyond redefining the standard of care for these patients, this study also establishes a new paradigm for the use of bispecific T-cell engager immunotherapies in our patients with lung cancer,” said Dr. Rudin.
