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Vincent Plagnol
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.02 - Prospective Clinical Validation of the InVisionFirst™ ctDNA Assay for Molecular Profiling of Patients with Advanced NSCLC (ID 13885)
13:35 - 13:40 | Author(s): Vincent Plagnol
- Abstract
- Presentation
Background
Clinical practice guidelines advocate molecular profiling as a part of the evaluation of advanced NSCLC, with ctDNA based profiling being an option for those with insufficient tissue. Thorough prospective clinical validation studies of NGS based ctDNA assays are lacking. Here we report the multi-centered prospective clinical validation of a ctDNA NGS panel for stratification of patients with advanced untreated NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
InVisionFirst™ (Inivata) is a ctDNA NGS assay for detection of genomic alterations in 36 genes commonly mutated in NSCLC and other cancers. 264 patients with untreated advanced NSCLC were prospectively recruited by 41 US centers. 178 patients had tumour tissue available for molecular profiling (predominantly by NGS) and the remaining 86 patients without tissue were included to compare ctDNA profiles obtained from patients with and without tissue for profiling.
4c3880bb027f159e801041b1021e88e8 Result
A total of 204 patients (77.3%) had detectable ctDNA alterations. Using tissue results as the reference, overall concordance for the full 36 genes in the InVisionFirst™ panel with matched tissue profiling was 97.8% with 82.9% PPV, 98.5% NPV, 70.6% sensitivity and 99.2% specificity. Considering a subgroup of 8 genes that can influence routine clinical patient management (EGFR, ALK, ROS1, ERBB2, MET, BRAF, KRAS, STK11) the PPV was 93.7%, 96.8% NPV, 72.4% sensitivity and 99.4% specificity. Excluding patients with undetectable ctDNA, these figures become 93.7% PPV, 98.4% NPV, 87.3% sensitivity and 99.3% specificity. The observed pattern of genomic changes seen in ctDNA was consistent across patients with and without tissue for profiling. Across the whole study, 44 patients with actionable alterations were identified by ctDNA testing compared to only 36 by tissue testing. 47% of patients tested by ctDNA had an actionable alteration or an alteration that is generally mutually exclusive for such actionable changes such as KRAS or STK11.
8eea62084ca7e541d918e823422bd82e Conclusion
The InVisionFirst™ assay demonstrates excellent concordance with tissue profiling in this multi-centered prospective clinical validation study. The performance of this assay in terms of overall sensitivity and specificity appears comparable if not higher than other established commercial ctDNA assays. Utilization of InVisionFirst™ ctDNA testing led to the detection of 22% more actionable alterations than standard of care tissue testing in this study supporting its use for the molecular stratification of patients with advanced NSCLC. Further analyses on the features associated with detectable ctDNA signatures are ongoing.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA16.09 - Feasibility, Clinical Relevance of ALK/ROS1 Fusion Variant Detection by Liquid Biopsy in Advanced Non-Small Cell Lung Cancer (ID 13492)
14:30 - 14:35 | Author(s): Vincent Plagnol
- Abstract
- Presentation
Background
Liquid biopsy offers an alternative non-invasive approach to reflect the tumor genomic landscape of NSCLC patients; however, the potential of liquid biopsies for ALK/ROS1 fusion detection is poorly described. Herein, we evaluated an amplicon-based NGS assay for ctDNA detection of ALK and ROS1 fusions in a large cohort of ALK and ROS1 NSCLC patients and correlation of variants with clinical data.
a9ded1e5ce5d75814730bb4caaf49419 Method
ALK- and ROS1-translocated advanced NSCLC patients, were prospectively enrolled from October 2015 to April 2018 in 9 French institutions. ALK or ROS1 positivity was as confirmed by immunochemistry and FISH or RNAseq. ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and mutations in a panel of 36 NSCLC-associated genes were investigated in ctDNA using InVisionFirst™ (Plagnol V PLoS ONE, 2018).
4c3880bb027f159e801041b1021e88e8 Result
A total of 120 patients were included: 96 ALK and 24 ROS1. 30 samples were collected from patients who were TKI-treatment-naive, 257 during follow-up and 73 at progressive disease (PD) under TKI. The median age was 55 years-old (range 23-75); most patients were female (57%) and had a non-smoking history (59%). At diagnosis, 20% of patients presented with brain metastasis. All patients received at least 1 ALK-TKI (median: 1.6; range:1-6).
Preliminary results are available for the first 54 patients: 21 at diagnosis and 33 at PD under TKI. ALK/ROS1 fusions were detected in 13/21 patients (62%) at diagnosis: 12/20 ALK-fusions (7 v1, 2 v2 and 3 v3) and in 1/1 ROS1-fusion (CD74-ROS1). No fusion was detected in 8 patients, which may be due to partner genes or variants not covered by this panel. However, 5 of these 8 patients had exclusive thoracic or brain PD.
Liquid biopsies collected at the radiographic evaluation under therapy revealed complete ctDNA clearance of the fusion when patients experienced PR (n=4). In samples at PD, fusion was detected in 44% of patients (24/55) with evidence of acquired resistance in patients both positive and negative for fusion.
Results for the remaining samples, correlation between fusion variant and survival, fusion variant and mechanism of resistance will be presented at the Congress.
8eea62084ca7e541d918e823422bd82e Conclusion
Our results suggest that ctDNA profiling is a promising non-invasive tool for identification of ALK/ROS1 fusions and monitoring of response in advanced NSCLC patients. Systematic identification of the fusion partner may help to better understand the heterogeneity and evolution (sensitivity profile to targeted inhibitors and associated-mechanisms of resistance) of NSCLC driven by ALK and ROS1 rearrangement.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-67 - Clinical Relevance of ALK/ROS1 Resistance Mutations and Other Acquired Mutations Detected by Liquid Biopsy in Advanced NSCLC Patients (ID 14279)
16:45 - 18:00 | Author(s): Vincent Plagnol
- Abstract
Background
Liquid biopsies (LB) for circulating tumor DNA (ctDNA) can be a tool for somatic mutation detectionin NSCLC patients. However, the applicability and clinical relevance of ALK/ROS1 and other acquired mutation detected by LB is poorly described. We evaluated ALK/ROS1 and other acquired mutations detected by ctDNA in a large cohort of ALK/ROS1+ NSCLC patients described to date.
a9ded1e5ce5d75814730bb4caaf49419 Method
Advanced ALK/ROS1+ NSCLC patients were prospectively enrolled from October 15 to April 2018 in 9 French institutions. ctDNA anlaysis was performed using ctDNA using InVisionFirst™ (36-gene panel) for ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and other somatic mutations.
4c3880bb027f159e801041b1021e88e8 Result
120 patients were included: 96 ALK, 24 ROS1. The median prior tyrosine kinase inhibitors (TKI) received was 2 (0-4). Blood samples (n=402) were collected: tyrosine kinase inhibitors (TKI)-naive (n=30), during (n=257) or at progression (PD) under TKI (n=73. Prior treated patients received at least 1 TKI (1-6). Preliminary results are available for the first 54 patients; ALK/ROS1 status was confirmed by ALK IHC (39), FISH (56) and RNAseq (2).
ALK mutations were detected in 36% of blood samples at PD to TKI (12/33): 8% (1/13) post-crizotinib and 55% (11/20) post next-generation TKI (F1174/F1174V/D1203N/R1192P/G1202R (6)/F1174L+G1202/G1202R+F1174L+C1156Y). Complex ALK mutations were observed in 2/12 samples (17%) post next-generation TKI (G1202R+F1174L+C1156Y/F1174L+G1202R). Other acquired mutations were found in 36% (12/33) of samples at PD: TP53 (10), NFE2L2 (4), PTEN (2), PI3KCA (1), CDKN2A (1). Complex ALK mut.+ non-ALK mut. were found in 6/33 (18%) samples, 1 post crizotinib (G1269A+R1264K+L1196Q+F1164L+C1156Y+NFE2L2(4)), and 5 samples post next-gen TKI (G1202R+PTEN/G1202R+TP53/F1174L+G1202R+TP53/TP53(2)+D1203N/TP53+R1192P). Non-ALK mut. were exclusive and could explain TKI resistance in 6/33 (18%) samples.
8eea62084ca7e541d918e823422bd82e Conclusion
Routine liquid biopsies can assess the heterogeneity of the TKI resistance, detecting ALK resistance and other acquired mutations in pretreated advanced ALK & ROS1 NSCLC patients. This could have an impact on clinical outcomes. The association of ALK mut. and complex ALK mut. +/- other acquired mut. with clinical outcomes will be presented at the congress.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-78 - Validation of InVisionFirst ctDNA NGS Profiling via ddPCR Testing in Patients with Non-Small Cell Lung Cancer (NSCLC) (ID 12220)
16:45 - 18:00 | Author(s): Vincent Plagnol
- Abstract
Background
Tumor tissue based molecular profiling is widely utilized to guide therapy in advanced NSCLC and recently, ctDNA assays have been developed to detect actionable alterations in a non-invasive manner. However, there are frequent reports of discordance between analysis platforms and here we compare the Inivata NGS ctDNA assay with ddPCR based ctDNA analysis and tissue NGS sequencing in patients with advanced NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
InVisionFirst (Inivata) is a ctDNA NGS assay for detection of genomic alterations in 36 genes commonly mutated in NSCLC and other cancer types. A cohort of 52 patients underwent ctDNA analysis by InVisionFirst and were tested in a blinded manner for 4 actionable gene alterations (EGFR L858R & Ex19del, KRAS G12C & G12D) and 30 of the cohort also had testing for 5 additional alterations (EGFR T790, EML4-ALK fusions, ROS1 fusions, KRAS G12V and BRAF V600E) at one of two independent ddPCR laboratories. Finally, tissue analysis by NGS was available in 21 patients to arbitrate any discordance between the results of the 2 liquid biopsy techniques.
4c3880bb027f159e801041b1021e88e8 Result
Across the 9 specific genetic alterations investigated by both ctDNA platforms, 26 alterations were detected by the InvisionFirst platform and 23 were detected by the ddPCR platforms. The overall concordance of gene alterations was 98.5% (320/342) with positive agreement of 95.5% and negative agreement of 98.8%. Discordance was observed in 6 detected gene alterations, with 1 EML4-ALK fusion, 1 EGFR exon19 deletion and 2 KRAS G12Cs being detected by InVisionFirst but not by ddPCR, and 1 EGFR L858R and 1 KRAS G12D detected by ddPCR but not InVisionFirst. One G12C, the EML4-ALK, and the L858R alteration were confirmed by tissue NGS. The KRAS G12D was not confirmed by tissue NGS. No tissue was available to examine for the detection of the EGFR exon 19 deletion or the other KRAS G12C mutation. All other results were concordant.
8eea62084ca7e541d918e823422bd82e Conclusion
This study in NSCLC patients demonstrates excellent concordance of the InVisionFirst ctDNA NGS assay with ddPCR based ctDNA analysis via blinded independent laboratories. The excellent sensitivity and specificity support the use of the InVisionFirst assay as a non-invasive “liquid biopsy” for molecular profiling.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-24 - Prospective Efficacy of Osimertinib in Circulating Tumour DNA (ctDNA) T790M-Mutant NSCLC Patients (ID 14031)
16:45 - 18:00 | Author(s): Vincent Plagnol
- Abstract
Background
Liquid biopsy circulating tumor DNA (ctDNA) analysis in advanced EGFR-mutant NSCLC patients is an approved tool for molecular profiling and disease surveillance when tissue is not available. Long-term efficacy of osimertinib in patients with the T790M resistance mutation positive detected only by ctDNA (without tissue information) has not been fully validated.
a9ded1e5ce5d75814730bb4caaf49419 Method
In a prospective study, EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKI, in whom a repeat tissue biopsy was not feasible, were assessed for ctDNA T790M mutational status using InVisionSeqTM. T790M-positive NSCLC patients received osimertinib (80 mg daily; extended access program or approval) at RECIST progression. The objectives were to assess: proportion of patients with acquired ctDNA-T790M positive; overall survival (OS) of the overall EGFR-mutant population as well as OS comparison for T790M +ve/-ve. Also, for those T790M-positive NSCLC patients who received osimertinib in a real world data we assessed: response rate (RR) according to RECIST 1.1 by investigator and progression free survival (PFS), calculated from the date of osimertinib initiation until the date of progression or death (whichever came first), or the date of last follow-up are also reported.
4c3880bb027f159e801041b1021e88e8 Result
We recruited 82 patients (71% female, median age 64 years, 72% Del19 EGFR mutation, 71% never-smokers). The ctDNA T790M mutation was detected in 55% (N=45) of NSCLC patients. Median OS of EGFR-mutant population was 38.2 months (mo.). According to T790M status, median OS was 41.2 months and 30.4 mo. for T790M-positive and T790M-negative NSCLC patients, respectively. Both cohorts had already received a median of 3 previous treatment lines. In 40 T790M-positive NSCLC patients who receive osimertinib, RR was 55% (PR: 55%, SD 27.5% and PD: 12.5%) and median PFS of 8.5 mo. Median OS on osimertinib among 10 patients with brain and/or leptomeningeal metastases at baseline was of 13.4 months.
8eea62084ca7e541d918e823422bd82e Conclusion
In patients with acquired resistance to first- or second-generation EGFR TKIs, ctDNA T790M detection by InVisionSeq™ is equivalent to what has been reported in tissue biopsy. Osimertinib has clinical benefit in patients for which the T790M resistance mutation is detected only through a liquid biopsy procedure.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.04-02 - Early Plasma ctDNA Response Anticipates Clinical Response to First-Line Immunotherapy in Advanced NSCLC (ID 14240)
12:00 - 13:30 | Author(s): Vincent Plagnol
- Abstract
Background
Shedding of circulating tumor DNA (ctDNA) into plasma can be an independent prognostic indicator in lung cancer, and changes in plasma ctDNA levels correlate with response to targeted therapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing (NGS) would enable early detection of response to immunotherapy in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced NSCLC who received first-line treatment with pembrolizumab alone or in combination with platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from patients prior to starting therapy and again at 3 and 3 weeks after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes (InVisionSeq). The trends of the ctDNA allele frequency were correlated with radiographic responses to therapy.
4c3880bb027f159e801041b1021e88e8 Result
Serial plasma samples were collected on 21 patients with the following characteristics: 67% female, median age 62, 90% adenocarcinoma, 10% squamous cell carcinoma. Pembrolizumab was administered as monotherapy to 18 (86%) patients and in combination with platinum/pemetrexed in 3 (14%) patients for a median of 6 cycles. Among the 8 (38%) patients with no detectable ctDNA at baseline, 5 patients who maintained no detectable ctDNA during serial analyses responded to treatment, and 3 patients with emergence of ctDNA within the first 6 weeks of treatment initiation experienced progressive disease. In the 13 (62%) patients with detectable ctDNA at baseline, radiographic responses were preceded by earlier changes in ctDNA allele frequency. Six of 7 patients with >50% decreases in ctDNA allele fraction responded to treatment while 4 of 6 patients with progressive disease had increases in ctDNA within 6 weeks.
8eea62084ca7e541d918e823422bd82e Conclusion
In advanced NSCLC treated with first-line immunotherapy, rapid decreases and clearance of ctDNA correlated with clinical benefit, while increasing or newly detectable ctDNA was a harbinger of progressive disease. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.
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