In a significant advancement within the landscape of lung cancer therapeutics, novel clinical data unveiled at the 2025 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC) in Barcelona provides compelling evidence supporting the efficacy and safety of combining tarlatamab with anti-PD-L1 therapy as a first-line maintenance strategy for patients suffering from extensive-stage small cell lung cancer (ES-SCLC). This promising immunotherapeutic approach could mark a paradigm shift by substantially extending overall survival in a disease historically marked by aggressive progression and limited treatment options.
The phase 1b DeLLphi-303 trial, led by K.G. Paulson, MD, from the Providence-Swedish Cancer Institute, represents a pioneering clinical investigation into the therapeutic utility of tarlatamab in conjunction with established anti-PD-L1 checkpoint inhibitors—atezolizumab or durvalumab—administered following initial platinum-etoposide chemotherapy. The trial enrolled 88 patients diagnosed with ES-SCLC who had completed 4–6 cycles of frontline chemo-immunotherapy without experiential disease progression. This carefully selected population received maintenance treatment beginning within eight weeks of completing their induction regimen, with tarlatamab dosed at 10 mg intravenously biweekly, alongside either atezolizumab (1680 mg IV every four weeks) or durvalumab (1500 mg IV every four weeks).
Tarlatamab is a bispecific T-cell engager (BiTE®) immunotherapy, an innovative class of agents designed to recruit and activate cytotoxic T lymphocytes against tumor cells by targeting delta-like ligand 3 (DLL3), a tumor-associated antigen widely expressed in small cell lung cancer but largely absent in normal adult tissues. This specificity confers a therapeutic window that minimizes off-target effects, enabling targeted immunologic attack on malignant cells. Prior investigations demonstrated tarlatamab’s potential in the second-line treatment setting, but DeLLphi-303 is the first to rigorously evaluate its integration as maintenance therapy in the first-line context.
The interim efficacy results of DeLLphi-303 are remarkable: at a median follow-up of 18.4 months, the median overall survival (OS) reached 25.3 months, far exceeding historical benchmarks for ES-SCLC, wherein median OS typically ranges between 8 to 12 months with standard therapies. This extraordinary survival outcome, accompanied by a median progression-free survival (PFS) of 5.6 months, underscores the durable disease control achievable through this combinatorial immunotherapy strategy. The upper confidence interval of the OS metric was not reached, implying ongoing survival benefit beyond the study’s current temporal scope.
The safety profile observed aligns with the mechanistic action of tarlatamab and immune checkpoint blockade, with cytokine release syndrome (CRS) reported in 56% of patients. Importantly, the majority of CRS events were grade 1, indicating mild severity and manageable clinical impact. Incidences of immune effector cell-associated neurotoxicity syndrome (ICANS), an immune-related adverse event associated with T-cell engager therapies, were low at 6%. This balance between potent antitumor activity and tolerable toxicity buttresses the therapeutic viability of this regimen for long-term administration in a typically frail patient population.
Mechanistically, tarlatamab functions by physically bridging T cells via CD3 to DLL3-expressing tumor cells, fostering cytolytic synapse formation and subsequent tumor cell apoptosis. The synergy observed when combined with anti-PD-L1 agents likely stems from the alleviation of PD-1/PD-L1 mediated immunosuppression, permitting sustained T-cell activation within the tumor microenvironment. This dual immunologic offensive targets tumor evasion pathways at multiple junctures, potentiating durable control over rapidly proliferating SCLC cells.
The trial design rigorously enforced patient selection criteria to mitigate confounding variables, enrolling participants only after completion of standard frontline chemotherapy plus anti-PD-L1 treatment without progression. The timing of maintenance initiation—within eight weeks of the last induction treatment cycle—afforded a critical window to consolidate response and preempt tumor relapse. Such strategic layering of immunotherapies showcases a precision medicine paradigm actively reshaping treatment algorithms.
Importantly, the longitudinal data revealed a decline in treatment-emergent and treatment-related adverse events over time, suggesting an adaptive tolerability with sustained pharmacologic exposure. This phenomenon is particularly relevant in an ES-SCLC cohort where chronic treatment toxicity often limits patient compliance and quality of life. Hence, the durability of therapeutic benefit accompanied by manageable safety enhances the clinical appeal of this treatment regimen.
The promising outcomes from this phase 1b trial have paved the way for the ongoing DeLLphi-305 phase 3 study (NCT06211036), designed to rigorously confirm the clinical benefit and safety of tarlatamab plus anti-PD-L1 as first-line maintenance in a larger patient population. If positive, these results could herald FDA approval and integration into clinical practice, providing a desperately needed advance in the therapeutic armamentarium for ES-SCLC patients.
The IASLC’s role in fostering such groundbreaking research is underscored by its global network, connecting over 10,000 oncology specialists dedicated to overcoming thoracic malignancies. The World Conference on Lung Cancer remains a premier venue for unveiling innovations that accelerate translational research and disseminate cutting-edge knowledge to the international medical community.
These findings exemplify a critical milestone in the evolution of immunotherapy for lung cancer, demonstrating how targeted engagement of tumor-specific antigens combined with immune checkpoint modulation can yield unprecedented survival benefits. As the oncology world closely watches the progression of the DeLLphi clinical program, tarlatamab and its bispecific T-cell engager approach may soon redefine the standard of care, illuminating a hopeful path for patients afflicted by this aggressive disease.
Subject of Research: First-line maintenance treatment of extensive-stage small cell lung cancer using tarlatamab in combination with anti-PD-L1 therapy
Article Title: Combination of Tarlatamab and Anti-PD-L1 Therapy Yields Unprecedented Survival in Extensive-Stage Small Cell Lung Cancer at IASLC 2025
News Publication Date: September 8, 2025
Web References:
– IASLC official website: www.iaslc.org
– ClinicalTrials.gov: NCT06211036 (DeLLphi-305 trial)
Keywords:
Lung cancer, small cell lung cancer, ES-SCLC, immunotherapy, bispecific T-cell engager, tarlatamab, anti-PD-L1 therapy, atezolizumab, durvalumab, cytokine release syndrome, immune checkpoint inhibitors, overall survival
