Search Results (53)

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy associated with rapid proliferation, early metastatic spread, and poor long-term survival. Despite high initial responsiveness to chemotherapy and radiotherapy, most patients experience relapse, and therapeutic progress historically remained limited. Recent years, however, have seen meaningful advances that are beginning to reshape the management of SCLC. In extensive-stage disease, the incorporation of PD-L1 inhibitors into platinum-etoposide chemotherapy has established chemoimmunotherapy as the first-line standard, while underscoring the continued need for more durable disease control. In limited-stage SCLC, consolidation durvalumab following concurrent chemoradiotherapy has emerged as a practice-changing strategy with significant survival benefit. In relapsed disease, DLL3-targeted therapy has opened a new therapeutic avenue, with tarlatamab demonstrating clinically relevant efficacy in previously treated extensive-stage SCLC and becoming the first approved bispecific T-cell engager in this setting. Alongside these milestones, ongoing investigation is focused on maintenance strategies, novel targeted agents, biomarker development, molecular subtyping, and more effective integration of systemic therapy with radiation-based approaches. Nevertheless, resistance, toxicity management, central nervous system involvement, and the absence of validated predictive biomarkers remain major barriers to sustained progress. This narrative review examines recent advances in the biology and clinical management of SCLC, with emphasis on practice-changing developments, emerging therapeutic platforms, and future strategies aimed at improving outcomes in this historically difficult-to-treat disease. Full article

Background/Objectives: Small-cell lung cancer (SCLC) remains one of the most therapeutically challenging malignancies despite recent advances in chemoimmunotherapy. Although platinum–etoposide combined with programmed death ligand 1 (PD-L1) blockade has modestly improved survival in extensive-stage disease, most patients ultimately develop treatment resistance. This review examines the evolving biological basis of therapeutic resistance and discusses how emerging treatment strategies may be integrated into biologically informed clinical development. Methods: We conducted a narrative review of recent translational studies, clinical trials, regulatory updates, and major oncology meeting presentations addressing emerging therapeutic strategies, biomarkers, and adaptive resistance mechanisms in SCLC. Results: Advances in molecular profiling have established that SCLC comprises dynamically evolving transcriptional states characterized by lineage plasticity, replication-stress dependency, immune suppression, and antigen remodeling. These biological insights have accelerated the development of delta-like ligand 3 (DLL3)-directed immune-redirection strategies, next-generation antibody–drug conjugates, DNA damage response-targeting therapies, and epigenetic approaches. Across these platforms, however, clinical translation remains constrained by antigen heterogeneity, biomarker instability, lineage plasticity, immune dysfunction, and cumulative toxicity. We organize the available evidence across three clinically relevant treatment windows—induction, post-induction residual disease, and relapse—to clarify how therapeutic timing may influence the role and expected clinical performance of each strategy. Conclusions: Future clinical development should prioritize the prospective validation of dynamic biomarkers and treatment strategies tailored to specific disease stages. Such an approach may improve patient selection, guide therapeutic sequencing, and increase the durability of treatment benefit in extensive-stage SCLC. Full article

Background: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with a high risk of recurrence. While adjuvant radiotherapy is standard following surgical resection in high-risk disease, the additional benefit of platinum–etoposide chemotherapy and the prognostic role of tumor anatomical location remain uncertain. Methods: We conducted a multicenter retrospective cohort study including patients with high-risk MCC (stage IIB–III) treated with surgery followed by adjuvant radiotherapy with or without platinum–etoposide chemotherapy. Tumor sites were classified according to sun-exposure status. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared using the log-rank test, with subgroup analyses by anatomical region and stage. Results: A total of 103 patients were included, of whom 77 (74.8%) received adjuvant chemoradiotherapy and 26 (25.2%) received radiotherapy alone. Patients with non-sun-exposed tumors demonstrated longer survival outcomes than those with sun-exposed tumors, with a median DFS of 57 months versus 42 months (p = 0.15), and a median OS of 179 months versus 109 months (p = 0.054), respectively. Among patients with sun-exposed tumors, chemoradiotherapy was associated with numerically improved DFS (42 vs. 34 months; p = 0.051) and OS (128 vs. 98 months; p = 0.08) compared with radiotherapy alone. In patients with non-sun-exposed tumors, chemoradiotherapy demonstrated a more pronounced improvement in OS (178 vs. 56 months; p = 0.054), while DFS also favored combined treatment (49 vs. 78 months; p = 0.078). Conclusions: In this multicenter cohort, adjuvant chemotherapy did not demonstrate a uniform survival benefit overall but was associated with improved outcomes in head and neck MCC, suggesting a potential site-specific effect. Similar outcomes across stage III subgroups suggest that chemotherapy may mitigate stage-related prognostic differences. These findings support a selective approach to adjuvant chemotherapy and highlight the need for prospective studies incorporating modern immunotherapy strategies. Full article

Background: Extensive-stage small cell lung cancer (ES-SCLC) carries a poor prognosis, with fewer than 7% of patients surviving for five years. While immune checkpoint inhibitors (ICIs) combined with platinum–etoposide have reshaped first-line treatment, no head-to-head trials exist comparing available regimens, leaving the optimal therapeutic choice undefined. Methods: A systematic literature search identified phase III randomized controlled trials (RCTs) evaluating first-line ICI-based regimens in ES-SCLC. Individual patient data (IPD) were reconstructed from Kaplan–Meier curves using the IPDfromKM algorithm. Indirect treatment comparisons were performed using Cox proportional hazards models, with chemotherapy alone as the common comparator. The indirect comparison of tiragolumab efficacy was unanchored due to the design of the SKYSCRAPER-02 study. Restricted mean survival time (RMST), truncated at 27 months, was calculated as an additional measure of treatment effect. Results: Six RCTs were included. All ICI-based regimens improved overall survival (OS) compared to chemotherapy alone, except ipilimumab (HR 0.97, 95% CI 0.86–1.09). Serplulimab demonstrated the most favorable OS benefit (HR 0.55, 95% CI 0.48–0.64; RMST 16.73 months), representing a gain of approximately 4 months over chemotherapy alone and 1.8–2.3 months over atezolizumab and durvalumab. The addition of tiragolumab to atezolizumab plus chemotherapy yielded no significant advantage over atezolizumab alone. Conclusions: This IPD-based indirect comparison suggests that serplulimab plus chemotherapy may offer the most favorable OS estimates S benefit among first-line ICI regimens for ES-SCLC, while durvalumab and atezolizumab remain effective standards of care. These findings are hypothesis-generating and highlight the need for prospective head-to-head comparative studies. Full article

Background and Objectives: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin malignancy associated with high rates of recurrence and disease-specific mortality. Although adjuvant platinum–etoposide chemotherapy is used in high-risk disease, the optimal number of treatment cycles has not been established. Materials and Methods: This multicenter retrospective cohort study included 104 patients with resected high-risk MCC (pathological stage IIB–III) treated at Israeli medical centers between September 1985 and February 2021. Patients were assigned to one of three treatment groups: radiotherapy alone, four cycles of platinum–etoposide plus radiotherapy, or six cycles of platinum–etoposide plus radiotherapy. The chemotherapy regimen consisted of cisplatin or carboplatin combined with etoposide in 21-day cycles, with the first two cycles administered concurrently with radiotherapy. Primary endpoints were disease-free survival (DFS) and overall survival (OS), analyzed using the Kaplan–Meier method and multivariable Cox proportional hazards regression. Results: Four cycles of adjuvant platinum–etoposide combined with radiotherapy were associated with the most favorable survival outcomes at all follow-up time points. Five-year DFS and OS in the four-cycle group were 65% (95% CI: 58–72%) and 75% (95% CI: 68–82%), respectively, compared with 55% and 60% in the six-cycle group, and 40% and 45% in the radiotherapy-only group (p < 0.001). The survival advantage of four cycles over radiotherapy alone was sustained at 10- and 20-year follow-up (p < 0.0001). In patients with stage III disease and nodal involvement, the four-cycle group achieved a median DFS of 93 months and a median OS of approximately 110 months, significantly exceeding outcomes in both the six-cycle and radiotherapy-alone groups. No statistically significant survival benefit from chemotherapy was identified in the small subgroup of patients with stage IIB/T4N0 disease. Conclusions: In patients with high-risk resected MCC, the addition of adjuvant platinum–etoposide chemotherapy to radiotherapy significantly improves DFS and OS, with the greatest benefit observed in patients with stage III disease and lymph node involvement. Four cycles represent an optimal treatment duration, delivering durable long-term survival benefit without the need for more prolonged chemotherapy exposure. These findings support a risk-adapted multimodality approach and provide real-world evidence to guide adjuvant therapy decisions in this rare and aggressive malignancy. Full article

Introduction: Inflammatory and immune-based prognostic markers such as the Lung Immune Prognostic Index (LIPI) and the Glasgow Prognostic Score (GPS) have gained increasing attention in ES-SCLC, particularly in patients receiving first-line chemoimmunotherapy. However, no prior study has explored a broader, integrated inflammatory framework that evaluates these parameters collectively. Methods: We retrospectively evaluated 166 patients with ES-SCLC treated with first-line platinum–etoposide plus atezolizumab or durvalumab between 2019 and 2025. LIPI could be calculated in 123 patients based on available dNLR and LDH values, while GPS and the Combined Inflammatory Prognostic Score (CIPS) could be assessed in 120 patients with accessible CRP and albumin data. Results: Median PFS and OS were 8.16 and 15.96 months, respectively. In univariate analyses, poor ECOG PS, liver and bone metastases, poor LIPI, poor GPS, and high-risk CIPS were associated with shorter PFS and OS. In multivariate analysis, only LIPI and GPS remained independent predictors of both PFS and OS, while ECOG PS was independently associated with OS. Although CIPS demonstrated clear prognostic separation in univariate analysis, it did not retain independent significance, likely due to sample size limitations and overlap with LIPI and GPS components. Conclusions: LIPI and GPS are strong independent prognostic markers in ES-SCLC receiving chemoimmunotherapy. While CIPS did not demonstrate independent prognostic value in multivariate analysis, its simplicity, balanced two-tier design, and use of routinely available biomarkers highlight its potential clinical utility. To our knowledge, this is the first study to assess a combined inflammatory prognostic model in this population. Prospective multicenter validation is warranted. Full article

Background/Objectives: Small cell lung cancer (SCLC) is a highly metastatic and lethal malignancy. Doublet chemotherapy consisting of a platinum compound and etoposide had remained the standard first-line regimen for decades, particularly for the majority of patients, who are diagnosed with extensive-stage disease. Over the past 5 years, results from the IMpower133 trial led to the approval of anti-PD-L1 agent atezolizumab as part of the first-line regimen for extensive-stage SCLC. The accumulation of real-world evidence on atezolizumab efficacy in this context is essential for corroborating trial results and further improving patient outcomes. Herein, we present real-world evidence from a Bulgarian cohort receiving atezolizumab as part of first-line extensive-stage SCLC treatment, comparing these data to the results of IMpower133. Methods: Data were extracted from the electronic health records of patients receiving atezolizumab plus chemotherapy as first-line treatment for extensive-stage SCLC in the period between 1 January 2022 and 31 December 2024. Analysis was conducted via the Danny Platform, an analytic platform for the integration of real-world evidence using embedded machine learning and LLM algorithms. Patients matching IMpower133 inclusion criteria were included in a group for comparison with trial results. Results: A total of 302 patients were included in the analysis. The real-world progression-free survival (PFS) in our study surpassed that in IMpower133 (7.6 versus 5.2 months), in addition to higher PFS rates beyond six months. A lower Objective Response Rate (ORR) (38.7% versus 65.4%) was noted in our real-world cohort, which we attribute to real-world documentation practices. Conclusions: Real-world evidence regarding PFS and treatment response generally align with the efficacy of adding atezolizumab to first-line extensive-stage SCLC treatment reported in the IMpower133 trial, while reflecting differences that may arise in routine clinical practice. Full article

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive tumor for which the most effective systemic therapy remains uncertain. In metastatic LCNEC, chemotherapy approaches typically alternate between small-cell lung cancer (SCLC)-like and non-small-cell lung cancer (NSCLC)-like regimens. Emerging data indicate that treatment selection may be optimized through molecular subtype classification. This study aimed to evaluate the outcomes of SCLC-like and NSCLC-like chemotherapy (CT) regimens in relation to LCNEC molecular subtypes. Methods: This retrospective analysis included all patients diagnosed with LCNEC at Gaziantep University between January 2010 and October 2024. Individuals with available tumor tissue and complete clinical data were enrolled. LCNEC cases were categorized as SCLC-subtype or NSCLC-subtype according to the presence of TP53 and RB1 alterations. Platinum combined with etoposide, irinotecan, or topotecan was defined as SCLC-like CT, whereas platinum with taxanes or gemcitabine was considered NSCLC-like CT. Survival outcomes of both treatment types were compared across molecular subgroups using the Kaplan–Meier method. Results: Sixty-one patients met the inclusion criteria. The median overall survival (mOS) was 11.0 months (95% CI: 6.3–15.7). No significant difference in mOS was observed between SCLC-like and NSCLC-like regimens in the total cohort. When stratified by molecular subtype, patients with the SCLC subtype who received SCLC-like CT showed a longer mOS compared to those treated with NSCLC-like CT (15 [9.9–20.1] vs. 6 [3.9–8.1] months, respectively; p = 0.47), although this difference did not reach statistical significance. Conclusions: These findings suggest that molecular subclassification may help inform the choice of optimal systemic therapy in patients with LCNEC. Full article

Background: Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid growth, early metastatic dissemination, and a dismal prognosis. For decades, treatment paradigms remained largely stagnant, particularly for extensive-stage disease (ES-SCLC). However, the last five years have witnessed a significant evolution in the therapeutic landscape. Methods: The information for this article was gathered by synthesizing data from several key sources. This article synthesizes the evidence supporting current standards of care for both limited-stage (LS-SCLC) and ES-SCLC, incorporating data from pivotal clinical trials, a network meta-analysis of first-line chemoimmunotherapy regimens, and a critical appraisal of international treatment guidelines, and a critical analysis of international treatment guidelines from prominent organizations like the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). This comprehensive approach allows for a robust and well-supported summary of the current therapeutic landscape. Results: For limited-stage SCLC (LS-SCLC), concurrent chemoradiotherapy (cCRT) remains the curative-intent standard, but its efficacy is now being augmented by consolidative immunotherapy, as demonstrated by the landmark ADRIATIC trial. The role of prophylactic cranial irradiation (PCI) in LS-SCLC is being re-evaluated in the era of high-sensitivity brain imaging and concerns over neurotoxicity. For ES-SCLC, the treatment paradigm has been fundamentally transformed by the integration of immune checkpoint inhibitors (ICIs) with platinum–etoposide chemotherapy, establishing a new standard of care that offers a modest but consistent survival benefit. Conclusions: The treatment of SCLC has been significantly advanced by the integration of immunotherapy, particularly for extensive-stage disease, which has established a new standard of care and improved patient outcomes. Looking to the future, the quest for predictive biomarkers and the development of novel therapeutic classes, such as Bi-specific T-cell Engagers (BiTEs) and antibody–drug conjugates, promise to build upon recent progress and offer new hope for improving the dismal prognosis associated with this disease. Full article

Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis despite initial responsiveness to chemotherapy. Platinum-based chemotherapy with etoposide has long been the standard first-line treatment, but recent advances in immunotherapy have improved outcomes. Phase III trials, including IMpower133 and CASPIAN, demonstrated that adding immune checkpoint inhibitors, such as atezolizumab and durvalumab, to chemotherapy significantly enhances overall survival (OS) and progression-free survival (PFS). This case report describes a 76-year-old former smoker diagnosed with extensive-stage SCLC (ES-SCLC) following the detection of a left lower lung mass. The patient underwent combination therapy with carboplatin, etoposide, and atezolizumab, followed by maintenance atezolizumab. The patient demonstrated a sustained response to treatment, with significant tumor regression and no evidence of disease progression. Despite advanced age and comorbidities, treatment was well-tolerated, with no severe adverse events. Serial imaging over 24 months confirmed sustained disease stability, with regression of mediastinal lymphadenopathy and no new lesions. This case highlights the potential for prolonged disease control in select SCLC patients treated with chemo-immunotherapy. The absence of significant toxicities underscores the feasibility of immunotherapy even in elderly patients with comorbidities. These findings support the role of atezolizumab as a key component of ES-SCLC treatment and suggest the need for further research on predictors of durable response. Full article

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29–0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09–0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23–0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14–0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02–0.70; p = 0.02, and OR 0.08, 95% CI 0.01–0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC. Full article

Progression-free survival (PFS) and overall survival (OS) curves generally approximate first-order kinetics. On log-linear plots, convex curves with downward inflection (indicating late acceleration of progression/death) might arise from stopping effective therapies. We digitized published PFS/OS curves for etoposide/platinum-treated extensive small-cell lung cancer (SCLC) and other malignancies and replotted the curves log-linearly. Of 26 SCLC PFS curves, 21 (81%) were highly convex (with a marked late down-turn), and 26 (100%) were moderately or highly convex vs. 35/888 (4%) highly convex and 186 (21%) moderately/highly convex curves for other cancers (p < 0.0001). For SCLC, all 32 OS curves were moderately or highly convex vs. 87/363 (24%) that were moderately/highly convex for other cancers (p < 0.0001). The SCLC PFS curves had an initial downward inflection at a median of 3.1 months (around the completion of first-line chemotherapy), then a second inflection at 5.4 months, with further acceleration of progression. The median PFS half-life was 11.9 months while receiving treatment vs. 1.7 months after the second inflection point. Immunotherapy benefit appeared to be limited to 6–10% of the population. SCLC PFS/OS curves are more often convex than for other cancers, reflecting SCLC chemotherapy sensitivity but rapid progression following the completion of first-line chemotherapy. Effective maintenance strategies are needed. Full article

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum–etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes. Full article

Background: Neuroendocrine carcinomas (NECs) are treated with a frontline platinum–etoposide combination with no standard second-line therapies. We explored a novel combination of nanoliposomal irinotecan (Nal-IRI), 5-fluorouracil (5-FU), and leucovorin (LV) in advanced refractory NECs and investigated the impact of UGT1A1*28 polymorphism on treatment outcomes and toxicity. Methods: We conducted an open-label, single-arm, multi-center Phase 2 trial in advanced NEC patients of gastroenteropancreatic (GEP) or unknown origin with progression or intolerance to first-line therapy. Eligible patients received nal-IRI 70 mg/m² and leucovorin 400 mg/m², followed by 5-FU 2400 mg/m² biweekly till disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Next-generation sequencing (NGS) was performed on blood/tissue samples at baseline and during treatment. Results: Eleven patients were enrolled, with nine evaluable for the primary endpoint. Seven were male, the median age was 66.7 years, and the median Ki-67 was 90%. We observed partial response in one patient, stable disease in six patients, and progressive disease in two patients. The median OS was 9.4 months (95% CI 2.9–29.3), and the median PFS was 4.4 months (95% CI 1.7–6.7). The most common adverse events were diarrhea (45%), nausea (45%), vomiting (45%), and fatigue (45%). The most common genetic mutations on NGS were TP53 (88.9%), CHEK2 (88.9%), and APC (33.3%). Patients with CHEK2 and APC mutation had longer PFS (p = 0.005 and p = 0.013, respectively). UGT1A1*28 polymorphism was not associated with OS, PFS, or toxicity. Conclusion: Nal-IRI with 5-FU/LV is a safe and effective treatment for refractory high-grade NECs of GEP or unknown origin. Future studies should explore novel combinations with Nal-IRI in high-grade NECs both in frontline and refractory settings. Full article