Updated cost-effectiveness analysis of adebrelimab plus chemotherapy for extensive-stage small cell lung cancer in China.

OBJECTIVE: The CAPSTONE-1 trial demonstrated that adebrelimab-based immunotherapy yielded a favourable survival benefit compared with chemotherapy for patients with extensive-stage small cell lung cancer (ES-SCLC). This study aims to evaluate the cost-effectiveness of this immunotherapy in the treatment of ES-SCLC from a healthcare system perspective in China. DESIGN: The TreeAge Pro software was used to establish a three-state partitioned survival model. Survival data came from the CAPSTONE-1 trial (NCT03711305), and only direct medical costs were included. Utility values were obtained from the published literature. Sensitivity analysis was performed to explore the robustness of the model. The cost-effectiveness of immunotherapy was investigated through scenario and exploratory analyses in various settings. OUTCOME MEASURES: Total costs, incremental costs, life years, quality-adjusted life-years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER). RESULTS: The basic analysis revealed that the adebrelimab group achieved a total of 1.1 QALYs at a cost of US$65 385, while the placebo group attained 0.78 QALYs at a cost of US$12 741. ICER was US$163 893/QALY. Sensitivity analysis confirmed that the model was robust. Results from scenario and exploratory analyses indicated that the combination of adebrelimab and chemotherapy did not demonstrate cost-effectiveness in any scenario. CONCLUSIONS: From the perspective of the Chinese healthcare system, adebrelimab in combination with chemotherapy for the treatment of ES-SCLC was not economical compared with chemotherapy.

Cost-effectiveness analysis of durvalumab, tremelimumab, and etoposide-platinum in first-line treatment of extensive-stage small cell lung cancer.

BACKGROUND: Durvalumab plus etoposide-platinum (DEP) showed sustained overall survival improvements in patients with extensive-stage small-cell lung cancer (ES-SCLC) compared to etoposide-platinum (EP), but adding tremelimumab to DEP (DTEP) did not significantly improve outcomes. A third-party payer perspective is taken here to evaluate the cost-effectiveness of DTEP, DEP, and EP for ES-SCLC. METHODS: The cost-effectiveness was evaluated by partitioning survival models into 3 mutually exclusive health states. In this model, clinical characteristics and outcomes were obtained from the CASPIAN. Model robustness was evaluated through 1-way deterministic and probabilistic sensitivity analyses. Outcome measurements included costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio, life-years, incremental net health benefit, and incremental net monetary benefit. The analysis was conducted with a 10-year lifetime horizon in a United States setting. RESULTS: Compared with EP, DEP, and DTEP were associated with an increment of 0.480 and 0.313 life-years, and an increment of 0.247 and 0.165 QALYs, as well as a $139,788 and $170,331 increase in cost per patient. The corresponding ICERs were $565,807/QALY and $1033,456/QALY, respectively. The incremental net health benefit and incremental net monetary benefit of DEP or DTEP were -0.685 QALYs and -$102,729, or -0.971 QALYs and -$145,608 at a willingness to pay threshold of $150,000/QALY, respectively. Compared with DTEP, DEP was dominated. DTEP and DEP were 100% unlikely to be cost-effective if the willingness to pay threshold was $150,000/QALY. DEP was cost-effective compared to EP when durvalumab was priced below $0.994/mg. Compared with EP, DEP, and DTEP were unlikely to be considered cost-effective across all subgroups. CONCLUSION: DEP and DTEP were not cost-effective options in the first-line treatment for ES-SCLC compared with EP, from the third-party payer perspective in the United States. Compared with DTEP, DEP was dominated.

Pamiparib as consolidation treatment after concurrent chemoradiotherapy of limited-stage small cell lung cancer: a single-arm, open-label phase 2 trial.

BACKGROUND: Small cell lung cancer (SCLC) is highly invasive with poor prognosis, and its treatment has historically been hindered due to the absence of targetable driver genomic alterations. However, the high genomic instability and replication stress in SCLC have made poly(ADP-ribose) polymerases (PARPs) inhibitors a focus of research. Pamiparib is an orally available PARP1/2 inhibitor with high selectivity, strong PARP trapping activity, and excellent brain penetration. Utilizing pamiparib as consolidation maintenance therapy in limited-stage SCLC holds promise for improving survival outcomes and offering a viable therapeutic approach. METHODS: This single-arm, open-label phase II trial will enroll patients aged 18-75 years with histologically/cytologically confirmed, limited-stage SCLC who have not progressed following definitive platinum-based cCRT and have an ECOG PS of 0 or 1. Patients will be excluded if they have histologically confirmed mixed SCLC or NSCLC, or have undergone previous tumor resection, or can be treated with surgery or stereotactic body radiation therapy/stereotactic ablative radiation therapy. Participants will receive pamiparib 40 mg twice daily every 3 weeks within 2 to 6 weeks after cCRT for up to 1 year or until disease progression according to RECIST v1.1. The primary endpoint is the 1-year progression-free survival (PFS) rate assessed by investigators per RECIST v1.1. Secondary endpoints include PFS, objective response rate, and duration of response assessed by investigators per RECIST 1.1, overall survival, time to distant metastasis, and safety. DISCUSSION: The study will provide valuable data on the feasibility, safety, and effectiveness of pamiparib as a consolidation therapy after cCRT in patients with LS-SCLC. The correlation between molecular typing or gene expression profile of the disease and curative response will be further explored. TRIAL REGISTRATION: NCT05483543 at clinicaltrials.gov.

PD-L1 inhibitors combined with whole brain radiotherapy in patients with small cell lung cancer brain metastases: Real-world evidence.

BACKGROUND: Numerous studies have demonstrated that brain metastases patients may benefit from intracranial radiotherapy combined with immune checkpoint inhibitors (ICIs). However, it is unclear whether this treatment is effective for patients with small cell lung cancer brain metastases (SCLC-BMs). METHODS: We conducted a retrospective study by analyzing medical records of patients with SCLC-BMs from January 1, 2017 to June 1, 2022. Data related to median overall survival (mOS), median progression-free survival (mPFS), and intracranial progression-free survival (iPFS) were analyzed. RESULTS: A total of 109 patients were enrolled, of which 60 received WBRT and 49 received WBRT-ICI. Compared to the WBRT alone cohort, the WBRT-ICI cohort showed longer mOS (20.4 months vs. 29.3 months, p = 0.021), mPFS (7.9 months vs. 15.1 months, p < 0.001), and iPFS (8.3 months vs. 16.5 months, p < 0.001). Furthermore, WBRT-ICI cohort had a better response rate for both BMs. (p = 0.035) and extracranial diseases (p < 0.001) compared to those receiving WBRT alone. Notably, the use of WBRT before ICI was associated with longer mOS compared to the use of WBRT after ICI (23.3 months for the ICI-WBRT group vs. 34.8 months for the WBRT-ICI group, p = 0.020). CONCLUSION: Our results indicated that WBRT combined with immunotherapy improved survival in SCLC-BMs patients compared to WBRT monotherapy. Administering WBRT prior to ICI treatment is associated with improved survival outcomes compared to WBRT following ICI treatment, for patients with SCLC-BMs. These findings highlight the significance of conducting further prospective researches on combination strategies of intracranial radiotherapy and ICI in SCLC-BMs patients.

Rethinking strategies in SCLC: Lessons learned from tiragolumab in the SKYSCRAPER-02 study.

The addition of tiragolumab, an anti-TIGIT inhibitor, to chemotherapy plus atezolizumab demonstrated promising early results for lung cancer. Unfortunately, the phase 3 study SKYSCRAPER-02 did not confirm the anticipated benefit of tiragolumab combination in recalcitrant small-cell lung cancer,1 reiterating the need for a more accurate population selection in clinical trials.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration. METHODS: The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM. RESULTS: The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01). CONCLUSION: The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Six versus four or five cycles of first-line etoposide and platinum-based chemotherapy combined with thoracic radiotherapy in patients with limited-stage small-cell lung cancer: A propensity score-matched analysis of a prospective randomized trial.

OBJECTIVES: The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT. MATERIALS AND METHODS: In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM). RESULTS: Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively. CONCLUSION: Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles.

Impact of immune-related adverse events on survival outcomes in extensive-stage small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors have recently become the standard of care in the first-line treatment of extensive-stage small cell lung cancer. Although immune-related adverse events have been reported to influence prognosis in non-small cell lung cancer patients, few studies have investigated the prognostic value of immune-related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune-related adverse events after first-line treatment with immune checkpoint inhibitor-based chemotherapy for extensive-stage small cell lung cancer. METHODS: We enrolled 90 patients with extensive-stage small cell lung cancer who received immune checkpoint inhibitor-based chemotherapy as first-line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune-related adverse events. RESULTS: There were 23 patients with and 67 without immune-related adverse events. Seventeen patients had grade 1-2 immune-related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune-related adverse event was a skin rash. The median survival time was 22 months in patients with immune-related adverse events and 9.3 months in patients without immune-related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19-0.83, p = 0.013). CONCLUSIONS: The results of this study show that immune-related adverse events are associated with improved survival outcomes in patients with extensive-stage small cell lung cancer.

Prognostic value of pretreatment procalcitonin and neutrophil-lymphocyte ratio in extensive-stage small-cell lung cancer.

BACKGROUND: To investigate the influence of pretreatment neutrophil-to-lymphocyte ratio (NLR) and procalcitonin (PCT) on progression-free survival (PFS) in extensive-stage small-cell lung cancer (SCLC) patients. METHOD: A total of 100 extensive-stage SCLC patients were enrolled in our study. Patients were stratified according to the median values of pretreatment NLR and PCT levels: low NLR group (NLR ≤3.17), high NLR group (NLR＞3.17), low PCT group (PCT ≤0.06; ng/ml), high PCT group (PCT＞0.06; ng/ml). The Kaplan-Meier method and multivariable Cox regression model were used to reveal the prognostic effects of pretreatment NLR and PCT on PFS. RESULTS: The median PFS of the total extensive-stage SCLC patients was 6.0 months. The median PFS of low pretreatment NLR group (NLR ≤3.17) was not significantly different from that of high pretreatment NLR group (6.2 months vs 5.8 months; p = .675). Patients with low pretreatment PCT (PCT ≤0.06; ng/ml) had significantly better PFS than patients with high pretreatment PCT (PCT＞0.06; ng/ml) (6.9 months vs 5.7 months; p = .043). With the multivariable Cox regression analysis, the response to first-line chemotherapy (p ≤ .001) and pretreatment PCT (HR = 0.516; 95%CI 0.326-0.817; p = .005) were identified as independent factors associated with PFS. CONCLUSION: Pretreatment PCT is an independent factor associated with PFS in extensive-stage SCLC patients treated with first-line chemotherapy, but pretreatment NLR reflects no significant prognostic value in our study.

The occurrence of asthma in an extensive-stage small-cell lung cancer patient after combination therapy with atezolizumab and anlotinib: a case report.

Background: Extensive-stage small-cell lung cancer (ES-SCLC) is highly malignant, with early metastasis and high recurrence. Since therapeutic options are limited, ES-SCLC has a characteristically short survival period and extremely poor prognosis. A combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs can achieve promising efficacy and safety in patients with ES-SCLC as a second-line or subsequent treatment, extending survival to some extent. However, the clinical outcomes remain mostly unsatisfactory and are sometimes affected by treatment-related adverse events. Case presentation: A 57-year-old woman with ES-SCLC was administered a combination therapy of atezolizumab (a PD-L1 inhibitor) and anlotinib [an oral multi-targeted tyrosine kinase inhibitor (TKI)]. She survived for 22 months, with no disease progression during the 28 courses of therapy. Unexpectedly, despite having no history of asthma, the patient developed asthma while receiving this regimen. This is possibly related to T-cell activation and the tumor immune microenvironment, which induce allergic inflammation after PD-L1 blockade. Conclusions: This is the first report of an asthma-negative ES-SCLC patient who developed asthma after receiving atezolizumab plus anlotinib. Although this combination therapy may effectively extend survival in SCLC patients, asthmatic symptoms should be closely monitored.

Role of CD38 in anti-tumor immunity of small cell lung cancer.

Introduction: Immune checkpoint blockade (ICB) with or without chemotherapy has a very modest benefit in patients with small cell lung cancer (SCLC). SCLC tumors are characterized by high tumor mutation burden (TMB) and low PD-L1 expression. Therefore, TMB and PD-L1 do not serve as biomarkers of ICB response in SCLC. CD38, a transmembrane glycoprotein, mediates immunosuppression in non-small cell lung cancer (NSCLC). In this brief report, we highlight the potential role of CD38 as a probable biomarker of immunotherapy response in SCLC. Methods: We evaluated the role of CD38 as a determinant of tumor immune microenvironment in SCLC with bulk and single-cell transcriptomic analyses and protein assessments of clinical samples and preclinical models, including CD38 in vivo blockade. Results: In SCLC clinical samples, CD38 levels were significantly correlated with the gene expression of the immunosuppressive markers FOXP3, PD-1 and CTLA-4. CD38 expression was significantly enhanced after chemotherapy and ICB treatment in SCLC preclinical models and clinical samples. A combination of cisplatin/etoposide, ICB, and CD38 blockade delayed tumor growth compared to cisplatin/etoposide. Conclusion: Our study provides a preliminary but important direction toward exploring CD38 as a potential biomarker of ICB response and CD38 blockade as a combination strategy for chemo-immunotherapy in SCLC.

Preparation of etoposide liposomes for enhancing antitumor efficacy on small cell lung cancer and reducing hematotoxicity of drugs.

Etoposide (VP16) is commonly used in the treatment of small cell lung cancer (SCLC) in clinical practice. However, severe adverse reactions such as bone marrow suppression toxicity limit its clinical application. Although several studies on VP16 liposomes were reported, no significant improvement in bone marrow suppression toxicity has been found, and there was a lack of validation of animal models for in vivo antitumor effects. Therefore, we attempted to develop a PEGylated liposomal formulation that effectively encapsulated VP16 (VP16-LPs) and evaluated its therapeutic effect and toxicity at the cellular level and in animal models. First, we optimized the preparation process of VP16-LPs using an orthogonal experimental design and further prepared them into freeze-dried powder to improve storage stability of the product. Results showed that VP16-LPs freeze-dried powder exhibited good dispersibility and stability after redispersion. In addition, compared to marketed VP16 injection, VP16-LPs exhibited sustained drug release characteristics. At the cellular level, VP16-LPs enhanced the cellular uptake of drugs and exhibited strong cytotoxic activity. In animal models, VP16-LPs could target and aggregate in tumors and exhibit a higher anti-tumor effect than VP16-injection after intravenous injection. Most importantly, hematological analysis results showed that VP16-LPs significantly alleviated the bone marrow suppression toxicity of drug. In summary, our study confirmed that PEGylated liposomes could enhance therapeutic efficacy and reduce toxicity of VP16, which demonstrated that VP16-LPs had enormous clinical application potential.

Phase III, multicenter, randomized trial of 45 Gy versus 30 Gy thoracic radiation for extensive-stage small cell lung cancer (ES-SCLC): Study protocol.

BACKGROUND: Consolidative thoracic radiotherapy (cTRT) has previously shown benefit to patients with extensive stage small cell lung cancer (ES-SCLC) who respond to chemotherapy. However, the optimum dose of cTRT is unknown. The purpose of this randomized trial is to compare the efficacy of 45 Gy in 15 fractions with 30 Gy in 10 fractions cTRT in ES-SCLC. METHODS: This phase III, multicenter, randomized trial is designed to evaluate the safety and efficacy of different cTRT dose in ES-SCLC. Eligible patients with pathologically confirmed ES-SCLC who responded to 4-6 cycles of etoposide plus cisplatin (EP) or carboplatin (EC) chemotherapy were randomized 1:1 to receive either 30 Gy in 10 fractions (standard dose) or 45 Gy in 15 fractions (high dose) cTRT. The primary endpoint is 2-year overall survival (OS). Secondary endpoints include 2-year progression-free survival (PFS), 2-year local control (LC) and treatment related toxicity as measured by adverse events according to the Common Terminology Criteria for Adverse Events (version 4.0). DISCUSSION: The present study is the first randomized phase III trial designed to evaluate the efficacy of higher versus lower dose cTRT in ES-SCLC, providing evidence for future clinical practice in prolonging survival of patients with ES-SCLC.

Prognostic significance of body mass index and serum albumin as the indicators of nutritional status in small cell lung cancer.

BACKGROUND: Body mass index (BMI) and serum albumin (ALB) level are long-established markers that reflect the nutritional status and eventually the prognosis of cancer patients. The objective of the study was to determine the clinical significance of these factors and specify their roles in outcomes compared with performance status (PS) and weight loss (WL), which are considered the most significant patient-related prognostic factors in small cell lung cancer (SCLC) treated with platinum-etoposide-based chemotherapy. METHODS: A total of 378 patients with SCLC were enrolled in the study and analyzed retrospectively. RESULTS: BMI values were similar by clinical stage, whereas the percentages of the patients with WL, low serum ALB, and particularly poor (≥2) PS were significantly higher in patients with extended disease SCLC (ED-SCLC) compared to those with limited disease SCLC (LD-SCLC). In LD-SCLC, patients with poor PS lived for a significantly shorter time than patients with good PS (HR: 7.791, p = 0.0001); however, BMI (HR: 1.035, p = 0.8), WL (HR: 0.857, p = 0.5), and ALB (HR: 0.743, p = 0.3) had no significant effect on the outcome. In ED-SCLC, PS (HR: 4.257, p = 0.0001), WL (HR: 1.677, p = 0.001), and ALB (HR: 0.680, p = 0.007) had an impact on survival, but BMI did not (HR: 0.791, p = 0.08). In LD-SCLC, the univariate analysis showed that only poor PS was correlated with increased mortality (HR: 7.791, p = 0.0001); yet it lost significance in multivariate analysis. In ED-SCLC, poor PS (HR: 4.257, p = 0.0001), WL (HR: 1.667, p = 0.001), and a low ALB level (HR: 0.680, p = 0.007) were shown to be factors for poor prognosis in the univariate analysis; yet only PS remained significant in multivariate analysis (HR: 2.286, p = 0.001). CONCLUSION: Even though BMI and serum albumin showed no prognostic value in SCLC patients treated with chemotherapy, PS was found to be the most significant prognostic factor in both LD- and ED-SCLC stages.

HMOX1 regulates ferroptosis via mic14 and its impact on chemotherapy resistance in small-cell lung cancer.

This study aimed to investigate the role and molecular mechanism of heme oxygenase-1 (HMOX1) in chemotherapy resistance in small-cell lung cancer (SCLC). Employed bioinformatics, qPCR, and Western Blot to assess HMOX1 levels in SCLC versus normal tissues and its prognostic relevance. CCK-8, flow cytometry, and thiobarbituric acid assays determined HMOX1's impact on SCLC chemosensitivity, ferroptosis markers, lipid peroxidation, and mic14's role in chemoresistance. In the GSE40275 and GSE60052 cohorts, HMOX1 expression was downregulated in SCLC tissues compared to normal tissues. Higher HMOX1 expression was associated with improved prognosis in the Sun Yat-sen University Cancer Hospital cohort and GSE60052 cohort. The RNA and protein levels of HMOX1 were reduced in drug-resistant SCLC cell lines compared to chemosensitive cell lines. Upregulation of HMOX1 increased chemosensitivity and reduced drug resistance in SCLC, while downregulation of HMOX1 decreased chemosensitivity and increased drug resistance. Upregulation of HMOX1 elevated the expression of ferroptosis-related proteins ACSL4, CD71, Transferrin, Ferritin Heavy Chain, and Ferritin Light Chain, while decreasing the expression of GPX4 and xCT. Conversely, downregulation of HMOX1 decreased the expression of ACSL4, CD71, Transferrin, Ferritin Heavy Chain, and Ferritin Light Chain, while increasing the expression of GPX4 and xCT. Upregulation of HMOX1 promoted cellular lipid peroxidation, whereas downregulation of HMOX1 inhibited cellular lipid peroxidation. Upregulation of HMOX1 reduced the RNA level of mic14, while downregulation of HMOX1 increased the RNA level of mic14. mic14 exhibited inhibitory effects on cellular lipid peroxidation in SCLC cells and contributed to reduced chemosensitivity and increased drug resistance in chemoresistant SCLC cell lines. HMOX1 plays a role in ferroptosis by regulating mic14 expression, thereby reversing chemoresistance in SCLC.

Metabolic Tumor Volume as Significant Predictor for Chemotherapy Containing PD-L1 Blocker in Extensive Stage Small Cell Lung Cancer.

BACKGROUND/AIM: Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker. PATIENTS AND METHODS: Forty-six patients with ES-SCLC who received 18F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated. RESULTS: PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUVmax, MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were significant predictors of OS. SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs. CONCLUSION: MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC.

P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation.

The genes coding for the tumor suppressors p53 and retinoblastoma (Rb) are inactivated in the vast majority of small cell lung cancer (SCLC) tumors. Data support the notion that these two deleterious genetic events represent the initial steps in the development of SCLC, making them essential for a lung epithelial cell to progress toward the acquisition of a malignant phenotype. With the loss of TP53 and RB1, their broad tumor suppressive functions are eliminated and a normal cell is able to proliferate indefinitely, escape entering into cellular senescence, and evade death, no matter the damage it has experienced. Within this setting, lung epithelial cells accumulate further oncogenic mutations and are well on their way to becoming SCLC cells. Understanding the molecular mechanisms of these genetic lesions and their effects within lung epithelial cells is of paramount importance, in order to tackle this aggressive and deadly lung cancer. The present review summarizes the current knowledge on p53 and Rb aberrations, their biological significance, and their prospective therapeutic potential, highlighting completed and ongoing clinical trials with agents that target downstream pathways.

Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Phase 1 study of pembrolizumab plus chemotherapy in Japanese patients with extensive-stage small-cell lung cancer.

BACKGROUND: Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC). METHODS: Patients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m2) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs). RESULTS: Fifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months). CONCLUSION: Pembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01840579.

Exosome inhibition improves response to first-line therapy in small cell lung cancer.

Exosomes are recognized as important mediators of cell-to-cell communication, facilitating carcinogenesis. Although there have been significant advancements in exosome research in recent decades, no drugs that target the inhibition of sEV secretion have been approved for human use. For this study, we employed GW4869 and Nexinhib20 as inhibitors of exosome synthesis and trafficking combined. First, we found that Nexinhib20 and GW4869 effectively inhibited RAB27A and neutral sphingomyelinase 2 (nSMase2) nsMase2. Interestingly, the inhibition of nsMase2 and RAB27A decreased expression of CD9, CD63 and Tsg101, both at RNA and protein levels. We used a combination treatment strategy of cisplatin/etoposide plus GW4869 or Nexinhib20 on small cell lung cancer (SCLC) cell lines. The combination treatment of GW4869 or Nexinhib20 effectively enhanced the inhibitory effects of first-line chemotherapy on the SCLC cells. Furthermore, we demonstrated that reducing exosome release through GW4869 and Nexinhib20 treatment effectively reduced cellular proliferation and significantly induced apoptosis in SCLC cells. Also, we showed that combining exosome inhibition with chemotherapy has a significant synergistic effect on cellular proliferation. We also found increased p53 and p21 expressions with western blot and significantly changing Bax, BCL2, caspase-3 and caspase-9 expressions. Inhibiting the exosome pathway offers opportunities for developing novel, effective treatment strategies for SCLC.