Small Cell Lung Cancer and Tarlatamab: A Meta-Analysis of Clinical Trials

Abstract Introduction Tarlatamab is a Delta-like ligand 3 (DLL3) -directed bispecific T-cell engager recently approved for use in patients with advanced small cell lung cancer (SCLC) after progression on platinum-based therapy. This meta-analysis evaluated the efficacy and safety of tarlatamab as monotherapy and in combination regimens in the treatment of SCLC. Methods A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. PubMed/MEDLINE and EMBASE were searched from inception through September 2025 to identify clinical trials evaluating tarlatamab in SCLC. Eligible studies reported quantifiable efficacy and/or safety outcomes. Random-effects models were used to pool objective response rate (ORR) and disease control rate (DCR), and Kaplan–Meier methods were applied to assess survival outcomes. Results Seven clinical trials involving 1,247 patients with advanced SCLC were included. The pooled ORR was 0.42 (95% CI 0.31–0.54), with response rates ranging from 21–47% in monotherapy studies and up to 48% in combination regimens. Across six studies, pooled DCR was 0.48 (95% CI 0.31–0.66), with DCR reaching up to 87% in combination settings. Median progression-free survival ranged from 3.5 to 5.6 months, while median overall survival ranged from 13.2 to 25.3 months. Pooled time-to-event analyses demonstrated significant reductions in the risk of disease progression and death. Grade 3 and grade 4 adverse events occurred in 5.4% and 1.4% of patients, respectively, although safety reporting was incomplete in several studies. Conclusion Tarlatamab demonstrates clinically meaningful antitumor activity with an acceptable safety profile in heavily pretreated SCLC. These findings support DLL3-targeted therapy as a promising treatment strategy and warrant further prospective studies to define its optimal role in the evolving SCLC treatment landscape. Introduction Small cell lung cancer (SCLC) is one of the most aggressive and fatal lung malignancies, accounting for approximately 13% to 17% of all lung cancer cases [1]. It is characterized by rapid tumor growth, early dissemination, and a strong tendency toward therapeutic resistance, which collectively complicate diagnosis and management [1,2]. For patients with limited stage disease, standard treatment consists of a combined modality approach using platinum-based chemotherapy, most commonly cisplatin or carboplatin with etoposide, administered concurrently with thoracic radiotherapy. In patients who achieve complete remission, prophylactic cranial irradiation is commonly used to reduce the risk of central nervous system metastases [3,4]. In extensive stage SCLC, treatment strategies have expanded to include immunotherapy, particularly Programmed Death-Ligand 1 (PD-L1) inhibitors, in combination with conventional chemotherapy [4,5]. Despite these advances, long-term survival remains poor due to rapid development of drug resistance, frequent relapse, and substantial treatment-related toxicity [1,6]. Although immune checkpoint inhibitors (ICIs) have transformed outcomes in several malignancies, their benefit in SCLC has been limited. While the high tumor mutational burden of SCLC suggests potential sensitivity to immunotherapy, only a subset of patients derive meaningful benefit from adding ICIs to first-line chemotherapy [7,8]. This limited efficacy has been attributed to factors such as reduced expression of major histocompatibility complex (MHC) molecules, impaired antigen presentation, and marked intratumoral heterogeneity [9,10]. Nevertheless, large international trials have demonstrated improved survival with the addition of PD-L1 inhibitors, including durvalumab, to chemotherapy, supporting the role of chemoimmunotherapy in SCLC [11]. Early evidence suggests that patients with more immunogenic tumors may be the primary beneficiaries of these combination approaches [1,4]. Given the limitations of current therapies, there is a clear need for novel treatment strategies in SCLC. Advances in molecular characterization and understanding of SCLC biology have enabled the development of targeted therapies designed to overcome disease progression and treatment resistance, advancing the potential for personalized therapeutic approaches [12,13]. Tarlatamab is a bispecific T cell engager (BiTE) immunotherapy that targets delta-like ligand 3 (DLL3) on tumor cells and the Cluster of Differentiation 3 (CD3) receptor on T cells, resulting in T cell activation, cytokine release, and selective cytotoxicity against DLL3-expressing cancer cells. Based on durable antitumor activity and a manageable safety profile observed in the DeLLphi-301 phase 2 trial, tarlatamab received accelerated approval from the United States Food and Drug Administration in May 2024 for patients with extensive stage SCLC who experienced disease progression after platinum-based chemotherapy [14]. This meta-analysis evaluates the efficacy and safety of tarlatamab as monotherapy and in combination with other therapies in the management of SCLC. Methods Study design and setting This systematic review and meta-analysis synthesized evidence from clinical trials assessing the therapeutic efficacy of tarlatamab in SCLC management. Treatment approaches were categorized into four arms: Group A comprising tarlatamab monotherapy, Group B combining tarlatamab with chemotherapy, Group C combining tarlatamab with the PD-L1 inhibitor atezolizumab, and Group D combining tarlatamab with the PD-L1 inhibitor durvalumab. All methodology and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Data sources and search strategy A comprehensive search was conducted across PubMed/MEDLINE and EMBASE from inception through September 2025 to identify clinical trials and observational studies evaluating tarlatamab in SCLC. The search strategy combined controlled vocabulary (MeSH terms) and free-text keywords using Boolean operators: (lung OR pulmonary OR bronchi* OR chest OR pleural OR alveol*) AND (tarlatamab OR DeLLphi-300 OR DLL3 OR "delta-like ligand 3" OR Imdelltra OR AMG 757) AND (cancer OR carcinoma OR malignancy OR metastasis). Truncation operators and wildcard searches were used to maximize sensitivity. No language restrictions were applied. Database searches were supplemented by hand-searching relevant journal articles and clinical trial registries to identify additional studies. Inclusion criteria Studies were eligible for inclusion if they: (1) evaluated tarlatamab as monotherapy or in combination regimens; (2) reported quantifiable clinical outcomes including response rate, overall survival (OS), progression-free survival (PFS), or time to progression; and (3) enrolled patients with extensive-stage or limited-stage who had received prior platinum-based chemotherapy or other systemic treatment. Studies evaluating tarlatamab as second-line, third-line, or subsequent-line therapy were eligible for inclusion. Exclusion criteria Studies were excluded if they: (1) were not clinical trials; (2) did not focus on tarlatamab treatment for SCLC; (3) presented overlapping or duplicate patient populations; (4) lacked adequate efficacy or safety data; (5) were published in languages other than English; (6) were preprints, abstract presentations only, or published in predatory journals. Study selection process Two independent researchers screened the titles and abstracts of all identified studies against pre-established inclusion and exclusion criteria. Retrieved articles that appeared potentially eligible underwent full-text review by both reviewers. Any disagreement regarding study eligibility was resolved through discussion and consensus. Data items Data extracted from eligible studies included: (1) study and patient characteristics (first author name, year of publication, sample size, trial phase); (2) demographic variables (median age, gender distribution, smoking status); (3) clinical baseline characteristics (ECOG performance status, metastatic sites, prior platinum-based chemotherapy, number of prior treatment lines, prior immunotherapy exposure, prior radiotherapy); (4) treatment details (tarlatamab dosing, administration frequency, median duration of therapy); (5) adverse event data (graded according to Common Terminology Criteria for Adverse Events [CTCAE], including Grade 1-5 events and serious adverse events); and (6) clinical efficacy outcomes (response rates, disease control rate, PFS, and OS). Data analysis and synthesis Data were extracted and organized using Microsoft Excel (2019). Descriptive statistical analyses were performed using Statistical Package for Social Sciences (SPSS) version 26.0, with results summarized as frequencies, percentages, medians, and ranges. Meta-analyses were conducted to synthesize efficacy outcomes. For binary outcomes (objective response rate and disease control rate), forest plots were generated using METAANALYSISONLINE to visualize pooled effect estimates and heterogeneity. For time-to-event outcomes (PFS and OS), Kaplan-Meier methods were used to estimate median survival and percentiles with 95% confidence intervals (CI) calculated using the Brookmeyer and Crowley method [15]. Results Study selection A systematic search of peer-reviewed databases initially identified 214 potentially relevant records related to tarlatamab and small cell lung cancer. Following removal of duplicates (n=2), non-English publications (n=2), and records with abstract-only availability (n=9), 201 studies underwent title and abstract screening. This process identified 188 studies for comprehensive full-text review. Application of pre-established eligibility criteria resulted in 14 studies selected for detailed evaluation. Of these, seven studies were subsequently excluded due to preprint status (n=4) and publication in predatory journals (n=3), resulting in a final cohort of 7 eligible clinical trials included i