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David S Ettinger
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ES 09 - Recent Progress in the Management of Small Cell Lung Cancer (ID 518)
- Event: WCLC 2017
- Type: Educational Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 5
- Moderators:David S Ettinger, Kenneth Obyrne
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 501
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ES 09.01 - Genomics and Translational Research (ID 7619)
14:30 - 14:50 | Presenting Author(s): Charles M Rudin
- Abstract
- Presentation
Abstract not provided
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ES 09.02 - Cytotoxic Chemotherapy (ID 7620)
14:50 - 15:10 | Presenting Author(s): Yoichi Nakanishi
- Abstract
- Presentation
Abstract:
Untreated small-cell lung cancer (SCLC) is highly sensitive to both chemotherapy and radiotherapy, although its growth is very rapid. Clinically, SCLC is classified into limited-diseases (LD) and extensive-disease (ED). Although there is no distinct criteria, LD is generally accepted to be a disease which is confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes without malignant effusion, i.e., a disease that curative radiotherapy is applicable. Nearly 30% of SCLC is LD at initial diagnosis. LD-SCLC is potentially curable disease, and standard treatment is chemo-radiotherapy, especially concurrent use of chemotherapy and radiotherapy is chosen if performance status of patient is 2 or less and organ function is good. Cisplatin plus etoposide is usually administered together with radiotherapy, since the combination chemotherapy is one of the most effective regimens and also risk of radiation pneumonia is low when the combination is chosen. Median survival time of LD-SCLC is 16 to 24 months and 5-year survival is nearly 15%. On the other hand, median survival time of ED-SCLC is 6-12 months, and long-term disease-free survival is rare. Chemotherapy alone is chosen to ED-SCLC. Globally, combination of cisplatin/carboplatin plus etoposide is recognized as a standard chemotherapy. In Japanese guideline, a combination with cisplatin plus irinotecan is the first choice if tolerable. One of the reasons why standard therapy is different between western and eastern countries is based on distribution of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms. Although drug therapy with cytotoxic agents to SCLC used be the only successful treatment modality for metastatic lung cancer in the past century, its development now appears to slow down. To maximize the effect of cytotoxic agents, combination with immune checkpoint inhibitors or novel targeted drugs would be critical.
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ES 09.03 - Immunotherapy (ID 7621)
15:10 - 15:30 | Presenting Author(s): Caicun Zhou | Author(s): M. Qiao
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor which accounts for 10-15% of all lung cancers[1]. It is extremely lethal with rapid recurrence and dismal prognosis. Although it is sensitive to chemotherapy with 50%-80% overall response rate (ORR), it inevitably recurs within 6 months, especially those in extensive-stage (ES) SCLC[2, 3]. However, treatment options are limited for those who relapse after first-line chemotherapy and standard options have few improvements in SCLC for several decades. How to tackle the chemo-resistant SCLC patients with rapid recurrence after first-line chemotherapy? How to prolong the effective duration of standard chemotherapy? How to improve the prognosis after the second line treatment? These tough concerns need to be addressed. Immunotherapy, especially the inhibitors targeting immune checkpoints such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1(PD-1) and programmed death ligand-1(PD-L1), achieved great success and durable anti-tumor response across multiple tumor types[4, 5]. In terms of SCLC, the high frequency of somatic mutations[6], along with the approximately 10% incidence rate of para-neoplastic and neoplastic triggered autoimmune disease, for instance, Lambert-Eaton myasthenia[7], prompts that the SCLC is a immunogenic type of cancer and possibly, responds to immunotherapy. Therefore, several clinical trials come up then. At present, in the context of high ORR of the first-line chemotherapy treatment, the purpose of the clinical studies based on the immune checkpoint inhibitors (ICI) in the treatment of SCLC can be divided into two categories: 1) integrating ICI into standard chemotherapy as first-line regimen or maintenance therapy 2) single ICI ( nivolumab/ipilimumab/atezolizumab)/ combined with chemotherapy/combined with multiple immune checkpoint inhibitors as compelling options as second or subsequent line regmen. In summary, these regimens could be subdivided into: 1) Ipilimumab plus chemotherapy 2) PD-1/PD-L1 inhibitors alone or together with chemotherapy 3) combination of CTLA-4 blockade and PD-1/PD-L1 inhibitors with or without chemotherapy. Since the outcome from a phase III trial regarding ipilimumab plus chemotherapy was dismal[8], the paradigm has been shifted from single CTLA-4 blockade plus chemotherapy to PD-1 inhibitor, and indeed, PD-1 inhibitor alone or combined with CTLA-4 blockade seem more promising in the treatment of SCLC. In 2017 ASCO, a phase II study evaluating the role of maintenance pembrolizumab in newly diagnosed SCLC patients demonstrated that this regimen didn’t improve the PFS (median PFS: 1.4 months). However, an exploratory analysis from this study suggested that patients with expression of PD-L1 in tumor stromal interface had better outcome( longer PFS: 5.5 months VS 1.3 months and OS: 10.1 VS 7.2 months)[9]. Multiple trials are ongoing to define the roles of this drug in SCLC patients, for instance, pembrolizumab plus chemotherapy in first-line settings (Keynote011), in second or subsequent settings. Additionally, a phase III study is ongoing to determine the effectiveness of nivolumab monotherapy compared to chemotherapy in relapsed SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is underway to evaluate the efficacy of combination of atezolizumab and carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER 133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade, Checkmate 032, the first trial evaluating the combination of nivolumab and ipilimumab in the treatment of patients with SCLC who had progressed after one or more treatment regimens was reported in ASCO recently. Both nivolumab monotherapy and nivolumab plus ipilimumab showed promising anti-tumor activity with durable responses and manageable safety profiles[10]. These data prompted nivolumab alone or nivolumab-ipilimumab combination regimen to be incorporated into NCCN guidelines for SCLC as second line treatment recommendation. Moreover, in 2017 ASCO, the updated data from Checkmate032 was reported. With longer follow up in non-randomized cohort, the response remains encouraging. 2-year OS could be achieved 14% and 26%, respectively in monotherapy and combination therapy[11]. In this setting, a phase III trial, termed Checkmate451 assessing the role of nivolumab monotherapy, nivolumab-ipilimumab combination and placebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI, in LS-SCLC were initiated. Plus, a phase II trial regarding the tremelimumab and durvalumab with or without radiation in relapsed SCLC patients is ongoing and more data are warranted . However, many questions remain. The immune microenvironment in SCLC is distinct from other tumor types for SCLC cells express low levels PD-L1, though with high mutation burdens. In Checkmate032, there is no observation on clear association between tumor PD-L1 expression and clinical benefit. However, as mentioned above, patients with positive PD-L1 expression in the stromal interface had better PFS and OS observed in a phase II trial[9]. The prediction value of PD-L1 expression is supposed to be shifted from tumor cells to surrounding immune cells in SCLC. Thus, it is important to define a specific biomarker to predict the response to immunotherapy and explore the distinct tumor microenvironment in SCLC. Moreover, potential toxicity is not supposed to be underestimated, especially the immune-related adverse effects. Immune related side effects will happen in the course of the treatment. Close monitoring is essential and oncologists are suggested to balance the risks and benefits of immunotherapy in the clinical practice. References 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical Oncology. 2017;35:8504-8504. 10. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895. 11. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. Journal of Clinical Oncology. 2017;35:8503-8503.
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ES 09.05 - Management of Paraneoplastic Syndromes in SCLC (ID 7623)
15:30 - 15:50 | Presenting Author(s): Lucio Crinò
- Abstract
- Presentation
Abstract:
Small cell lung cancer (S.C.L.C.) represents approximately 15% of lung cancers and offers a unique profile of clinical and biological features) S.C.C.L. is a fast growing tumor with are estimated doubling time of 10 days, high propensity to metastatic diffusion since the early beginning of the disease, high sensitivity to chemoradiotherapy but early and common development of pleiotropic drug resistance. Unfortunately in the past 30 years very few advances have been realized in the treatment of S.C.L.C. which in most of the patients is a fatal disease with a median survival of 16-18 months in limited thoracic and 11 months in extensive disease. S.C.L.C. is the most common cancer associated with paraneoplastic syndromes because of it’s propensity to release endocrine peptides, ectopic hormones and neoantigens that can develop the para neoplastic syndromes.Paraneoplastic syndromes constitutes different and heterogeneous clinical conditions associated with cancer development, affecting various tissues at remote locations from theprimary tumour , with an unpredictable clinical behavior. In SCLC, a large number of paraneoplastic syndromes have been reported, involving different organ functions and complicating the clinical course of the disease, including endocrine, neurological and miscellaneous less frequent manifestations. The most common paraneoplastic syndromes in SCLC, can be divided in ectopic hormone-associated syndromes, and immunomediated neurologic syndromes. According to the S.C.L.C. produced hormones we can recognized among the ectopic hormone-associated syndromes, the Hyponatremia (10%) of S.C.L.C., the ectropic Cushing syndrome (5%) Hypertension reninrelated (1%), galactorrhea (1%) and hyperamylasemia (1%). S.C.L.C. has the unique feature to be often heralded or accompanied by a number of immune-mediated neurologic syndromes, the Lambert-Eaton myastemic syndrome 1%, the limbic encephalopaty and the encephalomyelitis, the sensory polyneuropathy, the cerebellar degeneration the opsoclonus myoclonus, all accounting for less than 1%. In most of the cases the neurological symptoms develop before the onset of clinical overt S.C.L.C manifestation and the stage seems not to be related to the presence of paraneoplastic neurological syndrome, whose evolution usually mirrors the behavior and the clinical manifestation. In most of the cases the starting of systemic chemoterapy can induce a dramatic improvement of neurological symptoms in advance to clinical response, and viceversa the worsening of the neurological condition can indicate progressive disease and resistance to the treatment.The study and the improved understanding of pathophisiolgy mechanisms of paraneoplasic syndromes in SCLC can contribute to elucidate the natural history of a fascinating and still largely unknown disease which was erroneously predicted to be a potential curable disease in the eighty years. From that time the treatment strategies and the therapeutic results have been only marginally improved and the undersanding and resolution of paraneoplastic syndromes can contribute substantially to the cure improvement of SCLC.
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ES 09.06 - NCI’s Small Cell Lung Cancer Consortium: New Answers to Old Questions (ID 10941)
15:50 - 16:10 | Presenting Author(s): Peter Ujhazy
- Abstract
- Presentation
Abstract:
The worldwide toll in mortality due to small cell lung cancer (SCLC) is still unacceptable. Based on an analysis conducted by the National Cancer Institute US (NCI) in 2014, there are five priorities in SCLC that need to be addressed by scientists and clinicians: 1. Development of better research tools for the study of SCLC; 2. Conduct of comprehensive genomic profiling of SCLC; 3. Creation of new diagnostic and prevention approaches for SCLC; 4. Therapeutic development efforts; and 5. Study of mechanisms underlying both high rate of initial response and rapid emergence of drug and radiation resistance. These priorities are being currently addressed by the newly established NCIs SCLC Consortium, an effort to coordinate and network investigators focusing on pre-clinical studies of the disease. The SCLC Consortium currently includes a coordinating resource center, members with their individual projects, and associate members funded through other grant mechanisms. The Principal Investigator of the Coordinating Center is Dr. Charles Rudin from the Sloan Kettering Institute for Cancer Research in New York, NY and he is joined by Drs. John Minna (University of Texas South Western), Tyler Jacks (Broad Institute), You Shyr (Vanderbilt University), and Afshin Dowlati (Case Western Reserve University). The Coordinating Center provides administrative, meeting, and communication support, a bioinformatics database, centralized tissue banking and virtual biospecimen database, centralized biostatistics, cell line and animal model repository. The four Research Projects in the Consortium were selected by a standard peer review process and they focus on: 1) the use of extracellular vesicles for early detection of SCLC; 2) preclinical development of a DLL3-targeted theranostic for SCLC; 3) targeting the transcriptional and epigenetic landscape in chemo-refractory SCLC; and 4) novel therapeutic approaches for enhancing anti-tumor immunity in SCLC. The first project, led by Drs. Serge Nana-Sinkam from Virginia Commonwealth University and James Lee from Ohio State University attempts to carry out an analysis of nucleic acids found in exosomes using molecular beacons contained on biochips to detect specific mRNA and miRNA sequences. The hypothesis is that unique nucleic acid differences in exosomes exist that can differentiate among normal smokers and SCLC patients. The goal is to obtain a biochip that can be used as a biomarker for early stage SCLC that can be applied broadly to blood samples. The second project is conducted by Dr. John Thomas Poirer (Sloan Kettering Institute for Cancer Research) and it builds on the earlier clinical success of the antibody-drug conjugate against a ligand of the Notch pathway, DLL3, selectively expressed on the surface of SCLC cells. The new project will develop a radioimmunotherapy reagent targeted against DLL3, expressed in 70-80% of SCLC. If even moderately successful, this work may provide therapeutic options to some patients who currently have none. The third project designed by Drs. Kwok Kin Wong from New York University and Nathanael Schiander Gray from Dana-Farber Harvard Cancer Institute aims to define transcriptional and epigenetic factors that contribute to chemotherapy-resistance in both tumor cells and the surrounding microenvironment and assess the efficacy of transcriptional CDK inhibitors alone or in combination with novel investigational therapies, utilizing in vivo SCLC models. This is a compelling, well-rationalized, project that pursues an important new direction for both understanding the fundamental biology of SCLC tumor cells and exploiting that information for therapeutic development. The latest addition to the Consortium is project 4 by John Heymach, Lauren Byers (both from the University of Texas MD Anderson Cancer Center), and Julien Sage from Stanford University. The investigators seek to identify improved treatment strategies in SCLC using immunotherapeutic agents targeting the PD1 pathway. The overarching goals of this project are to exploit the intersection of DNA damage repair and immunotherapy in SCLC for new targets and therapies, and to enhance the benefit of existing therapeutic options or ongoing clinical studies. Besides the main Research Projects, the Consortium serves as a hub for Associate Members with additional SCLC projects funded through NCI grants. The topics of these projects include new determinants of acquired resistance, Notch signaling in SCLC, molecular and cellular mechanisms of metastasis, therapeutic strategies for targeting PARP1, kinase dependent chemotherapy resistance mechanisms, and investigating CREBBP as a tumor suppressor. The NCI accepts applications for membership in the SCLC Consortium through two program announcements PAR-16-049 and PAR-16-051. International teams are encouraged to apply.
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 8
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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- Abstract
- Presentation
Background:
Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance.
Method:
We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients.
Result:
Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS 7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation.
Conclusion:
PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.
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- Abstract
- Presentation
Background:
Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.
Method:
A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).
Result:
No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1
Conclusion:
Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.
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OA 08.03 - Effect of TOP2A and ERCC1 Genes Polymorphism on the Efficacy and Toxicity of Cisplatin and Etoposide Therapy in SCLC Patients (ID 8367)
11:20 - 11:30 | Presenting Author(s): Marcin Nico? | Author(s): P. Krawczyk, A. Rolska-Kopińska, A. Grenda, A. Bożyk, M. Szczyrek, J. Milanowski
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) shows an aggressive course with early metastases to distant organs. The main treatment regimen for SCLC patients involves platinum based chemotherapy (cisplatin or carboplatin) and etoposide. Genetic alternations, as single-nucleotide polymorphisms (SNPs) in TOP2A (topoisomerase II alpha) and in ERCC1 (endonuclease non-catalytic subunit) genes, were tested as a prognostic and predictive factors in patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. However, there is limited data about clinical relevance of these genetic alternations in SCLC. Therefore, we undertook the present retrospective study to determine the influence of SNPs in TOP2A (rs34300454; rs13695; rs11540720) and ERCC1 (rs11615; rs3212986) genes on efficiency and toxicity of chemotherapy with platinum and etoposide in patients with SCLC.
Method:
The studied group included 103 Caucasian SCLC patients (65 male, 38 female, median age 65 ± 7,5 years). We collected detailed clinical-demographical data including: smoking history, environmental/occupational exposure to carcinogens, performance status, disease stage, and the presence of distant metastases. The response to the treatment was carefully monitored according to RECIST criteria, as well as side effects as anemia, neutropenia or weight loss were noted. For SNPs genotyping, we used DNA isolated from peripheral blood leukocytes using Qiamp DNA Mini Kit (Qiagen, Germany) and TaqMan hydrolyzing probes (Applied Biosystem, USA) in real-time PCR technique on Eco Illumina (Illumina, USA) device.
Result:
Patients with C/C genotype in rs13695 of TOP2A gene had significantly lower risk of neutropenia during chemotherapy than C/T heterozygous patients (p=0,01894; χ²=5.51; OR=2,676; 95% CI=1,165-6,143). Patients harbouring homozygous C/C genotype in rs3212986 of ERCC1 gene had significantly higher risk of anaemia during chemotherapy than heterozygous C/A patients (p=0,04531; χ²=4,01; OR=0,417; 95% CI=0,175-0,991). Furthermore, homozygous A/A genotype in rs11615 of ERCC1 gene was associated with significant prolongation of overall survival (12 vs. 9 months) compared to heterozygous G/A genotype of this gene (p=0,0120; χ²=6,3063; HR=1,657; 95% CI=1,0710-2,5633).
Conclusion:
SNPs in ERCC1 and TOP2 genes are associated with the toxicities and overall survival of SCLC patients treated with platinum and etoposide based chemotherapy.
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OA 08.04 - Discussant - OA 08.01, OA 08.02, OA 08.03 (ID 10845)
11:30 - 11:45 | Presenting Author(s): Ikuo Sekine
- Abstract
- Presentation
Abstract not provided
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OA 08.05 - Major Drivers of Chemotherapy and Radiation Utilization for Limited-Stage Small Cell Lung Cancer in the United States (ID 8475)
11:45 - 11:55 | Presenting Author(s): Stephen G Chun | Author(s): T.A. Pezzi, A.S.R. Mohammed, D.L. Schwartz, J.W. Welsh, Ritsuko Komaki, S.M. Hahn, C.D. Fuller
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) accounts for 15-30% of newly diagnosed lung cancers. Although chemotherapy and radiation play a vital role in the initial management of limited-stage SCLC, rates of combined modality utilization in the United States have not been comprehensively studied. As such, the National Cancer Database (NCDB) is a valuable resource to understand patterns of care for limited-stage SCLC, as it captures the majority of newly diagnosed thoracic malignancies in the United States.
Method:
All cases of IASLC defined limited-stage SCLC in the United States National Cancer Database (NCDB) were identified from 2004 to 2013. Rates of chemotherapy and radiation utilization were determined along with key factors associated with their use. Kaplan-Meier analysis and multivariable analysis were used to determine factors independently associated with overall survival.
Result:
From 2004 to 2013, there were 70,247 cases with analyzable data in the NCDB that met IASLC criteria for limited-stage SCLC. Of these cases, 40% did not receive radiation and 20% received neither chemotherapy nor radiation. For the irradiated group, the mean radiation dose was 52.8 Gy with a 16.2 Gy interquartile range. On multivariable analysis, being uninsured (OR 0.75, 95% CI 0.67-0.85, p < 0.001), Medicaid (OR 0.79, 95% CI 0.72-0.87, p < 0.001), and Medicare (OR 0.86, 95% CI 0.82-0.91, p < 0.001) were independently associated with a lower likelihood of radiation delivery in comparison to private/managed care insurance (after adjusting for age, tumor stage, and co-morbidity score). The irradiated group had significantly better median survival than the non-radiated group (33 vs. 17 months, p < 0.001). Radiation (HR 0.62, 95% CI 0.6-0.63, p < 0.001) and chemotherapy (HR 0.55, 95% CI 0.54-0.57, p < 0.001) delivery were both independently associated with better survival on multivariable analysis. Adjusted analysis showed that non-academic programs (HR > 1, p < 0.001) and non-private/managed care insurance (HR > 1, p < 0.001) was independently associated with a survival detriment.
Conclusion:
This is the most comprehensive study currently available describing the utilization of combined modality therapy in the initial management of limited-stage SCLC in the United States. A remarkable number of patients received neither radiation nor chemotherapy as part of their initial oncologic treatment. Insurance status was a key determinant of radiation and chemotherapy delivery even after adjusting for potentially confounding factors. Our findings highlight substantial barriers to quality care delivery and challenges in accrual seen for cooperative group clinical trials for limited-stage SCLC.
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OA 08.06 - Exploratory Analysis for Predictors of Benefit of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 10321)
11:55 - 12:05 | Presenting Author(s): Taofeek K Owonikoko | Author(s): S. Dahlberg, John Poirier, G.L. Sica, Charles M Rudin, Suresh S Ramalingam
- Abstract
- Presentation
Background:
Veliparib, a potent inhibitor of Poly (ADP) ribose polymerase (PARP) enzyme potentiates standard chemotherapy against small cell lung cancer (SCLC) in preclinical studies. The combination of veliparib (V) with cisplatin/etoposide (CE) doublet as first-line therapy of extensive stage SCLC (ES-SCLC) showed significant signal of efficacy with adjusted PFS HR: 0.63 1-sided p=0.01. There was strata by treatment interaction indicating different efficacy benefit in patient subsets (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets). We explored clinical and tissue-based biomarkers as predictors of benefit from this treatment strategy.
Method:
Post-hoc analysis of clinical data was conducted to identify clinical differences in patients who derived significant benefit from the experimental therapy. Clinical differences were compared between patients in the control and experimental arms within the patient stratum with significant clinical benefit. Similarly, comparison was performed between the strata. Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis using immunohistochemistry to assessSLFN11 and DNA-PK expression. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing biomarker positive to negative patients using a one-sided 0.025 level logrank test.
Result:
There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Mutivariable analysis controlling for these imbalances still showed a benefit of veliparib (HR=0.26, p=0.001). Comparison of “in strata” group (N=46) to the “not in strata” group (N=82) showed significant imbalance in pleural effusion (p=0.058); elevated AST (p=0.0099) and bilirubin (p=0.0447). Median PFS was identical at 5.9 mos for both groups while median OS was 10.7 mos (95% CI 8.9-13.2) for “not in strata” subsests vs. 8.8 mos (95% CI 7.8-10.8) for “in strata” with a HR of 1.57 (p=0.027) comparing “in strata” to “not in strata”. Outcome differences based on SLFN11 and DNA-PK expression will be presented at the meeting.
Conclusion:
PFS benefit of PARP inhibitor therapy in extensive stage SCLC patients with elevated LDH and male gender was not associated with any other clinical characteristics.
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OA 08.07 - Pazopanib Maintenance for Extensive Disease Small Cell Lung Cancer: a Randomized, Placebo-Controlled Phase II study (KCSG-LU12-07) (ID 8239)
12:05 - 12:15 | Presenting Author(s): Jong-Mu Sun | Author(s): K.H. Lee, B. Kim, H. Kim, Y.J. Min, S.Y. Yi, H.J. Yun, S. Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
- Abstract
- Presentation
Background:
We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLD).
Method:
This study is a randomized, placebo-controlled, phase II study that enrolled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum combination 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).
Result:
Ninety-seven patients were enrolled 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 into the analyses. Grade 3 toxicities for pazopanib maintenance included thrombocytopenia (10.4%, including 1 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 [HR] 0.44, 95% CI: 0.29 – 0.69, p < 0.0001). Median PFS longer than 6 months were achieved by 9 patients (18.8%) in pazopanib arm and 2 (4.3%) in placebo. Median overall survival for the pazopanib and placebo arms were 10.6 months and 12.9 months, respectively (HR 1.14, 95% CI: 0.74 – 1.76, p = 0.54).
Conclusion:
Though this study met the primary endpoint of PFS, it failed to translate into improvement of overall survival with pazopanib maintenance. Given the unneglectable toxicity profiles, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.
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OA 08.08 - Discussant - OA 08.05, OA 08.06, OA 08.07 (ID 10846)
12:15 - 12:30 | Presenting Author(s): Karen L Reckamp
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 09 - The Current Status of Radiation Oncology (ID 666)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:Tomoki Kimura, Yong Chan Ahn
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 316
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MA 09.08 - Receipt of Chest Radiation and Immune-Related Pneumonitis in Patients with NSCLC Treated with Anti-PD-1/PD-L1 (ID 10075)
11:55 - 12:00 | Author(s): David S Ettinger
- Abstract
- Presentation
Background:
Immune-related pneumonitis (IR-pneumonitis) is a potentially fatal toxicity of anti-PD-1/PD-L1. This study investigates the role of chest radiotherapy (RT) and the development of IR-pneumonitis in NSCLC patients treated with anti-PD-1/PD-L1.
Method:
Between January 2011 and April 2017, NSCLC patients treated with anti-PD-1/PD-L1 either as part of a clinical trial or as standard-of-care at a tertiary academic cancer center, were identified. Patient demographics, treatment, adverse event and RT data including type of RT (SBRT, 2D/3D conformal RT, IMRT, multiple), timing of RT (pre or post PD-1/PD-L1), location of RT (chest/non-chest), and number of courses of chest-RT, were collected in an IRB-approved institutional database. IR-pneumonitis was diagnosed clinically by the treating investigator; patients with confirmed RT pneumonitis, progressive NSCLC, or active infection were excluded. Associations between patient, treatment and RT parameters, and development of any grade IR-pneumonitis were evaluated using Student’s t-test and Fisher’s exact tests.
Result:
Of 184 NCSLC patients identified: median age was 67 years (range: 39-88); 57% (n=105) were male, 75% (n=137) were former/current smokers, 64% (n=118) had adenocarcinoma histology, and 59% (n=109) had advanced NSCLC at diagnosis. Anti-PD-1/PD-L1 monotherapy was received in 74% (n=136, nivolumab: 107, pembrolizumab: 14, durvalumab: 7, other: 8) and combination therapy in 26% of patients (n=48, PD-1/CTLA-4: 13, PD-L1/CTLA-4: 5, PD-1/chemotherapy: 4, PD-1/other: 25, PD-L1/other; 1). Any RT was received by 129 patients (70%), and 96 patients received chest-RT (52%). Thirty-eight (21%) patients developed IR-pneumonitis of any grade. IR-pneumonitis incidence was numerically higher in patients receiving combination therapy compared with monotherapy (29%, n=14/48 vs. 18%, n=24/136, p=0.1). Former/current smokers had a higher incidence of pneumonitis compared with never smokers (25% vs. 12%, p=0.03). IR-pneumonitis incidence was numerically higher in patients receiving chest-RT compared with non-chest/no RT (25%, n=24/96 vs. 16%, n=14/88, p=0.15). Of 129 patients who received any RT, there was a trend towards increased IR-pneumonitis in patients who received chest RT compared with those who received non-chest RT (25%,n=24/96 vs 9%, n=3/33; p=0.08). Overall, there were no significant associations between chest-RT type, chest-RT timing, nor receipt of more than one chest-RT course, and development of IR-pneumonitis (p>0.05).
Conclusion:
IR-pneumonitis incidence is 21% and may be higher than reported in clinical trials. Smoking status is associated with the development of IR-pneumonitis. Receipt of chest-RT was numerically higher, but not statistically associated with, development of IR-pneumonitis after receipt of anti-PD-1/PD-L1 in patients with advanced NSCLC. Radiation parameters did not associate with the development of IR-pneumonitis.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-050 - Clinical Consequences, Quality of Life, and Management of Neutropenic NSCLC Patients in the REVEL Trial (ID 8279)
09:30 - 09:30 | Presenting Author(s): David S Ettinger
- Abstract
Background:
Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2 approved as a post-platinum progression therapy in non-small cell lung cancer (NSCLC). Chemotherapy-induced neutropenia is a major risk during cancer treatment and can be potentially dose-limiting, as well as play a significant role in infection-related morbidity and mortality. In the REVEL phase 3 global, placebo-controlled study of Stage IV NSCLC patients (NCT01168973), ramucirumab plus docetaxel treatment improved patient survival versus docetaxel monotherapy independent of histology; however, all grade and high-grade (Grade ≥3) neutropenia was numerically increased with ramucirumab versus placebo (Table 1). A post-hoc analysis was performed on the REVEL data to characterize neutropenia: clinical consequences, quality of life (QoL), and clinical management.
Method:
The duration of neutropenia, as well as the course and incidence of complications and their severity and related consequences associated with neutropenia were summarized. Time to deterioration in ECOG performance status (PS) was analyzed using Kaplan-Meier method, and stratified hazard ratios and 95% confidence intervals (CI, Wald) were estimated for average symptom burden index and lung cancer symptom scale items using Cox model. Clinical management summary data will be presented at the meeting.
Result:
Neutropenia events from the REVEL trial are summarized in terms of duration, course, incidence of complications, severity and resolution status in Table 1. All-grade neutropenia risk ratio is 1.197 (95% CI 1.072, 1.338) and Grade ≥3 is 1.226 (95% CI 1.081, 1.390). Figure 1
Conclusion:
Despite numerically increased rates of neutropenia observed in the ramucirumab plus docetaxel arm of the REVEL trial, the clinical consequences (resolution) of neutropenia, rate of hospitalization, and duration/incidence of Grade ≥3 infection were similar to placebo. In addition, the quality of life results do not indicate any significant differences between placebo and ramucirumab. Therefore, neutropenia in the NSCLC population is considered to be manageable during ramucirumab treatment.
