Agents In Small Cell Lung Cancer Research Articles

Prognostic Nomograms for Elderly Patients with Small Cell Lung Cancer Brain Metastasis: A Surveillance, Epidemiology, and End Results Population-Based Study with Temporal External Validation

This study aimed to pinpoint independent predictors influencing overall survival (OS) and cancer-specific survival (CSS) in elderly patients with small cell lung cancer (SCLC) brain metastasis (BM), and to create and validate nomograms for OS and CSS prediction. Data from elderly SCLC BM patients were extracted out of the Surveillance, Epidemiology, and End Results database, including 1200 patients identified from 2010 and 2015 who were randomly allocated into a training set and an internal validation set at a proportion of 7:3, and 666 patients diagnosed between 2018 and 2020 as a temporal external validation set. Independent predictors for OS and CSS were determined through univariate Cox analysis, least absolute shrinkage and selection operator analysis, and multivariate Cox analysis sequentially. Nomograms for OS and CSS were constructed, and validated by the internal and temporal external validation sets. Age, N stage, chemotherapy, and liver metastasis were determined as independent predictors of OS and CSS, while radiotherapy and surgery were not. Nomograms were constructed based on these independent predictors. The results of the receiver operator characteristic curves, the areas under the curve and calibration curve demonstrated that the nomograms exhibited commendable discriminative ability and calibration. Moreover, decision curve analysis, net reclassification improvement, and integrated discrimination improvement also suggested that the nomograms possessed superior clinical usefulness and predictive capability relative to the TNM system. Prognostic nomograms for elderly patients with SCLC BM have been developed, demonstrating good performance in terms of accuracy, reliability, and practicality.

Correlation of Systemic Inflammation Parameters and Serum SLFN11 in Small Cell Lung Cancer-A Prospective Pilot Study.

The objective of this research was to analyze the correlation of the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), soluble programmed cell death ligand 1 (sPD-L1), and Schlafen 11 (SLFN11) with the response to first-line chemotherapy in a cohort of small cell lung cancer (SCLC) patients, and to determine their potential as predictive serum biomarkers. A total of 60 SCLC patients were included. Blood samples were taken to determine CRP, sPD-L1, and SLFN11 levels. The first sampling was performed before the start of chemotherapy, the second after two cycles, and the third after four cycles of chemotherapy. The patients who died earlier during the study had NLR and SLFN11 concentrations significantly higher compared to the survivor group. In the group of survivors, after two cycles of chemotherapy, the NLR ratio decreased significantly (p < 0.01), but after four cycles, the NLR ratio increased (p < 0.05). Their serum SLFN11 concentration increased significantly (p < 0.001) after two cycles of chemotherapy, but after four cycles, the level of SLFN11 fell significantly (p < 0.01). CRP, NLR, and SLFN11 were significant predictors of patient survival according to Kaplan-Meier analysis. The combination of inflammatory parameters and SLFN11 with a cutoff value above the 75th percentile of the predicted probability was associated with significantly lower overall survival in SCLC patients (average survival of 3.6 months vs. 4.8 months). The combination of inflammatory markers and the levels of two specific proteins (sPD-L1, SLFN11) could potentially serve as a non-invasive biomarker for predicting responses to DNA-damaging therapeutic agents in SCLC.

A practical nomogram for predicting early death in elderly small cell lung cancer patients: A SEER-based study.

This study aimed to identify risk factors for early death in elderly small cell lung cancer (SCLC) patients and develop nomogram prediction models for all-cause and cancer-specific early death to improve patient management. Data of elderly patients diagnosed with SCLC were extracted from the SEER database, then randomly divided into training and validation cohorts. Univariate and stepwise multivariable Logistic regression analyses were performed on the training cohort to identify independent risk factors for early death in these patients. Nomograms were developed based on these factors to predict the overall risk of early death. The efficacy of the nomograms was validated using various methods, including ROC analysis, calibration curves, DCA, NRI, and IDI. Among 2077 elderly SCLC patients, 773 died within 3 months, 713 due to cancer-specific causes. Older age, higher AJCC staging, brain metastases, and lack of surgery, chemotherapy, or radiotherapy increase the risk of all-cause early death, while higher AJCC staging, brain metastases, lung metastases, and lack of surgery, chemotherapy, or radiotherapy increase the risk of cancer-specific death (P < .05). These identified factors were used to construct 2 nomograms to predict the risk of early death. The ROC indicated that the nomograms performed well in predicting both all-cause early death (AUC = 0.823 in the training cohort and AUC = 0.843 in the validation cohort) and cancer-specific early death (AUC = 0.814 in the training cohort and AUC = 0.841 in the validation cohort). The results of calibration curves, DCAs, NRI and IDI also showed that the 2 sets of nomograms had good predictive power and clinical utility and were superior to the commonly used TNM staging system. The nomogram prediction models constructed in this study can effectively assist clinicians in predicting the risk of early death in elderly SCLC patients, and can also help physicians screen patients at higher risk and develop personalized treatment plans for them.

Abstract 6554: Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and limited therapeutic options. Repression of the MHC-I and reduced tumor infiltration of cytotoxic T-lymphocytes is often associated with immunotherapy resistance in SCLC. Lurbinectedin is FDA-approved as a second-line treatment for SCLC and we previously showed lurbinectedin as an effective therapeutic strategy in SCLC preclinical models. There are ongoing clinical trials combining immune checkpoint blockade with lurbinectedin in ES-SCLC. However, there is no insight into the effect of lurbinectedin on the immune microenvironment in SCLC. In this study, we evaluated the effect of lurbinectedin on the immune microenvironment and the anti-tumor effect with or without PD-L1 blockade. Results: To determine the effect of lurbinectedin in SCLC models, we treated immunocompetent flank RPP (Rb1, Trp53, and p130) and RPM (Rb1, Trp53, and MYCT58A) tumor-bearing mice with lurbinectedin (0.2 mg/kg, 1/7days) and/or anti-PD-L1 (300µg, 1/7days) for 3 weeks. Mice treated with anti-PD-L1 alone showed no anti-tumor response, and single-agent lurbinectedin caused a delay in tumor growth. However, 6 of the 10 mice treated with the combination of lurbinectedin and anti-PD-L1, had a complete response (100% reduction) and the other 4 had 90% tumor regression. Tumors were resected and analyzed by multicolor flow cytometry for changes in tumor-infiltrating lymphocytes (TILs). Furthermore, analysis of immune cells infiltrating into the tumors post- treatment showed significant induction of cytotoxic T-cells and a reduction of exhausted and regulatory T cells in the combination treatment arm. Similarly, pro-inflammatory M1 type macrophages and dendritic cells were increased, while immunosuppressive M2 type macrophages and MDSC cells were decreased. These effects are consistent with data showing that lurbinectedin treatment leads to an activation of the cGAS/STING pathway, type I/II interferons (IFNα/β), and pro-inflammatory chemokines (CCL5, CXCL10) in tumors. Interestingly, lurbinectedin treatment led to significant upregulation of mRNA and surface expression of MHC class-I genes (HLA-A/B/C) in vitro and in vivo. Finally, bulk RNA sequencing as well as RT-PCR of pre- and post-lurbinectedin treatment demonstrated an increase in DAMPs associated with immunogenic cell death. Conclusion: We provide the first mechanistic insight into the lurbinectedin-induced multimodal immune modulation in SCLC leading to a dramatic anti-tumor activity accompanied by the establishment of a strong anti-tumor immune microenvironment. Since lurbinectedin is already approved as a second-line agent in SCLC, our preclinical data provide a strong rationale for combining this regimen with inhibitors of the PD-L1 pathway and also highlight the immune subsets that the combination targets. Citation Format: Subhamoy Chakraborty, Yazhini Mahendravarman, Utsav Sen, Avisek Banerjee, Charles Coleman, Deniz Demircioglu, Dan Hasson, Triparna Sen. Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6554.

Survival outcomes and prognostic nutritional index in very elderly small-cell lung cancer patients: importance of active treatment and nutritional support

Background Small-cell lung cancer (SCLC) is a highly aggressive tumor with a high metastatic potential, particularly affecting current or former heavy smokers. Treatment typically involves chemotherapy, often combined with radiotherapy, and immunotherapy for extensive disease. Prophylactic cranial irradiation is recommended to reduce brain metastases. Elderly SCLC patients face unique challenges due to frailty and comorbidities, leading to increased risks of treatment-related toxicity and malnutrition. The prognostic nutritional index (PNI), a composite marker of nutritional and immune status, has shown promise in predicting outcomes in various malignancies. However, the optimal treatment approach for very elderly SCLC patients remains unclear, as they are often excluded from clinical trials. Aims This study aimed to evaluate the survival outcomes of SCLC patients aged 75 years or older and their correlation with PNI. Study design Retrospective cohort study. Methods The study retrospectively analyzed data from 71 SCLC patients aged ≥75 years, focusing on age, gender, smoking status, chronic diseases, performance status, clinical stage, treatment modality, and pretreatment PNI. Survival estimates were calculated using the Kaplan–Meier method, and multivariate Cox regression analysis was performed to identify independent predictors of overall survival (OS). Results The results demonstrated that 26.8% of very elderly SCLC patients received no active treatment, resulting in a significantly shorter median survival time of 1.3 months. In contrast, patients who underwent aggressive treatment, such as palliative chemotherapy or chemotherapy plus radiotherapy, had significantly longer median survival times. Multivariate analysis revealed that receiving chemotherapy plus radiotherapy was associated with a significant survival benefit compared to no treatment. Furthermore, low PNI (≤40) was independently associated with decreased OS. Conclusion This study highlights the importance of active treatment and nutritional support in improving survival outcomes for very elderly SCLC patients. The findings suggest that low PNI and lack of oncological treatment are associated with worse survival outcomes. Therefore, integrating nutritional assessment, interventions, and appropriate treatment strategies are crucial in managing lung cancer patients. Larger, multicenter studies are needed to validate these findings and explore potential interventions to optimize nutritional status and improve outcomes for elderly patients with SCLC.

Lower optimal dose of amrubicin for relapsed small-cell lung cancer: a retrospective study.

Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose (40mg/m2) is problematic; the optimal dose remains undetermined. To evaluate the optimal dose of AMR in terms of efficacy and safety, we reviewed consecutive data on patients with relapsed SCLC who received AMR at doses of 40, 35, and 30mg/m2 (on days 1-3) at Nippon Medical School Hospital between October 2010 and November 2021. We reviewed the data of 86 patients (20, 45, 27 who received AMR doses of 40, 35, 30mg/m2, respectively) according to our study criteria. For patients ≥ 75years, the proportion who received second-line treatment tended to be higher in the 30-35mg/m2 group. Objective response rates were 37/46/35%, median progression-free survival (PFS) were 3.0/4.7/3.2months, and median overall survival (OS) were 7.8/16.3/8.0months, respectively. Grade 4 neutropenia occurred in 58/39/31% of patients, which was higher for the 40mg/m2 group. The incidence of febrile neutropenia did not differ between groups. Multivariate analysis identified the AMR dose was not associated with longer PFS and OS. Treatment with AMR between 30 and 35mg/m2 showed relatively mild hematologic toxicity compared with AMR at 40mg/m2, without any significant difference in efficacy. Lower dose of AMR for relapsed SCLC could be a promising treatment option.

Surgery vs. radiotherapy in a population-based cohort of elderly patients with early-stage small-cell lung cancer: an IPTW propensity-score analysis.

Due to the lack of treatment outcome data comparing surgical and non-surgical treatment modalities in the era of contemporary staging and treatments, the management of elderly patients with early-stage small cell lung cancer (SCLC) continues to be debated. This study sought to compare surgery and radiotherapy in elderly patients (aged ≥70 years) with early-stage SCLC using data from the Surveillance, Epidemiology, and End Results (SEER) database. The inverse probability of treatment weighting (IPTW) method was used to address the selection bias between the surgery and radiotherapy groups. The Kaplan-Meier method and multivariate Cox proportional hazards regression were used to compare the overall survival (OS) of the treatment cohorts before and after the IPTW adjustment. The competing risk survival analyses used Fine and Gray's method to compare the cancer-specific survival between the groups. Between 2004 and 2018, 685 elderly patients received local treatment for early-stage SCLC. Of these patients, 193 patients (26.6%) received surgery and 492 patients (73.4%) received radiotherapy. Surgery was associated with a longer OS time than radiotherapy (median OS time: 32 vs. 20 months; 5-year OS time: 30.6% vs. 17.6%; P=0.002). The survival advantage of surgery was consistent in the IPTW-adjusted cohort (median OS time: 32 vs. 20 months; 5-year OS time: 30.6% vs. 17.6%; P<0.002). In the multivariate analysis, an increased age (P=0.001), stage T2 (P=0.047), radiotherapy (P<0.001), and no chemotherapy (P=0.034) were associated with unfavorable OS. In the IPTW-adjusted cohort, the multivariate analysis showed a decreased age (P<0.001), stage T1 (P=0.038), and surgery (P<0.001) were associated with superior OS. The competing risk analyses demonstrated that surgery produced a consistent decrease in the cancer-specific mortality rate compared to radiotherapy among the patients aged 70-80 years (53.6% vs. 61.0%, P=0.01), but no difference was observed in the 5-year cumulative incidence rate of cancer-related death between the surgery and radiotherapy groups (66.3% vs. 64.9%; P=0.66) in patients aged ≥80 years. In this population-based study of the optimal local treatment for elderly early-stage SCLC, patients who underwent surgery had superior OS compared to those who underwent radiotherapy.

A prognostic nomogram to predict survival in elderly patients with small-cell lung cancer: a large population-based cohort study and external validation

BackgroundAge is an independent prognostic factor for small cell lung cancer (SCLC). We aimed to construct a nomogram survival prediction for elderly SCLC patients based on the Surveillance, Epidemiology, and End Results (SEER) database.MethodsA total of 2851 elderly SCLC patients from the SEER database were selected as a primary cohort, which were randomly divided into a training cohort and an internal validation cohort. Additionally, 512 patients from two institutions in China were identified as an external validation cohort. We used univariate and multivariate to determine the independent prognostic factors and establish a nomogram to predict survival. The value of the nomogram was evaluated by calibration plots, concordance index (C-index) and decision curve analysis (DCA).ResultsTen independent prognostic factors were determined and integrated into the nomogram. Calibration plots showed an ideal agreement between the nomogram predicted and actual observed probability of survival. The C-indexes of the training and validation groups for cancer-specific survival (CSS) (0.757 and 0.756, respectively) based on the nomogram were higher than those of the TNM staging system (0.631 and 0.638, respectively). Improved AUC value and DCA were also obtained in comparison with the TNM model. The risk stratification system can significantly distinguish individuals with different survival risks.ConclusionWe constructed and externally validated a nomogram to predict survival for elderly patients with SCLC. Our novel nomogram outperforms the traditional TNM staging system and provides more accurate prediction for the prognosis of elderly SCLC patients.

Novel Cytotoxic Chemotherapies in Small Cell Lung Carcinoma.

Simple SummarySmall cell lung cancer is a subtype of lung cancer and one of the deadliest thoracic tumours. Historically, chemotherapy consisting of either platinum plus etoposide or anthracycline-based regimens have been associated with a high response rate and rapid development of acquired resistance, contributing to the poor overall prognosis. Only a fraction of patients with local or early disease can be cured, whilst the treatment is palliative in those with extensive disease. In recent decades, few novel drugs have been developed, which are herein described.Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum–etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads to a poor prognosis in advanced SCLC. Only a fraction of patients with limited-disease can be cured by chemo-radiotherapy. Given the disappointing survival rates in advanced SCLC, new cytotoxic agents are eagerly awaited. Unfortunately, few novel chemotherapy drugs have been developed in the latest decades. This review describes the results and potential application in the clinical practice of novel chemotherapy agents for SCLC.

Lurbinectedin: A New Treatment Option for Relapsed/Refractory Small-Cell Lung Cancer.

To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC). PubMed database and ClincialTrials.gov were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms lurbinectedin and PM01183. English-language clinical trials of lurbinectedin were evaluated. Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin. Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration. With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens.

Survival and prognostic factors in elderly patients receiving second-line chemotherapy for relapsed small-cell lung cancer: Results from the Japanese Joint Committee of Lung Cancer Registry

ObjectivesMost patients with small-cell lung cancer (SCLC) experience relapse because of the emergence of drug-resistant tumor cells. Therefore, second-line therapy is subsequently required to prolong their survival. However, it is unclear whether second-line chemotherapy can provide a survival benefit to elderly patients with relapsed SCLC. Therefore, this study aimed to evaluate survival and identify prognostic factors in an elderly population. Materials and methodsBased on a nationwide registry database of patients with SCLC (the Japanese Joint Committee of Lung Cancer Registry), we retrospectively reviewed medical records of patients aged ≥ 75 years with relapsed SCLC who subsequently received second-line chemotherapy. Survival time since the initiation of second-line chemotherapy was evaluated. ResultsAmong 731 patients aged ≥ 75 years with SCLC who were accumulated by the nationwide registry database, this study included 228 patients, comprising 190 men and 38 women with a median age of 78 years. The number of patients with performance status (PS) of 0−1 and 2−4 was 196 and 32, respectively. The overall survival (OS) and 1-year survival rates were 7.5 months and 24 %, respectively. A multivariate analysis identified PS, clinical stage at the time of starting first-line therapy, and the interval from the start of first-line therapy to that of second-line therapy as independent prognostic factors. ConclusionThis study with the nationwide registry database showed that among the relapsed elderly SCLC patients who received second-line chemotherapy, a substantial OS may be expected in patients with good PS, at an early clinical stage at the time of starting first-line therapy, and with a longer interval from the start of first-line therapy to that of second-line chemotherapy.

Real-world treatment patterns, survival, and cost among elderly patients with small-cell lung cancer (SCLC).

e20647 Background: Given a dearth of literature, this study aimed to investigate real-world use of systemic therapies, survival, and costs among elderly SCLC patients (pts) in U.S. Methods: Pts (65+ years old) with an initial diagnosis of SCLC during 2007-2013 were identified using the SEER-Medicare data. Overall survival (OS), duration of treatment (DOT) and time to next treatment (TTNT) were estimated based on the Kaplan-Meier method. Costs (2016 US dollars) were derived from Medicare claims. Results: A total of 11 812 pts were identified with 7 797 (66%) being stage IV at diagnosis. During an average of 10 months (m) follow-up post diagnosis, 6 509 (55%), 2 238 (19%) and 679 (6%) received first line (1L), 2L and 3L therapy, respectively. The median OS was 9 m from 1L start and 6 m from 2L or 3L start, suggesting existing treatment providing limited survival benefit. Majority pts (93%) received platinum-based therapy for 1L with Car + etoposide (Eto, 59%) being the most commonly used regimen, followed by Cis + Eto (18%) and Car monotherapy (8%). Car + Eto, Top and Pac were the top 3 regimens used in 2L and 3L. Median DOTs were 4-6 m, yet TTNT ranged from 7 to 18 m across lines of therapy. The average per person per month (PPPM) costs were $9.4k for 1L, $8.9k for 2L, and $8.8k for 3L. Conclusions: Advanced SCLC remains an aggressive malignancy with poor prognosis, lack of ideal therapy and high medical cost, which highlighted high unmet medical need of SCLC among elderly pts. [Table: see text]

Population pharmacokinetics and individualized lobaplatin regimen for the treatment of Chinese small cell lung cancer in the elderly.

Background:Lobaplatin (LBP) is a third-generation platinum compound.Material and methods:This prospective study was performed in 7 institutions in 2014–2016. Elderly small cell lung cancer (SCLC) patients (≥65 years old) were divided into 2 groups to receive LBP regimens according to endogenous creatinine clearance rate (Ccr). LBP was administered at 30 and 20 mg/m2 in groups A (Ccr ≥ 80 ml/min) and B (60 ml/min ≤ Ccr < 80 ml/min), respectively. The primary endpoint was plasma LBP concentrations. Secondary endpoints were safety and efficacy parameters, including progression-free survival (PFS) and overall survival (OS).Results:One-hundred patients were enrolled. Median PFS and OS in groups A and B were 155 vs170 days and 306 vs 272 days, respectively. The rates of grade III/IV AEs in groups A and B were 60.8% (n = 31) and 51.0% (n = 25), respectively. In population pharmacokinetics, the area under the curve (AUC) value for group B was 39% lower than that of group A. With LBP administration based on body surface area (BSA), AUC differences between individuals were small.Conclusion:With Ccr ≥ 60 ml/min, BSA based administration is necessary. Meanwhile, LBP-based regimens are reliable in treating elderly patients with SCLC.

MS18.02 Treatment of Elderly Patients with SCLC

MS18.02 Treatment of Elderly Patients with SCLC

PRM6 - Defining and Estimating the Cure Fraction Bias in Survival Modelling of Novel Immuno-Oncology Therapy Agents in Small-Cell Lung Cancer

PRM6 - Defining and Estimating the Cure Fraction Bias in Survival Modelling of Novel Immuno-Oncology Therapy Agents in Small-Cell Lung Cancer

Immune checkpoint inhibitors in small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly progressive cancer that often debilitates patients within months of detection and quickly becomes refractory to the limited options of therapy. While SCLC is not generally considered an immunogenic tumor, clinical experience suggests that patients with robust immune response manifesting as paraneoplastic syndrome are more likely to present with limited stage of the disease and tend to have a better prognosis. Monoclonal antibodies targeting critical negative regulators of immune response, so called immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) have expanded the application of immune-based therapies to increasing number of advanced stage cancers. These agents overcome the inhibitory immune signals leading to a heightened immune response against cancer cells. These immune checkpoint inhibitors have established efficacy leading to regulatory approval for their use in many cancer types including non-small cell lung cancer (NSCLC). Evaluation of the CTLA-4 inhibitor, ipilimumab and PD-1 inhibitors, nivolumab and pembrolizumab in SCLC have shown encouraging signal but definitive studies are still ongoing. In this review, we discuss the rationale behind the use of checkpoint inhibitors in SCLC, contextualize the results of early trials of immunotherapy agents in SCLC and project the future evolution of this strategy.

A retrospective study of amrubicin monotherapy for the treatment of relapsed small cell lung cancer in elderly patients

PurposeAmrubicin is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). Previous studies reported its effectiveness and severe hematological toxicity. However, the efficacy of amrubicin monotherapy in elderly patients with SCLC has not been described. The objective of this study was to investigate the feasibility of amrubicin monotherapy in elderly patients and its efficacy for relapsed SCLC.MethodsA retrospective cohort study design was used. We retrospectively evaluated the clinical effects and adverse events of amrubicin treatment in elderly (≥70 years) SCLC patients with relapsed SCLC.ResultsBetween November 2003 and September 2015, 86 patients (aged ≥70 years) received amrubicin monotherapy for relapsed SCLC at four institutions. There were 42 cases of sensitive relapse (S) and 44 of refractory relapse (R). S cases with median age of 75 years (range 70–85 years) and R cases with median age of 74 years (range 70–84 years) were included in our analysis. The median number of treatment cycles was three (range 1–9), and the response rate was 33.7% (40.5% in the S and 27.2% in the R cases). Median progression-free survival time was 4.0 months in the S and 2.7 months in the R patients (p = 0.013). Median survival time from the start of amrubicin therapy was 7.6 months in the S and 5.5 months in the R cases (p = 0.26). The frequencies of grade ≥3 hematological toxicities were as follows: leukopenia, 60.4%; neutropenia, 74.4%; anemia, 11.6%; thrombocytopenia, 16.2%; and febrile neutropenia, 17.4%. Treatment-related death was observed in one patient.ConclusionAlthough hematological toxicities, particularly neutropenia, were severe, amrubicin showed favorable efficacy, not only in the S but also in the R cases, as shown in previous studies. Amrubicin could be a preferable standard treatment in elderly patients with relapsed SCLC. These results warrant further evaluation of amrubicin in elderly patients with relapsed SCLC by a prospective trial.

Clinical Characteristics and Prognosis of Elderly Small Cell Lung Cancer Patients Complicated with Hyponatremia: A Retrospective Analysis.

This study was designed to evaluate the clinical characteristics and prognosis of elderly small cell lung cancer (SCLC) patients complicated with hyponatremia, thus providing increased attention for appropriate intervention and improving outcomes in symptomatic subjects. The clinical data of 320 patients with SCLC in the Yuhuangding Hospital from March 1st, 2006, to March 1st, 2012, were studied retrospectively. The prognosis and possible association with hyponatremia was investigated. The incidence rate of hyponatremia in SCLC was 46.56% (149/320). The mean survival time was 1.10±0.42 years in patients with normal values and 0.83±0.35 years in patients with subnormal serum sodium. In the hyponatremia group, the mean survival time of corrected hyponatremia patients was 0.91±0.42 years, which was significantly longer than uncorrected hyponatremia patients whose mean survival time was 0.68±0.26 years (t=2.75, p<0.05) after symptomatic treatment. The mean survival time of the normal group and the hyponatremia group in elderly patients had a tendency to decrease when compared to another group of patients younger than 60 years old. Hyponatremia at 1- and 3-year follow-up was associated with worse survival rates (p<0.05). The severity of hyponatremia has unfavorable prognostic impacts. Elderly SCLC patients with hyponatremia are difficult to cure and associated with significantly shorter survival, especially in the uncorrected group. It is important that the cause of the hyponatremia is diagnosed at an early stage and precise medical treatment is provided.

Changing epidemiology of elderly small cell lung cancer patients over the last 40 years; a SEER database analysis.

Small cell lung cancer (SCLC) is a distinct clinical and pathological entity within the spectrum of lung cancer. It was observed that the relative age distribution of the disease changed over years. Surveillance, epidemiology, and end results (SEER) database (1973-2013) was utilized to determine the incidence, presentation and treatment outcomes of elderly patients (>70 years) with SCLC. Join point regression analysis was then conducted to analyze age-adjusted trends in incidence for the elderly as well as the whole SCLC population. Survival analysis was conducted through Kaplan-Meier analysis. Clinicopathological characteristics and survival outcomes were compared between patients diagnosed at 70-79 years old and those older than 80 years old (octogenarian group). The proportion of elderly patients among all cases of SCLC increased from 23% in 1975 to 44% in 2010. Moreover, the proportion of elderly female patients among all cases of elderly SCLC increased from 25% in 1975 to 49% in 2010. When categorizing patients into four subgroups "70-74," "75-79," "80-84," and "85+", there was a trend toward a lower cancer-specific survival with increasing age (P < .0001). A limited improvement in 5 year survival was observed during the study period and it is less apparent as the age increases. The proportion of elderly patients among all cases of SCLC has increased over the past 40 years. Further studies are needed to better select appropriate treatments for this subset of patients.

Abstract 1731: Preclinical testing demonstrates strong activity of STA-12-8666, an HSP90 inhibitor-SN-38 conjugate, in small cell lung cancer (SCLC)

Abstract Purpose/Objectives: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of all lung cancers, with 5 year survival rate of only 6%. While most patients respond initially to cytotoxic chemotherapies such as irinotecan, etoposide or carboplatin, resistance rapidly emerges and response to second line agents such as topotecan is limited, and in contrast to non-small cell lung cancer (NSCLC), few targetable oncogenes occur in SCLC. In this study, we tested new compound, STA-12-8666, which binds tumor-concentrated active form of shock protein 90 (HSP90) and has cleavable linker attached to SN-38, the active metabolite of irinotecan. Cleavage of the linker within the tumor provides time-release of SN-38 at high local concentration, while significantly limiting drug exposure and toxicity in non-transformed issue. The goal for this work was to evaluate STA-12-8666 for potential use as a new second line monotherapy, or as adjuvant in the frontline setting. Materials/Methods: Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, and chemotherapy combinations in 4 independent SCLC xenograft models, including parental and cisplatin-resistant derivative cell lines (SCLC1, SR2), and a patient-derived xenograft (PDX). STA-12-8666 was also evaluated in drug combinations. Intratumoral responses were profiled using a mass spectrometry based approach to evaluate kinase pathway activation, and results confirmed by immunohistochemistry and western blot analysis. Pharmacokinetic analysis was performed to benchmark retention of STA-12-8666 to isomolar irinotecan in lung tumors. Results: In all three models, high dose (150 mg/kg) STA-12-8666 was well tolerated. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for &amp;gt; 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. STA-12-8666 was also effective in limiting or eliminating tumors growth that had progressed following initial treatment on standard first and second line agents for SCLC. Low dose (50 mg/kg) STA-12-8666 controlled but did not eliminate tumors: however, it strongly enhanced the action of 30 mg/kg carboplatin, resulting in tumor elimination. Pharmacokinetic and proteomic analysis confirmed STA-12-8666 concentration in tumors, and identified a signature of DNA damage response biomarkers in STA-12-8666-treated tumors that strongly contrasted with the pattern induced by irinotecan. Conclusions: Together, these results indicate that STA-12-8666 may be a promising therapy in both frontline and second line settings for SCLC and strongly support the evaluation of this compound in Phase I/II clinical trials. Note: This abstract was not presented at the meeting. Citation Format: Anna Gaponova, AS Nikonova,A Deneka,BL Egleston,S Litwin,JS Duncan,K Duncan,H Borghaei,R Mehra,DA Proia,Y Boumber, Erica Golemis. Preclinical testing demonstrates strong activity of STA-12-8666, an HSP90 inhibitor-SN-38 conjugate, in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1731. doi:10.1158/1538-7445.AM2015-1731