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H. Akita
Moderator of
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 15
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MA 15.01 - LungBEAM: A Prospective Multicenter Trial to Monitor EGFR Mutations Using BEAMing Technology in Stage IV NSCLC Patients (ID 10145)
15:45 - 17:30 | Presenting Author(s): Pilar Garrido | Author(s): Enriqueta Felip, Luis Paz-Ares, Margarita Majem, T. Morán, J. Bosch, M. Trigo, Rosario García Campelo, J.L. González-Larriba, José Miguel Sánchez-Torres, D. Isla, N. Viñolas, C. Camps, A. Insa, Ó. Juan, Bartomeu Massuti, A. Paredes, Angel Artal Cortes, M. López-Brea, J. Palacios
- Abstract
- Presentation
Background:
Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.
Method:
Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.
Result:
112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting
Conclusion:
Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.
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MA 15.02 - Plasma CfDNA next Generation Sequencing in Non-Small Cell Lung Cancer: Clinical Outcomes and Comparison to Tissue (ID 9502)
15:45 - 17:30 | Presenting Author(s): Luis E Raez | Author(s): T. Mekhail, E. Rodriguez, B. Hunis, A. Nashed, Martin Frederik Dietrich, R.J. Nagy, L. Kiedrowski
- Abstract
- Presentation
Background:
Next-generation sequencing (NGS) of cell-free DNA (cfDNA) in plasma can be an alternative or complement to tissue biopsy for genomic analysis of non-small cell lung cancer (NSCLC), particularly for identifying driver and resistance alterations. We presented preliminary data in 67 patients comparing NGS in plasma vs. tissue (Santos et al. JTO; 11:10, S199-200) and found EGFR mutation agreement of 68% between plasma and tissue. We now present an expanded patient cohort with more extensive concordance analysis, longer follow-up, and clinical outcomes.
Method:
We analyzed data from advanced (stage III/IV) NSCLC patients seen at three cancer centers in Florida (US; Memorial Cancer Institute, Florida Hospital Cancer Center, Mount Sinai Cancer Center) that had alterations detected on Guardant360 (G360) testing through January 2017. G360 is a plasma cfDNA NGS assay that detects single nucleotide variations, amplifications, fusions, and indels in targeted genes using massively parallel digital sequencing; panel composition expanded from 54 to 73 genes over the course of the cohort. NGS performed on solid tumor biopsies from each subject were reviewed for comparison where available but may not have been collected contemporaneously to the plasma samples. Treatment information and clinical outcomes were collected for those patients with actionable mutations per NCCN guidelines (v3.2017).
Result:
A total of 190 G360 test results on 171 unique patients were identified (some patients underwent serial testing at multiple clinical timepoints, e.g. progression). Forty percent of patients were male; the median age was 65 (32-94). Excluding variants of uncertain significance, patients were most likely to have cfDNA alterations in TP53 (44%), EGFR (21%), KRAS (19%), BRAF (8%), and MET (8%). Forty-seven patients (28%) had at least one actionable mutation identified on G360, including SNVs, indels, fusions, and amplifications. Preliminary clinical outcomes data include durable (³10 months) partial responses on targeted therapy based on multiple plasma-detected alterations in EGFR and BRAF V600E; complete analysis will be presented at the meeting.
Conclusion:
Liquid biopsy plays an important role in genomic analysis of NSCLC, offering reliable information to guide therapeutic decision-making. Results in our cohort include a noteworthy proportion of patients with highly actionable mutations, like EGFR drivers and targetable resistance mutations, and G360 offers an alternative to tissue biopsy in these patients.
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MA 15.03 - Distribution of Circulating Tumor DNA in Lung Cancer: Analysis of Primary Lesion, Pulmonary Vein, Bone Marrow and Pripheral Blood (ID 7454)
15:45 - 17:30 | Presenting Author(s): Taichiro Goto
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA), extracted from plasma, is a non-invasive surrogate biomarker. However, the distribution of ctDNA in the body still remains to be elucidated. In this study, resected lung tumors, with simultaneous blood and bone marrow samples, were analyzed to elucidate the distribution of ctDNA.
Method:
Rib bone marrow, pulmonary venous blood (Pul.V) and peripheral blood (Peri.B) were obtained from 30 patients. The liquid samples were divided into cell pellets and supernatant by centrifugation; a total of 212 DNA samples were subjected to massively parallel sequencing.
Result:
ctDNA was detected in 5 patients. Given that the frequency of mutations in the primary tumor was considered to be 100%, those in the other specimens were as follows; Pul.V plasma 20%, Peri.B plasma 11%, and the other samples 0%. Furthermore, ctDNA reflected the predominant mutations in the primary lesion. Clinically, the presence of ctDNA was associated with significantly poorer survival.
Conclusion:
These results suggest ctDNA “spill over” into an immediate outflow tract (Pul.V), and from there is disseminated to the entire body. Thus, it can be inferred that ctDNA reflects the cancer progression and could function as a prognostic marker.
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MA 15.04 - Detection of ALK Rearrangements in Non-Small-Cell Lung Cancer (NSCLC) Patients by Liquid Biopsy (ID 8969)
15:45 - 17:30 | Presenting Author(s): Dongmei Lin
- Abstract
- Presentation
Background:
The ALK rearrangement (ALK+) is an important actionable genetic aberration of NSCLC, which is associated with high sensitivity to targeted agents such as crizotinib and alectinib. Currently, ALK+ is mainly detected by fluorescent in situ hybridization (FISH) or immunohistochemistry that strictly require the availability of tumor sample, however, in NSCLC, tumor tissue are not always valid or sufficient for testing and non-invasive analyzing methods are urgently needed. Recent years, next generation sequencing (NGS) based liquid biopsy has emerged as a useful complementary technique for the analysis of cancer genetic profile, in the present study, we aimed to evaluate the performance of liquid biopsy for the detection of ALK rearrangements in NSCLC.
Method:
From January 2016 to May 2017, paired tumor and cell-free plasma samples were collected form 360 histologically proven NSCLC patients. The presence of ALK+ was detected by fluorescent in situ hybridization (FISH) in tumor samples and by a NGS based liquid biopsy technology that targeted 96 genes, including ALK, in plasma samples. Genomic alterations in cancer-associated somatic variants are analyzed by massively parallel sequencing. The FISH results were set as golden-standard for the presence of ALK+. The specificity and sensitivity of liquid biopsy for the detection of ALK+ were evaluated.
Result:
ALK+ were detected in 28/360 (7.8%) of the tumor samples and 25/360 (6.9%) of the plasma samples. All the 25 ALK+ plasma samples were also ALK+ in their corresponding tumor samples. Liquid biopsy failed to detect ALK+ in 3 samples that were positive in tumor sample. Thus, the specificity and sensitivity of liquid biopsy for detection of ALK+ in plasma were 100% and 89.3%, respectively.
Conclusion:
NGS based liquid biopsy technology is a promising, non-invasive method for the detection of ALK rearrangement that may benefit NSCLC patients who have difficult to obtain tumor samples or need continuous monitor of ALK status.
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MA 15.05 - Discussant - MA 15.01, MA 15.02, MA 15.03, MA 15.04 (ID 10774)
15:45 - 17:30 | Presenting Author(s): Montse Sanchez-Cespedes
- Abstract
- Presentation
Abstract not provided
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MA 15.06 - ERBB Receptor Feedback Inhibitor-1 Alterations in Non-Small Cell Lung Cancer (ID 10454)
15:45 - 17:30 | Presenting Author(s): Jeffrey G Schneider | Author(s): P. Jain, K.A. Schalper, Christine Lovly, F. Gardner, Jeffrey S. Ross, A.B. Schrock, Siraj M Ali, V.A. Miller, Vamsidhar Velcheti
- Abstract
- Presentation
Background:
ERBB Receptor Feedback Inhibitor-1 (ERRFI-1) encodes MIG6, which is a negative regulator of EGFR and ERBB2 signaling. Loss of function alterations at ERRFI-1 would be expected to promote oncogenesis, but the role of ERRFI-1 alterations in conferring sensitivity to targeted therapies remains to be fully investigated.
Method:
We reviewed 19,347 cases of NSCLC in the Foundation Medicine data base for ERRFI-1 alterations that had been previously assayed by hybrid-capture based genomic DNA profiling of FFPE tissue specimens. Two patients, so identified, had been treated with EGFR pathway antagonist therapies and their outcomes are reported herein.
Result:
ERRFI-1 truncating mutations were identified in 0.62 % (120/ 19,347) of all screened NSCLC specimens. ERRFI-1 alterations were seen in all NSCLC histologic subtypes examined at similar frequencies: adenocarcinoma (0.7%), squamous carcinoma (0.3%), large cell carcinomas (0.8%), adenosquamous (0.6%), sarcomatoid (0.6%), and not otherwise specified (0.6%). Co-existing alterations included: P53 (59%), KRAS (19%), EGFR exon 19 del (9.2%), EGFR L858R (3.3%), EGFR T790M (3.3%), EGFR amp (6.7%), ERBB2 mut (7.5%), and ERBB2 amp (3.3%). Two female patients with ERRFI-1 mutations who were wildtype for known NSCLC driver mutations and targeted therapy naive, achieved RECIST criteria partial responses after treatment with single agent EGFR TKI therapies. Following subsequent disease progression, one of these patients also achieved a secondary response to single agent EGFR directed monoclonal antibody therapy. To our knowledge, these are the first two reported patient outcomes for targeted therapies in ERRFI-1 altered NSCLC.
Conclusion:
The index cases presented here suggest that NSCLC patients with genetic lesions in ERRFI-1 may respond to both anti-EGFR TKIs and monoclonal antibodies. However, co-occurrence between ERFFI-1 mutations and alterations in known NSCLC drivers such as EGFR exon 19 del and L858R may also indicate that in some contexts, ERRFI-1 alterations may provide a mechanism for acquired resistance to targeted therapies as well. Further investigation including assessment of ERRFI-1 loss of heterozygosity, ERRFI-1 VUSs , and clinical evaluation of additional cases including response and resistance to targeted therapy will be performed to more fully delineate the role of ERRFI-1 in NSCLC.
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- Abstract
- Presentation
Background:
Remarkable advances for clinical diagnosis and treatment in cancers including lung cancer involve cell-free circulating tumor DNA (ctDNA) detection through next generation sequencing. However, before the sensitivity and specificity of ctDNA detection can be widely recognized, the consistency of mutations in tumor tissue and ctDNA should be evaluated. The urgency of this consistency is extremely obvious in lung cancer to which great attention has been paid to in liquid biopsy field.
Method:
Averagely 10 ml preoperative blood samples were collected from 30 patients containing pulmonary space occupying pathological changes by traditional clinic diagnosis. cfDNA from plasma, genomic DNA from white blood cells, and genomic DNA from solid tumor of above patients were extracted and constructed as libraries for each sample before subjected to sequencing by a panel contains 50 cancer-associated genes covering 1654 hotspots by custom probe hybridization capture with average depth >40000, 7000, or 6300 folds respectively.
Result:
Detection limit for mutant allele frequency in our study was 0.1%. The sequencing results were analyzed by bioinformatic expertise based on our previous studies on the baseline mutation profiling of circulating cell-free DNA and the clinicopathological data of these patients. Among all the 27 lung cancer patients, 80 percent were predicted as positive by ctDNA sequencing when the standard was defined as at least one of the hotspot mutations detected in the blood (ctDNA) was also detected in tumor tissue. Pneumonia and pulmonary tuberculosis were detected as negative according to the above standard. When evaluating all hotspots, 949 of 1265 (75 percent) mutations detected in tumor tissue were also detected in patients' blood. When evaluating all genetic variations, including those present at high levels in tumor tissue (clonal, driver genes in the panel) as well as those at low levels (subclonal, passenger genes in the panel), 327 of 583 (56 percent) detected in tumor tissue were also detected in patients' blood. Mutations detected only in blood (ctDNA and genomic DNA in white blood cells) but not in tumor tissue are not well understood yet.
Conclusion:
We demonstrated the importance of sequencing both circulating cell-free DNA and genomic DNA in tumor tissue for ctDNA detection in lung cancer. We also determined and confirmed the consistency of ctDNA and tumor tissue through NGS according to the criteria explored in our studies. Our strategy can initially distinguish the lung cancer from other space occupying lesions of lung. Our work shows that the consistency will be benefited from the optimization in sensitivity and specificity in ctDNA detection.
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MA 15.08 - Safety and Efficacy of Osimertinib in Treating an EGFR-Mutant Lung Cancer Patient with a Germline EGFR T790M Mutation (ID 9712)
15:45 - 17:30 | Presenting Author(s): Tianhong Li | Author(s): W. Ma, J. Gong, J. Shan, D. Lewis, W. Xiao, J. Hung, E.H. Moore, Y. Zhang, N.Z. Mans, J. Welborn, K.S. Lam
- Abstract
- Presentation
Background:
Limited and conflicting data are available for the safety and clinical efficacy of EGFR TKIs, especially third-generation TKI osimertinib, in the rare (<0.1%) subset of NSCLC patients carrying a germline EGFR T790M mutation. We here report a patient with concurrent somatic EGFR L858R and germline EGFR T790M mutations detected by liquid biopsy and tumor genomic profiling assay.
Method:
A 67-year-old male, life-long never smoker was initially found to have bilateral, small lung nodules incidentally on a CT scan during the workup for a kidney stone. His family history suggests a hereditary predisposition to lung cancer given there were three other individuals (including two never smokers) across three generations with a history of lung cancer. The patient underwent annual surveillance chest CT scans over a two-year period before a biopsy-proven stage IA lung adenocarcinoma was found, which was treated with stereotactic body radiation. Unfortunately, this patient developed local tumor recurrence in the lung and wide spread bony metastases in less than one year. To determine the effect of EGFR TKIs on normal blood cells, we established a permanent Epstein-Barr Virus (EBV)-transformed lymphoblastoid cell line from the patient’s peripheral blood mononuclear cells (PBMCs) and determined the in vitro cytotoxicity of the cell line to first, second, and third generation EGFR TKIs. Serial tumor genomic profiling of plasma ctDNA by the Guardant360 assay was obtained each time clinical treatment was changed for this patient.
Result:
We found neither EGFR nor AKT expression in the PBMCs and the EBV-transformed lymphoblastoid cell line established from this patient. The EBV-transformed lymphoblastoid cells were resistant to all first, second and third generation EGFR TKIs tested. This patient achieved rapid clinical response to osimertinib after progression on radiation, chemotherapy, and afatinib. Serial genotyping of plasma ctDNA showed the alteration of EGFR L858R level correlated with tumor response while the mutant allelic frequency of EGFR T790M remained at ~50%. A heterozygous EGFR T790M germline mutation was confirmed by genetic testing.
Conclusion:
To our knowledge, this is the first combined in vitro and clinical data supporting the safety and efficacy of osimertinib in patients with the germline EGFR T790M mutation. Further mechanistic studies are needed to understand the tumorigenesis and clinical management for lung cancer patients and carriers with a germline EGFR T790M mutation.
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MA 15.09 - Circumferential Distribution and Distance from Main Tumor of Tumor Spread Through Air Spaces (STAS) Are Prognostic (ID 10143)
15:45 - 17:30 | Presenting Author(s): Koji Kameda | Author(s): R. Gaber, Takashi Eguchi, Z. Tano, D. Jones, William D Travis, Prasad S. Adusumilli
- Abstract
- Presentation
Background:
The prognostic impact of the presence of tumor spread through air spaces (STAS) has been reported in lung adenocarcinoma (ADC). The aim of this study is to investigate the prognostic impact of the distribution, distance from the primary tumor, and quantification of STAS.
Method:
A cohort of 394 patients with pathologic stage I lung ADC (2012-2014) were investigated. The distribution of STAS around the tumor was classified into focal or circumferential. The distance of STAS was evaluated by counting the number of air spaces between the farthest STAS and the tumor edge. STAS was quantified by counting the number of STAS areas in the three most STAS- dense 20x high power fields (HPFs). The recurrence free probability (RFP) was analyzed by the Kaplan-Meier method with a log-rank test.
Result:
STAS was present in 211 (54%) cases. The presence of STAS was associated with a higher risk of recurrence (5-y RFP in STAS-positive vs. STAS-negative; 78% vs 90%, p<0.001, Fig 1A). Circumferential STAS was associated with a higher risk of recurrence than focal STAS (5-y RFP in circumferential vs. focal; 67% vs 87%, p=0.027, Fig 1B). A longer distance of STAS was associated with a higher risk of recurrence (5-y RFP >7 alveoli vs.≤7 alveoli, 69% vs. 91%, p=0.003, Fig 1C). Quantification of STAS was not prognostic (5-y RFP in >3/HPFs vs. ≤3/HPFs, 75% vs. 88 %, p=0.15). Figure 1 X
Conclusion:
Beyond just the presence of STAS, the distribution and distance of STAS can further stratify the risk of recurrence in stage I lung ADC.
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MA 15.10 - Discussant - MA 15.06, MA 15.07, MA 15.08, MA 15.09 (ID 10775)
15:45 - 17:30 | Presenting Author(s): Natasha Rekhtman
- Abstract
- Presentation
Abstract not provided
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MA 15.11 - CCNE1, PTGS2, TGFA and WISP2 Predict Benefit from Bevacizumab and Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer (SAKK19/09) (ID 9592)
15:45 - 17:30 | Presenting Author(s): Sacha I Rothschild | Author(s): M. Amrein, C. Riether, O. Gautschi, N. Schuster, Q. Li, Spasenija Savic, M. Schneider, C. Biaggi, Lukas Bubendorf, M. Brutsche, A. Zippelius, T. Zander, D. Betticher, Martin Früh, Rolf A Stahel, R. Cathomas, D. Rauch, M. Pless, A. Ochsenbein, R. Jaggi
- Abstract
- Presentation
Background:
Bevacizumab (Bev; Avastin[®]) is a monoclonal antibody against the vascular endothelial growth factor. No predictive biomarkers for the use of Bev have been established so far. We aimed identifying genes predictive for progression-free survival (PFS) and overall survival (OS) of patients treated in the trial SAKK19/09 (NCT01116219).
Method:
SAKK19/09 was a non-randomized phase II trial with two sequential cohorts including patients with non-squamous NSCLC and EGFR wild-type. In Cohort 1, 77 patients were treated with cisplatin (C) 75mg/m[2], pemetrexed (Pem) 500mg/m[2] and Bev 7.5mg/kg, followed by Bev+Pem maintenance. Cohort 2 included 52 patients treated with C+Pem followed by Pem maintenance. RNA was isolated from baseline tumor tissue sections and processed for gene expression analysis by Nanostring. Using the Nanostring nCounter® System (Nanostring Technologies) gene expression of 201 genes, including 6 housekeeping genes was measured using a custom-designed codeset. For each gene, a Cox regression was performed with normalized gene expressions, treatment and the interaction for PFS and OS. No adjustment for multiple testing was done.
Result:
We analyzed 99 patient samples (61 in Cohort 1; 38 in Cohort 2) with 201 genes at baseline. We found 7 genes potentially predictive for PFS (AURKB, CCNE1, CDKN2B, MMP2, PTGS2, TGFA, WISP2), 4 of which were also potentially predictive for OS (CCNE1, PTGS2, TGFA and WISP2) (Table 1).Gene Accession HR (95% confidence interval) p-value of interaction Cohort 1 Cohort 2 Potential predictive markers for PFS AURKB NM_004217 1.09 (0.84-1.42) 0.78 (0.61-0.99) 0.0481 CCNE1 NM_001238 1.09 (0.87-1.36) 0.73 (0.53-1.02) 0.0312 CDKN2B NM_004936.3 0.80 (0.67-0.95) 1.10 (0.85-1.43) 0.0375 MMP2 NM_004530.2 0.81 (0.67-0.97) 1.10 (0.91-1.34) 0.0258 PTGS2 (COX-2) NM_000963.1 1.29 (1.06-1.58) 0.90 (0.78-1.04) 0.00352 TGFA NM_003236.2 1.13 (0.94-1.37) 0.74 (0.53-1.03) 0.0452 WISP2 NM_003881.2 0.82 (0.69-0.98) 1.24 (1.02-1.51) 0.0015 Potential predictive markers for OS CCNE1 NM_001238 1.08 (0.86-1.36) 0.71 (0.49-1.02) 0.0324 PTGS2 (COX-2) NM_000963.1 1.35 (1.10-1.65) 0.81 (0.69-0.95) <0.0001 TGFA NM_003236.2 1.17 (0.96-1.43) 0.55 (0.33-0.91) 0.00352 WISP2 NM_003881.2 0.87 (0.73-1.03) 1.14 (0.92-1.42) 0.0314
Conclusion:
We identified several potentially predictive genes for Bev activity in combination with chemotherapy. Several of these (AURKB, CCNE1, CDKN2B, TGFA) have previously been shown to play an important role in cell cycle regulation and cell proliferation supporting the hypothesis that Bev supports chemotherapy activity. Notably, also a gene involved in inflammation (PTGS2) was significantly predictive for outcome. Further work is ongoing to explore changes in gene expression using tumor rebiopsies at progression.
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MA 15.12 - Expanding the Lung Small RNA Transcriptome: Discovery of Unannotated microRNAs with Roles in Development and Tumourigenesis (ID 9100)
15:45 - 17:30 | Presenting Author(s): Brenda C. Minatel | Author(s): Victor D Martinez, Adam Patrick Sage, Erin Anne Marshall, K.W. Ng, C. Anderson, D.D. Becker-Santos, W.P. Robinson, I. Jurisica, W.L. Lam
- Abstract
- Presentation
Background:
MicroRNAs (miRNAs) are key regulators of gene expression. They participate in many biological and pathological processes, from organ development to malignant transformation. Their functions are widely conserved, involving post-transcriptional silencing of gene expression. Over 2500 mature miRNA sequences have been identified in humans; however, recent studies have showed that the number of annotated miRNAs represent only a fraction of the total pool of existing miRNAs, suggesting that there are still many potentially undiscovered biologically relevant miRNAs encoded by the human genome. Here, we perform a comprehensive study to identify novel miRNA sequences expressed in non-malignant lung tissues, as well as samples from developmental stages and pathological conditions.
Method:
A total of 422 samples were included in this analysis. First, 209 non-malignant samples from two cohorts (BCCA, n=118 and TCGA, n=91) were analyzed using our customized small RNA sequence analysis pipeline. Sequence reads were aligned to the hg38 build of the human genome (STAR algorithm) and novel miRNAs were predicted using mirDeep2. The results were compared to miRNA databases and further filtered by abundance and for miRNA-compatible structure. The same procedure was applied to matched tumours (n=209) and samples derived from fetal lungs (n=4). The biological relevance of the novel sequences was investigated by assessing their expression in tumours and fetal samples, together with gene target prediction and tissue-specific protein-protein interaction (PPI) network analyses using IID.
Result:
Our study discovered the expression of 294 novel miRNA sequences in lung tissue, significantly expanding the current human lung miRNA transcriptome. These novel miRNAs showed similar nucleotide composition and genomic distribution compared to known miRNAs, providing additional evidence of their miRNA-compatible nature. Interestingly, a subset of these miRNAs were also found to be expressed in tumour and fetal samples, indicating that they might play important roles in organ development and tumourigenesis. Likewise, target prediction analysis revealed that these novel miRNAs are involved in key cellular processes including cell proliferation, migration and survival, as well as pathways known to be deregulated in cancer, as comprehensively analyzed using pathDIP.
Conclusion:
Our study has significantly expanded the lung small RNA transcriptome, and provided evidence that the novel miRNAs are involved in molecular networks relevant to lung biology and pathology. These results also highlight their specific roles in developmental regulation and malignant transformation, suggesting their role as biological regulators and implicating their potential as therapeutic targets.
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MA 15.13 - The Transfer of Exogenous UCHL-1 via Mesenchymal Lung Cancer Exosomes to Mediate Phenotypic Alterations of Recipients (ID 9094)
15:45 - 17:30 | Presenting Author(s): Yoshihisa Shimada | Author(s): P. Yenerall, K. Huffman, K. Avila, H. Park, B. Timmons, B. Gao, D. Deb, Norihiko Ikeda, J. Minna
- Abstract
- Presentation
Background:
Cancer-derived exosomes are micro-vesicles released by tumor cells and are believed to be involved in intercellular signaling and communication. Recent evidence suggests exosomes help tumor cells invade neighboring tissues and prime metastatic sites for disease spread. Non-small cell lung cancer (NSCLC) is a highly metastatic disease and little is known about how tumor-derived exosomes may influence migration or invasion of lung cancer cells and prime metastatic niches.
Method:
Exosomes were recovered by a sequential centrifugation schema. Exosomes isolated from lung cancer cell line H1299, A549, H1993, and H2073, and non-malignant, immortalized human bronchial epithelial cell (HBEC) 3KT and 30KT were characterized. We examined the effects of cancer-derived exosomes on HBECs, oncogenically progressed HBECs (HBEC sh-p53+KRAS[v12]; HBEC3KTRL53) in vitro and their influence on metastasis in murine models. Mass spectrometry was performed to identify candidate proteins carried in tumor exosomes that induce phenotypic changes in recipient cells.
Result:
Cancer-derived exosomes but not HBEC-derived exosomes confer invasiveness and increased motility on recipient cells (HBEC3KT, HBEC3KTRL53) in wound healing and Boyden chamber assays. Mesenchymal NSCLC exosomes induce mesenchymal-like phenotypic changes (loss of EPCAM expression and upregulated EMT-transcriptional factors) in HBEC3KT in FACS and qRT-PCR analyses. Cancer-derived exosomes but not HBEC3KT exosomes enhance the lung endothelial permeability, promote lung metastasis, and recruit myeloid-derived suppressor cells in vivo. Mass spectrometry shows that H1299 exosomes contains a wide variety of deubiquitinating enzymes (DUBs) compared to HBEC3KT exosomes, and UCHL-1 (Ubiquitin carboxy-terminal hydrolase L1) is the most highly expressed DUB in H1299 exosomes. UCHL-1 expression is upregulated in mesenchymal NSCLC cells/exosomes, and HBEC3KT cells treated with mesenchymal NSCLC exosomes in vitro, and activated in metastatic sites after cancer-derived exosome treatment in vivo. UCHL-1 knockdown suppresses metastasis induced by cancer-derived exosomes. Exosomes derived from UCHL-1-knockdown H1299 show a decreased effect of the induction of migration, invasiveness, and epithelial/mesenchymal phenotypic changes on recipient cells.
Conclusion:
Mesenchymal NSCLCs-derived exosomes compared to HBECs-derived exosomes induced an increased migratory/invasive phenotype with lung vascular leakiness, metastatic niche formation, and higher xenograft tumor take rates. UHCL-1 was overexpressed only in mesenchymal NSCLCs/exosomes. UCHL-1 knockdown suppressed metastasis, and its exosomes also showed a decreased effect of the induction of tumor progression. These results suggest that understanding and targeting UCHL-1 likely as a key factor of mesenchymal NSCLC-derived exosome behavior could lead to novel therapeutic strategies.
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MA 15.14 - Long Non-Coding RNA Disruption in Lung Adenocarcinoma Reveals Novel Mechanisms of Metastasis (ID 8659)
15:45 - 17:30 | Presenting Author(s): Adam Patrick Sage | Author(s): Greg L. Stewart, Katey S.S. Enfield, Erin Anne Marshall, Victor D Martinez, W.L. Lam
- Abstract
- Presentation
Background:
Identifying the drivers of metastasis will yield new molecular targets for prognostics and therapeutics. Long non-coding RNAs (lncRNAs) are known to regulate gene transcription through their influence on the expression of nearby (cis) and distant (trans) genes. Emerging evidence suggests that lncRNAs are involved in key cellular processes, presenting an opportunity for large-scale identification of lncRNA genes critical to lung cancer progression. Here we investigate the contribution of this class of non-coding RNA to lung adenocarcinoma (LUAD) metastasis.
Method:
Stage T1 and T2 tumours with (N≥1 and/or M≥1) and without (N=0 and M=0) metastasis were examined for expression comparisons. Sequencing data from 265 non-metastatic and 130 metastatic tumours obtained from The Cancer Genome Atlas were used as our discovery cohort. Results were validated in 20 non-metastatic and 10 metastatic tumour samples microdissected to 90% purity and sequenced using the Illumina Hi-Seq platform. Normalized sequence read count comparisons were performed (Mann Whitney U-Test, FDR-BH p<0.05) to identify lncRNAs significantly deregulated in metastatic samples. LncRNAs over- and under-expressed in metastatic LUAD were compared to nearby protein-coding-target genes to identify putative mechanisms of regulation in cis.
Result:
We discovered 150 lncRNAs to be significantly differentially expressed between metastatic and non-metastatic tumours, including lncRNAs with previously described oncogenic roles in lung cancer, such as Lung Cancer Associated Transcript 1 and H19. As individual lncRNAs can positively or negatively regulate target-gene expression, it is noteworthy that we identified potential protein-coding-target genes that display both concordant and discordant expression patterns with specific lncRNAs. For example, we discovered the upregulation of linc00942 in metastatic LUAD (FDR-BH p=0.001) and the concordant overexpression of its corresponding protein-coding-target gene, ELKS/RAB6-Interacting/CAST Family Member 1 (ERC1) (FDR-BH p=0.02). Further, metastatic LUAD samples stratified by linc00942 expression also display corresponding elevation of ERC1 (p=0.0002), which holds true in the validation cohort. ERC1 (an upstream member of the NF-κB signaling pathway) is implicated in cell migration and focal adhesion, and displays deregulated expression in a number of cancer types. Thus, overexpression of linc00942 may act as a novel positive cis-regulator of ERC1, promoting metastasis.
Conclusion:
This work has led to the discovery of a large number of lncRNA genes deregulated in metastatic LUAD, suggesting that altered lncRNA expression contributes functionally to malignant progression. Understanding cis- or trans-mediated mechanisms of gene deregulation enacted by metastasis-associated lncRNAs will present novel opportunities for diagnosis and treatment.
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MA 15.15 - Discussant - MA 15.11, MA 15.12, MA 15.13, MA 15.14 (ID 10776)
15:45 - 17:30 | Presenting Author(s): David Rimm
- Abstract
- Presentation
Abstract not provided
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 9
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)
11:00 - 12:30 | Presenting Author(s): Y.Y. Elamin | Author(s): Jacqulyne Ponville Robichaux, Vincent K Lam, Anne Tsao, C. Lu, G. Blumenschein, J. Kurie, Julie R Brahmer, S. Li, T. Chen, A. Estrada-Bernal, A. Truini, M. Nilsson, A.T. Le, Z. Tan, S. Zhang, Robert C. Doebele, K. Politi, Z. Yang, S. Liu, Kwok-Kin Wong, John V Heymach
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.
Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).
Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.
Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.
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OA 12.02 - Final Results of a Phase 2 Study of the hsp90 Inhibitor Luminespib (AUY922) in NSCLC Patients Harboring EGFR Exon 20 Insertions (ID 10182)
11:00 - 12:30 | Presenting Author(s): Zofia Piotrowska | Author(s): D.B. Costa, M. Huberman, Geoffrey R. Oxnard, Justin F Gainor, R. Heist, I.T. Lennes, A. Muzikansky, Alice Shaw, C.G. Azzoli, Lecia V Sequist
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).
Method:
Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.
Result:
29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.
Conclusion:
The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.
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OA 12.03 - Clinical Features of Advanced Lung Cancer Harboring HER2 Aberrations: A Large Prospective Cohort Study (HER2-CS STUDY) (ID 8694)
11:00 - 12:30 | Presenting Author(s): Shinobu Hosokawa | Author(s): A. Bessho, K. Ninomiya, T. Tanaka, N. Ishikawa, M. Yamasaki, T. Shibayama, K. Aoe, T. Kozuki, N. Fujimoto, K. Gemba, Y. Ueda, M. Inoue, T. Murakami, Shoichi Kuyama, H. Kawai, K. Fujitaka, K. Inoue, M. Takata, H. Yanai, K. Hotta, K. Kiura
- Abstract
- Presentation
Background:
HER2 is a potential driver oncogene. HER2-targeted precision therapy has been tested in NSCLC. However, the demographics of HER2-positive NSCLC have not been defined systematically.
Method:
Pts with advanced NSCLC were registered. HER2-IHC and FISH assays were performed with commercial kits. HER2 mutations were identified by the direct sequencing. The aim of this study was to clarify the frequency, characteristics and outcome of HER2-positive NSCLC.
Result:
Of 1,126 tumors screened (Table A), 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 EGFR wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775_G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female pts had HER2 mutant tumors more frequently, while IHC/FISH+ tumors were detected more often in males (Table B). HER2-positive tumors had similar survival outcome to triple negative tumors, but significantly worse prognoses than EGFR-mutant and ALK-positive tumors (p < 0.05 each). The treament info will be presented at the meeting.
*including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations. ** 1 had an IHC2+/FISH+ tumor with mutation.A. The Genotype-Specific Subsets* HER2 (n = 88) EGFR (n = 358) ALK (n = 44) Triple negative /unknown (n = 662) Total (n = 1,126) Age, median Sex (male) Smoking habit Non-Sq Stage III/IV 69 61 (69%) 58 (66%) 78 (89%) 51 (58%) 69 142 (40%) 142 (40%) 351 (98%) 220 (61%) 62 21 (48%) 19 (43%) 44 (100%) 35 (80%) 69 516 (78%) 544 (82%) 503 (76%) 423 (64%) 69 726 (64%) 754 (67%) 951 (84%) 714 (63%) MST (mo) 1-yr OS rate 17.5 59% NR 85% NR 79% 15.1 59% 19.8 67% B. The Subsets of HER2 aberrations** IHC3+ (n = 34) IHC2+/FISH+ (n = 34) Mutant (n = 21) Age, median Sex (male) Smoking habit Non-Sq Stage III/IV 71 27 (79%) 24 (71%) 30 (88%) 17 (50%) 71 27 (79%) 26 (76%) 28 (82%) 21 (62%) 65 8 (38%) 9 (43%) 21 (100%) 14 (67%) MST (mo) 1-yr OS rate 10.5 46% 16.0 70% NR 59%
Conclusion:
This is the first prospective study showing a small fraction of NSCLC possessed HER2 aberrations. HER2-positive tumors had relatively poor prognosis. NSCLCs with HER2 IHC3+ and mutation seem to be distinct subsets.
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OA 12.04 - Discussant - OA 12.01, OA 12.02, OA 12.03 (ID 10799)
11:00 - 12:30 | Presenting Author(s): Christina S Baik
- Abstract
- Presentation
Abstract not provided
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OA 12.05 - Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer (ID 9984)
11:00 - 12:30 | Presenting Author(s): Trever G Bivona | Author(s): V.M. Raymond, R.B. Lanman, R.J. Nagy, K.C. Banks, Y.K. Chae, J.M. Clarke, Jeffrey Crawford, David R. Gandara, John V Heymach
- Abstract
- Presentation
Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.
Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.
Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.
Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.
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OA 12.06 - Plasma Genomic Profiling and Outcomes of Patients with MET Exon 14-Altered NSCLCs Treated with Crizotinib on PROFILE 1001 (ID 9385)
11:00 - 12:30 | Presenting Author(s): Alexander Drilon | Author(s): J.W. Clark, J. Weiss, Sai-Hong Ignatius Ou, D. Ross Camidge, Ben J Solomon, G. Otterson, L.C. Villaruz, Gregory J Riely, R. Heist, G.I. Shapiro, D.A. Murphy, Y. Liu, S.C. Wang, T. Usari, K.D. Wilner, Paul K. Paik
- Abstract
- Presentation
Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.
Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).
Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.
Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.
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OA 12.07 - LOXO-292, a Potent, Highly Selective RET Inhibitor, in MKI-Resistant RET Fusion-Positive Lung Cancer Patients with and without Brain Metastases (ID 10955)
11:00 - 12:30 | Presenting Author(s): Vamsidhar Velcheti | Author(s): T.M. Bauer, V. Subbiah, M.E. Cabanillas, N. Lakhani, L.J. Wirth, Geoffrey R. Oxnard, M.H. Shah, E.J. Sherman, S. Smith, T. Eary, S. Cruickshank, B.B. Tuch, K. Ebata, M. Nguyen, S. Corsi-Travali, S. Rothenberg, Alexander Drilon
- Abstract
- Presentation
Background:
RET fusions are validated therapeutic targets in human lung cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity is limited by a narrow therapeutic index from off-target effects and poor pharmacokinetics (PK). Moreover, MKIs have limited RET inhibition in the central nervous system (CNS), and patients often experience disease progression in the brain. LOXO-292 is a potent and highly selective RET inhibitor, with >100-fold selectivity versus important off-targets, and anti-tumor activity in the brain and periphery in RET-dependent tumor models in vivo.
Method:
Two RET fusion-positive lung cancer patients were treated with LOXO-292: a patient with CCDC6-RET-rearranged lung cancer with acquired resistance to RXDX-105; and a patient with KIF5B-RET-rearranged lung cancer with progressive disease in the brain while on alectinib treated under a single patient protocol with real-time, PK- guided intra-patient dose titration.
Result:
The first patient was enrolled on cohort 1 of the Phase 1 trial (20 mg daily) and was the first lung cancer patient to receive LOXO-292. She achieved a rapid, confirmed partial response (PR) by RECIST 1.1, with a 44% reduction in target lesion size. The second patient, the first to receive LOXO-292 in the setting of brain metastases, achieved a PR with escalating doses of LOXO-292 (20-60-100 mg twice daily) that included target lesion responses in both the lungs and brain (Figure 1), and resolution of cancer-related CNS symptoms. Early clinical experience with LOXO-292 has already established drug exposures that are consistent with significant RET inhibition in vitro and RET-dependent tumor regression in vivo. Importantly, LOXO-292 has been well-tolerated, with the majority of treatment-emergent adverse events reported as Grade 1-2, and none attributed to LOXO-292.
Conclusion:
LOXO-292 has demonstrated proof-of-concept tolerability, significant exposure, and efficacy in two patients with MKI-resistant, RET-dependent cancers, including a patient with progressive brain metastases after alectinib.Figure 1
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OA 12.08 - Genomic Analysis of Non-Small Cell Lung Cancer (NSCLC) Cases with Focal and Non-Focal MET Amplification (ID 9520)
11:00 - 12:30 | Presenting Author(s): Sai-Hong Ignatius Ou | Author(s): D. Pavlick, P.J. Stephens, Jeffrey S. Ross, V.A. Miller, Siraj M Ali, A.B. Schrock
- Abstract
- Presentation
Background:
MET amplification (METamp) is a known driver and a mechanism of resistance in EGFR-mutated lung cancers treated with targeted therapy. However, development of therapies targeting METamp has been hampered in part due to poor genomic stratification of patients. We investigated the natural distribution of the size of the MET amplicon and associated genomic characteristics.
Method:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed prospectively on DNA isolated from FFPE samples from NSCLC. Tumor mutational burden (TMB) was calculated from 1.1 Mbp of sequenced DNA and reported as mutations/Mb, as previously described (PMID: 28420421).
Result:
We identified 545 NSCLC cases with focal, defined as <20 Mbp (n = 457, 84%), or non-focal (n = 88, 16%) amplification of the MET gene using CGP. Within this set, the size of the MET amplicon ranged from 0.095 – 158 Mbp; 25[th], 50[th] and 75[th] quartiles were 1.63 Mbp, 3.46 Mbp, and 11.66 Mbp, respectively. In cases with focal METamp the median MET copy number was 11, compared to a median of 7 copies for cases with non-focal METamp (P <0.001). Median TMB in cases with focal vs. non-focal METamp was 10.8 and 9.0, respectively (P=0.47). MET exon 14 splice site alterations co-occurred with METamp in 45 cases (8%), of which 80% had focal METamp (median amplicon size of 2.02 Mbp). EGFR mutations co-occurred with METamp in 93 cases (17%) in this dataset, of which 78% had focal METamp (median amplicon size: 3.77 Mbp). In contrast, cases with other co-occurring alterations described in the NSCLC NCCN guidelines (ALK, ROS1 or RET rearrangements, BRAF V600E, or ERBB2 mutations) METamp was more commonly non-focal (3 focal and 6 non-focal cases), with a median amplicon size of 25.5 Mbp. Clinical outcomes will be presented, including a subset of cases in the setting of resistance to EGFR inhibitors.
Conclusion:
The size of the MET amplicon in MET-amplified NSCLCs is largely variable. Focal amplification is associated with a higher estimate of MET copy number. Neither TMB or co-occurring MET or EGFR mutations significantly correlated with size of the MET amplicon; however, other co-occurring known drivers were associated with non-focal METamp. Additional investigation is warranted to determine the clinical significance of the size of the MET amplicon in NSCLC.
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OA 12.09 - Discussant - OA 12.05, OA 12.06, OA 12.07, OA 12.08 (ID 10800)
11:00 - 12:30 | Presenting Author(s): Julien Mazieres
- Abstract
- Presentation
Abstract not provided
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