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J.W. Neal
Moderator of
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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 8
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.01 - Tyrosine Kinase Inhibitors (TKIs) for the Treatment of Brain Metastases (BMs) from Advanced Lung Cancer : A Large Retrospective Cohort Study (ID 2824)
10:45 - 10:56 | Author(s): C. Bennati, L. Paglialunga, A. Gili, R. Chiari, V. Minotti, G. Metro, A. Siggillino, S. Baglivo, L. Crinò
- Abstract
- Presentation
Background:
BMs are found in up to 30% of patients (pts) with advanced non small cell lung cancer (NSCLC), and are associated with a poor prognosis despite radiotherapy treatment, with a median survival of 6 months (mo). Several data are suggesting the potential brain activity of tyrosin kinase inhibitors (TKIs) alone in NSCLC pts with activating mutations. We retrospectively identified EGFR mutated and ALK rearranged NSCLCs with BMs, to evaluate the efficacy of TKIs and their role in the upfront setting.
Methods:
Out of a cohort of 270 never smoker (NS) NSCLC patients (pts) treated at our Institution from 2/2006 to 2/2015, 89 (32.9%) NSCLCs BMs were identified, synchronous in 27 pts (30.3%). 38 pts (42.7%) harboured an EGFR mutation, 33 pts (37.1%) were ALK rearranged, 18 pts (20.2%) negative for both, were used as a control cohort. Among the EGFR mutated, an in-frame deletion in exon 19 (mostly E746-A750) was found in 26 (68.4%) patients, while a point mutation in exon 21 (L858R) was detected in 10 (26.4%), 1 (2.6%) exon 18 mutation and 1 (2.6%) exon 20 insertion were identified. The majority of EGFR and ALK positive (+) pts with BMs were female (53.9%), median age 52, adenocarcinoma histology, and a good performance status.
Results:
Out of the 71 NSCLCs with BMs EGFR/ALK+, 58 pts (81.7%) received at least one line of chemotherapy, while 13 pts (18.3%) were only treated with TKIs. Of the entire series, 40 pts (56.3%) were treated with standard radiotherapy (WBRT or radiosurgery) prior to TKIs treatment, while 31 (43.7%) received a TKI upfront, distributed as follows: 13 pts (37.9%) were treated with an EGFR inhibitor (gefitinib/erlotinib/afatinib), while 18 pts (62.1%) with an ALK TKI (crizotinib/ceritinib/alectinib). All the pts in the molecular negative cohort, received WBRT and, at least, one line of chemotherapy. Within the entire series, Overall Intracranial Response Rate (OIRR: complete response CR + partial response PR) was evaluated: EGFR+ 31 pts (81.5%), ALK+ 28 pts (84.8%), control cohort 6 pts (33.3%) (p,0.003). Median [95% CI] overall survival (OS) for EGFR mutans, ALK + and EGFR/ALK negative was: 52 months (mo) (32.6-74.4),74 mo (not reached), 25 mo (9.4-40.03) (p,0.003). In the subgroup who received a TKI upfront, all EGFR+ achieved a PR, while all ALK+ obtained an objective response: 4 (22.2%) a CR and 14 (77.8%) a PR. No significant difference in OS between EGFR/ALK+ BMs treated with a TKI upfront versus further line.
Conclusion:
This retrospective study confirms that TKIs are strongly active in patients with BMs from NSCLCs harbouring a sensitive mutation. Brain disease control was achieved in an impressive 81.5% of the EGFR+ pts and 84.8% of the ALK+ subset. Of particular note, is the highest response rate in the TKI upfront arm, with 22.2% attaining a complete remission. We conclude that the use of TKIs in first line setting for BMs treatment may be a reasonable option for asymptomatic subgroup of patients with a long survival expectation, for whom WBRT may be postponed at a later disease stage.
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ORAL16.02 - Thromboembolic and Bleeding Risk with Adjuntctive LMWHs Anticoagulation in Lung Cancer Patients. Meta-Analysis of Randomized Trials (ID 2157)
10:56 - 11:07 | Author(s): M. Kowalewski, L. Zolna, A. Chrzastek, M.A. Lewandowska, M. Dancewicz, P. Wnuk, M. Bella, P. Bławat, T. Szczęsny, J. Kowalewski
- Abstract
- Presentation
Background:
Venous thromboembolism (VTE) has been demonstrated one of the leading causes of mortality in lung cancer patients. While incidence of VTE in cancer patients varies from 4-20%, at autopsy VTE accounts for as high as 50%. Various strategies of VTE prophylaxis have been proposed, among them low-molecular weight heparins (LMWHs). While different randomized controlled trials (RCTs) showed benefit with LMWHs in regard to VTE, none single RCT was adequately powered for major bleeding. In a meta-analysis of RCTs we aimed to investigate the relation between thromboembolic and bleeding risk associated with LMWHs anticoagulation in lung cancer patients.
Methods:
Established methods were used in compliance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement in healthcare interventions. PubMed, EMBASE, CINAHL, Cochrane, Scopus databases as well as major congress proceedings until April 2015 were screened for RCTs comparing LMWHs with control/placebo. Outcomes assessed were VTE and major bleeding. Odds ratios (OR) and 95% confidence intervals were used as summary statistics. Data were analysed according to Intention-to-treat principle.
Results:
Four RCTs (N=3097) were included in the meta-analysis (Table 1). Average follow-up was 237 days. In a fixed effects model, LMWHs were associated with a significant 50% reduction of the odds of VTE as compared to controls: OR (95% CI): 0.50 (0.35-0.71); p<0.0001; I[2]=0%; (Figure 1A); the number needed to treat =33. A significant, over 2-fold increase in the odds of major bleeding was observed with LMWHs: OR (95% CI): 2.16 (1.16-4.05); p=0.02; I[2]=0%; (Figure 1B); the number needed to harm was 104.Table 1. Characteristics of included studies
Figure 1Study N of pts LMWH Dose NSCLC/SCLC Follow-up (d) Agnelli et al. 2009 279 Nadroparin 3800 IU qd 79.9%-20.1% 112 Altinbas et al. 1-2, 2004 84 Dalteparin 5000 IU qd 0%-100% 301 Haas et al. 2012 546 Certoparin 3000 IU qd 100%-0% 168 Woodruff et al. 2013 2202 Dalteparin 5000 IU qd 82.2%-18.8% 365
Conclusion:
Low-molecular weight heparins significantly reduce the risk of venous thromboembolism at a price of increased major bleeding in patients with lung cancer. One episode of major bleeding occurred at every 3 VTEs prevented with LMWHs. Dose-escalation studies are certainly warranted to identify patients who would benefit most from LMWHs.
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ORAL16.03 - Acceptability of NSCLC, NOS in Advanced Disease: An Assessment of US Oncologists, Pulmonologists and Pathologists (ID 1255)
11:07 - 11:18 | Author(s): T. Herrmann, P. Fidias
- Abstract
- Presentation
Background:
In 2011 the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology issued a recommendation to classify patients with advanced NSCLC into specific histological and molecular subtypes and minimize the diagnosis of not otherwise specified (NOS) subtype. The objective of this study was to define the rate of NOS subtype being observed in practice as well as the NSCLC care team’s knowledge and beliefs about a diagnosis of NOS subtype in advanced-stage disease.
Methods:
A series of 5 questions were developed to identify the incidence of NOS subtype being observed in the community as well as relevant care team knowledge gaps and beliefs that may influence the findings. The case vignettes and questions and were based on current standards of care and evidence-base in the treatment of advanced NSCLC. The questions were made available online to healthcare providers either through a survey or as part of 2 certified medical education activities; without monetary compensation or charge. Confidentiality of survey respondents was maintained and responses were de-identified and aggregated prior to analyses. The series of 5 questions was launched in both formats in December 2014 and participant responses were collected over the following 4 months.
Results:
In total, 553 oncologists, pathologists and pulmonologists answered all 5 questions. Oncologists who responded to the questions on average saw about 6-10 patients with suspected or diagnosed NSCLC per month while pathologists and pulmonologists were more likely to see 1-5 per month. Almost 60% of oncologists, pathologists and pulmonologists stated that the incidence of NOS subtype should occur in less than 5% of all cases. Yet, 28% of participating oncologists, 37% of pathologists, and 40% of pulmonologists would find a diagnosis of NSCLC, NOS acceptable. Moreover, 45% of oncologists and 64% of pulmonologists stated that 11% or more of their patients are reported as having a diagnosis of NSCLC, NOS. Reasons for acceptability of NOS subtype differed between clinicians; with more pulmonologists stating it is always acceptable while pathologists and oncologists were more likely to cite age or smoking status, respectively. When asked what contributes to this belief a majority of oncologists and pathologists cited an inability to obtain adequate tissue while pulmonologists were more likely to state that subtyping was unnecessary to prescribe the appropriate therapy (30%) or it was a result of system barriers (25%).
Conclusion:
Despite recommendations from key organizations the incidence of NSCLC, NOS many members of the care team continue to accept a diagnosis of NOS in their patients. Our findings demonstrate a pressing need for additional education of the multidisciplinary care team involved in the diagnosis of advanced NSCLC so as to ensure appropriate diagnosis and treatment.
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ORAL16.04 - Discussant for ORAL16.01, ORAL16.02, ORAL16.03 (ID 3318)
11:18 - 11:28 | Author(s): R. Pirker
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
The majority of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer respond to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib) but nearly all eventually acquire resistance. The most common mechanism of acquired resistance is a second-site mutation in the EGFR kinase domain, T790M. The phase III, double-blind IMPRESS study evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin in patients with acquired resistance to first-line gefitinib. Study results did not support the continuation of gefitinib after disease progression (by RECIST criteria) when platinum-based doublet chemotherapy is used as second-line therapy. Here we report the results of a retrospective biomarker analysis of plasma circulating free, tumor-derived DNA (ctDNA) from patients in IMPRESS, including T790M profiling, to help understand the IMPRESS clinical trial outcome.
Methods:
Plasma samples for ctDNA isolation were collected at baseline and discontinuation from 151 randomized, non-Chinese patients in IMPRESS (58% of overall IMPRESS population). ctDNA levels of T790M, L858R, and Exon19 deletions were detected using both a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) and a qualitative QIAGEN[®] Therascreen ARMS assay (baseline only). Local EGFR tumor tissue (diagnostic) results were available for 133/151 patients. Mutation concordance rates between tissue and baseline plasma results, and comparisons between the two plasma detection methods, were calculated.
Results:
Baseline ctDNA EGFR mutation results were obtained for >99% (150/151) of patients. Using BEAMing, sensitivity and specificity between baseline plasma EGFR sensitizing mutations and local EGFR tumor tests were 78% (69/89) and 98% (42/43), respectively, for Exon19 deletions, and 82% (31/38) and 97% (91/94) for L858R. The T790M detection rate in baseline plasma samples using BEAMing was 56% (84/150). The Therascreen ARMS assay demonstrated a significantly reduced T790M detection rate of 13% (20/150). Likewise, the sensitivity of the Therascreen ARMS assay with respect to tissue for EGFR sensitizing mutations was also reduced compared with BEAMing: Exon 19: 54% (48/89), L858R: 47% (18/38), though the specificity remained near 100%. In the 97 evaluable plasma samples collected at discontinuation, T790M was detected by BEAMing in 52% (50/97) of patients. When compared with matched baseline plasma, 11 patients had newly acquired T790M mutation at discontinuation while T790M reverted to undetectable in 14 patients. Full plasma profiling data from the complete IMPRESS clinical study population (including 108 patients from China) and correlative analyses of plasma EGFR mutation status with clinical outcome (progression-free survival, overall survival, objective response rate) will be presented.
Conclusion:
In IMPRESS, T790M was detectable with BEAMing digital PCR in the baseline ctDNA samples of 56% of evaluable patients, a rate comparable to similar mutation analyses in this same second-line, EGFR-TKI-failed setting. EGFR mutation detection in plasma using the Therascreen ARMS assay demonstrated comparable specificity to BEAMing but reduced sensitivity. The T790M detection rate afforded by the BEAMing technology will allow for a comprehensive assessment of correlations between clinical outcome in IMPRESS and EGFR mutational status.
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- Abstract
- Presentation
Background:
The most important advantage of EGFR mutation analysis in circulating tumor DNA(ctDNA) from plasma is quantitative and dynamic evaluation. Here, we investigated the feasibility of droplet digital PCR(ddPCR) for quantitative and dynamic detection of EGFR mutation in ctDNA and next generation sequencing (NGS) for screening a range of resistance-relevant mutations in plasma DNA in the process of disease progression for patients diagnosed with advanced lung adenocarcinoma.
Methods:
Seventy-three patients were enrolled in this study. Tumor tissues were sampled before treatment, and paired plasma DNA samples were collected pre- and post- EGFR-TKI therapy. Sixty-seven of 73 patients obtained blood samples in the time-point of disease progression. All 73 patients presented EGFR mutation in tumor tissues tested by denaturing high performance liquid chromatography（DHPLC）method. We measured the absolute quantities of plasma EGFR mutant and wild-type alleles by ddPCR. Multi-genes testing was performed using NGS in twenty-seven plasma samples from the twelve patients.
Results:
Taking the EGFR mutation in tumor tissue as the standard, the EGFR mutations detection sensitivity in plasma DNA was 74%（54/73）. According to EGFR mutation status in TKI-naïve patients, all 73 patients were divided into two subgroups that carried mutation in both of specimens (B+/T+,n=54) and mutation only in tissues rather than in plasma ctDNA(T+ /B-,n=19) . The B+/T+ group showed superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P<0.0001) compared to T+ /B- group. The patients with high EGFR mutated abundance in plasma ctDNA (＞5.15%) showed better PFS (median, 15.4 vs 11.1months; P=0.021) compared with those with low EGFR abundance (≤5.15%). EGFR mutation dynamic alteration during EGFR-TKIs therapy was analyzed and showed patients with decreased quantity of EGFR mutated alleles after disease progression（n=29）showed better PFS compared with non-decreased quantity group(n=38) (median, 12.7 vs 7.1 months; P=0.001). However, NGS results came from 12 patients’ matched plasma DNA showed that 66.6% total mutational copies were elevated and 76.5% mutual mutation frequency increased after disease progression. Besides canonical EGFR pathway, mutated genes in plasma DNA were significantly enriched in cell cycle and TGF-β pathways when disease progressed. Quantification of mutant allele fraction by means of either NGS or ddPCR assay showed excellent agreement.
Conclusion:
Droplet digital PCR is a highly sensitive method for EGFR mutation analysis in plasma DNA of patients with advanced lung adenocarcinoma, while NGS shows good performance in multiple genes testing especially novel and uncommon genes. High EGFR sensitive mutated abundance（>5.15%） in plasma samples of TKI-naïve patients can predict better PFS of EGFR-TKI treatment.
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- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) can achieve dramatic response in EGFR activating mutation positive lung cancer patients. However, the duration of treatment is quite different. Some patients experienced longer progression-free survival (PFS) of more than 1 year, whereas some had PFS of shorter than 6 months. Our previous study showed that the relative EGFR mutation abundance in tumor tissues could predict benefit from EGFR-TKIs treatment. However, it still remains controversial whether the intratumor heterogeneity of EGFR activating mutation exists. This study explored the intratumor heterogeneity of EGFR activating mutation at the level of single cancer cell.
Methods:
Single H1975 cells which harbor EGFR exon 21 L858R mutation were isolated by flow cytometry (FCM). The whole DNA extracted from a single cell was submitted to perform nested polymerase chain reaction (PCR) amplification of EGFR exon 21. The amplified products from nested PCR were sequenced to evaluate the feasibility of single-cell analysis for EGFR exon 21. Then, six patients diagnosed with lung adenocarcinoma whose fresh frozen specimens harbored EGFR exon 21 mutation tested by direct sequencing were chosen. All of them received gefitnib treatment and the PFS of three patients was longer than 14 months (Group A) while the PFS of other three patients was shorter than 6 months (Group B). By using the established method based on single H1975 cells, EGFR exon 21 mutational status was analyzed in single tumor cells which were captured from tumor sample by Laser Capture Microdissection (LCM). At least 20 tumor cells were captured from each tumor sample. X[2] test was used to compare the amplification rate of nested PCR and EGFR mutational rate between the two groups.
Results:
A total of 104 individual H1975 cells were obtained to detect EGFR exon 21 mutational status through the application of single-cell nested PCR. The amplification rate and allele drop-out rate were 96.2% and 7.0%. A total of 135 tumor cells from six samples were captured. The amplification rate of nested PCR was 84.3% (59/70) in Group A and 93.8% (61/65) in Group B. There was no statistical difference between the two groups (X[2] =3.119, P=0.077). The mutational rate of EGFR exon 21 L858R was 89.5% (17/19), 89.5% (17/19), and 81.0% (17/21) in the three patients in Group A and 72.2% (13/18), 68.4% (15/22), and 66.7% (14/21) in the three patients in Group B respectively. The total mutational rate was 86.4%（51/59）in Group A, which was significantly higher than the total mutational rate 68.9%（42/61）in Group B (X[2] =5.321, P=0.021).
Conclusion:
It is feasible to perform EGFR mutation detection in single cancer cells. The intratumoral heterogeneity of EGFR activating mutation in lung adenocarcinoma does exist based on the analysis in single cancer cells and the abundance of EGFR activating mutation is relevant to the benefit from EGFR-TKIs treatment.
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ORAL16.08 - Discussant for ORAL16.05, ORAL16.06, ORAL16.07 (ID 3319)
12:01 - 12:11 | Author(s): P.C. Mack
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 08 - Prognostic/Predictive Biomarkers (ID 106)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI08.04 - VeriStrat® and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib +/- Erlotinib in Non-Small Cell Lung Cancer (ID 552)
17:10 - 17:15 | Author(s): J.W. Neal
- Abstract
- Presentation
Background:
VeriStrat is a blood-based multivariate proteomic test that predicts response to second line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy in non-small cell lung cancer (NSCLC). We report a retrospective blinded analysis of VeriStrat classification in plasma samples from a phase 1b/2 trial of cabozantinib (C) +/- erlotinib (E) in metastatic NSCLC patients who had all progressed after benefiting from EGFR TKI therapy. Cabozantinib inhibits the MET/hepatocyte growth factor (HGF) pathway, and VeriStrat may be a surrogate marker for this pathway.
Methods:
Patients enrolled into phase 1b (1A:60 mg C+150 mg E, 2A:60 mg C+100 mg E, 3A:100 mg C+100 mg E, 4A:100 mg C+50 mg E, 2B:40 mg C+150 mg E) and phase 2 (Arm A:100 mg C, Arm B:100 mg C+50 mg E). EGFR mutation (EGFRm) status was tested on archival tissue and/or plasma when available. The primary objective was to determine if pre-treatment VeriStrat (VS) classification, good or poor, was prognostic for patients treated with cabozantinib +/- erlotinib. Kaplan-Meier method and log-rank test was used to compare progression-free survival (PFS) of VS-good v. VS-poor patients. Outcomes were stratified by EGFRm status (mutated v. wild type WT/unknown UNK).
Results:
Of 79 evaluable patients, 71 were classified as VS-good and 8 as VS-poor. 55.7% had an activating EGFRm (majority exon 19 del/exon 21 L858R) and 12.7% had UNK EGFRm status. There were no significant differences in patient characteristics between VeriStrat-groups. VS-good patients had a statistically improved PFS: VS-good 3.7 mo. (95% CI 3.5-5.4) v. VS-poor 1.9 mo. (95% CI 1.1-3.4), p=0.014. This was still true after excluding 14 patients who had received cabozantinib alone (p=0.005). There was no difference in PFS for VS-good patients when stratified by EGFRm status. There was also no difference in PFS for VS-poor patients with WT/UNK EGFR v. VS-good patients irrespective of EGFRm status. However, VS-poor patients with WT/UNK EGFR had improved PFS compared to VS-poor patients with an EGFRm (3.1 mo. v. 1.6 mo., HR 0.15, 95% CI 0.03-0.68).
Conclusion:
VeriStrat is a strong prognostic marker in this study. This study suggests cabozantinib neutralized the worse prognosis of VS-poor patients with WT/UNK EGFR. Given the heterogeneity of treatment dosing, the small number of VS-poor patients, and a high proportion of unknown EGFRm (including T790M) status, this analysis should be considered exploratory.
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.05 - Discussant for MINI27.01, MINI27.02, MINI27.03, MINI27.04 (ID 3379)
17:05 - 17:15 | Author(s): J.W. Neal
- Abstract
- Presentation
Abstract not provided
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.04 - A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 (ID 404)
18:45 - 18:50 | Author(s): J.W. Neal
- Abstract
Background:
Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC.
Methods:
The primary objective of this randomized phase 2 study was to compare progression-free survival (PFS) of pts treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C.
Results:
125 pts were enrolled, of which 115 were eligible & treated (E, n=39; C, n=39; E+C, n=37). Pt characteristics were balanced between arms except for lower rate of brain mets history on E (p=0.02). Median follow up is 8.5 m. Compared with E (median 1.9 m), PFS was significantly improved on C (3.9 m, HR 0.33, p=0.0002, 80% CI 0.22-0.49) & E+C (4.1 m, HR 0.31, p=0.0002, 80% CI 0.21-0.46). Similarly, compared with E (median 4.0 m), OS was significantly improved on C (HR 0.52, p=0.02) & E+C arm HR 0.50, p=0.02). Grade 3-4 treatment-related hypertension & mucositis were higher on C and grade 3-4 diarrhea was higher on E+C. Overall worst grade toxicities were also significantly higher on C and E+C. MET IHC results were available on 88 patients from the primary analysis & 85% were positive (1-3+ membrane or cytoplasm staining with MET4 antibody). There was no correlation between MET status and PFS.
Conclusion:
C & C+E significantly improved PFS over E alone in pts with EGFR wt NSCLC. Cabozantinib-based regimens are promising for further investigation in this patient population. Funded by ECOG-ACRIN and NCI Contract No. HHSN261200800001E.
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ORAL 11 - Clinical Trials 1 (ID 100)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:A.K. Nowak, F. Detterbeck
- Coordinates: 9/07/2015, 10:45 - 12:15, 702+704+706
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ORAL11.05 - Phase II Trial of Single Agent Amrubicin in Patients with Previously Treated Advanced Thymic Malignancies (ID 1288)
11:28 - 11:39 | Author(s): J.W. Neal
- Abstract
- Presentation
Background:
Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM pts in this trial.
Methods:
This was an open-label single drug trial at 2 institutions. Eligible pts had TM (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles.
Results:
From 7/11 to 4/14, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30-81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White pts. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. In total, 7 pts experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 pt each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs TC and 100%/78% DCR in T vs TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 36 cycles as the highest number to date. Five patients remain on therapy.
Conclusion:
Amrubicin, at 35 mg/m[2 ]IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with an 18% RR and no unexpected toxicity. Response rate and disease control rate was higher in the thymoma patients compared to the thymic carcinoma patients. Further exploration of amrubicin as a single drug or in combination is warranted in thymic malignancies.
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ORAL11.07 - Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma (ID 1603)
11:50 - 12:01 | Author(s): J.W. Neal
- Abstract
- Presentation
Background:
Preoperative CT imaging assists in the management of thymic malignancies (TMs), discerning resectability and the need for neoadjuvant chemotherapy. Here, we examine preoperative CT imaging characteristics in relation to the newly proposed IASLC/ITMIG TNM pathologic staging system for TMs.
Methods:
Inclusion criteria for this retrospective study were as follows: 1) diagnosis of thymoma, thymic carcinoma, or thymic carcinoid, 2) definitive primary surgery performed at Stanford University, and 3) pretreatment CT imaging available for review. From 01/1997-03/2015, we identified 119 TM patients who had surgery, and 47 TM patients met all inclusion criteria. The most common reason patients were excluded was for either a missing pretreatment CT (outside imaging not routinely uploaded until 2008) or having surgery for biopsy or recurrent disease. The radiologist (D.T.) was blinded to clinical data, and examined baseline CT imaging per the International Thymic Malignancy Interest Group (ITMIG) standard report terms: contour, calcification, internal density, size of longest diameter, infiltration of mediastinal fat, abutment of mediastinal vessels, vascular endoluminal invasion, abutment/invasion of mediastinal structures, elevated hemidiaphragm, pleural nodules, pleural effusion, mediastinal lymph node enlargement. A univariate analysis and a Lasso regularized general transformation prediction model were performed with all variables to examine the association with pathologic IASLC/ITMIG TNM stage (p<0.05 significant; p<0.10 trend).
Results:
Of 47 TM patients, 9 received neoadjuvant chemotherapy. IASLC/ITMIG pathologic stage included 35 I, 1 II, 7 IIIA, 2 IIIB, 1 each of IVA and IVB. By T stage, there were 36 T1 (encapsulated or unencapsulated+extension into mediastinal fat or mediastinal pleura), 1 T2 (pericardium), 8 T3 (lung, brachiocephalic vein, SVC, chest wall, phrenic nerve, or hilar pulmonary vessels) and 2 T4 (aorta, arch, main pulmonary artery, myocardium, trachea, or esophagus). Only one patient each had N2 and M1a disease (separate pleural or pericardial nodule). Histologies included 5 A/micronodular thymoma, 13 AB, 5 B1, 14 B2, 5 B3, and 5 C/carcinoid. There was a significant positive association with aggressive histology and higher stage (OR=10.0;p=0.02). The following CT characteristics had a statistically significant positive association with higher stage (stage 1 vs. others, T1 vs. others) in a univariate analysis: lobulated contour, infiltration of mediastinal fat, invasion of mediastinal structures, vascular endoluminal invasion, elevated hemidiaphragm. There was a trend for higher stage with larger size and the presence of calcification. In a prediction model, vascular endoluminal invasion and elevated hemidiaphragm were the most important for predicting higher stage followed by invasion of mediastinal structures>abutment of mediastinal vessels>calcification>lobulated contour> mediastinal lymph node enlargement. When excluding clearly invasive CT characteristics, only abutment of mediastinal vessels was significantly associated with higher stage.
Conclusion:
Preoperative CT characteristics, especially those indicating clear invasion, are most useful in delineating more advanced stage disease by ITMIG/IASLC criteria in TMs. Other primary tumor characteristics including contour, calcification, and abutment of mediastinal vessels are moderately helpful. This study is limited by the small sample size, the predominance of stage I disease, the inclusion of patients who received neoadjuvant chemotherapy, and the inherent bias of a definitive surgically treated population.
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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)
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P2.01-081 - Case Series of HER2 Mutated Metastatic Lung Adenocarcinoma and Response to HER2 Targeted Therapies (ID 799)
09:30 - 09:30 | Author(s): J.W. Neal
- Abstract
Background:
HER2 has long been recognized as an oncogenic driver in some breast and gastro-esophageal cancers. More recently, somatic mutations in HER2 have been reported in 1-2% of patients with lung adenocarcinoma, and the promise of HER2 as a treatment target in lung cancer has been suggested using anti-HER2 small molecules and antibodies.
Methods:
Here we report the outcomes of three patients with metastatic lung adenocarcinoma with HER2 mutations being treated with HER2 targeted therapies at a single institution.
Results:
The first patient is a 65yo Caucasian woman, minimal smoking history, with stage IIIA lung adenocarcinoma who then developed recurrent metastatic disease mainly in the liver after completing definitive chemoradiotherapy. She progressed through three lines of chemotherapies, with near replacement of liver with tumor. At that time she was found to have HER2 exon 20 insertion mutation (A775_G776 insSVMA) and was started on vinorelbine and trastuzumab. The main side effect was fatigue, which was tolerable. She achieved radiographic stable disease with 13% reduction of her liver metastasis as her best response by RECIST v1.1 for 6 months and significant clinical improvement before progression of disease in all sites. The second patient is a 60yo Caucasian woman, former smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with extensive bony disease. She was treated with carboplatin, paclitaxel, bevacizumab, and an investigational anti-Met therapy with initial mild decrease in lung mass and nodules after one month, then mild progression for 14 months. She was taken off trial then and started on vinorelbine and trastuzumab, and so far shows no measurable growth after 5 months on therapy. The third patient is a 35yo Asian woman, non-smoker, diagnosed with stage IV lung adenocarcinoma with HER2 exon 20 insertion mutation (unknown exact sequence) with malignant pleural effusions, bilateral lung and brain lesions, and extensive lymph node involvement. She was treated with carboplatin, pemetrexed, and bevacizumab first followed by pemetrexed and bevacizumab maintenance, with initial mild improvement then progression after 4.5 months. She was then treated with erlotinib with rapid progression within 1 month. She was then treated with afatinib 40mg daily based on the HER2 mutation, improved disease after 2 months with best response 21% reduction, then progression after 3 more months (5 months total of clinical benefit). She was then started on vinorelbine and trastuzumab. Treatment was interrupted due to one new brain lesion requiring stereotactic radiation treatment. She has shown partial response with best response of 31% on the latest imaging done 4 months after starting therapy.
Conclusion:
From our single institution experience, HER2 targeted therapy can provide disease control for patients with metastatic HER-2 mutated NSCLC that has progressed on previous therapies. Our results are consistent with the study by Mazières et al. Vinorelbine was dosed as 25 mg/m2 and trastuzumab as 2 mg/kg every 1 week (with 4mg/kg first loading dose) or 6 mg/kg every 3 weeks. All three patients were able to tolerate therapies well with no significant toxicities nor cardiac toxicity.
