Small cell lung cancer is an aggressive malignancy with limited treatment options and poor prognosis, particularly at extensive stage. While first-line platinum-etoposide chemotherapy combined with anti-PD-L1 therapy improves survival, most patients relapse, highlighting the need for novel therapies.

B7-Homolog3 (B7-H3), an immune checkpoint molecule overexpressed in SCLC, has emerged as a promising therapeutic target. Ifinatamab deruxtecan (I-DXd) is an antibody-drug conjugate targeting B7-H3, delivering a topoisomerase I inhibitor. Early clinical trials (IDeate-PanTumor01 and IDeate-Lung01) have demonstrated encouraging results in pretreated ES-SCLC. In the 12 mg/kg cohort of IDeate-Lung01, I-DXd achieved an objective response rate of 54.8%, median progression-free survival of 5.5 months, and median overall survival of 11.8 months. Notably, it showed intracranial activity with a central nervous system-confirmed response rate of 37.8%.

I-DXd is currently being evaluated in the phase III IDeate-Lung02 trial. Its promising efficacy, manageable safety profile, and potential in combination strategies position it as a key candidate for future SCLC treatment.

The aim of the present study was to evaluate the clinical curative effects and toxicity of existing delta-like ligand 3 (DLL3) inhibitors in advanced solid tumors with high DLL3 expression. A systematic search across major databases was performed, adhering to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, and included clinical trials that assessed the efficacy and safety of DLL3 inhibitors in treating solid tumors. To be included, studies had to be randomized controlled trials (RCTs), quasi-RCTs, non-randomized comparative studies, single-arm trials and trials in which DLL3 inhibitors were used in both arms. The results of 21 trials, involving a total of 2,452 patients, which evaluated the efficacy of DLL3 inhibitors in treating solid tumors, were analyzed. The median overall survival was 6.54 months and the median progression-free survival (PFS) was 3.54 months. Combination immunotherapy demonstrated a longer PFS of 4.2 months compared with monotherapy, which had a PFS of 3.36 months. The disease control rate and objective response rate were 57 and 21%, respectively, with notable heterogeneity observed across studies. Adverse events were common, affecting 93% of patients, and included cytokine release syndrome (49%), thrombocytopenia (23%) and peripheral edema (28%), with variations depending on the specific inhibitor used. To conclude, DLL3 inhibitors hold promise for patients with elevated DLL3 expression in solid tumors; however, their efficacy and safety exhibit considerable variability, necessitating large-scale, phase III clinical trials to validate and refine therapeutic approaches. The present study was registered with PROSPERO (registration no. CRD42024561815).

Extensive-stage small cell lung cancer (SCLC) has a dismal prognosis. Despite initial responsiveness to first-line platinum-etoposide chemotherapy, most patients relapse within six months. Managing disease progression, particularly in platinum-resistant or refractory cases, remains challenging. Topotecan is the only drug approved in the European Union for the second-line treatment of SCLC but is associated with modest clinical activity and high rates of hematological toxicities. Temozolomide, an oral alkylating agent, has been investigated as a viable alternative for treating relapsed SCLC. This study presents the largest real-world cohort of SCLC-patients treated with temozolomide.

We performed a retrospective analysis of patients with relapsed SCLC treated with temozolomide at a single academic hospital in Belgium. Temozolomide was administered at a fixed dose of 250 mg orally once daily on days 1-5 of each 28-day cycle. Data on activity (overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS)) and safety (treatment related adverse events (TRAE)) were collected.

Between February 2011 and May 2023, a total of 48 patients with relapsed SCLC were treated with temozolomide of which 47 patients, median age 61 years, were included in this real-world analysis. The majority of the patients were heavily pretreated with 57.4 % having received two or more prior systemic therapies. An objective response was observed in 14.9 % and the DCR was 23.4 %. The median PFS was 1.7 months (95 % CI 1.5-1.9) and the median OS was 3.2 months (95 % CI 2.3-4.1). Grade 3-4 TRAEs occurred in 34 % of the patients.

Temozolomide demonstrated modest clinical activity in this real-world effectiveness analysis of patients with relapsed SCLC. Nevertheless, given its comparable response rate and milder toxicity profile compared to topotecan, temozolomide should be considered as a viable alternative to topotecan for treating relapsed SCLC.

The therapeutic landscape for small cell lung cancer (SCLC) has remained stationary for decades, with chemotherapy representing the sole treatment strategy, with a modest survival benefit. The addition of immune checkpoint inhibitors (ICIs) to standard first-line chemotherapy for SCLC was a considerable milestone. However, despite high overall response rates, this strategy failed to deliver long-term benefits for most patients, who continue to face a poor prognosis. Over the last few years, a deeper knowledge of the molecular biology of SCLC and the impressive advancements in drug development, have led to the generation of novel classes of systemic therapies that promise to revolutionize the current therapeutic scenario. Among the various therapeutic approaches in development, T-cell Engagers (TCE) and antibody-drug conjugates (ADCs) stand out due to their unique structural characteristics and mechanisms of action. These therapies represent a paradigm shift from traditional monoclonal antibody (mAb) and chemotherapy regimens, allowing direct engagement of multiple targets associated with tumor progression. In this review, we provide an overview of current drug development in SCLC, specifically focusing on these new agents, summarizing available evidence, and tracking future directions.

Tarlatamab demonstrated a durable response and promising survival outcomes in patients with previously treated small cell lung cancer (SCLC) in the phase 2, open-label DeLLphi-301 trial. Patient-reported outcomes (PROs) were evaluated to assess the benefit-risk profile of tarlatamab.

Patients received tarlatamab intravenously every 2 weeks at a dose of 10 mg (regulatory approved dose) or 100-mg until progression or loss of benefit. PROs, including European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire (EORTC-QLQ-C30) and 13-item lung cancer module (LC13), Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the GP5 question of the Functional Assessment of Cancer Therapy - General Form (FACT-GP5), were collected at Cycle 1 (days 1, 8, 22), Cycle 2 (days 1, 15) and every 6 weeks from Cycle 3 onwards. PROs were summarized descriptively alongside the amount and reason for missing data and analyzed using a mixed model for repeated measures. In addition, median time to deterioration (TTD) for symptom and functional scales was analyzed.

A total of 100 patients were PRO-evaluable at the selected target dose (10 mg). EORTC-QLQ-C30 and LC13 completion rates (proportion of PRO assessments expected to be completed) were high (> 80%) throughout the study. Least square mean changes from baseline showed a trend towards improvement for the QLQ-C30 subscale of global health status and stabilization for physical functioning. Patients experienced reduced symptom burden for dyspnea which was more pronounced for patients at later cycles (≥ 10 points), and stabilization for chest pain and cough. Median TTD exceeded 6 months for cough and dyspnea and was not estimable for chest pain. Overall, tarlatamab was well tolerated with the majority of patients reporting no bother or a little bit of bother from side effects post baseline. Patient-reported adverse events were generally of mild to moderate severity occurring rarely or occasionally.

Alongside previously reported antitumor activity, tarlatamab demonstrated a positive benefit-risk profile in previously treated SCLC with favorable PROs across a range of functional outcomes and symptoms, while showing manageable and sustained tolerability.

NCT05060016.

Tarlatamab, a bispecific T-cell engager, has shown promising results in previously treated small cell lung cancer (SCLC) patients in the DeLLphi-300 and DeLLphi-301 trials. However, reports on outcomes in more diverse, real-world patient populations are limited.

We retrospectively evaluated safety and efficacy outcomes of all patients who were treated with tarlatamab at the University of Virginia between May and October 2024.

Our analysis included 21 patients with SCLC and 1 patient with DLL-3 positive atypical carcinoid. The median age of patients was 66 years (range, 41-80 years), with 59.1% being females. Most patients (85.7%) had extensive stage SCLC at diagnosis. Brain metastases were present in 9 (40.9%) patients and liver metastasis in 14 (63.8%) patients. A total of 18 (81.8%) patients would not have met the DeLLphi-301 inclusion and exclusion criteria. Cytokine release syndrome (CRS) occurred in 16 (72.7%) patients; the median time of onset was 15.8 hours (9.1-18.8) after tarlatamab infusion. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9 (40.9%) patients, with higher rates and grades observed in patients with untreated brain metastases. The median time of onset was 14.8 h ([IQR] 7.7-22.1) after tarlatamab infusion. After a median follow-up of 6.7 months, the overall response rate (ORR) was 42.9% in SCLC patients.

Tarlatamab is a promising treatment option for heavily pretreated small cell lung cancer patients. We observed higher rates of CRS and ICANS during the first treatment cycle suggesting that real-world safety outcomes may differ from clinical trial data.

Small cell lung cancer (SCLC) is a highly aggressive disease, often diagnosed at an advanced stage and with limited treatment options. In recent years, immunotherapy has been approved in combination with chemotherapy in the first line setting of extensive stage disease (ES-SCLC). However, only 10-15 % of patients with ES-SCLC treated with chemoimmunotherapy (CT-IO) experience a long-term benefit. In addition, patients are often clinically frail due to advanced age, comorbidities, and disease-related symptoms, making SCLC a challenging condition. Real-world evidence (RWE) becomes particularly valuable in this scenario, not only to confirm the results of pivotal trials, but also to evaluate the outcomes of CT-IO in populations that are generally excluded from clinical trials. RWE could also define the role of integrative treatments such as thoracic consolidation radiotherapy and prophylactic cranial irradiation, which are used in selected patients in the clinical practice but were scarcely applied in pivotal trials. In this review, we focused on RWE in ES-SCLC, with the aim of improving clinical decision making. Notably, real-world data have largely confirmed the efficacy and safety of CT-IO observed in pivotal clinical trials, with a possible benefit even in more fragile patients. However, these studies also highlight that a significant proportion of the ES-SCLC population remains untreated due to poor clinical conditions.

Background: Small cell lung cancer (SCLC) is an aggressive cancer with rapid progression, limited treatment success, and high relapse rates. Chemotherapy and radiation are standard treatments but often result in chemoresistance. PD-L1 inhibitors have gained attention for their role in enhancing tumor immunity. Methods: This review summarizes clinical trials involving PD-L1 inhibitors, such as atezolizumab, durvalumab, pembrolizumab, and nivolumab, in SCLC treatment. Key trials include IMpower133, CASPIAN, KEYNOTE-604, and CheckMate 331, focusing on survival outcomes and treatment efficacy. Results: Studies such as IMpower133 and CASPIAN demonstrate improved overall survival when PD-L1 inhibitors were added to platinum-based chemotherapy. However, outcomes in trials such as KEYNOTE-604 and CheckMate 331 varied, showing the need for refined patient selection. Adverse events (AEs) associated with these treatments were also noted. PD-L1 inhibitors offer promise in SCLC treatment, but efficacy varies across trials and patient groups. Future research should focus on better patient selection and overcoming resistance mechanisms. Addressing immune-related AEs is essential for optimizing treatment strategies.

Multidrug resistance (MDR) poses one of the primary challenges for cancer treatment, especially in cases of metastatic disease. Various mechanisms contribute to MDR, including the overexpression of ATP-binding cassette (ABC) proteins. In this context, we reviewed the literature to establish a correlation between the overexpression of ABC proteins and MDR in cancer, considering both in vitro and clinical studies. Initially, we presented an overview of the seven subfamilies of ABC proteins, along with the subcellular localization of each protein. Subsequently, we identified a panel of 20 ABC proteins (ABCA1-3, ABCA7, ABCB1-2, ABCB4-6, ABCC1-5, ABCC10-11, ABCE1, ABCF2, ABCG1, and ABCG2) associated with MDR. We also emphasize the significance of drug sequestration by certain ABC proteins into intracellular compartments. Among the anticancer drugs linked to MDR, 29 were definitively identified as substrates for at least one of the three most crucial ABC transporters: ABCB1, ABCC1, and ABCG2. We further discussed that the most commonly used drugs in standard regimens for mainly breast cancer, lung cancer, and acute lymphoblastic leukemia could be subject to MDR mediated by ABC transporters. Collectively, these insights will aid in conducting new studies aimed at a deeper understanding of the clinical MDR mediated by ABC proteins and in designing more effective pharmacological treatments to enhance the objective response rate in cancer patients.

Objective: To investigate the preclinical efficacy and identify predictive biomarkers of polo-like kinase 1 (PLK1) inhibitors in small cell lung cancer (SCLC) models. Methods: We tested the cytotoxicity of selective PLK1 inhibitors (rigosertib, volasertib, and onvansertib) in a panel of SCLC cell lines. We confirmed the therapeutic efficacy of subcutaneous xenografts of representative cell lines and in four patient-derived xenograft models generated from patients with platinum-sensitive and platinum-resistant SCLC. We employed an integrated analysis of genomic and transcriptomic sequencing data to identify potential biomarkers of the activity and mechanisms of resistance in laboratory-derived resistance models. Results: Volasertib, rigosertib, and onvansertib showed strong in vitro cytotoxicity at nanomolar concentrations in human SCLC cell lines. Rigosertib, volasertib, and onvansertib showed equivalent efficacy to that of standard care agents (irinotecan and cisplatin) in vivo with significant growth inhibition superior to cisplatin in PDX models of platinum-sensitive and platinum-resistant SCLC. There was an association between YAP1 expression and disruptive or inactivation TP53 gene mutations, with greater efficacy of PLK1 inhibitors. Comparison of lab-derived onvansertib-resistant H526 cells to parental cells revealed differential gene expression with upregulation of NAP1L3, CYP7B1, AKAP7, and FOXG1 and downregulation of RPS4Y1, KDM5D, USP9Y, and EIF1AY highlighting the potential mechanisms of resistance in the clinical setting. Conclusions: We established the efficacy of PLK1 inhibitors in vitro and in vivo using PDX models of platinum-sensitive and resistant relapsed SCLC. An ongoing phase II trial is currently testing the efficacy of onvansertib in patients with SCLC (NCT05450965).

The phase 2 TROPiCS-03 study evaluated the efficacy/safety of sacituzumab govitecan (SG) as second-line treatment in patients with previously treated extensive-stage SCLC (ES-SCLC).

TROPiCS-03 (NCT03964727) is a multicohort, open-label, phase 2 basket study of solid tumors, including ES-SCLC. Adults with ES-SCLC that progressed after one previous line of platinum-based chemotherapy and anti-programmed death-(ligand) 1 (PD-[L]1) therapy received SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary end point was the investigator-assessed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Key secondary end points included investigator-assessed duration of response (DOR) and progression-free survival (PFS); blinded independent central review-assessed ORR, DOR, and PFS; overall survival (OS); and safety. Efficacy was evaluated in patients with platinum-resistant and platinum-sensitive disease.

Among 43 patients (median follow-up, 12.3 [range, 8.1-20.1] mo), investigator-assessed ORR was 41.9% (95% confidence interval [CI]: 27.0%-57.9%), with 18 confirmed partial responses; median (95% CI) DOR, PFS, and OS were 4.73 (3.52-6.70), 4.40 (3.81-6.11), and 13.60 (6.57-14.78) months, respectively. The efficacy results of the blinded independent central review assessments were similar. The investigator-assessed ORR (95% CI) was 35.0% (15.4%-59.2%) in patients with platinum-resistant disease (n = 20) and 47.8% (26.8%-69.4%) in patients with platinum-sensitive disease (n = 23). Furthermore, 32 patients (74.4%) had grade greater than or equal to 3 treatment-emergent adverse events (TEAEs). No TEAE led to SG discontinuation; one treatment-related TEAE (neutropenic sepsis) led to death.

SG has promising efficacy as second-line treatment of ES-SCLC, irrespective of platinum sensitivity. Safety was manageable and consistent with that observed in other SG studies.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with the poorest prognosis among all types of lung cancer. Developing an effective comprehensive strategy remains a key focus. We herein present the first documented case of a 68-year-old man with limited-stage SCLC who has maintained a complete response (CR) for over 30 months to date. CR was achieved with first-line chemotherapy using etoposide and carboplatin combined with chest volumetric-modulated arc therapy. Maintenance therapy with anlotinib extended the progression-free survival to 20 months after first-line therapy. When resistance developed, second-line therapy with albumin-bound paclitaxel, carboplatin, and the immune checkpoint inhibitor durvalumab sustained CR for 7 months. Third-line therapy with etoposide and cisplatin combined with durvalumab has maintained CR to date.

This study aimed to systematically analyze the efficacy and toxicity of lurbinectedin as a second-line or subsequent treatment for extensive-stage small cell lung cancer (ES-SCLC).

Candidate studies were identified in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases up to 1 May 2024. Objective remission rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted, respectively. The efficacy and toxicity of lurbinectedin in ES-SCLC were analyzed by meta-analysis.

Six eligible prospective studies were included in this meta-analysis, including 536 patients with ES-SCLC who received second-line or subsequent treatment. In pooled analysis, the ORR of lurbinectedin was 35% (95% confidence interval [CI] 29-41), DCR was 67% (95%CI 58-76), DOR was 5.33 months (95%CI 4.51-6.16), PFS was 3.38 months (95%CI 2.59-4.17), and OS was 7.49 months (95%CI 5.11-9.87). The incidence of AEs and severe adverse events (SAEs) was 92% (95%CI 78-100) and 37% (95%CI 19-57), respectively. The most common AEs were leukopenia, neutropenia, anemia, and thrombocytopenia, with incidences of 81% (68-91), 74% (57-88), 73% (35-98) and 57% (46-68), respectively.

As a promising alternative for second-line treatment for ES-SCLC, lurbinectedin has a certain level of efficacy and a favorable safety profile. The integration of lurbinectedin with other therapeutic modalities presents an emerging area warranting further investigation.

Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Delta-like ligand 3 (DLL3) is overexpressed in small cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with rovalpituzumab tesirine. In this study, we developed a novel DLL3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody, FZ-A038, and a valine-alanine (Val-Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line-derived xenograft and patient-derived xenograft models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable, and the highest nonseverely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of patients with SCLC.

Despite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients.

The study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment.

One hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction.

Irinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

Synthetic data may proxy clinical data. At the absence of direct clinical data, this study aimed to compare Irinotecan and Ifosfamide (II) with Topotecan in synthetic, recurrent small cell lung cancer (SCLC) patients within a simulated clinical trial.

Two simulation stages were conducted. Initially, 200 recurrent SCLC cases were simulated to replicate a previous phase 3 trial, testing the utility of Cox proportional hazards model and simulation methodology together, where patients were randomized to receive Cyclophosphamide, Adriamycin, Vincristine (CAV) or Topotecan. In the second stage, 600 recurrent SCLC patients were simulated and randomized to compare Topotecan versus II in terms of overall survival (OAS), using Reinforcement Learning (RL) and Cox proportional hazards model.

CAV versus Topotecan comparison showed no statistical difference in overall survival (hazard ratio (HR): 0.89, 95% CI: 0.67-1.18, P = 0.418), aligning with the original clinical trial. For the Topotecan versus II comparison, the RL framework significantly favored the II arm (mean reward points: 193.43 versus - 251.82, permutation P < 0.0001). Likewise, II arm exhibited superior median OAS compared to Topotecan arm (11.12 versus 6.30 months). HR was 0.44 (95% CI: 0.38-0.52) with P < 0.0001, in favor of II.

Artificial trial results for CAV versus Topotecan matched the original trial, confirming indifference of OAS. Additionally, II yielded superior overall survival compared to Topotecan in recurrent SCLC patients. These demonstrate the potential of RL and simulation in conjunction with Cox modelling for similar studies. However, definitive conclusions necessitate a randomized clinical trial between II and Topotecan in this patient cohort.

Second-line treatment for small-cell lung cancer (SCLC) is primarily guided by the time elapsed since the last platinum dose. Rechallenge with carboplatin and etoposide has demonstrated superior outcomes compared to topotecan if the platinum-free interval (PFI) is longer than 90 days and is considered the standard of care. However, these findings predate the chemo-immunotherapy era. This study investigates the effectiveness of the rechallenge strategy after chemo-immunotherapy in a real-world setting.

We retrospectively reviewed patients with the extensive stage (ES)-SCLC who received rechallenge with carboplatin and etoposide after first-line chemoimmunotherapy between September 2020 and August 2023 in nine European centres. Demographic and clinical data were collected and analysed.

A total of 93 patients were included. Sixty-six (71%) patients had a PFI between 3 and 6 months. Consolidation thoracic radiotherapy and prophylactic cranial irradiation had been administered in 31 (33.3%) patients and 20 (21.5%) patients, respectively. Overall response rate was 59.1%. Median progression-free survival (PFS) was 5 months (95% confidence interval (CI) 4.3-5.7) and median overall survival (OS) was 7 months (95% CI 5.7-8.3). Notably, PFS and OS were not different according to PFI (3-6 m vs > 6 m).

Rechallenge with carboplatin and etoposide is a valid second-line option in patients with ES-SCLC whose disease progresses after first-line chemoimmunotherapy. Our analysis shows similar results to previous studies. Furthermore, outcomes were consistent across patients with different PFIs, confirming its efficacy in patients with a PFI longer than 3 months.

This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC).

This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60 mg/m2, 80 mg/m2, and 100 mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety.

From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval <90 days. In all 66 patients, the ORR was 32% (21/66, 95% confidence interval [CI], 21-44), with a median DoR of 5.2 months (95% CI, 3.0-8.3). Median PFS and OS were 4.0 (95% CI, 2.9-5.5) and 9.7 (95% CI, 7.2-12.3) months, respectively. The ORR of 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose group were 33% (2/6), 33% (10/30), and 30% (9/30), respectively. The median DoR of 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose group were 4.2 (95% CI, 2.8-not reached), 6.9 (95% CI, 2.5-9.9), and 4.0 (95% CI, 2.7-6.8) months, respectively. The incidence of ≥ grade 3 treatment-related adverse events (TRAEs) in the 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose group were 33% (2/6), 47% (14/30), and 50% (15/30), respectively. The most common ≥ grade 3 TRAEs of all 66 patients were neutropenia (27%), leukopenia (24%) and anemia (15%).

LY01610 exhibited promising clinical efficacy and manageable safety profiles in patients with relapsed SCLC, the 80 mg/m2 dose group had the best benefit-risk ratio.

This study was supported by Luye Pharma Group Ltd.

Small-cell lung cancer (SCLC), accounting for 10-20 % of all lung tumors, represents the most aggressive high-grade neuroendocrine carcinoma. Most patients are diagnosed with extensive-stage SCLC (ES-SCLC), with brian metastases identified in ∼ 80 % of cases during the disease cours, and the prognosis is dismal, with a 5-year survival rate of less than 5 %. Current available treatments in the second-line setting are limited, and topotecan has long been the only FDA-approved drug in relapsed or refractory ES-SCLC, until the recent approval of lurbinectedin, a selective inhibitor of RNA polymerase II. Temozolomide (TMZ) is an oral alkylating agent, which showed single-agent activity in SCLC, particularly among patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Several studies have revealed the synergistic activity of temozolomide with poly-ADP-ribose polymerase (PARP) inhibitors, that prevent repair of TMZ-induced DNA damage. This review focuses on the rationale for the use of TMZ in ES-SCLC and provides an overview of the main trials that have evaluated and are currently investigating its role, both as a single-agent and in combinations, in relapse or refractory disease.

Chemotherapy combined with immunotherapy (CT-IO) is the standard treatment for patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC). This study evaluates the effectiveness of second-line (2L) following CT-IO.

All patients from 10 centers who received a 2L after a first-line CT-IO were included. They were divided into 3 groups: platinum-based, lurbinectedin or others (topotecan, CAV, taxanes). We assessed overall survival (OS) and 2L progression-free survival (2L-PFS) according to treatment and platinum free-interval (PFI) < or ≥ 90 days.

Among 82 patients included, median age was 67.0 years, 29.3 % had a Performans Status ≥ 2, 36.6 % had brain progression, 69.5 % were considered "platine-sensitive" and 30.5 % "platine-resistant" (PFI ≥ or < 90 days, respectively). As 2L, 37/82 patients (45.1 %) received platinum-doublet, 21/82 (25.6 %) lurbinectedin and 24/82 (29.3 %) others. Patients with a PFI ≥ 90 days received mainly platinum-based rechallenge (34/57, 59.6 %). With a median follow-up of 18.5 months, the median OS was 5.0 months (95 %CI, 1.5-7.9) / 6.8 months (95 %CI, 5.5-8.7) for platinum-resistant / sensitive, respectively (log rank p = 0.017). The median 2L-PFS was 1.9 months (95 %CI, 1.2-4.7) / 3.9 months (95 %CI, 2.9-6.0) for platinum-resistant / sensitive, respectively. Median OS was 8.1 (95 %CI, 6.3-12.9) / 4.9 (95 %CI, 3.7-6.8) / 5.1 months (95 %CI, 2.5-7.8) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.017). Median 2L-PFS was 4.6 (95 %CI, 3.9-7.2) / 2.7 (95 %CI, 1.6-3.9) / 2.2 months (95 %CI, 1.5-4.1) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.025).

Platinum-based rechallenge after a first-line CT-IO showed promising results despite particularly unfavorable characteristics within our real-word population. Lurbinectedin when used after IO demonstrated as low efficacy as other platinum-free regimens.

Patients with small cell lung cancer (SCLC) often respond to first-line chemoimmunotherapy. However, relapse is inevitable and is associated with a poor prognosis. Treatments for relapsed SCLC, such as lurbinectedin and topotecan, are limited by modest efficacy and significant hematologic adverse events, leaving a need for newer therapeutic agents or regimens. The combination of gemcitabine and nab-paclitaxel is active and safe in other types of malignancies, such as pancreatic cancer.

We conducted a phase II trial evaluating the efficacy and safety of gemcitabine and nab-paclitaxel in patients with relapsed/refractory SCLC. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with confirmed complete or partial response. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety.

Between October 2016 and May 2021, 32 patients were enrolled. Patients were followed for a median of 9.3 months (range 1.8-65.2). Median age was 65 years (range 48-81). Fifty percent of patients were female. Fifty-three percent of patients had platinum-resistant/refractory relapsed SCLC. The ORR was 28.1% (95% confidence interval [CI] 15.5-100%). Median PFS was 2.9 months (95% CI 2.4-3.6), and median OS was 9.3 months (95% CI 5.2-12.4). Seven patients (21.9%) developed grade 3 or 4 neutropenia.

Our study showed that the combination of gemcitabine and nab-paclitaxel led to encouraging outcomes in relapsed/refractory SCLC. Further studies are needed to compare this combination with other treatments used for relapsed SCLC, including lurbinectedin, temozolomide, and topotecan.

https://clinicaltrials.gov/study/NCT02769832?cond=NCT02769832&rank=1, identifier NCT02769832.

Small-cell lung cancer (SCLC) is a highly aggressive tumor, and overall survival (OS) remains poor despite intensive efforts to develop new treatment strategies. In second line, topotecan is the only approved drug, with a median OS of 5.9 months. However, real-world SCLC patients are often in worse condition and harbor more comorbidities than study populations. Therefore, the real-world performance of topotecan may differ from that seen in studies. Here, we analyzed outcomes of SCLC patients receiving topotecan and identified predictive and prognostic markers.

We retrospectively analyzed 44 consecutive SCLC patients receiving topotecan between 2015 and 2022. We analyzed baseline characteristics (age, ECOG-PS, topotecan cycles, and dosage) and pre-treatment blood values (LDH, CRP, sodium) as well as prognostic scores (neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), Glasgow Prognostic Score, prognostic nutritional score, systemic inflammation index (SII), and the prognostic index) extracted from electronic patients' charts to identify predictive and prognostic markers.

In our cohort, mPFS and mOS were only 1.9 and 5.6 months, respectively. Gender, ECOG-PS, active brain metastases, NLR, GPS, PNI, and SII significantly influenced PFS and OS in univariate analysis. ECOG-PS (p > 0.001), active brain metastases (p = 0.001), and SII (p = 0.008) were significant independent prognostic variables in a multivariate COX regression model. Selecting patients by these three markers achieved an mPFS of 5.7 months and thus increased the mPFS three-fold. Patients not meeting all criteria had an mPFS of 1.8 months (p = 0.006). Patients identified by prognostic markers had an mOS of 9.1 months (p = 0.002).

The efficacy of topotecan in SCLC real-world patients is poor, indicating that many patients were treated without any benefit. Easy-to-obtain markers can predict response and treatment efficacy and should therefore be validated in larger cohorts to identify patients who are more likely to benefit from topotecan.

This retrospective study evaluates the efficacy of camrelizumab combined with anlotinib versus chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) undergoing second-line treatment.

Data were sourced from medical records at a Chinese medical facility, involving 34 patients diagnosed with ES-SCLC after failing first-line treatment. Patients were divided into two groups: one received camrelizumab (200 mg every 3 weeks) with anlotinib (12 mg daily for 14 days followed by a 7-day rest), while the other group received physician-chosen chemotherapy administered every 3 weeks. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and disease control rate (DCR).

The combination therapy group showed a significant improvement in PFS compared to the chemotherapy group (median PFS: 7 months vs. 3 months; hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.15-0.77; p<0.001). However, there was no statistically significant difference in OS between the groups (16.3 months vs. 17.3 months; p=0.82). The ORR was 52.9% in the combination therapy group versus 23.5% in the chemotherapy group (p=0.08), and the DCR was 82.4% compared to 58.8% (p=0.26). Grade 3 or higher adverse events were observed in 17.6% of the combination therapy group and 29.4% of the chemotherapy group.

The findings suggest that the combination of camrelizumab and anlotinib offers a superior anti-tumor response with a manageable safety profile in a second-line setting for ES-SCLC patients. This combination regimen may be a viable option for second-line ES-SCLC treatment.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.

Small-cell lung cancer (SCLC) is a biologically aggressive subtype of lung cancer, a lethal disease characterized by rapid tumor growth, early relapse, a strong tendency for early widespread metastasis, and high genomic instability, making it a formidable foe in modern oncology practice. While the management of non-SCLC has been revolutionized in the era of immunotherapy, progress in SCLC has been more muted. Recent randomized phase III clinical trials have combined programmed death ligand-1 inhibitors to a chemotherapy backbone and demonstrated improved survival; however, the absolute benefit observed is short months. There is an undeniable urgent need for better responses, better agents, novel therapeutic approaches, and more rational, biomarker-driven clinical trials in SCLC. In this review, we discuss the rationale and current understanding of the biology of SCLC in the modern era of immunotherapy, discuss recent advances in front-line immunotherapeutic approaches that have changed clinical practice globally, provide an overview of some of the challenges and limitations that have staggered immune checkpoint blockade in SCLC, and explore some of the novel immunotherapeutic approaches currently being investigated.

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.

SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.

Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting.

The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 12 mg on days 1-14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792).

Forty-two patients were enrolled between August 29, 2019 and December 26, 2021 at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9-28.2). The median PFS was 6.1 months (95% CI: 5.0-7.3). The OS was 12.7 months (95% CI: 7.1-18.2). The ORR was 56.8% (21/37, 95% CI: 40.0-73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7-99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%).

Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC.

Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Small cell lung cancer (SCLC) is characterized by high initial responses to platinum-based chemotherapy plus immune checkpoint inhibitors; however, most patients quickly relapse and require subsequent treatment. Second-line treatment options in SCLC remain limited, and treatment algorithms are not completely consistent across the available guidelines in this setting. This review highlights key considerations regarding selection of second-line treatment for patients with relapsed SCLC. In particular, the role of lurbinectedin, which was first approved in 2020, representing the first significant addition to treatment algorithms in this setting for decades, is summarized. Future directions, including the identification of SCLC subtypes and the need for predictive biomarkers to guide patient selection and targeted therapy, are also discussed.

Current treatment guidelines refer to small cell lung cancer (SCLC), one of the deadliest human malignancies, as a homogeneous disease. Accordingly, SCLC therapy comprises chemoradiation with or without immunotherapy. Meanwhile, recent studies have made significant advances in subclassifying SCLC based on the elevated expression of the transcription factors ASCL1, NEUROD1, and POU2F3, as well as on certain inflammatory characteristics. The role of the transcription regulator YAP1 in defining a unique SCLC subset remains to be established. Although preclinical analyses have described numerous subtype-specific characteristics and vulnerabilities, the so far non-existing clinical subtype distinction may be a contributor to negative clinical trial outcomes. This comprehensive review aims to provide a framework for the development of novel personalized therapeutic approaches by compiling the most recent discoveries achieved by preclinical SCLC research. We highlight the challenges faced due to limited access to patient material as well as the advances accomplished by implementing state-of-the-art models and methodologies.

Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain.

We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation.

There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93).

We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.

This report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645-654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland.

Patients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients).

Lurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan.

With the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan.