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Sang-We Kim
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MS 07 - Neuroendocrine Tumors other than SCLC: Pathology to Patient Management (ID 529)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 6
- Moderators:C. Barrios, Sang-We Kim
- Coordinates: 10/16/2017, 15:45 - 17:30, F203 + F204 (Annex Hall)
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MS 07.01 - Pathology of Neuroendocrine Tumors other than SCLC (ID 7669)
15:45 - 16:00 | Presenting Author(s): Mary Beth Beasley
- Abstract
- Presentation
Abstract:
Neuroendocrine tumors (NET) of the lung comprise approximately 20% of all primary lung carcinomas overall and consist primarily of four malignancies: Typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma(SCLC) using 2015 World Health Organization (WHO) nomenclature. The four tumors have historically been regarded as a spectrum; however, there are significant differences between TC/AC and LCNEC/SCLC on many levels. Additionally, while most TC and AC arise de novo, a small percentage of cases with arise in the setting of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), a rare pre-neoplastic condition. DIPNECH has not been associated with the development of LCNEC or SCLC. TC and AC, comprise 1-2% of primary lung cancers with the vast majority being TC. Both TC and AC may occur in either a central or peripheral location, with central tumors resulting in symptoms related to obstruction while peripheral tumors are often asymptomatic and discovered incidentally. TC is considered a “low grade” or “well-differentiated” tumor; however, 5-20% of TC are associated with regional lymph node or distant metastases. AC, considered an “intermediate grade” or “moderately-differentiated” tumor, is associated with metastases in up to 40% of cases. The five and 10 year survival for TC is approximately 90% whereas it drops to 70% and 50% for AC. By current WHO criteria, TC is defined as a neuroendocrine tumor greater than 5mm in size with fewer than 2 mitoses per 2mm[2] and lacking necrosis, whereas AC is defined as a neuroendocrine tumor with 2-10 mitoses per 2mm[2] or necrosis. As mitotic activity and necrosis may be focal, the distinction between TC and AC can generally not be made on a small sample. Both tumors classically show an organoid or trabecular pattern of growth and are composed of a relatively uniform population of round to oval cells with granular nuclear chromatin, but may show a wide range of histologic growth patterns, particularly in TC. Given that the main feature distinguishing AC from TC is mitotic activity, one would expect that proliferation markers such as Ki-67 would be of potential value in discriminating these two tumors. Numerous studies have attempted to evaluate this parameter with various cut offs being proposed; however, ultimately there is too much overlap between the Ki-67 scores of TC and AC for it to be reliably useful in discriminating between the two tumors. The Ki-67 score can be useful in separating high-grade from low-grade tumors on small distorted biopsies, and some studies have shown it to have utility as a prognostic marker in TC/AC. As such it may be used to potentially guide treatment and is included as a parameter in the European Neuroendocrine Tumor Society (ENETS) guidelines. Surgery remains the only curative treatment option for TC/AC but there is a lack of consensus in regard to treatment of un-resectable or metastatic disease. Results of the RADIANT-4 trial have led to the approval of everolimus for advanced TC/AC. There is additional evidence that somatostain analogs may be useful in selected patients. Molecular analysis of TC and AC demonstrate distinctly different molecular profiles compared to the high grade NET’s, with MEN1 alterations found essentially exclusively in carcinoids whereas alteration of RB1 cell cycle regulation genes and the PI3K/AKT/mTOR pathway were found less frequently in TC/AC and enriched in the higher grade tumors. TC/AC also tend to show frequent mutations of chromatin remodeling genes, as well as mutations of PSIP1 and ARID1A. Actionable mutations such as EGFR mutations and ALK rearrangements are not found in TC/AC and thus far evaluation of PD-L1 in carcinoids has been negative, suggesting a lack of a role for current targeted therapy or immunotherapeutic agents used in non-small cell lung carcinomas (NSCLC). Several clinical trials are either ongoing or currently recruiting to evaluate the efficacy of several small molecular inhibitors. LCNEC was originally described in 1991 and was initially included as a subtype of large cell carcinoma in subsequent WHO classification, but in the current WHO it is classified as a type of neuroendocrine carcinoma. The tumor is defined as a tumor with neuroendocrine morphology with large cell morphology and greater than 10 mitoses/2mm[2], although most cases have substantially higher mitotic rates. By definition, tumors must show evidence of neuroendocrine differentiation, usually identified by immunohistochemical methods. While distinction of LCNEC from SCLC may appear straightforward on the surface, in reality LCNEC can be heterogeneous and the distinction is not always clear cut. Currently, there is no immunostain or other definitive test to discriminate between the two and distinction ultimately rests of subjective evaluation of the tumor morphology. The extreme rarity of this tumor, combined with the tumor heterogeneity and resultant subjectivity inherent in classification has likely contributed to conflicting reports in the literature regarding prognosis, although it is generally agreed that LCNEC is a high-grade tumor with a poor prognosis. Similarly, variable results have been reported in regard to the responsiveness of LCNEC to treatment regimens typically used for SCLC leading to a lack of consensus regarding whether LCNEC should be managed similar to SCLC or similar to other non-small cell carcinomas. Molecular studies have additionally shown variable results. The majority of studies have shown overlapping features with SCLC. Some studies, however, have shown alterations characteristic of other tumor types, most notably occasional EGFR, ALK and KRAS mutations even in the absence of an overt mixed adenocarcinoma component, which have not been found in SCLC. Interestingly, in 2016, Rekhtman, et al, evaluated 45 LCNEC and pared normal tissue by NGS with 241 cancer gene analysis. This study demonstrated that LCNEC, while having some commonly altered genes, largely fell into two major and one minor subset (SCLC-like, NSCLC-like and a small number of “carcinoid like” tumors). These findings may explain the variability of results in treatment trials and may indicate that more comprehensive analysis of this rare groups of tumors may yield more optimal treatment strategies.
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MS 07.02 - Novel Chemotherapy for LCNEC (ID 7670)
16:00 - 16:15 | Presenting Author(s): Seiji Niho
- Abstract
- Presentation
Abstract:
Given that large cell neuroendocrine carcinoma (LCNEC) of the lung is rare and histological diagnosis from small samples is difficult, no large-scale clinical trials has yet evaluated the optimal chemotherapy for LCNEC. In a retrospective study of 45 consecutive patients with advanced LCNEC, response rates for small cell lung cancer (SCLC; n=11) and non-small cell lung cancer (NSCLC; n=34) regimen groups receiving first-line chemotherapy were 73% and 50% (P=0.19), median progression-free survival (PFS) was 6.1 and 4.9 months (P=0.41), and median overall survival (OS) was 16.5 and 9.2 months (P=0.19), respectively. SCLC regimens included platinum plus paclitaxel (PTX) and irinotecan plus platinum, while NSCLC regimens included pemetrexed, erlotinib, and gemcitabine[1]. A second retrospective study of the efficacy of first-line chemotherapies in 22 consecutive patients with advanced LCNEC reported an objective response in five of nine patients receiving CDDP+irinotecan (56%) and in three of five receiving carboplatin (CBDCA)+PTX (60%) [2]. Of the two prospective phase II studies of platinum-based chemotherapies for LCNEC (Table), a French study (GFPC 0302) used a chemotherapy regimen comprising CDDP+etoposide (ETP), while a Japanese study used CDDP+irinotecan. Objective response rate (ORR) was about 40% and median PFS was 5 to 6 months in both studies. Central pathological reviews in both studies demonstrated that about a quarter of patients had SCLC or undifferentiated NSCLC [3, 4]. Everolimus is an oral mTOR inhibitor that has been approved for the treatment of well-differentiated neuroendocrine tumors of the lung. A recent phase II study of CBDCA+PTX+everolimus as first-line chemotherapy for advanced LCNEC was discontinued prematurely due to low recruitment after enrolling only 49 patients versus a planned sample size of 71. Among them, ORR was 45%, disease control rate was 74%, median PFS was 4.4 months, and median OS was 9.9 months [5]. Ongoing studies include a randomized phase II study comparing CBDCA+ETP and CBDCA+PTX for advanced LCNEC and a randomized phase II/III study of CDDP+ETP with or without veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with extensive stage SCLC or metastatic LCNEC.
Reference 1. Sun JM, Ahn MJ, Ahn JS, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer 2012;77:365-370. 2. Fujiwara Y, Sekine I, Tsuta K, et al. Effect of platinum combined with irinotecan or paclitaxel against large cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol 2007;37:482-486. 3. Niho S, Kenmotsu H, Sekine I, et al. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol 2013;8:980-984. 4. Le Treut J, Sault MC, Lena H, et al. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol 2013;24:1548-1552. 5. Christopoulos P, Engel-Riedel W, Grohe C, et al. Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial. Ann Oncol 2017.Study GFPC 0302 Japanese study German study Regimen CDDP+ETP CDDP+Irinotecan CBDCA+PTX+Everolimus N 42 44 49 ORR (%) (95%CI) 38 55 (39-70) 45 (31-60) Median PFS (months) (95%CI) 5.2 (3.1-6.6) 5.9 (5.5-6.3) 4.4 (3.2-6.0) Median OS (months) (95%CI) 7.7 (6.0-9.6) 15.1 (11.2-19.0) 9.9 (6.9-11.7)
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MS 07.03 - Novel Systemic Therapy for Carcinoid of the Lung (ID 7671)
16:15 - 16:30 | Presenting Author(s): Primo Lara
- Abstract
- Presentation
Abstract:
Carcinoid tumors of the lung belong to a broad group of neoplasms called neuroendocrine tumors (NETs). These tumors are highly heterogeneous and represent a broad spectrum of phenotypes and clinical behavior. Often, the clinical behavior of these tumors corresponds with their underlying pathologic features. For example, in those tumors deemed as “typical carcinoid/NETs”, clinical behavior is often very indolent. At the other end of the spectrum, NETs can present as small cell lung cancer (SCLC) which is characterized by virulent and highly metastatic behavior. Those tumors deemed as “atypical carcinoid/NETs” usually have an intermediate clinical phenotype. Lung NETs are rare: the annual incidence rate is estimated to be approximately 1 in 100,000. In those patients whose lung NETs are no longer surgically resectable and/or have metastasized distantly, the treatment goals are principally disease control and symptom palliation. Because of their rarity, there are very limited prospective Level 1 data to guide optimal management of lung NETs. Treatment recommendations are often based on extrapolation from clinical experience in gastrointestinal NETs (specially pancreatic NET), subset analyses from other NET trials, anecdotal reports (case series), and expert opinion (e.g., consensus panels). Thus, the optimal management strategy for Lung NETs is not yet fully defined. Systemic therapy options range from somatostatin analog therapy, mTOR inhibitor therapy, and cytotoxic chemotherapy. Somatostatin analog therapy is offered in selected patient subsets that have slowly progressing disease and whose tumors express somatostatin receptors as detected by nuclear medicine scanning (Octreoscan). Somatostatin analog therapy is only modestly efficacious, with disease stabilization as the expected clinical benefit. Inhibition of the mTOR with everolimus has demonstrated efficacy in randomized trials. In the RADIANT-2 trial of everolimus+octreotide vs. placebo+octreotide in NETs, a small subset of patients with lung NETs (n=44) was analyzed. This showed an improvement in progression free survival with everolimus+octreotide vs. the control arm (median PFS 8.8 months vs 2.8; Hazard Ratio (HR) = 0.62; p=0.1). Subsequently, the phase III RADIANT-4 trial of everolimus vs placebo in non-functional lung and GI NETs was conducted. In this trial, approximately 30% of the 302 randomized patients had lung NETs. RADIANT-4 showed a PFS and overall survival (OS) benefit in favor of everolimus (PFS HR=0.39, p<0.0001; OS HR=0.64, p=0.037). More recently, a randomized phase II trial (LUNA) of pasitreotide alone, everolimus alone, or the combination showed a trend for improved PFS for the combination arm (PFS at 9 months was 39.0% for pasitreotide alone, 33.3% for everolimus alone, and 58.5% for the combination). In patients who are not candidates for somatostatin analog therapy or everolimus, or have failed these therapies, cytotoxic chemotherapy is often considered. The most commonly used regimens include platinum-etoposide (similar to that employed for SCLC) and temozolomide. Response rates to chemotherapy are reportedly much lower in lung NETs (vs SCLC) in retrospective studies; for example, platinum-etoposide is reported to yield response rates of 20-30% in lung NETs compared to rates greater than 50% in SCLC. It is thought that tumor responses are possibly influenced by the degree of tumor de-differentiation. Other agents with anecdotal activity include 5FU, capecitabine, oxaliplatin, and anthracyclines. Prospective trials of systemic therapy in lung NETs are essential to define the optimal standards of care. Selected References: 1. Hendifar, AE et al. J Thor Oncol 2016; 12(3):425-436 2. Yao, J. et al. Lancet 2016; 387: 968-77 3. Fazio N, et al. Chest 2013; 143(4):955-962
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MS 07.04 - Surgical Treatment for Neuroendocrine Tumors other than SCLC (ID 7672)
16:30 - 16:45 | Presenting Author(s): Akira Iyoda | Author(s): Yoko Azuma, T. Makino, H. Otsuka, S. Koezuka, N. Tochigi, K. Shibuya, T. Mikami, Kazutoshi Isobe, S. Homma
- Abstract
- Presentation
Abstract:
In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1]. In 1999, the World Health Organization (WHO) classified large cell neuroendocrine carcinoma (LCNEC) as a fourth neuroendocrine tumor of the lung. Although LCNEC was classified as a variant of large cell carcinoma in 1999 [2], it was classified as a neuroendocrine tumor in 2015. To date, for neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [3], and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [4]. Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [4]. TC is classified as a malignant epithelial tumor of the lung [2, 5]. However, the overall survival rate is better for TC than for AC [5, 6], and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [6]. Therefore, some investigators have advocated limited resection in patients with TC [7]. Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with TC tumor [7]. However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms [8]. Moreover, preoperative diagnoses and/or diagnoses from intraoperative frozen sections are often difficult for differentiating AC from TC, because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. A randomized controlled trial is the best method to compare surgical efficacy. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. Several reports [9] revealed that the clinical behavior, morphology, and prognosis of LCNEC were similar to those of SCLC, even though there might be several clinicopathological differences between SCLC and LCNEC in peripheral, small-sized, and high-grade neuroendocrine tumors [10]. Because it is difficult to diagnose patients with LCNEC pre-operatively, and most cases have been diagnosed postoperatively from surgically resected specimens, many reports on LCNEC have referred to surgical cases, of which the majority [9] revealed that patients with LCNEC had poor prognoses. Even patients with pathological stage I LCNEC have had poor prognoses, with five-year survival rates of 27-67% [9]. In patients with LCNEC who underwent radical surgery and complete resection, many recurrent tumors were observed as distant metastases [10]. Therefore, surgery alone is not sufficient to treat patients with LCNEC, and subsequent adjuvant therapy may be necessary [10]. Although there were high response rates with platinum-based and SCLC-based chemotherapies in patients with LCNEC, almost all patients had only partial responses [9, 10]. Patients with LCNEC may not be able to expect complete responses with platinum-based and SCLC-based chemotherapies compared with patients with SCLC, even though these chemotherapies are as effective as adjuvant treatment. Therefore, patients with advanced-stage LCNEC had a poor prognosis because they could not always achieve a complete response. Although the indication for surgery is limited to stage I in patients with SCLC, surgery and adjuvant chemotherapy may achieve satisfactory results in terms of survival for patients with LCNEC with not only stage I but also stage II/III [10]. Therefore, surgical indications for patients with LCNEC may not be limited to clinical stage I cases, and surgery with adjuvant chemotherapy should be attempted for resectable LCNEC. References [1] Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64:413-21. [2] Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999. [3] Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg. 1996;62:798-810. [4] Onuki N, Wistuba II, Travis WD, Virmani AK, Yashima K, Brambilla E, Hasleton P, Gazdar AF. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600-7. [5] Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004. [6] Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high grade neuroendocrine tumors. Ann Thorac Surg. 2002;73:1049-54. [7] Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8. [8] Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7. [9] Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T. Pulmonary large cell neuroendocrine carcinoma- its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg. 2007;84:702-7. [10] Iyoda A, Makino T, Koezuka S, Otsuka H, Hata Y. Treatment options for patients with large cell neuroendocrine carcinoma of the lung. Gen Thorac Cardiovasc Surg. 2014;62:351-6.
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MS 07.05 - ESTS Registration for Neuroendocrine Tumors (ID 7673)
16:45 - 17:00 | Presenting Author(s): Pier Luigi Filosso | Author(s): F. Guerrera, P. Lyberis, E.L.N.S. Committee
- Abstract
- Presentation
Abstract:
Lung Neuroendocrine Tumors (NETs) are rare neoplasms derived from the neuroendocrine cells of the bronchopulmonary epithelium. They represent about 25% of all the neuroendocrine tumors, and no more than 2%-3% of all the primary tumors of the lung. Their incidence has recently increased by approximately 6% per year, probably due to the improved awareness as well as for the diffusion of lung cancer screening programs worldwide. NETs’ incidence now ranges from 0.2 to 2 per 100,000 individuals per year in the United States. Their rarity, along with the lack of randomized clinical trials, make lung NETs’ global management still questioned, especially in case of advanced diseases, and only few clinical recommendations currently exist. In 2012, during the Annual Meeting in Essen (Germany), the European Society for Thoracic Surgeons (ESTS) created a new Working Group (WG) specifically dedicated to the Lung NETs. The Steering Committees was composed by the following Thoracic Surgeons: Pier Luigi Filosso (Torino, Italy-Chair), Pascal Alexandre Thomas (Marseille, France), Mariano Garcia-Yuste (Valladolid, Spain), Eric Lim (London, UK), Federico Venuta (Rome, Italy), Alessandro Brunelli and Konstantinos Papagiannopoulos (Leeds, UK), Hisao Asamura (Tokyo, Japan). The aim of this WG was to create a group of physicians expert on Lung NETs in order to improve scientific knowledge on such rare neoplasms, and disseminate it among the scientific community. A specific database was rapidly designed, to retrospectively collect data of patients operated for lung NETs, and it was sent to all the ESTS Members who expressed their interest to this project. Moreover, a survey concerning lung NETs’clinical management was prepared and its results were recently published (Future Oncol. 2016;12:1985-1999). Up to now, 2040 operated NETs patients have been collected amongst 17 high-volume International Thoracic Surgery Institution worldwide. This retrospective database was used for several studies about lung NETs clinical behavior and outcome. In particular, the outcome and prognostic factors of two aggressive lung NETs: atypical carcinoids (ACs) and large-cell neuroendocrine carcinomas (LCNCs) were the object of the first publication (Eur.J.Cardiothorac Surg. 2015;48:55-64). For ACs, age (P<0.001), tumour size (P=.015) and sub-lobar resections (P=0.005) were independent negative prognostic factors; for LCNCs, only pTNM stage III tumors (P=0.016) negatively affected outcome in the multivariate analysis. Local recurrences and distant metastases were statistically more frequent in LCNCs (P=0.02), as expected. A prognostic model of survival for typical carcinoids (TCs) was the matter of the second publication (Eur.J.Cardiothorac Surg. 2015;48:441-447): an analysis of 1109 TC patients was performed. A prediction model for mortality, evaluating age, gender, previous malignancies, peripheral tumour location, TNM stage and ECOG PS was elaborated, and the final model showed a good discrimination ability with a C-statistic equal to 0.836 (bootstrap optimism-corrected 0.806). Moreover, this model has been recently validated by Cattoni and Coll. The treatment of biologically aggressive/advanced lung NETs was recently investigated in a paper published by the Journal of Thoracic Disease (J.Thorac. Dis. 2015;7:S163-S171). Surgery, whenever feasible, remains the mainstay of treatment, and chemo/radiotherapy should be reserved to progressive diseases. In case of resected N1-N2 carcinoids, a "watch and see" policy and a close clinical/radiological follow-up is also recommended. Surgery alone is not sufficient to treat high-grade NETs (e.g.: LCNC): adjuvant CT is suggested even in early stages. Platinum-Etoposide regimen demonstrated to be the most effective; Irinotecan and other biological drugs are also regarded to be very promising. The management of advanced lung NETs should be tailored by multidisciplinary teams including Medical and Radiation Oncologists, Surgeons, Pathologists, Pulmonologists, Endocrinologists, Interventional Radiologists; patients’ prognosis is mainly dependent on tumor grade and its anatomical extent. Large-cell neuroendocrine carcinoma (LCNC) is a rare tumor characterized by an aggressive biological behaviour and poor prognosis; its optimal treatment is still under debate. Some recent reports indicate that adjuvant chemotherapy (CT) may have a beneficial effect on survival. Data from 400 patients with resected LCNC were analyzed. The 3- and 5-year survival rates were 54.1% and 45%, respectively. With the multivariable model, increasing age, ECOG ≥2 and advanced TNM stage were indicators of poor prognosis. Weak evidence of a higher overall survival in patients receiving adjuvant CT (adjusted hazard ratio 0.73; 95% confidence interval: 0.56-0.96, P = 0.022) was also observed (Eur.J.Cardio-Thorac.Surg. 2017;52:339-345). In Stage I TCs (SITCs) non-anatomical resections (wedge) are sometimes advocated because of their indolent behavior. An analysis on effect of surgical procedure on SITC patients’ survival was therefore done (Eur.J.Cardiothorac.Surg. 2017 submitted paper). Eight-hundred seventy-six SITC patients (569 females,65%) were included in this study; the 5-year OS rate was 94.3% (95%CI:92.2 –95.9). At univariable analysis, wedge resection resulted to be associated with a poor prognosis (5-year OS 82%,95%CI:0.71-0.89,P<.001) compared to other anatomical resections. At multivariable score-adjusted analysis, wedge resection confirmed to be an independent predictor of poor prognosis (HR2.17,95%CI: 1.19-3.96,P=.012). Since 2106, a lung NETs prospective database is active through the official ESTS European Database, and up to now, more than 150 new cases have been collected. Through this new platform, very easy to be used, we are confident to collect, in few years, more data especially on possible tumor recurrences and their treatment, as well as on the role of emerging biological drugs used in the adjuvant setting in advanced diseases. An active participation of Medical/Radiation Oncologists to this scientific project would be also desirable. The active role of the most important Scientific Societies could strongly support the success of this scientific project.
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MS 07.06 - Which Chemotherapy or Targeted Therapy is Better for Treatment of LCNEC Patients: SCLC-based versus Non-SCLC-based Regimens? (ID 7674)
17:00 - 17:15 | Presenting Author(s): Sumitra Thongprasert
- Abstract
- Presentation
Abstract:
Staging of large cell neuroendocrine carcinoma (LCNEC) was classified based on non-small cell type (TNM stage). The treatment of early stage (I, II) was mainly surgery; the use of neo - adjuvant and adjuvant chemotherapy are in consideration but there's not a standard approach; for stage III which limited to the thoracic area, the role of concurrent chemotherapy and radiotherapy is one of the options. Whether the regimen of chemotherapy should be similar to small cell lung cancer (SCLC) or the regimen of non -small cell lung cancer (NSCLC) is not clear. Most of the data are in favor of SCLC regimen which is Cisplatin plus etoposide; however the data came from retrospective and small numbers of patients, thus there's an unmet need to improve the treatment of LCNEC. Large Cell Neuroendocrine Carcinoma and Small Cell Lung Cancer are both consider high grade neuroendocrine carcinoma of the lung. Small cell is the most frequent type of lung neuroendocrine tumor, occurs around 15% of lung cancer while Large Cell neuroendocrine carcinoma was only about 3% of lung cancer. According to WHO classification in 2004 LCNEC was classified as a variant of large-cell carcinoma; however in 2015 WHO classification LCNEC was classified into a group of neuroendocrine tumor which includes SCLC, typical carcinoid, atypical carcinoid and LCNEC. According to genomic analysis, LCNEC was separated into two groups. Some have genomic characteristic of SCLC and some have genomic characteristic of NSCLC. The new modalities such as anti-angiogenesis and in the case of EGFR mutation the treatment with EGFR inhibitor should be considered. The role of met inhibitors in LCNEC should be explored. Thus there is a long way to go in order to improve the outcome of this rare lung cancer type.
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Author of
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.03 - Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations (ID 7889)
16:05 - 16:15 | Author(s): Sang-We Kim
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.
Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.
Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).
Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.
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OA 05.05 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (ID 8027)
16:30 - 16:40 | Author(s): Sang-We Kim
- Abstract
- Presentation
Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.
Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.
Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.
Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.Investigator Assessment Independent Review[a] Arm A (n=112) Arm B (n=110) Arm A (n=112) Arm B (n=110) Confirmed ORR, % 46 (35–57[b]) 55 (44–66[b]) 51 (41–61[c]) 55 (45–64[c]) Median DoR in responders,[d] months 12.0 (9.2–17.7[c]) 13.8 (10.2–17.5[c]) 13.8 (7.4–NR[c]) 14.8 (12.6–NR[c]) Median PFS,[d] months [% of events] 9.2 (7.4–11.1[c]) [65] 15.6 (11.1–19.4[c]) [50] 9.2 (7.4–12.8[c]) [54] 16.7 (11.6–NR[c]) [41] Median OS,[d] months [% of events] NR (20.2–NR[c]) [38] 27.6 (27.6–NR[c]) [29] — — 1-year OS probability,[d ]% 70 (61–78[c]) 80 (71–87[c]) — — DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate
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OA 05.07 - Efficacy and Updated Safety of Ceritinib (450 Mg or 600 Mg) with Low-Fat Meal vs 750 Mg Fasted in ALK+ Metastatic NSCLC (ID 9366)
16:50 - 17:00 | Author(s): Sang-We Kim
- Abstract
- Presentation
Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.
Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.
Result:
LBA shell - not applicable
Conclusion:
LBA shell - not applicable
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.03 - TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI (ID 8985)
11:20 - 11:30 | Author(s): Sang-We Kim
- Abstract
- Presentation
Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).
Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.
Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.
Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-001 - Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial (ID 8035)
09:30 - 09:30 | Author(s): Sang-We Kim
- Abstract
Background:
Depth of target lesion response to crizotinib has been associated with overall survival (OS) (J Clin Oncol 2016;34:abstract 2590). ALTA (NCT02094573) is an ongoing randomized phase 2 trial of brigatinib, an ALK inhibitor, in crizotinib-refractory advanced ALK+ NSCLC patients. As the ALTA primary endpoint of confirmed objective response rate (cORR), a binary outcome, might not fully capture clinical benefit, we examined the association of maximum decrease in target lesions with progression-free survival (PFS) and OS.
Method:
Patients were randomized to receive brigatinib at 90 mg qd (arm A; n=112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110). Arms were pooled in this analysis. Patients with any target lesion shrinkage were sorted into 4 groups based on greatest decrease from baseline per RECIST v1.1; outcomes in these groups were compared with outcomes in patients with no shrinkage.
Result:
As of February 21, 2017, cORR in arm A/B (ITT population) was 46%/55% per investigators. 201/222 patients had ≥1 evaluable response assessment with 18.4-month median follow-up. Median age of these patients was 53 years; 57% were female. Patients with target lesion shrinkage (vs none) had numerically longer PFS (hazard ratios [95% CIs]: 0.61 [0.30–1.22], 1%–25% shrinkage; 0.47 [0.24–0.91], 26%–50%; 0.54 [0.28–1.05], 51%–75%; 0.30 [0.15–0.63], 76%–100%) and numerically higher estimated 1-year OS (Table). In a multivariable analysis, 76%–100% shrinkage (vs none) was independently associated with longer PFS/OS (hazard ratios [95% CIs]: 0.37 [0.18–0.76]/0.35 [0.14–0.89]); arm B (vs A) was independently associated with longer PFS.
Conclusion:
In this exploratory post hoc analysis, brigatinib-treated patients with target lesion shrinkage, including those without confirmed partial response, had improved PFS/OS vs patients without shrinkage. Patients with the deepest response (76%–100% shrinkage) appeared to have the longest PFS and higher estimated 1-year OS.Best Target Lesion Shrinkage n (%)[a] Median PFS,[b,c] Months (95% CI) Median OS,[b ]Months (95% CI) 1-year OS,[b ]% (95% CI) None 18 (9) 3.7 (1.9–11.0) 8.3 (4.7–NR) 48 (22–99) 1%–25% 40 (20) 9.3 (4.0–21.2) NR (14.5–NR) 75 (58–99) 26%–50% 60 (30) 12.8 (9.2–15.7) NR (NR–NR) 82 (70–99) 51%–75% 44 (22) 11.1 (7.4–18.2) 27.6 (20.2–NR) 77 (62–99) 76%–100% 39 (19) 19.5 (12.6–NR) NR (22.3–NR) 92 (78–99) NR, not reached [a]Evaluable patients [b]Kaplan-Meier estimate [c]Per investigator
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P1.01-070 - BIW-8962, an Anti-GM2 Ganglioside Monoclonal Antibody, in Advanced/Recurrent Lung Cancer: A Phase I/II Study (ID 10421)
09:30 - 09:30 | Author(s): Sang-We Kim
- Abstract
Background:
GM2 ganglioside is a tumor-associated antigen that is overexpressed in a high proportion of several malignancies, e.g. SCLC, NSCLC, mesothelioma, melanoma, neuroblastoma, multiple myeloma. BIW-8962 is a recombinant, humanized, non-fucosylated immunoglobulin G1 monoclonal antibody to GM2 ganglioside that shows pre-clinical activity towards lung cancer cell lines and in an animal model bearing SCLC xenografts. The aim of this study was to determine the safety and preliminary clinical efficacy of BIW-8962 administered as monotherapy in patients with previously treated lung cancer.
Method:
In phase I, patients (N=16) with advanced, recurrent lung cancer (8 each with SCLC and NSCLC) received increasing doses of BIW-8962 (1–10 mg/kg) intravenously every 3 weeks using a standard 3+3 design to determine the maximum tolerated dose (MTD). The highest dose (10 mg/kg) was administered to patients with advanced, recurrent SCLC (N=21) in phase II.
Result:
It was only possible to obtain pre-study biopsy samples for two patients, both of which showed cell surface GM2 overexpression of moderate intensity on immunohistochemistry testing. In phase I and II, all patients received the total planned dose. There were no dose-limiting toxicities in phase I and the MTD was not established. BIW-8982 10 mg/kg therefore used as the recommended phase II dose. The phase II study was prematurely terminated due to lack of efficacy. The objective response rate was 5.0% (95% CI, 0.1%–24.9%) in the efficacy evaluable population (N=20). Median overall survival was 304.0 days (95% CI, 70.0–406 days) and median progression free survival (PFS) was 43.0 days (95% CI, 38.0–43.0 days). One patient showed a durable partial response with PFS of 463 days and response duration of 382 days. There were a few patients with stable disease, which was generally not durable. No pattern of consistent toxicity was observed across the phases: there were no treatment-related adverse events (AEs) Grade ≥3, serious AEs, AEs leading to discontinuation of BIW-8962, or deaths. No unexpected trends or safety concerns were identified from laboratory parameter, vital sign, or electrocardiogram assessments. Anti-BIW-8962 antibodies were not detected in serum of any patient before or following treatment. Exploratory analysis of circulating tumor cells and other potentially predictive or pharmacodynamic markers did not reveal any results consistent with an effect from BIW-8962.
Conclusion:
This study was prematurely terminated due to lack of efficacy, for which the reason is unknown. Clinical development of BIW-8962 has been discontinued.
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P1.15 - SCLC/Neuroendocrine Tumors (ID 701)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.15-004 - An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC (ID 9388)
09:30 - 09:30 | Author(s): Sang-We Kim
- Abstract
Background:
The prognosis of small cell lung cancer (SCLC) remains poor and there is a high unmet need for effective therapies. Poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapies hold promise due to expression of PARP and high mutational burden in SCLC. PARP inhibition leads to upregulation of anti-programmed cell death ligand-1 (PD-L1) and enhanced cancer immunosuppression. This led us to investigate the combination of olaparib and the PD-L1 inhibitor, durvalumab in SCLC (NCT02734004).
Method:
Individuals with relapsed SCLC at least 12 weeks after platinum-based therapy were eligible. Patients received olaparib tablets 300 mg PO BID for a 4-week run-in, followed by a combination of olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks. The combination was continued until progressive disease by RECIST 1.1. Tumor assessments were done at baseline, 4 weeks and every 8 weeks thereafter. The primary endpoints were disease control rate (DCR) at 12 weeks, as well as safety and tolerability. The secondary endpoints included DCR at 28 weeks, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes (TILs). A target DCR of 60% was used to calculate the sample size in a Bayesian predictive probability design.
Result:
Among the 38 patients, the median age was 63 years (range 44-76) and median line of prior chemotherapies 1 (range 1-3). At the time of analysis, each patient was followed up for at least 12 weeks. The most common grade 3 or higher AEs included anemia (34.2%), hyponatremia (10.5%), lymphopenia (10.5%), chronic obstructive pulmonary disease (5.3%), increased GGT (5.3%) and increased lipase (5.3%). DCR at 12 weeks was 29%. Confirmed responses included one partial response and one complete response. Three additional patients had unconfirmed responses. The updated primary and secondary endpoints, as well as biomarker and PK data will be presented.
Conclusion:
Although AEs of all grades were seen commonly, the combination of olaparib and durvalumab was relatively well tolerated, as most of the AEs were attributed to underlying disease. While efficacy of the combination in this SCLC population did not reach the target DCR and is below the futility boundary (<40%), a minority of patients obtained significant benefit and will be followed up for further clinical and translational analyses.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-005 - ASTRIS: A Real World Study of Osimertinib Treatment in Patients with EGFR T790M Positive Advanced NSCLC; Interim Analysis (ID 7884)
09:30 - 09:30 | Presenting Author(s): Sang-We Kim
- Abstract
Background:
Osimertinib is a third-generation, CNS active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations in non-small cell lung cancer (NSCLC). We report interim clinical and molecular diagnostic testing results from a predefined interim analysis of the ongoing ASTRIS study (NCT02474355).
Method:
Patients (pts) received osimertinib 80 mg once daily. Eligible pts had advanced NSCLC that had progressed on prior EGFR-TKI therapy and with a T790M mutation determined by local validated molecular test, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included local test methods, specimen type, EGFR mutations identified, investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported.
Result:
From 18 Sept 2015 to the planned 3 Nov 2016 data cut-off (DCO), 1217 pts received osimertinib 80 mg once-daily across 14 countries with a median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M; T790M was reported alone in 185 pts (15%). The most common testing methods were PNA-Clamp 317 pts (27%), Qiagen therascreen 254 pts (22%), and Roche cobas 204 pts (17%). Exon 19 deletion was the most common co-occurring mutation with T790M (57%), followed by L858R (27%). Tissue or cytology specimens were used in 720 pts (59%), plasma in 433 pts (36%), and other specimens in 64 pts (5%). At DCO, the median duration of exposure was 3.8 months (<1–13.2 months) with a median follow-up time of 4.1 months (<1−14 months). In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 pts (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 28 pts (2%).
Conclusion:
ASTRIS is the largest reported global study of osimertinib in pts with T790M-positive NSCLC identified by a wide array of molecular testing methods and from various specimen types. Considering this breadth of T790M testing, the clinical activity of osimertinib is like that observed in the clinical trial program and no new safety signals were identified.
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P3.01-050 - A Real World Treatment Study of Osimertinib: ASTRIS Study Korean Subgroup Analysis (ID 9678)
09:30 - 09:30 | Author(s): Sang-We Kim
- Abstract
Background:
ASTRIS (NCT02474355) is an open-label, single-arm, multination, real world treatment study, investigating the safety and efficacy of osimertinib in patients with T790M-positive advanced non-small cell lung cancer (NSCLC), who have previously received EGFR-TKI. We report the first results of Korean subset from ASTRIS which is the largest real world treatment study of osimertinib to date.
Method:
Eligible patients had advanced NSCLC harbouring a T790M mutation determined by local validated molecular tests, received prior EGFR-TKI therapy, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Enrollment of patients with asymptomatic, stable CNS metastases were permitted. Patients received osimertinib 80 mg once daily. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival (PFS) and time to treatment discontinuation (TTD). Safety assessment was also conducted. Data cut-off (DCO) was 3 November 2016; results from 1,217 patients in the global study have been presented previously (ASCO 2017 Abstract 9036).
Result:
A total of 371 patients received at least one dose of osimertinib from 30 Korean sites (full analysis set); at DCO, 319 patients (81.4%) were ongoing and median follow-up time was of 3.1 (0–8) months. Baseline patients’ characteristics were median age 61.1 (27–85) years old, female 65.5%, PS 0/1 88%, prior chemotherapy 47%, prior radiotherapy 48%. Tissue was the most common specimen source to test T790M mutation as well as other EGFR mutations (287/371, 77.4%) and plasma was the next (39/371, 13.1%). Fifty two patients (13.3%) had discontinued treatment; median duration of exposure 3.3 (0–7) months, 30 pts (7.7%) had disease progression and 24 patients (6.5%) died. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, the investigator-assessed RR was 72.1% (212/294; 95% CI 66.6 – 77.2). Due to limited follow-up period, OS, PFS, and TTD were immature to analyze. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 26 patients (7%) and 14 patients (3.8%), respectively. Serious AEs were reported in 50 patients (13.5%) and AEs leading to death in 8 patients (2.2%). ILD/pneumonitis-like events were reported in 9 patients (2.4%), and QTc prolongation (>470ms) in 5 patients (1.3%).
Conclusion:
At DCO for the 1[st] interim analysis of ASTRIS, Korean subgroup results demonstrated similar clinical activities (RR) to that observed in the osimertinib clinical trial program with no new safety signals.
