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R. Salgia
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MINI 19 - Surgical Topics in Localized NSCLC (ID 138)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:D. Jablons, B. Stiles
- Coordinates: 9/08/2015, 16:45 - 18:15, 605+607
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MINI19.01 - Benefits of Surgical Treatment and Complementary Utility of Metabolic Tumor Volume in Selecting Therapy for Stage III NSCLC (ID 3143)
16:45 - 18:15 | Author(s): R. Salgia
- Abstract
- Presentation
Background:
Stage III NSCLC has large variations in primary and nodal metastatic tumor burden and its treatment is controversial.We determined the benefit to overall survival (OS) of these patients from surgery, and potentially complementary role of FDG-PET/CT-based metabolic tumor volume of primary tumor (MTV~T~), nodal metastasis (MTV~N~), and whole-body (MTV~WB~) in selecting patients for surgery.
Methods:
With IRB approval, we retrospectively reviewed 239 stage III NSCLC cases with pre-therapy FDG-PET/CT scans treated 2004 – 2013 (141 IIIA and 98 IIIB, 115 men and 124 women, median age 67.2 years), and measured MTV~T~,MTV~N~, and MTV~WB~. Kaplan-Meier curves and log-rank test were used for determining survival differences between surgically and non-surgically treated patients. Multivariate Cox regression analyses were conducted. Logistic regression analysis was used to evaluate whether each covariate was associated with receiving surgery(including surgery alone and surgery in combination with chemo or radiation). Wilcoxon rank-sum tests were performed for determining differences of primary, nodal, and whole-body MTV between the groups.
Results:
30% (42/141) of IIIA patients and 10% (10/98) of IIIB patients had surgical treatment (p<0.001, Chi-square test). OS was different between surgically and non-surgically treated patients (p<0.001) at 1 year(86% vs. 54%), 2 years(64% vs. 32%), 3 years(52% vs. 21%), and 5 years(39% vs. 14%), with median survival of 37.3 months vs.13.6 months, respectively. Covariates associated with OS were: surgery (0.43 ≤ HR ≤ 0.46, p≤0.001), log~10~MTV~T~ (HR=1.54, p<0.001), log~10~MTV~N~ (HR=1.63, p<0.001), and log~10~MTV~WB~ (HR=2.06, p<0.001) (Figure 1). Log~10~MTV~T~, Log~10~MTV~N~, and Log~10~MTV~WB ~were inversely associated with receiving surgery, with odds ratio of 0.53(p=0.01), 0.55(p=0.036), and 0.38 (p=0.002), respectively. MTV~T~, MTV~N~, and MTV~WB~ were smaller in surgically treated patients, with median of surgically vs. non-surgically treated patients of 17.8 vs. 55.0, 5.3 vs. 15.1, and 27.8 vs. 92.0 cc, respectively (p≤0.004). Additionally, those with stage IIIB disease were significantly less likely to receive surgery after controlling for age, gender, and MTV. No statistically significant interactions were found between surgery and stage or between surgery and log~10~MTV~T~, log~10~ MTV~N~, or log~10~MTV~WB~.Figure 1
Conclusion:
Surgery and smaller MTV are associated with better OS of stage-III NSCLC patients. Smaller MTV and stage IIIA (vs. IIIB) are associated with receiving surgery. FDG PET/CT-based metabolic tumor volume can potentially inform surgical treatment decisions to further improve survival outcome.
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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
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MINI21.06 - Role of the Focal Adhesion Protein Paxillin in Lung Cancer - From Genetic Alterations to Novel Mitochondrial Functionality (ID 2188)
16:45 - 18:15 | Author(s): R. Salgia
- Abstract
- Presentation
Background:
Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer including lung cancer, which is attributed to a greater number of deaths than prostate, breast and colorectal cancers combined. Paxillin is a 68 kDa protein that is an integral part of the focal adhesion and acts as an adaptor molecule. We initially cloned the gene for paxillin, and localized it to chromosome 12q24. We have previously reported that paxillin can be mutated (approximately 8%), amplified (5-7%), and/or overexpressed in almost 80% of lung cancer patient samples. Paxillin protein is upregulated in more advanced stages of lung cancer compared with earlier stages and is a prognostic factor for non-small cell lung cancer (NSCLC). Paxillin gene is amplified in some pre-neoplastic lung lesions as well as neoplastic lesions. We identified 22 different variants of paxillin mutation in our initial investigation especially between the LD and the LIM domains (Jagadeeswaran et al. 2008). There are mutations that have been validated in the TCGA set. We selected six mutants to perform further studies ((P52L, A127T, P233L, T255I, D399N, and P487L as well as wild-type as control). Our investigations focused on an effort to understand the contribution of molecular abnormalities found in paxillin and their relationship to mitochondrial functionality.
Methods:
HEK293 cells as well as a paxillin null NSCLC cell line H522 was used to overexpress the above paxillin mutants and wild-type paxillin. Live cell confocal microscopy was performed to evaluate cell motility, immunoprecipitation to determine interaction with other proteins, and gene expression analysis was performed to evaluate effects on gene expression.
Results:
Among the mutations we investigated, we found that the most common paxillin mutant A127T in lung cancer cells enhanced cell proliferation, focal adhesion formation and co-localized with the anti-apoptotic protein B cell CLL/Lymphoma 2 (BCL-2), which among other sites also localizes to the mitochondria. We further found that when these variant clones of activating mutations were expressed in HEK293 cells, they conferred phenotypic changes resembling neoplastic cells. In gene chip microarrays assay investigating gene expression modulation conferred by these mutations in these same HEK293 cells, we found that P52L, A127T, T255I, P233L and D399N mutations, compared to wild-type paxillin, indeed modulated the expression of a significant number of genes. In particular, there were a number of mitochondrial signature proteins that were altered in the various mutants. Analyzing mitochondrial functions by measuring the interaction of these mutants with mitochondrial proteins MFN2, and DRP1, we identified that they alter mitochondrial dynamics, with significant fission rather than fusion. Paxillin also translocated from the focal adhesion to the mitochondrial membrane. In relationship to cisplatin responsiveness, PXN and mutant overexpression lead to cisplatin resistance.
Conclusion:
These data suggest that wild-type and mutant paxillin variants play a prominent role in neoplastic changes with direct implications in lung cancer progression and hence, its potential as a therapeutic target needs to be explored further.
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.04 - Discussant for MINI26.02, MINI26.03 (ID 3376)
16:45 - 18:15 | Author(s): R. Salgia
- Abstract
- Presentation
Abstract not provided
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MS 22 - Variety in the Oncogene (Does the Exact Mutation Matter?) (ID 40)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:R.C. Doebele, G.V.V. Scagliotti
- Coordinates: 9/09/2015, 14:15 - 15:45, Mile High Ballroom 4a-4f
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MS22.03 - MET - Gene Amplification vs. Overexpression vs. Exon 14 Skipping (ID 1947)
14:15 - 15:45 | Author(s): R. Salgia
- Abstract
- Presentation
Abstract not provided
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ORAL 03 - New Kinase Targets (ID 89)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:F. Blackhall, R. Juergens
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL03.08 - Discussant for ORAL03.05, ORAL03.06, ORAL03.07 (ID 3293)
10:45 - 12:15 | Author(s): R. Salgia
- Abstract
- Presentation
Abstract not provided
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ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
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ORAL10.01 - A DLL3-Targeted ADC, Rovalpituzumab Tesirine, Demonstrates Substantial Activity in a Phase I Study in Relapsed and Refractory SCLC (ID 1598)
10:45 - 12:15 | Author(s): R. Salgia
- Abstract
Background:
Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.
Methods:
SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.
Results:
52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.
Conclusion:
Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.06 - Brigatinib (AP26113) Efficacy and Safety in ALK+ NSCLC: Phase 1/2 Trial Results (ID 2125)
16:45 - 18:15 | Author(s): R. Salgia
- Abstract
- Presentation
Background:
Brigatinib (AP26113), an investigational oral tyrosine kinase inhibitor with FDA breakthrough therapy designation for the treatment of patients with crizotinib-resistant advanced ALK+ NSCLC, has preclinical activity against both rearranged ALK and clinically identified crizotinib-resistant mutant ALK.
Methods:
This is an ongoing phase 1/2, single-arm, open-label, multicenter study in patients with advanced malignancies (N=137; NCT01449461). Patients received escalating total daily doses of brigatinib from 30–300 mg during phase 1. Daily regimens of 90 mg, 180 mg, or 90 mg for 7 days followed by 180 mg were evaluated in phase 2. Safety is reported for all treated patients; antitumor efficacy (ORR and PFS per RECIST v1.1) is reported for ALK+ NSCLC patients.
Results:
Seventy-nine (58%) patients had ALK+ NSCLC. Median age was 54 (29–83) years, 49% were female, 90% had prior crizotinib, and 47% had ≥2 prior chemotherapy regimens. As of February 17, 2015, 45/79 (57%) ALK+ NSCLC patients remained on study, with median time on treatment of 12.6 months (1 day to 35.5 months; n=79); ORR/PFS for evaluable ALK+ NSCLC patients was 74%/13.4 months (additional data shown in Table). In a post hoc independent radiological review of patients with brain metastases at baseline (as of January 19, 2015), 8/15 (53%) patients with measurable brain lesions ≥10 mm had an intracranial response (≥30% decrease in sum of longest diameters of target lesions) and 9/30 (30%) patients with only nonmeasurable lesions had disappearance of all lesions. Treatment-emergent AEs in ≥30% of total patients, generally grade 1/2, included nausea (52%), fatigue (42%), diarrhea (40%), headache (33%), and cough (32%). Early-onset pulmonary events, which occurred ≤7 days after treatment initiation and included dyspnea, hypoxia, and new pulmonary opacities on chest CT consistent with pneumonia or pneumonitis, were reported in 13/137 (9%) patients overall (6/44 [14%] at 180 mg qd; 2/50 [4%] at 90 mg qd [maintained or escalated to 180 mg qd after 7 days]).Response and PFS With Brigatinib All Evaluable ALK+ NSCLC Patients n=78 Prior Crizotinib n=70 No Prior Crizotinib n=8 Response, n(%) OR (CR+PR) 58(74) 50(71) 8(100) [95% CI] [63–84] [59–82] [63–100] CR 7(9) 4(6) 3(38) PR 51(65) 46(66) 5(63) SD 11(14)[a] 11(16)[a] 0 PD 6(8) 6(9) 0 Termination before scan 3(4) 3(4) 0 Median duration of response,[b] mo 11.2[c] 9.9[d] Not reached[e] Median PFS,[b] mo 13.4 13.4 Not reached [a]Includes non-CR/non-PD for 4 patients with no measurable disease at baseline [b]Kaplan-Meier estimate [c]n=55 evaluable [d]n=48 evaluable [e]n=7 evaluable
Conclusion:
Brigatinib has promising antitumor activity in ALK+ NSCLC patients with (71% ORR; PFS 13.4 months) or without (100% ORR) prior crizotinib, including patients with brain metastases (53% ORR in patients with measurable brain lesions). Early-onset pulmonary events were less frequent when starting at 90 vs 180 mg qd. A pivotal global phase 2 trial (ALTA) of brigatinib 90 mg qd vs 90 mg qd for 7 days followed by 180 mg qd in crizotinib-resistant ALK+ NSCLC is ongoing.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.04 - Comprehensive Genomic Profiling (CGP) of Advanced Cancers Identifies MET Exon 14 Alterations That Are Sensitive to MET Inhibitors (ID 3156)
16:45 - 18:15 | Author(s): R. Salgia
- Abstract
- Presentation
Background:
Amplifications and activating mutations in the c-MET proto-oncogene are known oncogenic drivers that have proven responsive to targeted therapy. Mutations causing skipping of MET exon 14 are also oncogenic, but less well characterized. We undertook comprehensive genomic profiling (CGP) of a large series of advanced cancers to further characterize MET exon 14 alterations.
Methods:
DNA was extracted from 40 microns of FFPE sections from 38,028 advanced cancer cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >500x using three versions of the FoundationOne test. Hybridization capture baits for the MET gene were identical for all three versions of the test. Base substitution, indel, copy number alteration, and rearrangement variant calls were examined to identify those nearby to the splice junctions of MET exon 14. These genomic alterations were then manually inspected to identify those likely to affect splicing of exon 14, or delete the exon entirely.
Results:
221 cases harboring MET ex14 alterations were identified. These patients had a median age of 70.5 years (range 15-88), with 97 males and 124 females. The cases were lung carcinoma (193), carcinomas of unknown primary (15), brain glioma (6), and one each of adrenal cortical carcinoma, hepatocellular carcinoma, histiocytic sarcoma, renal cell carcinoma, rhabdomyosarcoma, skin merkel cell carcinoma, and synovial sarcoma. The majority were stage IV. Identification of this alteration has lead to treatment with MET inhibitors such as crizotinib, and to durable partial responses or better exceeding 3 months in histiocytic sarcoma (1), sarcomatoid lung carcinoma (1), and nsclc (1+). Multiple patients (5+) have initiated treatment on either crizotinib or MET inhibitors in clinical development, and additional outcome data will be reported. One patient with locally advanced unresectable disease harbored a MET exon 14 skipping alteration. On initiation with treatment with an MET inhibitor, symptomatic relief was observed in 3 days, radiographic response was observed at two weeks, and resection was performed 8 weeks after initiation of the MET inhibitor.
Conclusion:
MET exon 14 alterations define a hereto unrecognized population of advanced cancer cases, particularly in NSCLC. Multiple case reports demonstrate that these alterations confer sensitivity to multiple small molecule MET inhibitors. This finding expands the population of advanced NSCLC patients who can derive benefit from MET-targeted therapies.
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ORAL 38 - Liquid Biopsies (ID 147)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M.S. Tsao, J. Wang
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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ORAL38.02 - Biopsy-Free Circulating Tumor DNA Assay Identifies Actionable Mutations in Lung Cancer (ID 2163)
16:45 - 18:15 | Author(s): R. Salgia
- Abstract
- Presentation
Background:
The National Comprehensive Cancer Network (NCCN) non-small cell lung cancer guidelines recommend testing for seven genomic targets amenable to matched therapies, including point mutations and insertions/deletions (indels) in EGFR and ERBB2 (HER2), point mutations in BRAF, fusions in ALK, RET and ROS1, and amplification of the MET gene. Novel digital sequencing technology allows assessment of these biomarkers without an invasive tissue biopsy.
Methods:
We prospectively tested cell free DNA from 43 advanced non-small cell lung cancer patients using a cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) panel of 54 cancer genes (Guardant360). Single nucleotide variants (SNVs) in 54 genes and copy number variants (CNVs) in 3 genes (EGFR, ERBB2 and MET) were reported quantitatively as the mutant allele fraction (MAF) in cell-free DNA and the absolute copy numbers in plasma, respectively.
Results:
79% of patients had at least one ctDNA alteration detected. Five (11.6%) had sensitizing mutations in EGFR: EGFR L858R (n=1), EGFR exon 19 deletions (n=4), which may respond to first line tyrosine kinase inhibitors (TKIs) such as erlotinib and afatinib. Three patients with EGFR exon 19 deletions had concurrent T790M resistance mutations, which develop in over half of patients on early generation TKIs. MET amplification, which may respond to crizotinib, was identified in one patient. Clinical outcomes will be reported at the time of presentation. Of the 43 patients in our series, actionable findings were identified in 35 patients (81.4%), with an approved therapy in 5 (11.4%), off label therapies in 19 (44.2%), and clinical trials in 28 (65.1%).
Conclusion:
In our series of NSCLC patients with advanced disease, digital sequencing of cell-free circulating tumor DNA yielded results in approximately 80% of patients. Of these, over 80% had an actionable alteration, including 5 cases with EGFR alterations that could benefit from an approved therapy. Biopsy-free comprehensive sequencing of a patient’s cancer can empower informed treatment decisions from a simple blood draw, especially when repeat tissue biopsy is not feasible or tissue NGS is uninformative.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-061 - The Chicago Thoracic Oncology Database Consortium: A Multi-Site Database Initiative (ID 946)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
An increasing amount of clinical data is available to biomedical researchers, but specifically designed databases and informatics infrastructures are needed to handle this data effectively. Multiple research groups should be able to pool and share this data in an efficient manner. The Chicago Thoracic Oncology Database Consortium (CTODC) was created to standardize data collection and facilitate the pooling and sharing of data at institutions throughout Chicago and across the world.
Methods:
The Salgia Laboratory has implemented the Thoracic Oncology Program Database Project (TOPDP) Microsoft Access, the TORP Velos, and the TORP REDCap databases for translational research efforts. Standard operating procedures (SOPs) were created that document the construction and proper utilization of these databases. These SOPs have been made available freely to other institutions that have implemented their own databases patterned on these SOPs. In order to evaluate the effectiveness of this consortium, we have performed an investigation examining patients receiving erlotinib at three institutions belonging to the CTODC: The University of Chicago Medical Center, Ingalls Health System, and NorthShore University Health System.
Results:
A cohort of 373 lung cancer patients who are taking erlotinib was identified by querying data from all three institutions of the consortium. The patients’ demographic and clinical data were compiled. In addition, the EGFR statuses of patients were analyzed, showing that out of the 70 patients that were tested, 55 had mutations while 15 did not have any mutations. The overall survival and duration of treatment were calculated from the data that was provided. It was shown that patients with an EGFR mutation had longer duration of erlotinib treatment and longer overall survival compared to patients who received erlotinib and were EGFR wild type.
Conclusion:
The investigation described herein demonstrates the successful data collection from multiple institutions in the context of a collaborative effort. However, the investigation identified many challenges in this type of collaboration, such as difficulty of transferring data between institutions and potential duplication of patient data. Overall, these issues do not lessen the findings of the investigation or the effectiveness of the CTODC. With greater cooperation and communication between institutions of the consortium, these issues can be readily resolved. The data presented here can be utilized as the basis for further collaborative efforts and/or development of a larger, more streamlined collection of databases within the consortium.
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P1.01-073 - MET and Invasive Function in NSCLC (ID 2951)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
There is molecular heterogeneity of lung cancers, especially non-small cell lung cancer (NSCLC). Even though pathways such as EGFR and ALK are understood much more, we are beginning to understand the role of MET receptor tyrosine kinase (RTK). The initial trial of EGFR with MET inhibitor was no better than single agent, we strongly believe that it is a subset of MET abnormalities that lead to the pathogenesis of lung cancer. In order to better define this, we are studying the MET function in invasion of NSCLC. We are utilizing the novel ECIS method to study biological behavior.
Methods:
Immunofluorescence of Met/pMet staining was performed with the following antibodies: c-MET (NovusBio) and p-METet (Tyr1230,1234,1235, Invitrogen). Immunoblot analyses of MET/pMET and related signal transduction molecules were performed on H1993 (MET amplified cell line) and A549 (KRAS mutated cell line, with activated MET) cell lysates. ECIS instrument (Applied Biophysics Inc) was used for motility assay and proliferation assay. Confluent cell monolayer was electrically abrased at 6V for 30 seconds. Impedance and resistance of the cell layer were immediately recorded for a period of up to 20 hours. For proliferation assay cells were seeded in 8W10E plates without or with inhibitors. Impedance and resistance were measured for 48 hours at 15 kHz. MET inhibitors were also utilized in the study.
Results:
In our study we investigated the inhibition potential of MET inhibitors. Staining with MET antibody resulted in nuclear and perinuclear staining of both of the cell lines. HGF treatment (100 nM, 20 min) increased nuclear staining. p-MET also increased in the presence of HGF and had plasma membrane, perinuclear and nuclear pattern. 48 hours pre-incubation with MET inhibitors reduced cellular MET staining and abolished MET phosphorylation. Moreover immunoblotting assay demonstrated significant reduction of MET phosphorylation in untreated and HGF treated cells. We measured biological activity of the cells in the presence of inhibitors. MET inhibitors significantly reduced growth rate compared with untreated cells as assessed by electrical resistance measurement. Next we did ECIS based wound-healing assay for a quantitative determination of MET inhibitors on migration potential of NSCLC cells. Voltage pulse led to drastic decrease of cell resistance. MET inhibitors delayed for 35% return to resistance value of the resting cells.
Conclusion:
MET inhibitors reduced NSCLC cell motility, migration and invasion. Novel MET inhibitors can be used for therapeutic intervention against NSCLC. The nuclear localization of MET is a novle function and needs to be explored further. ECIS also is a novel technique to study the biology of epithelial cancers.
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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: 3
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-001 - MET/RON Inhibition in KRAS Mutated Non Small Cell Lung Cancer (ID 2174)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
Molecular genetics have allowed us to categorize non-small cell lung cancer (NSCLC) based on their genetic profile. KRAS mutations occur in 25-30% of NSCLCs. KRAS regulates cellular function in response to growth factors and their receptors. When mutated, KRAS is constitutively active and is responsible for driving tumor oncogenesis. Direct inhibition of KRAS has not been a successful clinical strategy. The strategy of synthetic lethality (targeting a non-lethal defect in cancer cells combined with a second defect, that together make the cancer cell more susceptible to treatment) has gained traction in recent years. Several synthetic lethal targets have been identified with KRAS. We have previously shown that MET plays an important role in the oncogenic addiction observed in KRAS mutated NSCLC and contributes to both tumor growth and metastasis. However, the development of resistance in MET targeting due to upregulation of RON, a related receptor tyrosine kinase, is also evident. Our hypothesis is that dual targeting of MET and RON may be synthetic lethal to KRAS mutated NSCLC and studies to investigate this as a potential therapeutic strategy are warranted.
Methods:
MET- and RON-specific siRNAs (small molecule inhibitors), crizotinib, and the ligand for MET (hepatocyte growth factor), were used in in vitro assays. Immunoblotting, cell viability, and cell migration assays were carried out in a panel of KRAS mutated as well as KRAS wild type NSCLC cells. In addition, human bronchial epithelial cells (HBECs) that were rendered tumorigenic with sequential mutations in CDk4, hTERT, p53, and KRAS genes were also used.
Results:
Our analysis of a panel of NSCLC cells showed that most KRAS mutant cell lines express both MET and RON, and stimulation with HGF activated KRAS effector pathways such as MAPK, AKT and S6RP. When we silenced MET expression with siRNA, it led to upregulation of RON, indicating the interaction between MET and RON. Cell viability assays using crizotinib showed that KRAS mutant cell lines (A549 and H460) are three-fold more sensitive than KRAS wild type cells (H1975 and H1437), and cells with MET amplification (H1993) showed the highest response. Preliminary data with the KRAS-transformed HBECs also showed that they are more sensitive to crizotinib inhibition than the non-transformed control HBECs. Wound healing assays with these same cells showed a similar trend in MET specific inhibition of cell migration in KRAS-mutated cells compared to wild type cells.
Conclusion:
These data highlight the potential therapeutic benefit of targeting MET and RON simultaneously in a subpopulation of KRAS mutated NSCLC patients who may have MET overexpression or amplification. Based on KRAS oncogenic addiction to MET, we propose that NSCLC cells that are MET amplified and KRAS mutated are potentially synthetic lethal and will benefit from dual MET/RON treatment
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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 - 17:00 | Author(s): R. Salgia
- 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.
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P1.04-051 - C. Elegans, an in Vivo Model for Lung Cancer: Effect of Chronic Exposure of Nicotine on Specific Mutants Relevant to Lung Cancer (ID 1552)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
There are a number of genetic abnormalities that can occur in lung cancer. We, and others, have shown that receptor tyrosine kinases (RTKs), such as EGFR, c-MET, RON, and Eph, frequently harbor gain-of-function mutations in addition to being overexpressed in lung cancer. We also have shown that the soil nematode C. elegans overexpressing a c-Met mutant revealed an abnormal vulval phenotype with hyperplasia. Interestingly, exposure to nicotine significantly aggravated the phenotype suggesting that C. elegans can be used as an in vivo model for rapid screening of RTK mutants as well as carcinogens.
Methods:
C. elegans strains vab-1 (Eph receptor), RB2088 (MET receptor), SD551 (temperature sensitive strain expressing constitutively active form of KRAS), and three sli-1 mutants PS2728, PS1258, and MT13032 (inactive, c-CBL) were compared to wild-type N2 worms for survival, fertility, egg-laying capacity, locomotion, and phenotypic changes in the absence or presence of nicotine. Gene expression analysis was also performed on each of the strains in the absence or presence of nicotine.
Results:
Nicotine treatment reduced the lifespan of worms for all strains (p=.0034). Nicotine treatment adversely affected egg-laying capacity of all strains, including N2 control, reducing egg production by 13% at 50μM nicotine and 31% at 500 μM nicotine. Furthermore, the fertility (the number of eggs laid/worm) was significantly reduced in SD551 mutant worms compared to N2 worms (p=.003). Overall locomotion velocity did not change with increasing concentration of nicotine except in MT13032, a c-Cbl mutant. Heat map analysis of gene expression profiling data clearly revealed that the various kinases and phosphatases in C. elegans that are marginally expressed in N2 worms were significantly enhanced upon chronic nicotine exposure. The expression of these genes was already elevated in SD551 and that was further increased in response to nicotine.
Conclusion:
Taken together, chronic nicotine exposure adversely affects various biological functions of C. elegans and these effects are exaggerated in the mutants. Interestingly, nicotine treatment also upregulates the expression of various kinases and phosphatases thereby strengthening our contention that the initial screening studies for the oncogenic mutants detected in humans can be rapidly carried out in C. elegans.
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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)
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P1.08-005 - Met and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma (ID 1700)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
There are a number of genetic alterations such as BAP1 and NF2 that can occur in malignant pleural mesothelioma (MPM). Various studies have shown that both MET and its downstream key intracellular signaling partners PI3K and mTOR are known to be overexpressed and frequently mutated in MPM. Here we have examined the therapeutic efficacy of a new generation small molecule inhibitor of MET receptor tyrosine kinase ARQ 197 and phosphatidylinositol 3-kinase and mTOR (PI3K/mTOR) inhibitors BEZ-235 and GDC-0980 in MPM.
Methods:
The mesothelioma cells were treated with ARQ 197, NVP-BEZ235, or GDC-0980 alone or in combination for 72 hours and cell proliferation was measured by using Alamar Blue assay. Synergistic efficacy was determined by isobologram and combination-index methods of Chou and Talalay. Signaling was assessed by immunoblotting. The mechanism of inhibition was further studied by using apoptosis assays and cell cycle analysis. Cell motility was studied by using scratch assays. We also examined efficacy of the combination of ARQ 197 and GDC-0980 on in vivo tumor growth by using mouse xenograft models.
Results:
MPM cell lines over-express MET and its active form p-MET, PI3K, and p-AKT and total AKT. ARQ 197, NVP-BEZ235, and GDC-0980, when used alone, significantly inhibited the cell proliferation of mesothelioma cells in a dose dependent manner. The combination of MET and PI3K/mTOR inhibitors was synergistic in suppressing MPM cell growth as compared to any single drug alone. Treatment of ARQ 197, NVP-BEZ235, and GDC-0980 alone or in combination inhibited the phosphorylation of AKT and S6 kinase in mesothelioma cells. MET and PI3K/mTOR inhibitors affect cell growth of mesothelioma cells by cell cycle inhibition (cyclin D1) and induction of apoptosis (presence of cleaved PARP, by IF/ confocal microscopy). MET inhibitor ARQ 197 alone inhibits the cell motility of mesothelioma cells in scratch assay. The combination of ARQ 197/ GDC-0980 was much more effective than each single agent alone in inhibiting the tumor growth of mesothelioma xenografts in nude mice. Compared to the control mice (2946±403 mm[3]), the tumors of mice treated with ARQ 197(2262±317 mm[3]) and GDC-0980 (1631±229.57mm[3]) alone had a significant decrease in the tumor volume. The tumor volume of mice treated with the combination of ARQ 197 and GDC-0980 further decreased it to six fold (475±97.43 mm[3]) compared to the control mice.
Conclusion:
Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than single drug use in suppressing MPM cell motility and growth in vitro and tumor growth in vivo and therefore merits further translational studies.
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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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P2.01-037 - Genomic Alterations of KRAS, EGFR, and ALK in Patients with Non-Small Cell Lung Cancer, Single Institution Experience (ID 1722)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS.
Methods:
Thoracic Oncology Research Program (TORP) Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. Three hundred and sixty four patients included in this analysis had advanced NSCLC and underwent genotype testing by FoundationOne, Caris Molecular Intelligence, and Response Genetics.
Results:
99.4% (159/160) of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor types. However, mutations were not mutually exclusive. For the entire cohort 28% of patients were African Americans; adenocarcinoma was the most commonly tested tumor subtype; 91% of KRAS mutations were detected in smokers; 46% of EGFR alterations and 50% of ALK translocations were detected in never smokers. The majority of ALK translocations were detected in adenocarcinomas.
Conclusion:
Personalized medicine is a significant step forward in the realm of lung cancer treatment. In conjunction with NGS to identify and characterize tumor specific molecular abnormalities, biomarker-driven therapies have improved patients’ overall survival. NGS in this study identified potentially actionable genetic alterations across various tumor histology subtypes, races and smoking status. NGS also provided additional information by uncovering targetable concurrent alterations or alterations of unknown significance at this point in time, but potentially targetable in the future.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-010 - Phase II Study of the Anti-PD-1 Antibody Pembrolizumab in Patients with Malignant Mesothelioma (ID 3020)
09:30 - 17:00 | Author(s): R. Salgia
- Abstract
Background:
Mesothelioma is a frequently "inflamed" tumor. We previously identified PD-L1 expression, a CD8 infiltrative pattern, and the presence of PD-1/PD-L1 immune checkpoints in about 1/3 of mesothelioma tumors, similar to the phenotype found in malignancies such as melanoma that benefit from immune checkpoint blockade (Kindler and Seiwert, ASCO 2014). Based on these data, we have initiated a single-center phase II trial (NCT02399371) of the anti-PD-1 antibody pembrolizumab in previously-treated mesothelioma patients. The rationale for this study is further supported by recent data from a phase IB multi-cohort study of pembrolizumab in PD-L1 positive solid tumors, in which an objective response rate of 28% and a disease control rate of 76% was observed in 25 pleural mesothelioma patients, who received 10 mg/kg pembrolizumab every 2 weeks (Alley, AACR 2015).
Methods:
Eligible patients have histologically-confirmed pleural or peritoneal mesothelioma, measurable disease, PS 0-1, disease progression on or after treatment with pemetrexed plus cis- or carboplatin, no more than 2 prior lines of cytotoxic therapy, normal organ function, and tissue available for correlative studies. Patients receive a flat dose of 200 mg pembrolizumab intravenously every 3 weeks. CT scans are obtained every 9 weeks. The primary objectives are: 1) to determine the objective response rate in A] an unselected population and in B] a PD-L1 positive population, and 2) to determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay. Secondary objectives include progression-free and overall survival, disease control rate, and toxicity. Correlative studies are intended to characterize the T-cell inflamed phenotype in mesothelioma via CD8, CD4, and PD-L1 staining, immune related gene expression signatures (Nanostring), and determination of other immune escape mechanisms including T-regulatory cells (FOXP3 expression), IDO expression, MDSCs, and other checkpoints/co-stimulatory signals by immunohistochemistry and/or flow cytometry. A single-stage binomial design will be used. Part A requires ≥ 3 responses in 35 patients. Part B, which uses PD-L1 pre-selection (optimal expression pattern and threshold determined in cohort A), requires ≥ 6 responses in 30 patients. Funded in part by a grant from the Mesothelioma Applied Research Foundation.
Results:
Not applicable.
Conclusion:
Not applicable.
