Virtual Library
Start Your Search
S. Popat
Moderator of
-
+
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
-
+
MS03.01 - Current Understanding of the Biology (ID 1856)
14:20 - 14:40 | Author(s): J.V. Heymach
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
Author of
-
+
MINI 01 - Pathology (ID 93)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:W.A. Franklin, A.G. Nicholson
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
-
+
MINI01.03 - Pathology-Imaging Agreement in Distinguishing Separate Primary Tumours and Intrapulmonary Metastasis in Staging of Multiple Lung Cancers (ID 2659)
10:55 - 11:00 | Author(s): S. Popat
- Abstract
- Presentation
Background:
The 7[th] TNM staging system for lung cancer recommended staging for cases with multiple nodules viewed as intrapulmonary metastases (IM) as T3 (same lobe), T4 (ipsilateral different lobe) and M1a (contralateral lobe), whilst those classified as separate primary tumours (SPTs) as T(x)NM where “x” is the number of primary tumours, either as a number or “m” for multiple. With an increase in patients presenting with multiple nodules, we sought to develop a set of criteria for c-staging on imaging and to determine the agreement between clinical and pathological staging in a cohort of resected lung cancers who had multiple nodules.
Methods:
In 2013 and 2014, there were a total of 48 consecutive cases with available imaging resected with multiple tumours, ranging from 2 to 5 nodules. Of these, one case was excluded as it was a carcinoid with background DIPNECH. These cases were classified as SPT or IM based on previously published criteria (Girard et al. Am J Surg Pathol 2009;33:1752-64). Imaging criteria were generated based on clinical experience in similar fashion with indicators of SPT being 1) Lesions of equivalent size (one not more than 100% of the other) 2) Smaller lesion is spiculated , 3) At least one lesion is subsolid, 4) Presence of field change. (For signs 1 and 2, if the lesions were in different lungs, an absence of mediastinal disease on imaging was required). Cases with at least one positive sign were classified as SPTs. The interobserver agreement between radiologists and pathologist were then generated.
Results:
Of the 47 cases, the additional nodules were not identifiable on CT in 7 cases. In the remaining 40 cases, there was agreement in 28 cases, of which 16 were SPTs and 12 were IM. Of 12 cases where there was disagreement, only 3 were SPTS and the majority were cases classified on pathology as IM. There was 70% agreement, greater than that expected by chance (p = 0.002) with a kappa value of 0.41.
Conclusion:
Moderate agreement can be achieved in terms of clinical and pathological staging of lung cancers presenting with multiple nodules using imaging and pathologic criteria. Using pathology as the gold standard, there was greater agreement in categorisation of SPTs (84% (16/19)) than IM (57% (12/21)).
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
-
+
MINI21.05 - Discussant for MINI21.01, MINI21.02, MINI21.03, MINI21.04 (ID 3421)
17:05 - 17:15 | Author(s): S. Popat
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 28 - Psychological Impact of Lung Cancer and its Treatment (ID 150)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:A. Oton
- Coordinates: 9/09/2015, 16:45 - 18:15, 102+104+106
-
+
MINI28.11 - Randomised Study of Acupuncture, Morphine and Combination in NSCLC/Mesothelioma (ID 108)
17:45 - 17:50 | Author(s): S. Popat
- Abstract
- Presentation
Background:
Dyspnoea is a common symptom of lung cancer. Morphine is widely used to control dyspnoea.
Methods:
We randomised 173 patients with advanced non-small cell lung cancer or mesothelioma with a dyspnoea score ≥ 4 on visual analogue scale (VAS) to one of three arms (acupuncture [A], morphine [M] or combination [AM]). A was delivered to upper sternal, paravertebral, hand and trapezius trigger points. Patients on arm A were given rescue morphine if needed. We recorded VAS dyspnoea and relaxation, lung function tests, respiratory rate, and EORTC QLQ-30/ QLQ-LC13 questionnaires at baseline, 30mins, 90mins, 4 hours, day 2, 7 and 14. Primary endpoint was proportion of patients achieving ≥1.5 improvement in VAS dyspnoea at 4 hours.
Results:
The median age of the study population was 73. 53% were performance status 2-3. The baseline median VAS dyspnoea score was 6.5. All patients scored >7 on HAD depression score. 44.3% scored >10 on HAD anxiety. Dyspnoea improved by ≥1.5 points on the VAS in 74% of patients in arm A, 60% in arm M and 66% in arm AM (A versus M p-value 0.12, AM versus M p-value 0.50). On VAS scales there was improved anxiety, relaxation and tiredness of A over M. Analysis of EORTC questionnaire data showed a mean change from baseline global health % score for arm A of 7.08 compared to -2.08 for arm M (p-value = 0.009). There was a mean change from baseline in dyspnoea % score for arm A of -7.89 compared to -1.05 for arm M (p=0.029, not significant at 1% level). There was no improvement in lung function or respiratory rate. 21% of patients in arm A, 87% in arm M and 87% in arm AM took one of more doses of morphine (p<0.001). 123 patients had toxicity data. All toxicities were CTCAE grade 1/2 and in line with morphine’s toxicity profile, with 8% of patients in arm A, 35% in arm M and 39% of patients in arm AM reporting toxicities. Two patients stopped morphine because of side effects. There were two cases of skin irritation attributable to acupuncture site dressings. Score Changes from BaselineA M AM Mean VAS relaxation (SD) -1.06 (±2.60) 0.19 (±2.43) -1.48 (±2.05) p<0.001 Day 7 median LAR relaxation (range) -1 (-6.7–4.5) 0 (-3.5–4.4) -0.9 (-5.6–4) p=0.006 Day 7 median LAR anxiety (range) 1.5 (-2.5–8) 0 (-4–6.2) 1.2 (-5.4–6.3) p=0.003 Mean LAR tiredness (SD) -0.82 (±2.61) 0.02 (±2.20) -0.94 (±2.37) p=0.002 Mean EORTC global health % (SD) 7.08 (±25.54) -2.08 (±17.70) 2.72 (±16.96) p=0.009 Mean EORTC dyspnoea % (SD) -7.89 (±17.382) -1.05 (±17.704) -6.37 (±17.797) p=0.029 Median dose morphine (range) 32mg (1-60) 53mg (13-163) 40.63mg (3-154) p=0.007
Conclusion:
This study population was of poor performance status. A is as effective as M in the treatment of dyspnoea and has additive value for anxiety, relaxation and global health. Acupuncture is morphine sparing. Acupuncture should be a treatment available to lung cancer patients with dyspnoea and as a morphine adjunct.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 29 - Meta Analyses and Trial Conduct (ID 156)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:D. Morgensztern, M. Redman
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2a-3b
-
+
MINI29.14 - Using a Bayesian Adaptive Phase II Trial Design to Test Multiple Genetic-Marker-Directed Drugs in the National Lung Matrix Trial (ID 1241)
19:45 - 19:50 | Author(s): S. Popat
- Abstract
- Presentation
Background:
The National Lung Matrix Trial is a flagship trial in the United Kingdom being the first to combine the development of a technology platform that screens for multiple genetic aberrations in tumours with testing of multiple novel genetic-marker-directed drugs. The trial is focused on patients with advanced non-small cell lung cancer and currently includes 8 different drugs and 23 different drug-biomarker combinations. The aim of statistical analysis is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation and this paper evaluates the novel statistical design that has been implemented.
Methods:
The primary outcome measure representing signal of activity is best objective response rate (ORR) in most cases and progression-free survival (PFS) in others. Each drug-biomarker combination could be considered as a single arm phase II trial and could have been designed using standard statistical approaches such as Simon’s two stage design. However, a Bayesian adaptive design was chosen because it gives a more realistic approach to decision-making in this complex setting. It has flexibility to make conclusions without fixing the exact sample size which will be important with the uncertainty around the prevalence of each biomarker. The design allows early stopping of recruitment to any drug-biomarker combinations that do not show sufficient promise at an interim analysis to warrant continuation. It also allows, when appropriate, for information about the primary outcome measure to be shared across different biomarker cohorts within any single drug to aid decision-making. Decision-making is based on the posterior probability distribution for the primary outcome measure, given the observed data and any prior knowledge, calculated using bayesian conjugate analysis. For ORR, the critical threshold which defines a signal of activity is 30% for single drugs and 40% for combinations and for PFS the critical threshold is median 3 months. The interim and final sample sizes were selected to ensure the design achieved pre-defined desirable operating characteristics.
Results:
For both ORR and PFS as primary outcomes, sample sizes of 15 and 30 patients per drug-biomarker cohort for interim and final analyses respectively were selected as giving the required operating characteristics. Simulations of trials for single drugs with ORR as the primary outcome showed that this would ensure a high probability (82%) of correctly stopping early when the true ORR was only 10% and a high probability (90%) of correctly recommending further investigation when the true ORR was as high as 40%. Operating characteristics for the combination drug arms were similar. Operating characteristics for trial arms with PFS as the primary outcome are dependent on the recruitment rate and give high probabilities (>95%) of stopping early when the true median PFS is only 1 month and high probabilities (>80%) of recommending further investigation when the true median PFS is as high as 4 months.
Conclusion:
The Bayesian adaptive design with 15 and 30 patients per drug-biomarker cohort for interim and final analyses respectively gives a flexible, efficient design with good operating characteristics to investigate multiple genetic-marker-directed drugs within a single phase II trial.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
-
+
MINI38.03 - Validation of a Specific Missense GTF2I Mutation in More Indolent Thymic Epithelial Tumours (ID 3017)
18:40 - 18:45 | Author(s): S. Popat
- Abstract
- Presentation
Background:
Thymic epithelial tumours (TETs) are rare intrathoracic cancers that can be invasive and very difficult to treat. There is currently a huge gap in the understanding of the basic science behind their development as well as great clinical need for development of effective treatments. Recently a missense mutation (T>A, at the same position on chromosome 7, 74146970) was identified in GTF2I at high frequency (78%) in the more indolent type A and AB thymomas. We examined the frequency of this alteration in an independent cohort of well clinically characterized patients from the UK.
Methods:
Tumour samples were collected from 94 patients from a single tertiary cardiothoracic centre in the UK, the Royal Brompton & Harefield NHS Foundation Trust (London). These were subject to histological assessment by expert Consultant Histopathologists to confirm the diagnosis and determine tumour abundance. DNA was extracted with Quiagen’s QIAamp DNA FFPE Tissue Kit (Catalogue No. 56404). PCR and Sanger sequencing was performed with semi-nested primers.
Results:
We assessed the frequency of the GTF2I mutation in a total of 94 TETs with a tumour abundance of at least 70%. The mean age for all patients was 57 and the male: female ratio was 1:1.25 The GTF2I mutation was seen in 25 of 87 evaluable TETs (29%) and was present more commonly in type A (85%) and AB (46%) thymomas. The frequency decreased to 9% in type B1 (1/11) and 5% in type B2 thymomas (1/19). In our cohort the mutation was not detected in any B3 thymomas or carcinomas, including neuroendocrine tumours or two cases of thymic hyperplasia. Interestingly all AB thymomas with the mutation had a much lower percentage of mutant alleles compared to the majority of the A thymomas. Twenty-three of the 25 patients (92%) with the mutation had Stage I – II disease at presentation and had complete resection of their thymoma.
Conclusion:
Our results confirm the presence of the GTF2I mutation at a high frequency in type A and AB thymomas in an entirely different patient cohort. Although the frequency of the mutation in type A thymomas in our cohort is very similar to what was reported originally (85% and 82% respectively) it was lower in the AB thymomas (46% and 74% respectively). Explanations for this include the smaller sample number in our cohort and a higher percentage of the lymphocytic component in our samples than that in the original series. The lower mutation frequency in the B subtypes and carcinomas compared to the original series could be due to the smaller numbers in our cohort. We aim to address these issues by expanding our validation series to over 200 samples. Whole exome and RNA sequencing of TETs is ongoing and will allow us to further confirm and extend this finding.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
-
+
ORAL40.02 - Molecular Landscape of Malignant Mesothelioma from Whole Exome Sequencing (ID 2439)
16:56 - 17:07 | Author(s): S. Popat
- Abstract
- Presentation
Background:
Whole exome sequencing has revealed key genetic events in several cancer types that have been successfully translated into clinical benefits. These advances are still lacking in malignant mesothelioma (MM), a highly aggressive malignancy with limited effective therapy. Frequent BAP1 mutations occur in a subset of this disease but the full molecular landscape of MM is still poorly characterized.
Methods:
We have therefore conducted whole exome sequencing of tumours from the pleura for 36 cases of MM. DNA from matched blood was available for 7 of the cases and was also sequenced. The variants were identified with GATK tools and annotated with ANNOVAR. Variants were filtered with the following criteria: quality score ≤ 50, present in dbSNP138, 1000 genomes variants and NHLBI ESP 6500 variants. Mutations with deleterious functional consequences predicted by Polyphen-2, SIFT and Mutation Taster tools were confirmed by Sanger sequencing.
Results:
A total of 9,064 variants (3,256 somatic) were identified. We confirmed mutations in genes previously described to be mutated in MM in 5 cases: BAP1 (R227C, Q684X, H141P), NF2 (76_76del, R221X) and TP53 (I195N). In BAP1 wt tumours (6 of the 7 cases with matched blood), we confirmed somatic mutations in 5 genes encoding components of either MAPK or WNT signaling pathways. In addition, we validated somatic mutations in 12 genes across 4 of the 6 cases, many of which are novel in MM and are involved in chromatin modification. We also observed these genes to be mutated in BAP1 wt tumours in the 29 additional unmatched MM cases.
Conclusion:
Thus our data suggests that in addition to BAP1, mutations in genes associated with MAPK, WNT signaling and the chromatin remodeling complex may represent a consistent pattern of molecular alterations in MM.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P1.01-086 - TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC (ID 949)
09:30 - 09:30 | Author(s): S. Popat
- Abstract
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.
Methods:
Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014
Results:
Not applicable
Conclusion:
Not applicable
-
+
P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P1.08-011 - Clinical Outcome and Prognostic Factors for Advanced Malignant Mesothelioma (MM) Patients (pts) Treated on Phase I Trials (ID 2595)
09:30 - 09:30 | Author(s): S. Popat
- Abstract
Background:
Relapse after approved anticancer treatments is inevitable in MM pts. Novel agents in phase I trials may benefit such pts and the development of a prognostic score can help identify those who are likely to benefit most. We review the outcome of pts with relapsed MM who have participated in phase I trials in the drug development unit (DDU) of the Royal Marsden Hospital (RMH).
Methods:
The RMH prognostic score (RPS) (albumin < 35 g/L, lactate dehydrogenase [LDH] > upper limit of normal [ULN], and > 2 sites of metastases) is an objective tool used to select pts for phase I trials. In view of the pattern of disease spread in MM, we sought to define a MM-specific RPS (m-RPS), by assessing baseline patient factors. Data from consecutive patients who participated in 33 phase I trials between 09/2003 and 12/2014 were included in this analysis. The endpoints were time to progression (TTP) overall survival (OS) and safety. Kaplan-Meier analysis using a log rank test was used to determine survival outcomes.
Results:
Data from 54 pts, M:F (36:18), median age 62 years (range, 25-76) were studied. All pts had ECOG PS 0-1. TTP was 2.5 (95% CI 1.7-3) months, OS was 7.6 (95% CI 5.3-8.4) months and the clinical benefit rate was 15%; Three (6%) pts had RECIST confirmed partial response (to PI3K pathway inhibitors [n=2] and immunotherapy [n=1]); 5 (9%) pts had RECIST stable disease ³6 months. Male gender was highlighted as a factor of poor prognosis (p=0.004) in a multivariate analysis and therefore, we propose m-RPS for MM pts that now incorporates gender instead of the number of metastatic sites (Table). The good prognosis group [A] (m-RPS 0-1; n=23) had a median OS of 13.7 (95% CI 7.9-24) months and the poor prognosis group [B] (m-RPS 2-3; n=28) had a median OS of 4 (95% CI 2.8-7.5) months, p<0.001. 13 pts (24%) had an OS < 12 weeks: 3 (11%) pts from Group [A] and 10 (36%) pts from Group [B]. 39 (72%) pts experienced G1-G2 toxicities, ³G3 toxicities were seen in 8 (15%) pts and 7 (13%) pts discontinued trial due to toxicity.Variable Score LDH ≤Upper limit of normal (ULN) 0 >ULN 1 Albumin ³35g/L 0 <35g/L 1 Gender Female 0 Male 1 Table. modified RMH prognostic score (m-RPS)
Conclusion:
Experimental agents in the phase 1 setting appeared to be well tolerated with preliminary signals of benefit in selected advanced MM pts. The m-RPS should be prospectively validated as a screening tool for MM pts considered for phase I studies
-
+
P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P2.01-077 - A Phase 1b Trial of the Combination of Capecitabine and Erlotinib in Advanced Lung Cancer (ID 239)
09:30 - 09:30 | Author(s): S. Popat
- Abstract
Background:
Erlotinib is active in tumors with an EGFR mutation. Capecitabine, a thymidylate synthetase inhibitor, has shown some activity in advanced lung cancer (ALC). The combination of erlotinib and capecitabine has not been studied in ALC.
Methods:
We conducted a phase 1b trial, using a standard 3+3 dose escalation design to define the maximum tolerated dose (MTD) and safety of the combination of erlotinib and capecitabine, given on a 3-weekly cycle in 2[nd] line patients unselected for EGFR status. DLT was any grade≥2 toxicity. After MTD was defined in the 2[nd] line patients, we planned expansion of the trial to 1[st] line patients for further dose escalation. Dosing levels are listed in Table 1. Toxicity was assessed using CTCAE v3.0, response rate was assessed using RECIST 1.1, and survival assessed using Kaplan-Meier method.
Results:
We recruited 40 patients with adenocarcinoma. 55% were male, with median age of 67 years (range 38-84). 65% were ex-smokers and 28% were current smokers. Performance status was ECOG 1 in 65% and 2 in 35% of patients. 85% of patients had received platinum-doublet chemotherapy for 1[st] line ALC, with 10% having maintenance pemetrexed. One patient had an EGFR mutation. Dose escalation stopped at level 3 in 2[nd] line patients with expansion to 6 patients due to dose limiting toxicities (DLTs) of grade (G) 2 creatinine rise, G2 anemia, G3 atrial fibrillation, and G3 pneumonia in 2/6 patients. The MTD was thus at level 2 that was also expanded to 6 patients, confirming safety. First line patients were then recruited at MTD but resulted in DLTs in 3/4 patients with G3 troponin rise, G2 rash, and G2 bilirubin rise in 2 patients. Hence the 1[st] line approach was abandoned. The MTD in 2[nd] line patients was further expanded for toxicity and activity. The overall response rate was 3% with a disease control rate of 34%. A partial response was seen in 1 patient with EGFR mutation of 11.3 months duration. The median progressive free survival was 1.6 months (95%CI 1.4 – 3.5) and the median overall survival was 6.1 months (95%CI 5.1 – 12.5).
Conclusion:
The MTD for capecitabine is 750mg/m[2] bd days 1–14 and erlotinib 100mg od on a 3-weekly cycle. The addition of capecitabine does not improve the efficacy of erlotinib in unselected ALC. This combination could be explored further in ALC selected for EGFR mutation. Table 1: Patient disposition.Dose escalation No. of pts No. of pts with DLTs Level 1 - Erlotinib 100mg od, Capecitabine 500mg/m[2], bd, days 1-14 3 Level 2 - Erlotinib 100mg od, Capecitabine 750mg/m[2], bd, days 1-14 3 + 3 Level 3 - Erlotinib 100mg, od, Capecitabine 1000mg/m[2] bd, days 1-14 3 + 3 2 1[st] line ALC at level 2 4 3 Dose Expansion 2[nd] line ALC 21
-
+
P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P2.04-085 - A Comparative Analysis of Cancer Hotspot Mutation Profiles in Circulating Tumour Cells, Circulating Tumour DNA and Matched Primary Lung Tumour (ID 2451)
09:30 - 09:30 | Author(s): S. Popat
- Abstract
Background:
Blood based mutation profile analyses are becoming an increasingly important non-invasive form of mutation screening in cancer. Many have reported on single mutation comparisons between blood based and primary tumour tissue, but limited information is available on multiplex comparisons between the DNA extracted from circulating tumour cells (CTC), circulating free tumour DNA in the plasma (ctDNA) against the current standard of FFPE analysis of primary tumour.
Methods:
Pre-operative whole blood samples were collected from 30 patients who underwent thoracic surgery. CTCs were isolated using ScreenCell MB devices from 6ml of whole blood, and 1ml aliquots of plasma were removed from 9ml of EDTA samples. Matching FFPE samples were retrieved from post-resection primary tumour tissue in three 10µm PCR rolls. DNA was extracted from the CTCs, ctDNA and matched FFPE tissues using Qiagen kits (QIAamp DNA Micro kit, QIAamp DNA blood mini kit and QIAamp FFPE tissue kit, respectively). The 90 (30 matched triplicates) DNA samples were sequenced by Illumina HiSeq using Z3 cancer panel (Illumina, San Diego). Agreements of variant calls were compared between the three DNA substrates and a kappa statistic was reported using Stata 13.
Results:
Between 2011 and 2013, samples from 30 consenting patients were obtained. In total, 10 had primary lung cancer, 19 had secondary lung cancer, and 1 (intentionally included) had no evidence of cancer. From the 90 samples, a total of 18,821 variant calls were identified after the removal of known 1,048 germline variants. Within the hotspot panel alone, the mean (SD) number of variant calls per patient was 151 (44) on FFPE samples, 136 (49) on CTC samples and 463(108) on ctDNA samples. There was good agreement between CTCs and FFPE of 79.8% with a Kappa statistic of 0.42 (P<0.001). Agreement between ctDNA and FFPE was much poorer at 12.7% with a Kappa statistic of -0.40 (P=1.000). The results also suggested poor agreement between CTC and ctDNA of 16.1% with a Kappa statistic of -0.32 (P=1.000). Focusing on single gene comparisons on the multiplex platform, agreement was considerably better for KRAS and EGFR for CTCs compared to ctDNA at 44% versus 11% for KRAS and 92% versus 9% for EGFR respectively. Discordances were largely due to an increased number of variants that were identified in ctDNA and not in CTC or FFPE tissue.
Conclusion:
Our results suggest on a next generation sequencing platform that the global genetic variant profile between DNA extracted from CTC had good agreement with FFPE primary tumour tissue, and the agreement for ctDNA and FFPE was much poorer. This was observed to be an increase in the number of variants detected on single gene analysis and may be due to processing, sample or analytic difficulties with ctDNA.
-
+
P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P3.04-011 - A Validation Study for the Use of ROS-1 Immunohistochemistry in Screening for ROS-1 Translocations in Lung Cancer (ID 2826)
09:30 - 09:30 | Author(s): S. Popat
- Abstract
Background:
ROS-1 translocations are a rare genetic abnormality in lung cancers that, when identified, are a target for personalised therapy. The current test of choice is FISH, although with a rate of no more than 1-2%, screening using FISH is an expensive proposition. A further possibility is using immunohistochemistry (IHC) as a screening tool and commercial antibodies are now available that identify the ROS-1 protein in tumour cells. We present our data in undertaking a validation study for potential diagnostic usage.
Methods:
Given the relative rarity of the translocation and the fact the most driver mutations occur in isolation, a test cohort of cases was selected from patients recruited to phase 1 of the Cancer Research UK-Stratified Medicine Project (CRUK-SMP), who were identified as negative for EGFR, KRAS and/or BRAF mutations, as well as ALK translocations. Negative cases were then screened with an antibody for ROS-1 (D4D6, Cell Signalling, 1 in 300 dilution) and scored as negative, weakly positive or moderately positive, along with the percentage of positive cells. Cases were then sent for FISH analysis for the ROS-1 translocation, with a cut-off of > or = to15%, and the sensitivity and specificity of positive staining for ROS-1 was generated.
Results:
From 170 patients recruited from our institution into CRUK-SMP phase 1, a total of 103 patients were wild type for the above mutations (90 for all 4 genetic abnormalities. 9 further cases had failed tests for one and 4 for two mutations (6 carcinoids, 38 squamous cell carcinomas, 5 small cell carcinoma, 2 adenosquamous carcinoma, 1 pleomorphic carcinoma, 3 large cell carcinoma, 2 large cell neuroendocrine cell carcinoma, 7 non-small cell carcinoma (on biopsy) and 39 adenocarcinomas). 39 cases were tested (adenocarcinoma = 37, adenosquamous carcinoma = 2) with FISH, and one case was positive (78% positive cells). FISH testing was negative in 35 cases with scores of 1-8%, and three cases failed. The one positive case was positive on IHC (>90% of cells, moderate staining). In the 35 cases negative for FISH, four cases showed variable positivity on IHC (20, 40,50, 90%, moderate staining) and five cases showed weak focal staining (<5, <5, 10, 20, 30%, weak staining). The remainder were negative on IHC. All non-adenocarcinomas were negative on IHC. Several cases show positive staining of entrapped background pneumocytes and alveolar macrophages, making scoring problematic in some adenocarcinomas.
Conclusion:
Moderate staining for ROS-1 using IHC, independent of percentage positive cells, showed high sensitivity (100%) for tumours that contained a high level of translocated cells. However, specificity was at best 50%, even if a cut-off of 50% positive cells was applied. Pathologists also need to be aware of background staining so cases are not interpreted as false positives.
-
+
P3.04-053 - SPECTAlung: Screening Patients with Thoracic Tumors for Efficient Clinical Trial Access (ID 1386)
09:30 - 09:30 | Author(s): S. Popat
- Abstract
Background:
The identification of molecular alteration and its targeting has completely changed the treatment and prognosis of lung cancer. However, designing and implementing clinical trials in small subsets of patients with a particular molecular alteration is challenging because of lack of uniform screening program. Across Europe, screening for molecular alterations is center or country dependent and, generally limited to a small subset of genes. SPECTAlung is the first European standardized, quality-assured molecular screening program of the European Organization for the Research and Treatment of Cancer (EORTC) in collaboration with the European Thoracic Oncology Platform (ETOP) to facilitate clinical trial access for patients with thoracic tumors. It is expected to test 500 to 1000 patients each year with the overall goal of offering patients clinical trials with targeted agents.
Methods:
Patients sign the informed consent for their tumor tissue to be collected, centralized and processed according to defined international quality control standards at Gustave Roussy Biobank (Villejuif, France). Next Generation Sequencing (NGS) is performed at Sanger Institute (Cambridge, UK) where a panel of about 360 genes is analyzed for mutation, rearrangements and gene copy number. Eligible patients will be those having a pathological diagnosis of any thoracic tumor (lung cancer, malignant pleural mesothelioma and thymic malignancies) at any stage of disease, availability of tumor tissue, age at least 18 years, PS 0-2, life expectancy > 3 months, no active malignancy in the 5 years before study entry and absence of any exclusion criteria that may prevent inclusion into clinical trials. A molecular report will be released to the investigator highlighting identified molecular alterations and also the trials for which the patients might be eligible. The study has been submitted to ethical committees of 15 selected highly specialized and qualified thoracic centres in 12 countries in Europe. EORTC and ETOP will promote the implementation of clinical trials in molecularly selected groups of patients at the SPECTAlung centers. SPECTAlung offers innovative and attractive models of collaboration with commercial and research organizations, by improving patient access to novel therapeutic clinical trial and support the development of personalized medicine. Clinical trial registry number NCT02214134.
Results:
Not applicable
Conclusion:
Not applicable
