Two studies investigating efficacy of bispecific T-cell engager tarlatamab and lurbinectedin–atezolizumab combination met their primary endpoints of survival
Small cell lung cancer (SCLC) remains a peculiar clinical challenge, showing high initial chemosensitivity followed by near-universal relapse and with limited effective options beyond the first-line. At the 2025 ASCO Annual Meeting, two pivotal phase III trials reported long-awaited progress in the field, holding potential for shifting the therapeutic standard in both the second-line and maintenance settings for patients with extensive-stage SCLC (ES-SCLC).
The DeLLphi-304 trial evaluated the bispecific T-cell engager tarlatamab, targeting DLL3 and CD3, versus standard-of-care chemotherapy (topotecan, lurbinectedin, or amrubicin) in patients with ES-SCLC who had progressed after platinum-based chemotherapy (J Clin Oncol 43, 2025; suppl 17; abstr LBA8008). DLL3 is highly expressed in SCLC and is rarely expressed in normal tissues, making it an ideal target for T-cell redirection. In this randomized phase III trial, 509 patients were assigned to receive tarlatamab (n = 254) or chemotherapy (n = 255).
The trial met its primary endpoint by reporting a median overall survival (OS) of 13.6 months in the tarlatamab arm versus 8.3 months in the chemotherapy arm (hazard ratio (HR) 0.60; 95% CI, 0.47–0.77; p < .001). Median progression-free survival (PFS) was also significantly improved with tarlatamab compared to standard treatment (4.2 versus 3.7 months; HR 0.71, 95% CI, 0.59–0.86; p < .001). The benefit extended across all predefined subgroups, including those with prior checkpoint inhibitor exposure. Importantly, tarlatamab was associated with fewer grade ≥3 treatment-related adverse events, fewer dose modifications, and clinically meaningful improvements in patient-reported symptoms, including cough and dyspnoea.
These results confirm and extend phase II findings from the study, and support the use of tarlatamab as a new standard of care in the second-line setting for ES-SCLC, marking the first randomised evidence of efficacy for a bispecific T-cell engager in lung cancer.
Also presented at ASCO 2025, the phase III IMforte trial investigated a novel approach in the maintenance setting (J Clin Oncol 43, 2025; suppl 16; abstr. 8006). After completion of induction chemo-immunotherapy (carboplatin, etoposide, and atezolizumab), patients without disease progression were randomised to continue atezolizumab alone or in combination with lurbinectedin, a selective transcription inhibitor with prior single-agent activity in SCLC.
The interim analysis demonstrated a significant improvement in both co-primary endpoints. Improvements in median PFS and median OS were reported in the combination arm compared to the atezolizumab arm (respectively, 5.4 vs. 2.1 months (HR 0.54), and 13.2 vs. 10.6 months (HR 0.73). Results were consistent across all key subgroups. The combination was generally well tolerated, with no new safety signals emerging beyond the known profiles of atezolizumab and lurbinectedin.
These findings support the hypothesis that combining immunotherapy with a DNA-damaging agent in a maintenance setting can delay progression and prolong survival in a population at high risk of early relapse. If confirmed with longer-term follow-up, this regimen could establish a new standard of care for maintenance in ES-SCLC.
Taken together, the results of DeLLphi-304 and IMforte trials signal a turning point in the treatment of ES-SCLC. Tarlatamab sets a new benchmark for second-line care, while the lurbinectedin–atezolizumab combination introduces a viable maintenance strategy aimed at consolidating initial response and prolonging benefit. As additional biomarker analyses and sequencing strategies emerge, these studies are redefining the therapeutic landscape of a disease long considered resistant to innovation.
