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E. Vokes
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ED 10 - Controversies in Stage IIIA Disease (ID 10)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 4
- Moderators:C.P. Belani, E. Vokes
- Coordinates: 9/09/2015, 14:15 - 15:45, 201+203
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ED10.01 - Staging and Decision Making in Patient Selection-Surgery (ID 1810)
14:20 - 14:40 | Author(s): K. Suzuki
- Abstract
- Presentation
Abstract:
There are two clinical trial investigating the role of surgery in stage IIIA NSCLC.
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ED10.02 - Multiple Modality Choices: Combinations, Sequences, Subsets (ID 1811)
14:40 - 15:00 | Author(s): K. Albain
- Abstract
- Presentation
Abstract not provided
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ED10.03 - Induction Chemotherapy as an Investigational Strategy (ID 1812)
15:00 - 15:20 | Author(s): W.E.E. Eberhardt
- Abstract
- Presentation
Abstract:
Introduction: Standard treatment of stage IIIA non-small-cell lung cancer consists of definitive concurrent chemoradiotherapy (CTx/RTx) protocols. Based on the broad heterogeneity of stage IIIA alone, there are selected patients (single mediastinal lymph node involvement, IIIA3 Robinson) where induction chemotherapy (CTx) followed by definitive surgery may be an alternative and valid approach preferably to test within prospective clinical trials with a close documentation of the toxicity/efficacy ratio. Patients and Methods: The medical literature (PUBMED) was reviewed looking for the search terms “induction chemotherapy“ and “stage III“ and “non-small cell lung cancer“. Furthermore large clincal trials were added that had been presented at important clinical conferences such as ASCO, WCLC and ESMO. Prospective phase-III clinical trials and prospective phase-II clinical trials were examined and cathegorized for efficacy and outcome parameters. We looked specifically for general patterns in the reporting of clinical trials results. Results: General outcome parameters for efficacy that have been reported were: 1) objective response rates 2) overall survival (median) 3) progression-free survival rates 4) complete resection rates (R0-resection) 5) pathological complete response rates (pCR) in the primary tumor and 6) pathological complete response rates (pCR) in the mediastinum. On the other hand important benchmarks for toxicity were 1) grade 3 and grade 4 maximum toxicity rates during induction 2) perioperative toxicity rates grade 3 and 4 3) treatment related death rates. Very few investigations have looked at patient reported outcome parameters such as symptom improvement or quality of life evaluation during the complete treatment protocol. Several groups have tried to improve outcome data by the use of 1) three-drug regimen as induction treatment 2) second- and third-generation platinum-based combinations 3) introduction of new molecular targeted agents (VEGF, EGF-R etc) especially looking closely at the pathological complete response rates induced by induction therapy 4) inclusion of different radiation schemas within a concurrent or sequential preoperative application protocols. Several reported trials have also tried to alternatively give a definitive CTx/RTx protocol with increased radiation doses and have not included a definitive surgical approach. These studies could not report data on pathological responses and some have alternatively looked at FDG-PET response to induction therapy as a surrogate marker for pathological response. Currently the treatment protocols with the highest reported pathological response (pCR) rates were based on cisplatinum and taxane (paclitaxel and docetaxel) combinations and induction protocols including concurrent cCTx/RTx regimen were those with the highest pathological efficacy in the mediatinum as well as in the primary tumor. Conclusions and Outlook: With the existing broad heterogeneity in patient selection within the different clinical studies performed it is currently difficult to give an overall recommendation about the most optimal treatment approach in this setting of stage IIIA NSCLC. Induction CTx could potentially serve as a backbone for including new treatment principles (eg. molecular targeted agents, immunotherapy, CTx/RTx protocols) into these multimodality treatment protocols and closely monitoring outcome by translational investigations and pathological response evaluations.
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ED10.04 - Case Presentation (ID 1813)
15:20 - 15:40 | Author(s): K. Kernstine
- Abstract
- Presentation
Abstract not provided
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 8
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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- Abstract
Background:
Patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. Accumulating evidence suggests that the host immune response might determine tumor behavior and influence the survival prognosis; however, the clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.
Methods:
From January 2005 to June 2012, all consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital were retrospectively reviewed. Inclusion criteria for this study were as follows: complete resection through a surgical procedure of either lobectomy or pneumonectomy with microscopically tumor-free resection margins; systematic nodal dissection with a minimum of three N2 stations dissected; and histologically proven NSCLC of stage pT1-3N2M0 (according to the 7th UICC TNM classification). Patients who received neoadjuvant chemotherapy and/or radiotherapy were excluded. Full-face hematoxylin- and eosin-stained sections from surgical specimens from each case were evaluated for the density of TILs by two qualified specialized pathologists. A published recommended TILs scoring scale was followed. The degree of lymphocyte infiltration into the tumor was scored as none (score 0), low (score 1), moderate (score 2), or high (score 3). Patients were stratified into TIL-negative (none to low infiltration) or TIL-positive (moderate to high infiltration) group based on pathologic evaluation.
Results:
Of the eligible 320 patients included in the analysis, 135 (42%) patients were categorized as TIL-positive; and the 185 (58%) patients were defined as TIL-negative. The median follow-up duration was 30.8 months (range, 12-101.4 months) for the living patients. In the entire cohort, the median survival time (MST) was 42.5 months, and the 1-, 3-, and 5-year overall survival (OS) rates were 90.9%, 54.3%, and 35%, respectively. For the patients in the TIL-negative and TIL-positive groups, the MST was 35.7 and 45.5 months, respectively. The 1-, 3-, and 5-year OS rates were 88.6%, 49.5%, and 34%, respectively, in the TIL-negative group and 94.1%, 61.2%, and 35.6%, respectively, in the TIL-positive group. A higher density of TILs (TIL-positive) was associated with improved OS and the differences trended toward significance (P=0.06). Multivariate analyses confirmed that TIL-positive was an independent prognostic factor for improved OS (HR=0.70, 95%CI 0.50-0.99, P=0.05). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; HR=0.44, 95%CI 0.21-0.94, P=0.03). Of the 93 patients with SCC, TIL-positive was significantly associated with improved distant metastasis-free survival (DMFS; P=0.02) and OS (P=0.03). The TIL-positive was a strong prognostic factor in the multivariate model, both for prolonged DMFS (HR=0.39, 95%CI 0.17-0.87, P=0.02) and OS (HR=0.47, 95%CI 0.22-1.00, P=0.05).
Conclusion:
Our data suggested a potential role of TILs in predicting the survival prognosis of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced for the prediction of DMFS and OS in patients with SCC. Studies assessing outcomes and therapeutic efficacies in prospective clinical trials should consider stratification for this immunological parameter.
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ORAL36.02 - Efficacy of Chemo-Radiotherapy (CRT) in Stage III Non-Small Cell Lung Cancer (NSCLC) and PD-L1 Expression (ID 2432)
16:56 - 17:07 | Author(s): J. Adam, A. Boros, B. Lacas, L. Lacroix, J. Pignon, C. Caramella, D. Planchard, A. Levy, B. Besse, C. Le Pechoux
- Abstract
- Presentation
Background:
Inhibition of the PD1/PD-L1 axis has been successfully developed in advanced NSCLC, and its role in locally advanced NSCLC is under investigation. The prognostic and predictive values of PD-L1 expression is still debated in advanced NSCLC and unknown in stage III NSCLC patients definitely treated by CRT
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intentfor stage III NSCLC in a single institution. Paraffin embedded tissue block were collected, immunohistochemistry was performed on a Ventana Benchmarck Ultra platform using the E1L3N clone (Cell Signaling Technologies). All tumors were centrally reviewed and tumor cells were scored accordingly (Herbst et al., Nature 2014).Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method
Results:
Between January 2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Chemotherapy, mostly based on doublets with platin salt was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Fifty NSCLC were evaluable for PD-L1 expression, 22 (44%) being positive. Fourteen (28%) were female, 24 (48%) were current-smoker, 17 (34%) had adenocarcinoma and there were 23/27 stage IIIA/IIIB. Evaluable and unevaluable populations for PD-L1 were not different. There were no clinical or pathological factors related to PD-L1 positivity. Median follow-up was 7.6 years (minimum: 0.7 year). Median OS was 1.1year(95% confidence interval (CI) 0.6-1.5) in PD-L1 positive (pos) and 2.0 years (95% CI 1.5-3.8) in PD-L1 negative (neg) (p=0.01), HR=2.3 (95% CI 1.2-4.5, p=0.01). Median PFS was 0.7 year (95% CI 0.6-0.8) in PD-L1pos and 1.0 year (95% CI 0.8-1.5) in PD-L1neg (p=0.04), HR=2.1 (95% CI1.1-4.0, p=0.03). There was no difference in terms of acute toxicity according to PD-L1 status (positive or negative):25 had oesophagitis (grade≥2) and 16 had pneumonitis (p=0.57 and p=0.23 respectively).
Conclusion:
PD-L1 positivity was associated to a poorer survival in stage III NSCLC patients treated by definitive chemo-radiotherapy. Its prognostic and/or predictive value should be further evaluated in this population.
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ORAL36.03 - Discussant for ORAL36.01, ORAL36.02 (ID 3566)
17:07 - 17:17 | Author(s): E.E. Vokes
- Abstract
- Presentation
Abstract not provided
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ORAL36.04 - Nintedanib Safely Reduces Late Radiation-Induced Lung Damage: A Preclinical Study with a High Precision Image-Guided Small Animal Irradiator (ID 1456)
17:17 - 17:28 | Author(s): D. De Ruysscher, P.V. Granton, N.G. Lieuwes, S. Van Hoof, L. Wollin, F. Verhaegen, L. Dubois
- Abstract
- Presentation
Background:
The indolinone small-molecule derivative nintedanib has been originally designed as an anti-angiogenic drug targeting the receptor tyrosine kinases VEGFR, FGFR and PDGFR for the treatment of cancer. Additionally, preclinically nintedanib has demonstrated potent anti-fibrotic and anti-inflammatory activity. Nintedanib was recently approved in the US and EU for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the efficacy and safety of nintedanib in a mouse model of partial lung irradiation.
Methods:
266 C57BL/6 adult male mice were irradiated with a single fraction radiation dose of 0, 4, 8, 12, 16 or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung with a precision image-guided small animal irradiator (PXRAD225Cx, PXI Inc, USA) sparing heart and spine based on micro-CT images acquired at 200 µm resolution. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment with 0, 30 or 60 mg/kg respectively for a total of 39 weeks. Micro-CT imaging was repeated on a monthly basis. At the end of the experiment, lungs were removed and processed for H&E, Van Gieson’s and Masson’s trichrome staining to evaluate the fibrotic phenotype.
Results:
Increased lung density could be visually observed by CT in the late stage imaging time points of irradiated mice after 20 Gy and was spatially limited to the irradiated portion of the lung. This increased density was consistent with the development of fibrosis, confirmed by an increased fibrotic phenotype scored by an increase in alveolar wall thickness, interstitial edema, interstitial and perivascular fibrosis and inflammation, interstitial and alveolar macrophages, atelectasis and vasculitis. Although no macroscopic decrease in CT density could be observed, nintedanib was able to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation and vasculitis, without adverse effects.
Conclusion:
Nintedanib efficiently and safely reduces radiation-induced lung fibrosis after partial lung irradiation. Since, as expected, nintedanib did not affect alveolar wall thickness and macrophage involvement, no significant changes in lung density could be observed by CT imaging. Based on its protective effect, nintedanib might be safely introduced in clinical trials for patients treated with irradiation to the lungs.
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ORAL36.05 - Results of a National Database Review of Video-Assisted Thoracoscopic versus Open Lobectomy after Induction Therapy (ID 1533)
17:28 - 17:39 | Author(s): J.L. Wilson, T. Curran, S.P. Gangadharan, R.I. Whyte, M.S. Kent
- Abstract
- Presentation
Background:
Minimally invasive lobectomy has become the standard of care approach for early stage non-small cell lung cancer (NSCLC); however video assisted thoracoscopic (VATS) lobectomy after induction therapy remains controversial. We sought to evaluate perioperative outcomes of VATS and open lobectomy after induction therapy using a national database.
Methods:
A cohort study of patients that underwent VATS and open lobectomy after induction chemotherapy and/or radiotherapy was conducted using the National Surgical Quality Improvement Program (NSQIP) database from 2005 through 2012. Perioperative complications and mortality were compared between groups. Comparisons were made using two-sided student’s t-test or chi square test as appropriate.
Results:
A total of 6730 patients underwent lobectomy during the study period and 166 patients had prior induction therapy (open = 132, VATS = 34). There were no statistically significant differences in age, comorbidities or ASA class between groups. There were no significant differences in the surgeon specialty between groups (cardiac, thoracic, general, and vascular). Operative time was similar (VATS: 228 minutes, Open: 190 minutes; p = 0.07). Perioperative complications, return to OR, respiratory complication, mortality, and hospital length of stay were similar between groups. Table 1. Patient Demographics
VATS = video assisted thoracoscopic, COPD = chronic obstructive pulmonary disease, ASA= American Society of Anesthesia class Table 2. Post-Operative OutcomesN (%) All (N = 166) Open (N = 132) VATS (N = 34) P-value Age, yrs; Mean (SD) 62.9 (10.2) 62.4 (10.7) 65.2 (7.6) 0.077 Female 88 (53) 72 (55) 16 (49) 0.563 Diabetes 16 (10) 11 (8) 5 (15) 0.325 COPD 35 (21) 26 (20) 9 (27) 0.479 Creatinine > 1.2 17 (10) 13 (10) 4 (12) 0.757 ASA Class ≥4 18 (11) 14 (11) 4 (12)
VATS= video assisted thoracoscopic, LOS = length of stay, OR= operating roomN (%) All (N = 166) Open (N = 132) VATS (N = 34) P-value LOS, days; mean (SD) 7.3 (6.1) 7.4 (6.1) 6.6 (6.3) 0.471 Wound complication 5 (3) 5 (4) 0 0.584 Pneumonia 16 (10) 15 (11) 1 (3) 0.197 Reintubation 18 (11) 15 (11) 3 (9) 1.000 Respiratory complication 25 (15) 22 (17) 3 (9) 0.419 Return to OR 15 (9) 14 (11) 1 (3) 0.311 In hospital mortality 9 (5) 8 (6) 1 (3) 0.687 30 day mortality 13 (8) 12 (9) 1 (3) 0.471
Conclusion:
This is the first review of a prospective national database comparing outcomes for VATS and open lobectomy after induction therapy for NSCLC. VATS lobectomy appears to be safe with no increased morbidity or mortality compared to open in patients that had prior induction therapy. A larger series of matched VATS and open approaches after induction therapy is needed.
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ORAL36.06 - 4D-VQ-PET/CT Imaging Allows Strong Correlation Between Radiotherapy Dose and Change in Lung Ventilation, Perfusion and Density (ID 211)
17:39 - 17:50 | Author(s): S. Siva, N. Hardcastle, T. Kron, M. Bressel, J. Callahan, M. Macmanus, M. Shaw, N. Plumridge, R. Hicks, D.P. Steinfort, M. Hofman, D. Ball
- Abstract
- Presentation
Background:
[68]Ga-V/Q PET/CT is a novel imaging modality for assessment of perfusion(Q), ventilation(V) and lung density changes in the context of radiotherapy (RT) for non-small cell lung cancer.
Methods:
In a prospective clinical trial, 20 patients underwent 4D-V/Q PET/CT before treatment, 4 weeks into treatment and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT and isodose volumes averaged into 10 Gy bins. Within each dose bin, relative loss in SUV was recorded for ventilation and perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models and goodness of fit assessed using Akaike Information Criterion (AIC).
Results:
A total of 179 imaging datasets were available for analysis (1 scan unrecoverable). An almost perfectly linear dose-response relationship was observed for perfusion and air-filled fraction (r[2] = 0.99, p < 0.01), with ventilation also strongly linear (r[2] = 0.95, p < 0.01) [Figure]. Logistic models did not provide a better fit as evaluated by AIC [Table]. Perfusion, ventilation and the air-filled fraction changed by -7.5% ± 0.3%, -7.1% ± 0.6% and 4.9% ± 0.02% per 10 Gy, respectively. Within high-dose regions, higher baseline SUV was associated with greater rate of loss. At 50Gy and 60Gy the rate of loss was 1.35% (p = 0.07) and 1.73% (p = 0.05) per SUV, respectively. Of 8/20 patients with peri-tumoral reperfusion / re-ventilation during treatment, 7/8 did not sustain this effect post-treatment. Figure 1 Figure 2
Conclusion:
RT induced regional lung functional deficits occur in a dose dependent manner and can be estimated using simple linear models with 4D-V/Q PET/CT imaging. These findings may inform functional lung sparing by planning RT using this novel imaging technology.
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ORAL36.07 - Results of a National Test Run of Treatment Plans for the Standard Arm of a Dose Escalation Trial for Locally Advanced NSCLC (ID 1766)
17:50 - 18:01 | Author(s): T.B. Nielsen, C. Brink, D.S. Møller, L. Hoffmann, C.M. Lutz, A.L. Appelt, M.D. Lund, M.S. Nielsen, P. Sibolt, C. Larsen, W. Ottoson, T. Schytte
- Abstract
- Presentation
Background:
A national quality assurance program was conducted in order to compare standard radiation treatment plans for locally advanced non-small cell lung cancer (NSCLC) patients in Denmark.
Methods:
The five participating centres represented 71% of all radiotherapy centres in Denmark. They were provided with the CT images and delineations of GTV, CTV, PTV and organs at risks for five different NSCLC patients. Each centre created treatment plans based on the following optimization objectives: required dose distribution for target coverage 95%-107% of the prescribed dose of 66Gy/33fr to at least 95% of the PTV volume (90% for volume located in lung tissue); constraints for organs at risks D(max) < 50Gy to the spinal cord, D(max) < 70Gy to the oesophagus, V50 < 20% to the heart, V20 < 35% and D(mean) < 20Gy for the total lung volume (excluding the GTV). The treatment planning was done in accordance with the local centre practice; i.e. choice of IMRT versus VMAT, coplanar vs. non-coplanar technique, feasible functionalities for treatment planning optimisation (mean value versus different points at the DVH curve), and any additional local dose constraints (e.g. D(max) < 45Gy to spinal cord and/or V5 < 60% to the total lung volume). Finally, all treatment plans were collected and analysed cooperatively.
Results:
All objectives for target coverage and organs at risk were met. There was a wide variability in the dose volume histograms (DVHs) for some of the organs at risk, especially the lungs. This is illustrated in the figure, where the lung DVH from seven different treatment plans, created for the same patient by the five participating centres, is shown. The lung DVHs are overlapping around 20Gy, as all centres had a dose constraint on V20. Some centres had an additional local dose constraint on V5, which resulted in decreased doses to the lungs and increased doses to the mediastinal structures compared with centres that had no dose constraints on V5 for the lungs. Figure 1
Conclusion:
Differences in the dose distribution to the organs at risk can have an impact on treatment morbidity (e.g. pneumonitis, oesophagitis). These differences were seen for standard treatment plans, which are often used in multicentre clinical trials as the baseline compared to an experimental arm, where such differences can be even more pronounced. It is highly recommended to perform test runs across centres prior to entering clinical trials in order to uncover differences as the ones presented.
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ORAL36.08 - Discussant for ORAL36.04, ORAL36.05, ORAL36.06, ORAL36.07 (ID 3567)
18:01 - 18:11 | Author(s): P. Van Houtte
- Abstract
- Presentation
Abstract not provided
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PRC 03 - Press Conference 3 (ID 198)
- Event: WCLC 2015
- Type: Press Conference
- Track: Other
- Presentations: 7
- Moderators:E. Vokes
- Coordinates: 9/08/2015, 09:45 - 10:45, 108+110+112
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2015 WHO Classification of the Pathology and Genetics of Tumors of the Lung - Dr. William Travis, Attending Thoracic Pathologist, Dept. of Pathology, Memorial Sloan Kettering Cancer Center, New York (ID 3627)
09:59 - 10:06 | Author(s): W.D. Travis
- Abstract
- Presentation
Abstract not provided
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Abstract – Increasing Incidence of Never Smokers in Non Small Cell Lung Cancer (NSCLC) Patients Dr. Lorraine Pelosof, Assistant Professor, UT Southwestern Medical Center, Dallas, Texas (ID 3630)
10:13 - 10:20 | Author(s): L. Pelosof
- Abstract
- Presentation
Abstract not provided
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Abstract – Increasing Incidence of Non-Smoking Lung Cancer: Presentation of Patients with Early Disease to a Tertiary Institution in the UK - Dr. Eric Lim, Royal Brompton and Harefield NHS Trust, London (ID 3629)
10:06 - 10:13 | Author(s): E. Lim
- Abstract
- Presentation
Abstract not provided
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Abstract – Oncogenic Profiling in Lung Adenocarcinoma Emerged in the Youth - Dr. Kosuke Tanaka, Department of Cancer Genetics, Nagoya University Graduate School of Medicine; Division of Molecular Oncology, Aichi Cancer Center Research Institute, Japan (ID 3631)
10:20 - 10:27 | Author(s): K. Tanaka
- Abstract
- Presentation
Abstract not provided
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Abstract – The Genomics of Young Lung Cancer Study - Dr. Barbara Gitlitz, Associate Professor of Clinical Medicine at USC Keck School of Medicine, Los Angeles (ID 3632)
10:27 - 10:34 | Author(s): B.J. Gitlitz
- Abstract
- Presentation
Abstract not provided
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Daily Theme: Lung Cancer: A Women's Disease - Dr. Silvia Novello, Associate Professor, Department of Oncology, University of Turin-Italy (ID 3625)
09:45 - 09:52 | Author(s): S. Novello
- Abstract
- Presentation
Abstract not provided
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Revised (8th) Edition of TNM Staging System for Lung Cancer - Dr. Ramon Rami-Porta, Thoracic Surgery Service, Hospital Universitari Mutua Terrassa, Barcelona, Spain (ID 3626)
09:52 - 09:59 | Author(s): R. Rami-Porta
- Abstract
Abstract not provided
Author of
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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.07 - PCI Survival Improvement for Extensive Stage SCLC Limited to Patients on Maintenance Systemic Therapy: A Secondary Analysis of CALGB 30504 (ID 861)
19:05 - 19:10 | Author(s): E. Vokes
- Abstract
- Presentation
Background:
PCI has become standard of care for extensive stage small cell lung cancer (ES-SCLC) patients. However, one recent randomized study establishing this standard did not require brain imaging prior to enrollment, and another, which did, failed to show a benefit for PCI. CALGB 30504 (Alliance) was a randomized phase II study of sunitinib vs placebo in ES-SCLC patients responding to at least 4 cycles of platinum based therapy requiring baseline brain imaging at enrollment. As this study spanned the introduction of PCI for ES-SCLC, PCI was left to the discretion of the treating team. Therefore, we performed a secondary analysis of CALGB 30504 to determine the impact of PCI on ES-SCLC patients.
Methods:
CALGB 30504 was a phase II randomized study in ES-SCLC comparing maintenance sunitinib versus placebo following SD or CR/PR to 4-6 cycles of etopside 100 mg/m[2] d1-3 and either carboplatin AUC=5 or cisplatin 80 mg/m[2] d1 q 21 days. Sunitinib was 150 mg PO d 1 then 37.5 mg PO qd until progression. The primary objective was to determine if maintenance sunitinib would improve PFS, as was recently reported. PCI was recommended at 25 Gy in 2.5 Gy fractions, within 4-6 weeks of chemotherapy, but not required. Sunitinib was to be held 2 days prior, during, and 2 days after the completion of PCI. All statistical analyses were performed by the statisticians at Alliance/CALGB Statistical and Data Center on the platform of SAS (version 9.3; SAS Institution Inc., Cary, North Carolina).
Results:
85 patients received maintenance therapy(41placebo, 44 sunitinib). 41 (48%) received PCI, 44 didn’t. All patients and tumor characteristics were balanced between PCI and no-PCI patients. PCI dose was 25 Gy for 31 patients (range: 25-37.5 Gy). Median time to PCI was 21 wks (range: 12-27 wks) from enrollment. For all patients, PCI was associated with an improvement in PFS (median 7.8 vs 6.5 mo HR=0.63 (95% CI: 0.41-0.98), p=0.037), but not OS (median 12.9 vs 13.2 mo, HR=1.01 (95% CI: 0.64-1.62), p=0.955). In placebo patients, there was no PFS or OS difference between patients receiving PCI or not. In patients randomized to sunitinib, PCI conferred a PFS benefit (9.7 vs 6.8 mo, HR=0.49 (95% CI: 0.26-0.92), p=0.024), but not an OS benefit (14.1 vs 13.5 mo, HR=0.85 (95% CI: 0.44-1.66), p=0.636). When restricted to patients who did not receive PCI, there was no difference in survival between sunitinib or placebo patients. In PCI patients, those receiving sunitinib had non-significant improvement in PFS (9.7 vs 6.7 months, HR=0.63 (95% CI: 0.34-1.20), p=0.158) and trended towards an improvement in OS (14.1 vs 10.6 months, HR=0.56 (95% CI: 0.29-1.10), p=0.087), which was magnified and approached significance when crossover patients were excluded (14.1 vs 10.0 mo, HR=0.49 (95% CI: 0.22-1.06), p=0.064).
Conclusion:
PFS, and trends for OS improvement were limited to patients receiving the combination of PCI and maintenance sunitinib. Placebo patients did not benefit from PCI. Improved outcomes for ES-SCLC patients with PCI are likely limited to patients who achieve both intracranial and extracranial disease control.
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)
10:45 - 10:56 | Author(s): E. Vokes
- Abstract
- Presentation
Background:
Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.
Methods:
Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.
Results:
Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1
Conclusion:
CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.
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ORAL 20 - Chemoradiotherapy (ID 124)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, J.Y. Chang
- Coordinates: 9/08/2015, 10:45 - 12:15, 201+203
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ORAL20.02 - Safety Results of the Consolidation Phase of a Phase III (PROCLAIM): Pemetrexed, Cisplatin or Etoposide, Cisplatin plus Thoracic Radiation Therapy followed by Consolidation Cytotoxic Chemotherapy in Locally Advanced Nonsquamous Non-Small Cell Lung Cancer (ID 645)
10:56 - 11:07 | Author(s): E. Vokes
- Abstract
- Presentation
Background:
Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.
Methods:
PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).
Results:
Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase
CTCAE Arm A (N=229) n (%) Arm B (N=202) n (%) Neutrophils 27 (11.8) 76 (37.6)* Leukocytes 19 (8.3) 29 (14.4) Hemoglobin 6 (2.6) 9 (4.5) Platelets 5 (2.2) 10 (5.0) Febrile neutropenia 7 (3.1) 7 (3.5) Lymphopenia 8 (3.5) 5 (2.5) Pneumonitis/pulmonary infiltrates 5 (2.2) 2 (1.0) Fatigue 2 (0.9) 4 (2.0) Pneumonia 5 (2.2) 0 Esophagitis 0 3 (1.5) *p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.
Conclusion:
During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-005 - Concurrent EGFR and ALK Mutations in KRAS-Mutant Lung Adenocarcinomas and Their Clinical Behavior (ID 1493)
09:30 - 09:30 | Author(s): E. Vokes
- Abstract
Background:
KRAS represents the most commonly mutated oncogene in non-small cell lung cancer (20-30%). Multiple studies have suggested mutations of KRAS, epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) to be mutually exclusive[i], though there are few case studies showing coexisting EGFR and KRAS mutations[ii].
Methods:
We reviewed clinical genotyping data from 118 patients with stage I – IV KRAS mutated NSCLC. We investigated prevalence of concomitant EGFR and ALK mutations and evaluated clinical behavior in regards to overall survival (OS) and response to tyrosine kinase inhibitor therapy.
Results:
Among these 118 samples with KRAS alterations (codon 12 =98, 13 = 8, 61 = 3, 146 = 2, 189 =1, amplification = 6), median OS was 61.97 months (Graph 1). Concomitant EGFR mutations were noted in 6 subjects (5.0%) and ALK mutations were noted in 2 subjects (1.7%). One patient was found to have mutations of KRAS, EGFR, and ALK. These patients’ stage at diagnosis, response to TKI therapy (if utilized), and OS is documented in Table 1. Figure 1 Figure 2
Conclusion:
This analysis demonstrates it is possible for KRAS mutations to occur concurrently with EGFR and ALK missense mutations (not translocation) and emphasizes that a complete molecular analysis should be performed on all NSCLC patients. Further data is needed to more firmly elucidate how these concurrent mutations affect clinical behavior. Citations [I] Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFR and KRAS in non-small cell lung cancer. Clin Cancer Res. 2013 Aug 1; 19(15): 4273-81. [II] Zhu CQ, Sants GC, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group study BR.21. Journal of Clinical Oncology. 2008 Sep 10; 26(26): 4268-4275.
