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MS 03 - Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC? (ID 21)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
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MS03.01 - Current Understanding of the Biology (ID 1856)
14:20 - 14:40 | Author(s): J.V. Heymach
- Abstract
- Presentation
Abstract not provided
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MS03.02 - Anti-Angiogenic Therapy: Current and Future Agents (ID 1857)
14:40 - 15:00 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Abstract:
Neo-angiogenesis, critical for sustenance and growth of cancers, is regulated by a number of pro- and anti-angiogenic factors. The vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and has therefore been pursued as a target for cancer therapy. Bevacizumab, a monoclonal antibody against VEGF, was the first anti-angiogenic agent to be approved for the treatment of non-small cell lung cancer (NSCLC). It provides modest improvements in overall survival when given in combination with carboplatin and paclitaxel for patients with advanced non-squamous NSCLC (12.3 m vs. 10.3 m).[1] A second phase 3 study of bevacizumab in combination with cisplatin and gemcitabine improved progression-free survival (PFS), but survival was not prolonged.[2] Bevacizumab can also be safely combined with the combination of carboplatin and pemetrexed, though there was no survival benefit for this combination when compared to carboplatin-paclitaxel-bevacizumab. [3] In all of these studies, bevacizumab was also given as maintenance therapy following 4-6 cycles of combination therapy for patients that achieved stable disease or an objective response. An ongoing phase III study (E5508) compares the role of bevacizumab, pemetrexed or both as maintenance therapy following initial therapy with carboplatin-paclitaxel-bevacizumab for 4 cycles. Based on its therapeutic utility in advanced stage NSCLC, bevacizumab was studied in earlier stages of the disease. However, administration of bevacizumab with concurrent chemoradiotherapy in the treatment of stage III NSCLC was deemed unsafe by a study conducted by SWOG. The results of a phase III study that evaluated bevacizumab in combination with chemotherapy in the adjuvant setting for early stage NSCLC (E1505) will be reported at the 16[th] World Conference on Lung Cancer. In another encouraging development, the combination of bevacizumab and erlotinib was associated with improved progression-free survival (PFS) in patients with epidermal growth factor receptor (EGFR) mutations compared to erlotinib alone in a phase II study conducted in Japan.[4] The median PFS was approximately 16 months for the combination compared to 9.7 months with erlotinib. This is the first study to show incremental efficacy over that of an EGFR tyrosine kinase inhibitor in this patient population. An ongoing study in the Western population will verify the results of the Japanese trial. Taken together, bevacizumab has proven to be a valuable addition to the therapeutic armamentarium against NSCLC. The use of bevacizumab is not recommended for patients with squamous cell histology due to the higher risk of hemoptysis. A number of small molecule VEGFR tyrosine kinase inhibitors were studied in patients with advanced NSCLC. Though many of these agents including sunitinib, sorafenib and axitinib were active as monotherapy, combination studies with chemotherapy or other targeted therapy failed to demonstrate survival benefit. Consequently, the development of nearly all of these agents has been discontinued in NSCLC. Recently, nintedanib, a small molecule tyrosine kinase inhibitor of VEGFR, fibroblast growth factor and platelet-derived growth factor, has been approved in Europe for the treatment of advanced lung adenocarcinoma in combination with docetaxel. Nintedanib has demonstrated single agent activity in advanced NSCLC and was subsequently studied in combination with docetaxel as salvage therapy in a large phase III study.[5] There was a statistically significant improvement in overall survival for patients with adenocarcinoma histology that received the combination of docetaxel and nintedanib compared to docetaxel alone (12.6 m vs. 10.3 m, HR 0.83). A second confirmatory study is presently ongoing in patients with lung adenocarcinoma. Ramucirumab is a monoclonal antibody against the VEGF-R2 receptor. It has recently been approved for the treatment of advanced NSCLC in the salvage therapy setting in combination with docetaxel. This was prompted by the REVEL study that compared docetaxel given with ramucirumab or placebo in patients with advanced NSCLC following progression with a prior platinum-based regimen.[6] There was an improvement in overall survival with the addition of ramucirumab to docetaxel (10.5 m vs. 9.1 m, HR 0.86). The median PFS was also improved for the combination (4.5 m vs. 3.0 m, HR 0.76). The incidence of grades 3/4 febrile neutropenia (16% vs. 10%), fatigue (14% vs. 10%) and hypertension (6% vs. 2%) were higher in the ramucirumab group. The overall results are noteworthy since this is the first study to demonstrate improvement in overall survival for a combination regimen in salvage therapy of advanced NSCLC. In summary, though the role of novel anti-angiogenic agents in NSCLC has been well established, their impact has been relatively modest in improving patient outcomes. The lack of predictive biomarkers has proven to be a major hurdle to identify patients that are likely to gain robust benefits. Efforts to identify combination strategies to improve the efficacy of anti-angiogenic agents have also been unsuccessful to date. Activation of alternate pathways that regulate angiogenesis could be an important reason for the limited success of anti-angiogenic therapy. The recent data on the combination of VEGF inhibition and EGFR inhibition in patients with an activating EGFR mutation warrant further evaluation, particularly to understand the mechanistic basis for the interaction. If confirmed, this approach is likely to be studied in patients with other ‘driver’ oncogenic events.References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England journal of medicine 2006; 355(24): 2542-50. 2. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2010; 21(9): 1804-9. 3. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013; 31(34): 4349-57. 4. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. The lancet oncology 2014; 15(11): 1236-44. 5. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The lancet oncology 2014; 15(2): 143-55. 6. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384(9944): 665-73.
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MS03.03 - Where Are We with Defining Potential Biomarkers (ID 1858)
15:00 - 15:20 | Author(s): G. Liu
- Abstract
- Presentation
Abstract:
Angiogenesis-targeting drugs have been evaluated in a multitude of lung cancer settings, with variable results. Unlike other pathways, these drugs target host related pathways and host responses to lung tumors. Thus there is the potential for both host and tumor mechanisms to lead to variable responses to therapy. In the advent of precision medicine, there has been a concerted effort to evaluate whether there are known genetic and genomic, epigenomic, serologic, and tissue biomarkers of response or toxicity to both anti-angiogenesis monoclonal antibodies and small molecule inhibitors of the angiogenesis pathways. Such studies will be reviewed in detail. Nonetheless, the evaluation of such biomarkers has been challenging, as the relevant anti angiogenesis pathways are large, mechanisms of drug function are often incompletely understood, and tumor-stromal interactionsare particularly difficult to measure. There are currently no clear examples of biomarkers that can define the anti-angiogenesis drug responsive patient. However, this review will focus on both the key opportunities and challenges associated with defining potential biomarkers related to anti-angiogenesis drug therapy in lung cancer, and the current state of ths research. Biomarker development has mostly focused on the discovery of novel marekrs of the VEGF pathway. The roles of assessing magnitudes and directions of association must still be supplemented by the evaluation of test performance, namely biomarker discriminatory performance and calibration. The need to move biomaker association studies towards these other specific evaluations will help move the field of VEGF-related biomarker research forward.
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MS03.04 - An Update on Clinical Trials: Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC? (ID 1859)
15:20 - 15:40 | Author(s): H.A. Wakelee
- Abstract
- Presentation
Abstract:
When the results of E4599 were presented over a decade ago the era of anti-angiogenesis in the treatment of advanced stage NSCLC began. Though the overall survival benefit with the addition of the vascular endothelial growth factor (VEGF) antibody, bevacizumab, to carboplatin/ paclitaxel was only 2 months, it was not only the first randomized phase III trial to show a survival benefit with the addition of any agent to a first line platinum doublet, but also the first to break the 12 months overall survival barrier in a first-line advanced stage NSCLC trial.(Sandler 2006) The enthusiasm lessened with the results of AVAiL, which failed to show an overall survival benefit when bevacizumab was added to cisplatin/gemcitabine.(Reck 2010) However, significant response improvement has been seen in all trials with bevacizumab and many patients benefit from this anti-angiogenesis approach. Recent data from China confirmed the overall survival data from E4599 with a carboplatin/ paclitaxel chemotherapy backbone.(Zhou 2015) The use of bevacizumab with multiple different chemotherapeutics has been explored, and many agents have been added to the E4599 backbone regimen, unfortunately with limited success to date. Ongoing trials continue to utilize this strategy including with everolimus, vorinostat, cixutumumab, GDC-0941, TG4010, and innumerable others. Of particular note, S0819 is a large randomized phase III study in the United States exploring the addition of cetuximab to carboplatin/paclitaxel +/- bevacizumab.(ClinicalTrials.gov Identifier: NCT00946712) A biosimilar bevacizumab (Pf 06439535) is under investigation in a randomized phase III trial of 798 patients in combination with carboplatin/paclitaxel, compared to the E4599 regimen.(ClinicalTrials.gov Identifier: NCT02364999) Key research questions about bevacizumab at this time focus on duration of therapy. E5508 (ClinicalTrials.gov Identifier: NCT01107626), which recently completed accrual, addresses the question of maintenance with bevacizumab. This trial builds on E4599 such that all patients receive carboplatin/ paclitaxel/ bevacizumab for 4 cycles. Those without progression at that time then continue on bevacizumab alone until progression (as per E4599) or stop bevacizumab and start pemetrexed, or receive both agents. The results of this randomized phase III trial of over 1200 patients are eagerly awaited to determine an optimal maintenance approach. The results will also determine the benefit of prolonged bevacizumab use. Earlier work with bevacizumab in a maintenance setting included the AVAPERL trial which showed promising results with the combination of pemetrexed/bevacizumab maintenance compared to bevacziumab maintenance alone after a cisplatin/ pemetrexed/ bevacizumab first line regimen in advanced nonsquamous NSCLC.(Barlesi 2013) Based on positive data in colorectal and ovarian cancer, and retrospective data in lung cancer, demonstrating a survival benefit with continuation of bevacizumab beyond progression, the phase IIIb study AvaALL (MO22097) (ClinicalTrials.gov Identifier:NCT01351415) randomizes patients to continuation of bevacizumab, or not, at the initiation of second line chemotherapy after progression on a bevacizumab containing first-line regimen.(Gridelli 2011) Overall survival is the primary endpoint and a clear survival benefit in this trial will significantly alter the treatment landscape for those patients with adenocarcinoma, without a driver mutation, who are treated with first line bevacizumab. Similar smaller studies are also ongoing. The use of bevacizmab with EGFR targeted therapy in patients with tumors harboring EGFR mutations is an area of particular interest after positive phase II trial results with the combination were published in 2014.(Seto 2014) This Japanese study showed a significant progression free survival advantage with the combination compared to single agent erlotinib as first line therapy in this patient population. Several ongoing trials seek to confirmation these results including a randomized phase II study in the United States (ClinicalTrials.gov Identifier: NCT01532089) and a non-randomized trial in Europe (BELIEF ClinicalTrials.gov Identifier: NCT01562028). Trials looking at bevacizumab in combination with newer immune targeted drugs such as the checkpoint inhibitors targeting PD-1 and PD-L1 are ongoing. The largest is a 3-arm phase III study looking at carboplatin/ paclitaxel with or without bevacizumab PLUS the PD-L1 targeted atezolizumab (MPDL3280A) compared to a control arm of carboplatin/ paclitaxel/ bevacziumab.(ClinicalTrials.gov Identifier: NCT02366143) The study will enroll 1200 patients. Smaller phase I trials of other PD-1 agents in combination with multiple different regimens include carboplatin/ paclitaxel/ bevacizumab arms. Examples include a multi-arm pembrolizumab study (ClinicalTrials.gov Identifier: NCT02039674) and a trial with nivolumab which includes a bevacizumab maintenance with nivolumab arm.(ClinicalTrials.gov Identifier:NCT01454102) Bevacizumab is not the only anti-angiogenesis agent. The VEGFR-2 antibody ramucirumab had recent approval by the US FDA when given in combination with docetaxel in the 2[nd] line setting.(Garon 2014) In contrast to bevacizumab, which is restricted to non-squamous NSCLC, ramucirumab is approved for any histology of NSCLC. Ongoing trials with ramucirumab include a large (N=462) randomized double-blind study of erlotinib with ramucirumab or placebo in EGFR mutation positive NSCLC (ClinicalTrials.gov Identifier: NCT02411448) and a phase 1 study of the agent in combination with pembrolizumab.(ClinicalTrials.gov Identifier: NCT02443324) The VEGFR TKIs continue to have unrealized potential in NSCLC. Combination studies with first-line chemotherapy have been universally negative for an overall survival benefit, though response rates and progression free survival were positive in many studies. Second line trials with docetaxel have also shown response and PFS benefit and subset overall survival benefits, particularly with nintedanib.(Reck 2014) Single agent activity of many is seen, but in a small percentage of patients. However, enthusiasm for these agents in NSCLC has waned and current trials with these drugs are limited. Bevacizumab remains an important component of first-line platinum combination therapy for many patients with advanced stage NSCLC. Ongoing trials are exploring duration of therapy questions with this drug and best ways to incorporate its use with newer immunotherapeutics. Combinations with molecularly targeted agents hold promise. Ramucirumab use may also be expanded to combinations with targeted agents pending results of ongoing trials. Resurrection of the VEGFR-TKIs in NSCLC will require further understanding of best combination therapies and better understanding of how to target them to the proper patients. The biggest challenge with anti-angiogenesis therapy remains a lack of reliable biomarkers. REFERENCES: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al.; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, et al. BEYOND: A randomized, double-bline, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer.J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. Epub 2011 Jun 25. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. Lancet. 2014 Aug 23;384(9944):665-73.. Epub 2014 Jun 2. Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.
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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 8
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.01 - Tyrosine Kinase Inhibitors (TKIs) for the Treatment of Brain Metastases (BMs) from Advanced Lung Cancer : A Large Retrospective Cohort Study (ID 2824)
10:45 - 10:56 | Author(s): C. Bennati, L. Paglialunga, A. Gili, R. Chiari, V. Minotti, G. Metro, A. Siggillino, S. Baglivo, L. Crinò
- Abstract
- Presentation
Background:
BMs are found in up to 30% of patients (pts) with advanced non small cell lung cancer (NSCLC), and are associated with a poor prognosis despite radiotherapy treatment, with a median survival of 6 months (mo). Several data are suggesting the potential brain activity of tyrosin kinase inhibitors (TKIs) alone in NSCLC pts with activating mutations. We retrospectively identified EGFR mutated and ALK rearranged NSCLCs with BMs, to evaluate the efficacy of TKIs and their role in the upfront setting.
Methods:
Out of a cohort of 270 never smoker (NS) NSCLC patients (pts) treated at our Institution from 2/2006 to 2/2015, 89 (32.9%) NSCLCs BMs were identified, synchronous in 27 pts (30.3%). 38 pts (42.7%) harboured an EGFR mutation, 33 pts (37.1%) were ALK rearranged, 18 pts (20.2%) negative for both, were used as a control cohort. Among the EGFR mutated, an in-frame deletion in exon 19 (mostly E746-A750) was found in 26 (68.4%) patients, while a point mutation in exon 21 (L858R) was detected in 10 (26.4%), 1 (2.6%) exon 18 mutation and 1 (2.6%) exon 20 insertion were identified. The majority of EGFR and ALK positive (+) pts with BMs were female (53.9%), median age 52, adenocarcinoma histology, and a good performance status.
Results:
Out of the 71 NSCLCs with BMs EGFR/ALK+, 58 pts (81.7%) received at least one line of chemotherapy, while 13 pts (18.3%) were only treated with TKIs. Of the entire series, 40 pts (56.3%) were treated with standard radiotherapy (WBRT or radiosurgery) prior to TKIs treatment, while 31 (43.7%) received a TKI upfront, distributed as follows: 13 pts (37.9%) were treated with an EGFR inhibitor (gefitinib/erlotinib/afatinib), while 18 pts (62.1%) with an ALK TKI (crizotinib/ceritinib/alectinib). All the pts in the molecular negative cohort, received WBRT and, at least, one line of chemotherapy. Within the entire series, Overall Intracranial Response Rate (OIRR: complete response CR + partial response PR) was evaluated: EGFR+ 31 pts (81.5%), ALK+ 28 pts (84.8%), control cohort 6 pts (33.3%) (p,0.003). Median [95% CI] overall survival (OS) for EGFR mutans, ALK + and EGFR/ALK negative was: 52 months (mo) (32.6-74.4),74 mo (not reached), 25 mo (9.4-40.03) (p,0.003). In the subgroup who received a TKI upfront, all EGFR+ achieved a PR, while all ALK+ obtained an objective response: 4 (22.2%) a CR and 14 (77.8%) a PR. No significant difference in OS between EGFR/ALK+ BMs treated with a TKI upfront versus further line.
Conclusion:
This retrospective study confirms that TKIs are strongly active in patients with BMs from NSCLCs harbouring a sensitive mutation. Brain disease control was achieved in an impressive 81.5% of the EGFR+ pts and 84.8% of the ALK+ subset. Of particular note, is the highest response rate in the TKI upfront arm, with 22.2% attaining a complete remission. We conclude that the use of TKIs in first line setting for BMs treatment may be a reasonable option for asymptomatic subgroup of patients with a long survival expectation, for whom WBRT may be postponed at a later disease stage.
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ORAL16.02 - Thromboembolic and Bleeding Risk with Adjuntctive LMWHs Anticoagulation in Lung Cancer Patients. Meta-Analysis of Randomized Trials (ID 2157)
10:56 - 11:07 | Author(s): M. Kowalewski, L. Zolna, A. Chrzastek, M.A. Lewandowska, M. Dancewicz, P. Wnuk, M. Bella, P. Bławat, T. Szczęsny, J. Kowalewski
- Abstract
- Presentation
Background:
Venous thromboembolism (VTE) has been demonstrated one of the leading causes of mortality in lung cancer patients. While incidence of VTE in cancer patients varies from 4-20%, at autopsy VTE accounts for as high as 50%. Various strategies of VTE prophylaxis have been proposed, among them low-molecular weight heparins (LMWHs). While different randomized controlled trials (RCTs) showed benefit with LMWHs in regard to VTE, none single RCT was adequately powered for major bleeding. In a meta-analysis of RCTs we aimed to investigate the relation between thromboembolic and bleeding risk associated with LMWHs anticoagulation in lung cancer patients.
Methods:
Established methods were used in compliance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement in healthcare interventions. PubMed, EMBASE, CINAHL, Cochrane, Scopus databases as well as major congress proceedings until April 2015 were screened for RCTs comparing LMWHs with control/placebo. Outcomes assessed were VTE and major bleeding. Odds ratios (OR) and 95% confidence intervals were used as summary statistics. Data were analysed according to Intention-to-treat principle.
Results:
Four RCTs (N=3097) were included in the meta-analysis (Table 1). Average follow-up was 237 days. In a fixed effects model, LMWHs were associated with a significant 50% reduction of the odds of VTE as compared to controls: OR (95% CI): 0.50 (0.35-0.71); p<0.0001; I[2]=0%; (Figure 1A); the number needed to treat =33. A significant, over 2-fold increase in the odds of major bleeding was observed with LMWHs: OR (95% CI): 2.16 (1.16-4.05); p=0.02; I[2]=0%; (Figure 1B); the number needed to harm was 104.Table 1. Characteristics of included studies
Figure 1Study N of pts LMWH Dose NSCLC/SCLC Follow-up (d) Agnelli et al. 2009 279 Nadroparin 3800 IU qd 79.9%-20.1% 112 Altinbas et al. 1-2, 2004 84 Dalteparin 5000 IU qd 0%-100% 301 Haas et al. 2012 546 Certoparin 3000 IU qd 100%-0% 168 Woodruff et al. 2013 2202 Dalteparin 5000 IU qd 82.2%-18.8% 365
Conclusion:
Low-molecular weight heparins significantly reduce the risk of venous thromboembolism at a price of increased major bleeding in patients with lung cancer. One episode of major bleeding occurred at every 3 VTEs prevented with LMWHs. Dose-escalation studies are certainly warranted to identify patients who would benefit most from LMWHs.
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ORAL16.03 - Acceptability of NSCLC, NOS in Advanced Disease: An Assessment of US Oncologists, Pulmonologists and Pathologists (ID 1255)
11:07 - 11:18 | Author(s): T. Herrmann, P. Fidias
- Abstract
- Presentation
Background:
In 2011 the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology issued a recommendation to classify patients with advanced NSCLC into specific histological and molecular subtypes and minimize the diagnosis of not otherwise specified (NOS) subtype. The objective of this study was to define the rate of NOS subtype being observed in practice as well as the NSCLC care team’s knowledge and beliefs about a diagnosis of NOS subtype in advanced-stage disease.
Methods:
A series of 5 questions were developed to identify the incidence of NOS subtype being observed in the community as well as relevant care team knowledge gaps and beliefs that may influence the findings. The case vignettes and questions and were based on current standards of care and evidence-base in the treatment of advanced NSCLC. The questions were made available online to healthcare providers either through a survey or as part of 2 certified medical education activities; without monetary compensation or charge. Confidentiality of survey respondents was maintained and responses were de-identified and aggregated prior to analyses. The series of 5 questions was launched in both formats in December 2014 and participant responses were collected over the following 4 months.
Results:
In total, 553 oncologists, pathologists and pulmonologists answered all 5 questions. Oncologists who responded to the questions on average saw about 6-10 patients with suspected or diagnosed NSCLC per month while pathologists and pulmonologists were more likely to see 1-5 per month. Almost 60% of oncologists, pathologists and pulmonologists stated that the incidence of NOS subtype should occur in less than 5% of all cases. Yet, 28% of participating oncologists, 37% of pathologists, and 40% of pulmonologists would find a diagnosis of NSCLC, NOS acceptable. Moreover, 45% of oncologists and 64% of pulmonologists stated that 11% or more of their patients are reported as having a diagnosis of NSCLC, NOS. Reasons for acceptability of NOS subtype differed between clinicians; with more pulmonologists stating it is always acceptable while pathologists and oncologists were more likely to cite age or smoking status, respectively. When asked what contributes to this belief a majority of oncologists and pathologists cited an inability to obtain adequate tissue while pulmonologists were more likely to state that subtyping was unnecessary to prescribe the appropriate therapy (30%) or it was a result of system barriers (25%).
Conclusion:
Despite recommendations from key organizations the incidence of NSCLC, NOS many members of the care team continue to accept a diagnosis of NOS in their patients. Our findings demonstrate a pressing need for additional education of the multidisciplinary care team involved in the diagnosis of advanced NSCLC so as to ensure appropriate diagnosis and treatment.
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ORAL16.04 - Discussant for ORAL16.01, ORAL16.02, ORAL16.03 (ID 3318)
11:18 - 11:28 | Author(s): R. Pirker
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
The majority of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer respond to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib) but nearly all eventually acquire resistance. The most common mechanism of acquired resistance is a second-site mutation in the EGFR kinase domain, T790M. The phase III, double-blind IMPRESS study evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin in patients with acquired resistance to first-line gefitinib. Study results did not support the continuation of gefitinib after disease progression (by RECIST criteria) when platinum-based doublet chemotherapy is used as second-line therapy. Here we report the results of a retrospective biomarker analysis of plasma circulating free, tumor-derived DNA (ctDNA) from patients in IMPRESS, including T790M profiling, to help understand the IMPRESS clinical trial outcome.
Methods:
Plasma samples for ctDNA isolation were collected at baseline and discontinuation from 151 randomized, non-Chinese patients in IMPRESS (58% of overall IMPRESS population). ctDNA levels of T790M, L858R, and Exon19 deletions were detected using both a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) and a qualitative QIAGEN[®] Therascreen ARMS assay (baseline only). Local EGFR tumor tissue (diagnostic) results were available for 133/151 patients. Mutation concordance rates between tissue and baseline plasma results, and comparisons between the two plasma detection methods, were calculated.
Results:
Baseline ctDNA EGFR mutation results were obtained for >99% (150/151) of patients. Using BEAMing, sensitivity and specificity between baseline plasma EGFR sensitizing mutations and local EGFR tumor tests were 78% (69/89) and 98% (42/43), respectively, for Exon19 deletions, and 82% (31/38) and 97% (91/94) for L858R. The T790M detection rate in baseline plasma samples using BEAMing was 56% (84/150). The Therascreen ARMS assay demonstrated a significantly reduced T790M detection rate of 13% (20/150). Likewise, the sensitivity of the Therascreen ARMS assay with respect to tissue for EGFR sensitizing mutations was also reduced compared with BEAMing: Exon 19: 54% (48/89), L858R: 47% (18/38), though the specificity remained near 100%. In the 97 evaluable plasma samples collected at discontinuation, T790M was detected by BEAMing in 52% (50/97) of patients. When compared with matched baseline plasma, 11 patients had newly acquired T790M mutation at discontinuation while T790M reverted to undetectable in 14 patients. Full plasma profiling data from the complete IMPRESS clinical study population (including 108 patients from China) and correlative analyses of plasma EGFR mutation status with clinical outcome (progression-free survival, overall survival, objective response rate) will be presented.
Conclusion:
In IMPRESS, T790M was detectable with BEAMing digital PCR in the baseline ctDNA samples of 56% of evaluable patients, a rate comparable to similar mutation analyses in this same second-line, EGFR-TKI-failed setting. EGFR mutation detection in plasma using the Therascreen ARMS assay demonstrated comparable specificity to BEAMing but reduced sensitivity. The T790M detection rate afforded by the BEAMing technology will allow for a comprehensive assessment of correlations between clinical outcome in IMPRESS and EGFR mutational status.
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- Abstract
- Presentation
Background:
The most important advantage of EGFR mutation analysis in circulating tumor DNA(ctDNA) from plasma is quantitative and dynamic evaluation. Here, we investigated the feasibility of droplet digital PCR(ddPCR) for quantitative and dynamic detection of EGFR mutation in ctDNA and next generation sequencing (NGS) for screening a range of resistance-relevant mutations in plasma DNA in the process of disease progression for patients diagnosed with advanced lung adenocarcinoma.
Methods:
Seventy-three patients were enrolled in this study. Tumor tissues were sampled before treatment, and paired plasma DNA samples were collected pre- and post- EGFR-TKI therapy. Sixty-seven of 73 patients obtained blood samples in the time-point of disease progression. All 73 patients presented EGFR mutation in tumor tissues tested by denaturing high performance liquid chromatography（DHPLC）method. We measured the absolute quantities of plasma EGFR mutant and wild-type alleles by ddPCR. Multi-genes testing was performed using NGS in twenty-seven plasma samples from the twelve patients.
Results:
Taking the EGFR mutation in tumor tissue as the standard, the EGFR mutations detection sensitivity in plasma DNA was 74%（54/73）. According to EGFR mutation status in TKI-naïve patients, all 73 patients were divided into two subgroups that carried mutation in both of specimens (B+/T+,n=54) and mutation only in tissues rather than in plasma ctDNA(T+ /B-,n=19) . The B+/T+ group showed superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P<0.0001) compared to T+ /B- group. The patients with high EGFR mutated abundance in plasma ctDNA (＞5.15%) showed better PFS (median, 15.4 vs 11.1months; P=0.021) compared with those with low EGFR abundance (≤5.15%). EGFR mutation dynamic alteration during EGFR-TKIs therapy was analyzed and showed patients with decreased quantity of EGFR mutated alleles after disease progression（n=29）showed better PFS compared with non-decreased quantity group(n=38) (median, 12.7 vs 7.1 months; P=0.001). However, NGS results came from 12 patients’ matched plasma DNA showed that 66.6% total mutational copies were elevated and 76.5% mutual mutation frequency increased after disease progression. Besides canonical EGFR pathway, mutated genes in plasma DNA were significantly enriched in cell cycle and TGF-β pathways when disease progressed. Quantification of mutant allele fraction by means of either NGS or ddPCR assay showed excellent agreement.
Conclusion:
Droplet digital PCR is a highly sensitive method for EGFR mutation analysis in plasma DNA of patients with advanced lung adenocarcinoma, while NGS shows good performance in multiple genes testing especially novel and uncommon genes. High EGFR sensitive mutated abundance（>5.15%） in plasma samples of TKI-naïve patients can predict better PFS of EGFR-TKI treatment.
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- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) can achieve dramatic response in EGFR activating mutation positive lung cancer patients. However, the duration of treatment is quite different. Some patients experienced longer progression-free survival (PFS) of more than 1 year, whereas some had PFS of shorter than 6 months. Our previous study showed that the relative EGFR mutation abundance in tumor tissues could predict benefit from EGFR-TKIs treatment. However, it still remains controversial whether the intratumor heterogeneity of EGFR activating mutation exists. This study explored the intratumor heterogeneity of EGFR activating mutation at the level of single cancer cell.
Methods:
Single H1975 cells which harbor EGFR exon 21 L858R mutation were isolated by flow cytometry (FCM). The whole DNA extracted from a single cell was submitted to perform nested polymerase chain reaction (PCR) amplification of EGFR exon 21. The amplified products from nested PCR were sequenced to evaluate the feasibility of single-cell analysis for EGFR exon 21. Then, six patients diagnosed with lung adenocarcinoma whose fresh frozen specimens harbored EGFR exon 21 mutation tested by direct sequencing were chosen. All of them received gefitnib treatment and the PFS of three patients was longer than 14 months (Group A) while the PFS of other three patients was shorter than 6 months (Group B). By using the established method based on single H1975 cells, EGFR exon 21 mutational status was analyzed in single tumor cells which were captured from tumor sample by Laser Capture Microdissection (LCM). At least 20 tumor cells were captured from each tumor sample. X[2] test was used to compare the amplification rate of nested PCR and EGFR mutational rate between the two groups.
Results:
A total of 104 individual H1975 cells were obtained to detect EGFR exon 21 mutational status through the application of single-cell nested PCR. The amplification rate and allele drop-out rate were 96.2% and 7.0%. A total of 135 tumor cells from six samples were captured. The amplification rate of nested PCR was 84.3% (59/70) in Group A and 93.8% (61/65) in Group B. There was no statistical difference between the two groups (X[2] =3.119, P=0.077). The mutational rate of EGFR exon 21 L858R was 89.5% (17/19), 89.5% (17/19), and 81.0% (17/21) in the three patients in Group A and 72.2% (13/18), 68.4% (15/22), and 66.7% (14/21) in the three patients in Group B respectively. The total mutational rate was 86.4%（51/59）in Group A, which was significantly higher than the total mutational rate 68.9%（42/61）in Group B (X[2] =5.321, P=0.021).
Conclusion:
It is feasible to perform EGFR mutation detection in single cancer cells. The intratumoral heterogeneity of EGFR activating mutation in lung adenocarcinoma does exist based on the analysis in single cancer cells and the abundance of EGFR activating mutation is relevant to the benefit from EGFR-TKIs treatment.
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ORAL16.08 - Discussant for ORAL16.05, ORAL16.06, ORAL16.07 (ID 3319)
12:01 - 12:11 | Author(s): P.C. Mack
- Abstract
- Presentation
Abstract not provided
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Author of
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ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:B.C. Cho, R.L. Keith
- Coordinates: 9/09/2015, 16:45 - 18:15, 201+203
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ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)
17:07 - 17:18 | Author(s): Q. Zhou
- Abstract
- Presentation
Background:
The MAGRIT study was a worldwide, multicenter, phase-3 double-blind, randomized trial evaluating efficacy of the MAGE-A3 Cancer Immunotherapeutic in resected non-small cell lung cancer (NSCLC) (www.clinicaltrials.gov NCT00480025). We examined baseline patient and disease characteristics associated with overall survival (OS) and disease-free survival (DFS) among patients assigned to placebo.
Methods:
Study participants were ≥18 years, with histologically proven, MAGE-A3-positive stage IB, II or IIIA NSCLC (AJCC 6.0). Participants had undergone complete anatomical resection of the tumor (lobectomy or pneumectomy) with mediastinal lymph node (LN) dissection or sampling according to standard of care. Up to four cycles of platinum-based adjuvant chemotherapy were allowed. Cox regression models were used to explore characteristics that could predict DFS and OS. Factors statistically significant in univariate analysis (p<0.05) were included in multivariate models using a stepwise approach (p<0.05 to enter/remain in the model).
Results:
There were 757 placebo patients in the total treated population; median age 63 years, 76% male, 53% with squamous cell carcinoma (SCC), 34% with adenocarcinoma, 98% with performance status 0-1, 52% had received adjuvant chemotherapy.In univariate analyses, SCC, lower N-category and earlier disease stage were associated with improved DFS. Lower N-category, earlier stage and smaller tumor size were associated with improved OS. In multivariate analysis, N-category (HR 1.34, 95%CI [1.16-1.55]) and histological type (HR for SCC vs non-SCC 0.64, 95%CI [0.51-0.81]) remained significant for DFS. N-category (HR 1.47, 95%CI [1.21-1.79]) and tumor size (HR by unit increase 1.08, 95%CI [1.01-1.15]) did so for OS. No association was found between DFS or OS and age, gender, race, region, baseline performance status, quantitative MAGE-A3 expression, chemotherapy administration or type of chemotherapy, smoking status or type of LN sampling (minimal/systematic). Among patients with SCC, univariate analysis identified increased number of chemotherapy cycles and operative technique (pneumectomy) as associated with improved DFS (p<0.05). Only operative technique remained in the multivariate model. When including N-category (p<0.10 in univariate analysis) in the multivariate model, N-category and number of chemotherapy cycles were also selected. Lower N-category and smaller tumor size were significantly associated with improved OS, in univariate and multivariate analyses. Among patients with non-SCC, univariate analysis identified younger age, being female, lower N-category and earlier disease stage with improved DFS, and lower N-category, earlier disease stage and region (East Asia) with improved OS. N-category and gender, and N-category and region remained significant in the multivariate analysis for DFS and OS, respectively.
Conclusion:
This is the first prognostic factor analysis in resected NSCLC performed on data from a large, prospective randomized study. It highlighted that in terms of DFS, SCC patients have a better prognosis than non-SCC patients. N-category plays a major role in determining prognosis. Operative technique (pneumectomy), number of chemotherapy cycles (SCC) and gender (non-SCC) are also associated with outcome. Variables predictive for OS are N-category and tumor size (all) and region (non-SCC). These results confirm retrospective studies done within the context of TNM classification, but add that histopathology subtype is a strong determinant for DFS in resected NSCLC.
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