Extensive-disease Small-cell Lung Cancer Research Articles

83P Radiotherapy improves the survival of patients with extensive disease small cell lung cancer: A propensity matched analysis of surveillance, epidemiology and end results database

Background: The survival advantage of radiotherapy (RT) for patients with extensive disease small cell lung cancer (ED-SCLC) has not been adequately evaluated. Methods: We analyzed stage IV SCLC patients enrolled from a large data from the Surveillance, Epidemiology, and End Results (SEER) registry through January 2010 and January 2012. Propensity score (PS) analysis with 1:1 matching and the nearest neighbor matching method were performed to ensure well-balanced characteristics of all comparison groups. Kaplan-Meier and Cox proportional hazardous model were used to evaluate the overall survival (OS), cancer-specific survival (CSS), and corresponding 95% confidence interval (95%CI). Results: Overall, for all metastatic ED-SCLC, receiving radiotherapy was associated with both improved OS and CSS. Generally speaking, radiotherapy for thoracic lesion and any metastatic sites could significantly improve the OS and CSS, except for brain metastasis. Before PS matching, radiotherapy significantly improved the survival of ED-SCLC patients with metastasis to brain (OS, HR = 0.71, with 95% CI = 0.61–0.83), however, the OS improvement became insignificant after PS matching (OS, HR = 0.91, with 95% CI = 0.74–1.12). For those M1a-SCLC patients without pleural effusion, radiotherapy, most likely to the primary site, also significantly improved the survival (P < 0.001). Furthermore, for those ED-SCLC patients with ≥ 2 metastatic sites, i.e., poly-metastatic ED-SCLC patients, radiation significantly improved the median OS from 6.0 months to 8.0 months (P = 0.015) and the median CSS from 7.0 months to 8.0 months (P = 0.020). Conclusions: The results suport radiotherapy in addition to chemotherapy might improve the survival of patients with metastatic ED-SCLC in a PS-matched patient cohort from the large SEER database. Although it should be adequately studied in phase III trials, it is prudent to select patients for radiotherapy in metastatic ED-SCLC. Legal entity responsible for the study: Dr. Zhenming Fu, Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China Funding: National Science Foundation of China (NSFC) Disclosure: All authors have declared no conflicts of interest.

Randomized Phase III Trial of Irinotecan Plus Cisplatin versus Etoposide Plus Cisplatin in Chemotherapy-Naïve Korean Patients with Extensive-Disease Small Cell Lung Cancer

PurposeThis randomized phase III study was designed to compare the efficacy and safety of irinotecan plus cisplatin (IP) over etoposide plus cisplatin (EP) in Korean patients with extensive-disease small-cell lung cancer (SCLC).Materials and MethodsPatients were randomly assigned to receive IP, composed of irinotecan 65 mg/m2 intravenously on days 1 and 8+cisplatin 70 mg/m2 intravenously on day 1 every 3 weeks, or EP, composed of etoposide 100 mg/m2 intravenously on days 1, 2, 3+cisplatin 70 mg/m2 intravenously on day 1, every 3 weeks for a maximum of six cycles, until disease progression, or until unacceptable toxicity occurred. The primary endpoint was overall survival.ResultsA total of 362 patients were randomized to IP (n=173) and EP (n=189) arms. There were no significant differences between IP and EP arms for the median overall survival (10.9 months vs. 10.3 months, p=0.120) and the median progression-free survival (6.5 months vs. 5.8 months, p=0.115). However, there was a significant difference in response rate (62.4% vs. 48.2%, p=0.006). The pre-planned subgroup analyses showed that IP was associated with longer overall survival in male (11.3 months vs. 10.1 months, p=0.036), < 65 years old (12.7 months vs. 11.3 months, p=0.024), and Eastern Cooperative Oncology Group performance status 0/1 (12.4 months vs. 10.9 months, p=0.040) patient groups. The severity of treatment-related adverse events such as grade 3/4 anemia, nausea and diarrhea was more frequent in patients treated with IP.ConclusionThe IP chemotherapy did not significantly improve the survival compared with EP chemotherapy in Korean patients with extensive-disease SCLC.

Modeling the relationship between baseline lactate dehydrogenase and prognosis in patients with extensive-disease small cell lung cancer: a retrospective cohort study.

Elevated pretreatment lactate dehydrogenase (LDH) has been reported to be associated with poor survival in small cell lung cancer (SCLC). The present study aimed to investigate the continuous relationship between baseline LDH level and survival in patients with extensive-disease SCLC (ED-SCLC). Data were retrospectively collected from Shanghai Health Information Network. Patients primarily diagnosed as ED-SCLC from April 2011 to August 2014 were eligible for our study. Patients' survival status was checked in March 2016. A multivariate Cox proportional hazard model was used to detect the association between baseline serum LDH and overall survival. The corresponding continuous relationship was analyzed by using natural spline functions in the Cox model. A total of 132 eligible ED-SCLC patients were analyzed. Elevated LDH at baseline was associated with poor survival (HR =1.92; 95% CI, 1.29-2.86). An increment of LDH would still raise the risk of death even in abnormal range. Among patients with elevated LDH, those who had relatively higher LDH levels (>370 U/L) would have a poorer prognosis than those with moderately elevated LDH levels (245-370 U/L; median survival time, 114 vs. 274 days; P value of log rank test, 0.007). LDH is a significant prognostic biomarker for ED-SCLC patients. The interpretation of continuous relationship between LDH and patients' survival can provide more accurate information for clinical practice.

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Background:We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLC).Methods:This study is a randomised, placebo-controlled, phase II study that enroled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum therapy. Eligible patients were randomly assigned (1 : 1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).Results:97 patients were enroled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n=48; placebo, n=47) and were included in the analyses. Grade 3 toxicities for pazopanib maintenance were thrombocytopenia (10.4%, including one case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (hazard ratio 0.44, 95% confidence interval: 0.29–0.69, P<0.0001).Conclusions:Pazopanib maintenance significantly prolonged PFS in patients with ED-SCLC. Given the toxicity profiles, however, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.

Efficacy and Safety of Ipilimumab plus Chemotherapy for Advanced Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related deaths worldwide, with poor prognosis in advanced lung cancer patients. Platinum-based chemotherapy has always been a first-line treatment for the majority of advanced lung cancer patients, but its long-term survival benefit is limited. Ipilimumab is an immune drug that targets the CTLA-4 protein in T cells. Therefore, we evaluated the efficacy and safety of adding ipilimumab to simple chemotherapy for patients with advanced lung cancer. We searched literatures in PubMed, Web of Science, EMBASE, the Cochrane Library and cliniclatrials.gov. The primary end points of this assessment were overall survival (OS), progression-free survival (PFS) and immune-related PFS(irPFS) of lung cancer patients. Other end points were objective response rate (ORR), disease control rate (DCR) and safety. The results of this study will be presented by the risk ratio (RR) of the endpoints and the 95% confidence interval (CI) of the various effect sizes. And when the p value is less than 0.05, we think there is a statistical difference. Finally, 6 RCTs and 2,037 patients including 953 with advanced or recurrent non-small cell lung cancer (NSCLC) and 1084 with extensive-disease small-cell lung cancer (ED-SCLC) were identified. Among them, 1089 received immunochemotherapy, and 948 patients received chemotherapy alone. Immunochemotherapy can't improve OS (6months: risk ratio (RR)=0.97 P=0.11; 1year: RR=1.05 P=0.36), ORR (RR=1.00 P=0.95) and DCR (RR=0.92, 95%CI 0.85-1.00, P=0.04) of patients with lung cancer compared to pure chemotherapy, but it can improve the PFS (6months: RR=1.16 P=0.02; 1year: RR=1.39 P=0.02) and 6months-irPFS(RR=1.60 P=0.004). However, due to the addition of ipilimumab, the immune-related toxicities are more apparent in immunochemotherapy group.

P3.15-013 The Addition of Antiangiogenic Agents to Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Meta-Analysis

The combination chemotherapy of etoposide and a platinum salt represents the standard therapy for almost 30 years in patients with ED-SCLC (extensive-disease small-cell lung cancer). While, the survival benefit of chemotherapy is not obvious. Antiangiogenic agents have been confirmed to have survival benefits for patients with NSCLC (non-small cell lung cancer). However, there is no established role for antiangiogenic therapy in SCLC. we conducted this meta-analysis to evaluate antiangiogenic agents plus chemotherapy in patients with ED-SCLC. Pub-med, EMBASE, Cochrane Library and ClinicalTrials.gov website were systematically searched for RCTs (randomized controlled trials) that compared antiangiogenic agents plus chemotherapy with chemotherapy alone in ED-SCLC. We firstly found that antiangiogenic agents plus chemotherapy was well tolerated and could provide a statistically significant improvement in PFS (progression-free survival) for patients with ED-SCLC (HR = 0.76 [95% CI 0.65, 0.88], P = 0.0003). The results of ORR (objective response rate) (RR = 1.06 [95% CI 0.96, 1.18], P = 0.23) and OS (overall survival) (HR = 0.98 [95% CI 0.80, 1.21], P = 0.85) showed no benefit for antiangiogenic agents plus chemotherapy. Our study firstly shows that the addition of antiangiogenic agents to standard chemotherapy is well tolerated and can provide a statistically significant improvement in PFS for patients with ED-SCLC. Further, maintenance therapy with antiangiogenic agents is an effective treatment option for ED-SCLC patients who received four to six cycle of chemotherapy. Additionally, four-drug chemotherapy plus antiangiogenic agents may be better for ED-SCLC patients with PS of 1 to 2. However, whether antiangiogenic agents plus chemotherapy can influence OS for ED-SCLC needs further validation.

P2.04-002 CASPIAN: Phase 3 Study of First-Line Durvalumab ± Tremelimumab + Platinum-Based Chemotherapy vs Chemotherapy Alone in ED-SCLC

New therapies are urgently needed for patients with extensive-disease small cell lung cancer (ED-SCLC). High mutation burden in SCLC suggests a potential role for immune checkpoint blockade. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. Durvalumab ± tremelimumab in combination with chemotherapy has shown acceptable tolerability and evidence of clinical activity in a Phase 1b study (NCT02537418) in patients with advanced solid tumors, including NSCLC and SCLC.

P2.04-001 BALTIC: A Phase 2, Open-Label Study of Novel Combinations of Immunotherapies or DDR Inhibitors in Platinum-Refractory ED-SCLC

Immunotherapy and DNA damage repair inhibitors have the potential to play a role in the treatment of patients with extensive-disease small cell lung cancer (ED-SCLC), due to high mutation load and genomic instability in this disease setting. Durvalumab, a selective, high-affinity, engineered human IgG1 mAb blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb targeting CTLA-4. Durvalumab plus tremelimumab demonstrated clinical activity and manageable tolerability in a Phase 1b study in NSCLC (NCT02000947).

MTE 04.02 General Principles of PCI in the Treatment of SCLC

The brain is a well-recognized sanctuary site for micrometastases in patients with small cell lung cancer (SCLC) treated with chemotherapy. The administration of prophylactic cranial irradiation (PCI) in patients responding to chemotherapy reduces the incidence of clinically detectable brain metastases in patients with both limited1 and extensive disease.2,3 In patients with limited disease, this translated into a survival benefit in a meta-analysis of 987 complete responders, but in patients with extensive disease, one trial of 286 responders to chemotherapy showed a survival benefit2, whilst in another of 224 patients it did not.3 The design of this latter trial suggested that regular surveillance with MRI and treatment at the time of metastasis detection might be an equally effective strategy. This could reduce the incidence of the most serious toxicity of PCI which is delayed neurotoxicity. Limiting the total dose is another possible means of reducing neurotoxicity. A randomized trial of three dose prescriptions restricted to patients with limited disease showed no difference in rate of brain metastases between 25 Gy in 10 fractions versus two higher dose schedules, but there was a higher mortality associated with the higher doses, due to an unexplained increase in disease progression.4 In spite of this high level evidence there are still numerous uncertainties facing the clinician when deciding whether to recommend PCI. 1. Is the classification limited versus extensive disease still appropriate when selecting patients? 2. Are there subgroups of patients with metastatic disease more likely to benefit from PCI than others because their overall prognosis is better?5 3. Should there be an upper age limit? 4. Are pre-existing neurologic conditions or paraneoplastic syndromes contraindications? 5. In patients with extensive disease, is pretreatment MRI required? 6. Is MRI surveillance cost effective? 7. Is there a role for hippocampal sparing techniques or neuroprotective agents? 8. Is there a place for lower dose/shorter fractionation schedules? 9. In patients with extensive disease having consolidative chest irradiation, is there any difference between giving PCI simultaneously versus sequentially? 10. What will be the role of PCI in the era of immunotherapy? Question 7 is currently the subject of an actively recruiting randomized trial (NRG-CC003), but for the other questions, physician and patient discretion will be required for the foreseeable future. 1. Auperin, A., et al., Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med, 1999. 341: 476-84. 2. Slotman, B., et al., Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer N Engl J Med, 2007. 357: 664-672. 3. Takahashi, T., et al., Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2017. 18: 663-671. 4. Le Pechoux, C., et al., Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol, 2009. 10:467-74. 5. Eberhardt, W.E., et al., The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol, 2015. 10:1515-22. small cell lung cancer, prophylactic cranial irradiation

The role of prophylactic cranial irradiation for patients with small-cell lung cancer.

Small-cell lung cancer (SCLC) has a particular propensity to metastasize to the brain, affecting ~10% of SCLC patients at diagnosis, but may occur in more than 50% of 2-year survivors. Most cytotoxic drugs have limited ability to cross the blood-brain barrier, and the effectiveness of chemotherapy for brain metastasis is limited. Therefore, prophylactic cranial irradiation (PCI) has been proposed to treat SCLC. A meta-analysis revealed that PCI significantly decreased the risk of brain metastasis and increased the 3-year survival rate; it has been established as a standard therapy for limited-disease SCLC. However, certain aspects of PCI remain unclarified, including the roles in resected SCLC and extensive-disease SCLC, and its neurotoxicities. In addition, information on PCI has been obtained from old clinical trials without the use of new imaging devices, such as magnetic resonance imaging. Evidence from advanced imaging techniques is needed in this era.

Efficacy and safety of amrubicin-based regimen used as first-line for extensive-disease small-cell lung cancer: A meta-analysis of randomized controlled trials.

Currently, amrubicin is used as first-line in the treatment of patients with small-cell lung cancer (SCLC). However, the effect of amrubicin-based treatment in extensive-disease (ED) SCLC remains controversial. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of amrubicin-based regimen in the treatment of patients with ED-SCLC. RCTs published in PubMed, Web of Science, Embase, and ClinicalTrials.gov were systematically reviewed. Eligible studies were these that evaluated the efficacy and safety profiles of amrubicin-based regimen in ED-SCLC. Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and adverse events. Results were expressed with hazard ratio (HR) with 95% confidence intervals (CIs), and risk ratio (RR) with 95% CIs. Four RCTs involving a total of 740 patients met the inclusion criteria and were included in this meta-analysis. Amrubicin-based regimen was not associated with significantly prolonged PFS (HR=1.07, 95% CI: 0.90-1.30; P=0.463) and OS (HR=1.07, 95% CI: 0.89-1.29; P=0.443) in patients with ED-SCLC. However, it significantly improved ORR (RR=1.14, 95% CI: 1.04-1.25; P=0.008). Subgroup analysis demonstrated that neither amrubicin alone nor in combination with cisplatin prolonged the PFS and OS, and only the combination therapy significantly increased ORR. The incidence of grade ≥3 adverse events was comparable between amrubicin-containing and other treatment groups (RR=1.42, 95% CI: 0.78-2.58; P=0.248). However, amrubicin-based treatment induced a significantly higher incidence of febrile neutropenia (RR=3.32, 95% CI: 2.04-5.41; P<0.001), anemia (RR=1.44, 95% CI: 1.06-1.97; P=0.022), leukopenia (RR=2.17, 95% CI: 1.41-3.33; P<0.001), neutropenia (RR=1.33, 95% CI: 1.04-1.70; P=0.021), and interstitial lung disease (RR=1.58, 95% CI: 1.21-1.98; P<0.001). Amrubicin-based regimen used as first-line had no survival benefits in patients with ED-SCLC. But it significantly improved ORR. Further well-conducted, large-scale trials are needed to validate these findings.

The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature.

BackgroundSmall cell lung cancer (SCLC), the most aggressive form of lung carcinoma, represents approximately 15% of all lung cancers; however, the economic and healthcare burden of SCLC is not well-defined.ObjectiveThe aim of this study was to explore the impact of SCLC on healthcare costs through a systematic literature review (SLR).MethodsUsing the OVID search engine, the SLR was conducted in PubMed, MEDLINE In–Process, EMBASE, EconLIT and the National Health Service Economic Evaluation Database (NHS EED). Searches were limited to studies published between January 2005 and 24 February 2016, and excluded preclinical studies. Additional internet-based searches were conducted. In total, 229 abstracts were retrieved and systematically screened for eligibility, with 17 publications retained.ResultsThe majority of publications provided data on limited and extensive disease of SCLC. The reported burden was categorised as direct costs and indirect costs, with the majority of the publications (n = 16) reporting on direct costs and one reporting on both direct and indirect costs. The only indirect costs reported for SCLC were lost productivity (premature mortality costs) and caregiver burden. Chemotherapy, diagnostic costs and treatment costs were identified as significant costs when managing SCLC patients, including the associated treatment costs such as hospitalisation, nurse visits, emergency room visits, follow-up appointments and outpatient care.ConclusionsSCLC and its treatment have a substantial impact on costs. The scarcity and heterogeneity of economic cost data negated meaningful cost comparison, highlighting the need for further research. Capturing the economic burden of SCLC may help patients and clinicians make informed treatment choices and improve SCLC management.

Circulating tumor cell interactions with macrophages: implications for biology and treatment.

Cancer and metastasis are closely associated with inflammation. Macrophages are important effector cells in enhancing tumor proliferation, invasion and providing protection against the immune system. Despite advanced knowledge of tumor-macrophage interactions, the role of macrophages in emergence and invasion of circulating tumor cells (CTCs) is not known. A series of six CTC cell lines have been derived from blood of patients with extensive disease small cell lung cancer (ED-SCLC) in our lab, most likely representing a homogenous cell population of the actual metastasis-initiating cells (MIC) of CTCs. SCLC has an unfavorable prognosis due to rapid dissemination and early chemoresistant relapses. SCLC CTCs recruit macrophages and elicit secretion of various cytokines and the six CTC lines express chitinase-3-like-1 (CHI3L1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) in abundance. CHI3L1 is cytokine/growth factor expressed in inflammation and cancer and found to be correlated to metastasis and a dismal prognosis. In conclusion, SCLC CTCs have acquired the essential means for aggressiveness and invasion in a tumor microenvironment specifically shaped by macrophages and inflammation.

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937

IntroductionNRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1-year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive-disease SCLC. MethodsPatients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required. ResultsA total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2–74.7) for PCI and 50.8% (95% CI: 34.0–65.3) for PCI+cRT (p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32–0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT. ConclusionsOS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS.

The Humanistic Burden of Small Cell Lung Cancer (SCLC): A Systematic Review of Health-Related Quality of Life (HRQoL) Literature.

Background: Little is known about the humanistic burden of small cell lung cancer (SCLC), specifically the impact on health-related quality of life (HRQoL). The aim of this systematic literature review was to explore the impact of SCLC on HRQoL and the patient reported outcomes (PROs) used to capture this impact.Methods: We conducted a systematic search of Medline®, Embase, and PsycINFO, oncology organization websites and conference proceedings within the past 10 years. Articles reporting HRQoL outcomes of SCLC patients were selected.Results: Twenty-seven eligible publications were identified. Global or overall impact on HRQoL (n = 21) was reported most often, with considerably fewer reporting individual domains that comprise HRQoL. Results indicated that HRQoL was negatively impacted in SCLC patients in comparison to the normal population in most domains. Overall, the domains measuring physical functioning and activities of daily living were most impacted. However, results on cognitive and emotional functioning were inconclusive. The impact on HRQoL may be least in both limited disease and extensive disease (ED) SCLC patients who have responded to treatment, and greatest in ED patients who were treatment naïve. The most frequently used PROs were the EORTC QLQ-C30 core cancer instruments, the lung cancer specific module the EORTC QLQ-LC13, LCSS, and EQ-5D.Conclusion: There exists a paucity of reporting on SCLC HRQoL outcomes. This extends to the reporting of domain level scores and by patient sub-group. Greater reporting at a granular level is recommended to allow for more robust conclusions to be made.

Treatment patterns and survival among patients with extensive disease small cell lung cancer (ED-SCLC).

e20026 Background: There has been little change to the ED-SCLC treatment landscape in the past 30 years. Patients with ED-SCLC have limited treatment options after recurrence and poor overall survival (OS). Prior work has described OS in patients with ED-SCLC but did not report OS beyond first-line (1L) therapy. Methods: This study used linked data from the Surveillance, Epidemiology, and End Results program and Medicare claims. Patients aged ≥66 years with a first primary, pathologically confirmed ED-SCLC diagnosis between 01/01/2007 and 12/31/2011 and who had Medicare Parts A and B coverage were included. Patients were followed from diagnosis until death, end of follow-up, second primary cancer diagnosis, or switch to managed care coverage. OS from ED-SCLC diagnosis and from initiation of 1L and second-line (2L) outpatient chemotherapy were estimated. Cox proportional hazards models were used to identify factors associated with OS from diagnosis. Results: Of 5498 patients with ED-SCLC (mean age: 75 years [range: 66, 98]) included in this study, 49% were male, 86% were white, 40% had ≥1 indicator of mobility limitations, and 23% lived in an area with high poverty (≥20%). Median OS for all patients was 4.7 months (untreated [n = 2484]: 1.3 months; treated with outpatient chemotherapy within 90 days of diagnosis [n = 3014]: 8.3 months). Among all patients, factors associated with shorter OS included older age, male sex, ≥1 indicator of mobility limitations, and residence in a high poverty area. In the 3014 patients who received 1L outpatient chemotherapy (86% platinum/etoposide; 4% platinum/irinotecan; 10% other), median OS from initiation of 1L therapy was 7.9 months overall (platinum/etoposide: 8.0 months; platinum/irinotecan: 7.8 months; other: 6.4 months). A total of 1162 patients received 2L chemotherapy (38% topotecan monotherapy; 28% platinum regimens; 34% other). Median OS from initiation of 2L therapy was 4.4 months overall (topotecan: 4.0 months; platinum regimens: 6.4 months; other: 3.7 months). Conclusions: OS was poor in this cohort of real-world patients with ED-SCLC especially in those not treated with outpatient chemotherapy. These findings underscore the need for new treatments for this population.

A phase 3, randomized study of first-line durvalumab (D) ± tremelimumab (T) + platinum-based chemotherapy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.

TPS8586 Background: SCLC accounts for ~13% of all lung cancers and is characterized by rapid growth and early metastases development. Standard of care CT for pts presenting with ED-SCLC is associated with the development of resistance, leading to poor treatment outcomes. As such, new therapies are needed. The high mutation burden associated with SCLC provides a rationale for investigating immune checkpoint blockade in this tumor type. D is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. T is a selective human IgG2 mAb against CTLA-4. D alone and in combination with T has demonstrated a manageable safety profile and encouraging antitumor activity in non-small cell lung cancer (NSCLC). D ± T in combination with CT has also shown acceptable tolerability and preliminary signs of clinical activity in advanced NSCLC and thus may provide benefit in SCLC. Methods: CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study to determine the efficacy of CT in combination with D ± T as first-line treatment in ED-SCLC (Stage IV). Treatment-naïve pts (N = ~795; WHO/ECOG PS 0 or 1) will be randomized 1:1:1 to receive D (1500 mg) + T (75 mg) i.v. every 3 weeks (q3w) + CT (Arm 1); D (75 mg) i.v. q3w + CT (Arm 2); or CT alone (Arm 3). D ± T will be concurrently administered with CT in Arms 1 and 2 and will continue post-CT (1 further dose for T; until confirmed progressive disease for D). CT (etoposide [80–100 mg/m2] i.v. on Days 1–3 q3w + carboplatin [AUC 5–6] i.v. on Day 1 q3w or cisplatin [75–80 mg/m2] i.v. on Day 1 q3w) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS) using blinded independent central review (RECIST v1.1), for Arm 1 vs Arm 3. Secondary endpoints include OS and PFS for Arm 2 vs Arm 3 and Arm 1 vs Arm 2, ORR, OS at 18 months, proportion of patients alive and progression free at 6 and 12 months, PK, immunogenicity, HRQoL, and safety and tolerability. Exploratory endpoints include PFS after subsequent anticancer therapy and correlation of biomarkers with response to treatment. Recruitment is ongoing. Clinical trial information: NCT03043872.

A phase II, open-label, multi-arm study of novel combinations of immunotherapies or DDR inhibitors in platinum-refractory, extensive disease small-cell lung cancer (ED-SCLC): BALTIC.

TPS8585 Background: The prognosis of platinum-refractory ED-SCLC is poor, with ~95% of pts failing to respond to topotecan, the only approved 2ndline treatment. SCLC is associated with a high mutation load and genomic instability, and data suggest that enhanced DNA repair could be a resistance mechanism. As such, immunotherapies and DNA damage repair inhibitors may be beneficial in this disease setting. Durvalumab (D) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study in NSCLC (NCT02000947), D + T showed encouraging activity and manageable tolerability. AZD1775 is a small-molecule inhibitor of the DNA damage checkpoint kinase WEE1 that potentiates genotoxic chemotherapies and is being developed for the treatment of advanced solid tumors with genetic deficiencies in DNA repair mechanisms. In a Phase 2 study in platinum-refractory p53 mutated ovarian cancer (NCT01164995), AZD1775 + carboplatin showed promising activity and an acceptable safety profile. Methods: BALTIC (NCT02937818) is a Phase 2, open-label, multicenter, multi-arm, exploratory, signal-searching study to assess the preliminary activity of novel treatment combinations in refractory ED-SCLC. Eligible pts will have progressed during, or within 90 days of completing 1st line platinum-based chemotherapy, and have life expectancy ≥8 wks. Each arm is independent and will open sequentially to enroll up to 20 pts. The study will open initially with 2 arms: D 1500 mg + T 75 mg i.v. q4w for 4 doses, followed by D monotherapy 1500 mg i.v. q4w (Arm A); and oral AZD1775 225 mg bid for 2.5 days from Day 1 + carboplatin AUC 5 on Day 1 i.v. q3w (Arm B). Pts will receive treatment until confirmed disease progression or discontinuation. Further arms may be added to assess other combinations once safe and tolerable doses and schedules have been established. The primary endpoint is investigator-assessed ORR (RECIST v1.1). Secondary endpoints include duration of response, disease control rate, time to response, PFS, OS, PK, safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT02937818.

Phase I study of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) in limited-disease small cell lung cancer (LD-SCLC).

e20023 Background: Amrubicin and cisplatin is one of active regimens for patients with extensive-disease small cell lung cancer (ED-SCLC). Combined modality of combination chemotherapy and concurrent thoracic radiotherapy has been recognized as standard treatment for LD-SCLC. This study aimed to determine the maximum tolerated dose (MTD), and dose limiting toxicity (DLT) of amrubicin and cisplatin with concurrent TRT in LD-SCLC. Methods: Patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naïve, PS0-1, age = &lt; 75, LD-SCLC, and adequate organ function. Patients received escalating doses of amrubicin on days 1, 2, and 3, under a fixed 60 mg/m2 of cisplatin on day 1. Four cycles of chemotherapy were repeated every 4 weeks. TRT of once-daily 2Gy/day commenced on day 2 of the first cycle of chemotherapy. The initial doses of amrubicin was 20 mg/m2, and the dose was escalated to 25 and 30 mg/m2. Results: Eight patients (male/female = 3/5; PS 0/1 = 4/4; median age (range) = 68.5 (60-73)) were enrolled at three dose levels. Three patients in 20 mg/m2 and three patients in 25 mg/m2 dose levels did not experienced DLT. Two of two patients in 30 mg/m2 dose level experienced DLTs. The presentation of DLTs included grade4 neutropenia and leukopenia lasting more than four days. Evaluation of responses were 7 partial response and 1 progressive disease (response rate 87.5%) and the median survival time was 24.7 months. The MTD of amrubicin and cisplatin were determined as 30 mg/m2 and 60 mg/m2. A dose of 25 mg/m2 amrubicin and cisplatin 60 mg/m2 was recommended in this regimen. Conclusions: This regimen with concurrent TRT in LD-SCLC is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting. Clinical trial information: UMIN000005816.

Retrospective analysis to compare the efficacy of oral (O) vs. intravenous (IV) etoposide given in combination with carboplatin for small cell lung cancer (SCLC), extensive disease (ED).

e20020 Background: Approximately two thirds of patients diagnosed with SCLC will have ED at the time of diagnosis. Response rates to chemotherapy are high but median overall survival for patients treated with chemotherapy is only 9 to 10 months. Patients with ED SCLC considered fit for chemotherapy is normally treated with combination chemotherapy including cisplatin or carboplatin, and etoposide or irinotecan. The usual dosing scheme is 3 weeks intervals with the platin administered on day 1 and etoposide given day 1-3 or 1-5. Etoposide is available in as well intravenous as oral formulations. Concerns about the incomplete and variable bioavailability of oral etoposide have been raised. A randomized study of cisplatin with either oral or IV etoposide found no significant difference in treatment outcome but increased rate of severe or life-threatening hematologic toxicity. Methods: The two cancer hospitals serving the Copenhagen area are using carboplatin + etoposide for palliative treatment of SCLC ED. While carboplatin is used identically (AUC5, IV d1), etoposide is given IV by HUH (120mg/m2, IV d1-3) and orally by CUH (200mg/m2 O, d1-3). From the hospital patient database, we identified patients with SCLC, ED treated in 2011-2013. Route of etoposide administration, dose reductions and GCSF use was noted. PFS and OS was calculated from hospital records. Results: 200 SCLC, ED patients received treatment (116 at HUH, 84 at CUH). A non-significant higher proportion of women were treated at HUH while median age was identical. PFS was longer at HUH than CUH (195 vs 140 days), but the OS was identical (235 vs 227 days). Conclusions: The two dosing schemes: O and IV yield similar OS, but longer PFS with the IV schedule. The survival seen is in line with results from randomized trials although the present study includes all patients irrespectible of PS or comorbidity. We have no information on adverse events, quality of life or rates of hospitalization.