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R.B. Lanman



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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCES01.10 - Serial Quantitative Assessment of Plasma Circulating Tumor DNA by Digital NGS in Patients with Lung Cancer (Now Available) (ID 7054)

      R.B. Lanman

      • Abstract
      • Presentation
      • Slides

      Background:
      Next generation sequencing (NGS) has been increasingly used in oncology practice but proven practically difficult when serial tumor specimens are needed. The objectives of this study were to determine feasibility and explore clinical utility of serial NGS analyses of circulating tumor DNA (ctDNA) in patients (pts) with advanced solid tumors undergoing treatment.

      Methods:
      ctDNA digital NGS was performed by a CLIA-certified lab (70-gene panel with mutant allele fraction (MAF) quantification). ctDNA results were retrospectively analyzed and decreases/increases/stability of molecular tumor load (MTL) defined here as MAFs of truncal driver mutations were correlated with clinical and radiographic response to treatment (response, progression, or stable disease, respectively).

      Results:
      From Jan 2015 to July 2016, 38 consecutive pts with advanced lung tumors (84% LUAD, 5% LUSC, 5% SCLC, 5% NOS) receiving treatment (Table) had serial ctDNA analyses (median 2, range 2-7). ctDNA alterations were detected at least once in 37 (97.4%) pts. Changes in MTL correlated with or predicted all (95% CI, 82.0-99.8%) radiological and/or clinical responses except for the patient with no genomic alteration detected. MTL results clarified response status when radiographic responses were difficult to assess in 9 (28%) of pts with either complex pleural disease (n=6), pneumonitis during PD-1 inhibitor therapy (2). Two MTL change patterns were observed: 1) clonal changes while receiving targeted therapy, including EGFR (12), ALK (3), MET (2), ERBB2 (2); 2) global changes to PD-1 inhibitors, chemotherapy or radiation. Representative tumor response maps will be presented. Table. Summary of tumor types and cancer treatment.

      Cancer Type Targeted Therapy Immunotherapy Chemotherapy Radiation TOTAL
      LUAD 14 8 7 3 32
      LUSC 1 1 0 0 2
      SCLC 0 0 2 0 2
      NOS 1 0 1 0 2
      All 16 9 10 3 38


      Conclusion:
      Serial liquid biopsies and ctDNA digital NGS are feasible and clinically useful in monitoring MTL and genomic alterations during cancer treatment, especially in situations when radiographic responses are equivocal. Prospective evaluation of impact on clinical decision making is warranted.

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    OA06 - Prognostic & Predictive Biomarkers (ID 452)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      OA06.01 - Clinical Utility of Circulating Tumor DNA (ctDNA) Analysis by Digital next Generation Sequencing of over 5,000 Advanced NSCLC Patients (Now Available) (ID 6096)

      R.B. Lanman

      • Abstract
      • Presentation
      • Slides

      Background:
      Detection of actionable genomic alterations is now required for NCCN guideline-compliant work-up of NSCLC adenocarcinoma. Next-generation sequencing (NGS) of ctDNA, if sufficiently sensitive and specific, could provide a non-invasive, comprehensive genotyping platform relevant to clinical decision-making when tissue is insufficient or at time of progression on targeted therapies.

      Methods:
      A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients accrued between 6/2014 – 4/2016. The frequency and distribution of somatic alterations in key genes were compared to those described in TCGA (Pearson and Spearman correlations). The clinical impact of ctDNA testing was evaluated by identification of resistance mechanisms emergent at progression on targeted therapies, and through analysis of additional driver mutations detected by ctDNA at baseline in 362 consecutive NSCLC patients with tissue mutation data available. The positive predictive value (PPV) of ctDNA sequencing was assessed in 229 patients with known tumor driver alterations.

      Results:
      ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17%, MET amplification in 4%, BRAF mutations in 3% and other rare but potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r=0.92, 0.99, 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants was 100% for EGFR[L858R], 98% for EGFR[E19del], 96% for ALK, RET, or ROS1 fusions, and 100% for KRAS[G12/G13/Q61] mutations. In 362 cases with tissue information available, 63% (229/362) were tissue quantity-insufficient or undergenotyped (QNS/UG). ctDNA analysis identified driver mutations in 51 of the 229 QNS/UG cases, a 38% increase in detection rate over tissue alone. Among 1,111 EGFR-mutant cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFR[T790M] 47%, MET amp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%. In 143 consecutive NSCLC patients with detailed follow-up and serial analysis seen at the UC Davis Cancer Center, informative driver mutations were observed in 48 (34%).

      Conclusion:
      This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. At baseline, ctDNA augmented tissue analysis by identifying additional, actionable mutations when tissue was QNS/UG. ctDNA NGS conducted at progression identified emergent resistance mutations that could inform subsequent courses of therapy.

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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-057 - Clinical Utility of ctDNA for Detecting ALK Fusions and Resistance Events in NSCLC: Analysis of a Laboratory Cohort (ID 6247)

      R.B. Lanman

      • Abstract

      Background:
      Advanced NSCLC patients whose tumors harbor ALK fusions benefit from first line treatment with ALK inhibitors (ALKi). However, insufficient tissue for testing (QNS) occurs ~25% of the time. Patients treated with ALKi ultimately progress. Historically, identification of the resistance mechanism/s required repeat tumor biopsy. Circulating tumor DNA (ctDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without a repeat biopsy.

      Methods:
      The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 57 patients (2/2015-6/2016) with 58 ctDNA-detected ALK fusions. G360 is a CLIA-laboratory ctDNA test that detects point mutations in 70 genes and select amplifications, fusions and indels. Available records were reviewed to characterize patients at baseline and at progression.

      Results:
      Identified fusion partners included EML4 (n=51, 88%), STRN (7%), KLC1 (3%), KIF5B (2%). Thirty patients had no history of targeted therapy (new diagnosis or no prior genotyping, “cohort 1”); 23 patients were drawn at ALKi progression (“cohort 2”). In 6 samples, the patients’ clinical status was unknown. Three additional cases had ALK resistance mutations (F1174C, F1269A/I1171T, D1203N) detected in ctDNA but no fusion detected; historical tissue testing was ALK+. Conversely, in cohort 1, 10 (33%) were tissue QNS (7) or tissue ALK negative (3) while 4 (13%) were tissue ALK+ and 16 (54%) had unknown tissue status. As expected, no documented or putative resistance mechanisms were identified in cohort 1, although TP53 mutations were identified in 43%. Among 18 patients progressing on an ALKi, 7 (39%) contained 1 (4 patients), 2 (1 patient) or 3 (2 patients) ALK resistance point mutations (F1174C/V: 3 occurrences; G1202R: 3; L1196M: 3; G1128A: 1; L1189F: 1; I1171T: 1). Additional events co-occurring in the resistance cohort included 1 each of: BRAF[V600E], MET[E14skip], KRAS[G12], KRAS[G13], HRAS[Q61], EGFR[E330K], KIT[amp], BRAF[amp]. 5 EGFR-mutant NSCLC cases at progression harbored ALK fusions (4 STRN, 2 EML4; 1 patient had both) representing 1% of all EGFR-mutant progressing NSCLC cases in the G360 database. Four of these patients also harbored EGFR[T790M], but the presence of an ALK fusion may represent further subclonal evolution following the selective pressure of an EGFR inhibitor.

      Conclusion:
      These results add to the growing body of literature demonstrating that comprehensive ctDNA assays provide a non-invasive means of detecting targetable alterations in the first line when tissue is QNS as well as detecting known and novel resistance mechanisms that may inform treatment decisions at progression.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-009 - Serial Quantitative Assessment of Plasma Circulating Tumor DNA by Digital NGS in Patients with Lung Cancer (ID 6267)

      R.B. Lanman

      • Abstract

      Background:
      Next generation sequencing (NGS) has been increasingly used in oncology practice but proven practically difficult when serial tumor specimens are needed. The objectives of this study were to determine feasibility and explore clinical utility of serial NGS analyses of circulating tumor DNA (ctDNA) in patients (pts) with advanced solid tumors undergoing treatment.

      Methods:
      ctDNA digital NGS was performed by a CLIA-certified lab (70-gene panel with mutant allele fraction (MAF) quantification). ctDNA results were retrospectively analyzed and decreases/increases/stability of molecular tumor load (MTL) defined here as MAFs of truncal driver mutations were correlated with clinical and radiographic response to treatment (response, progression, or stable disease, respectively).

      Results:
      From Jan 2015 to July 2016, 38 consecutive pts with advanced lung tumors (84% LUAD, 5% LUSC, 5% SCLC, 5% NOS) receiving treatment (Table) had serial ctDNA analyses (median 2, range 2-7). ctDNA alterations were detected at least once in 37 (97.4%) pts. Changes in MTL correlated with or predicted all (95% CI, 82.0-99.8%) radiological and/or clinical responses except for the patient with no genomic alteration detected. MTL results clarified response status when radiographic responses were difficult to assess in 9 (28%) of pts with either complex pleural disease (n=6), pneumonitis during PD-1 inhibitor therapy (2). Two MTL change patterns were observed: 1) clonal changes while receiving targeted therapy, including EGFR (12), ALK (3), MET (2), ERBB2 (2); 2) global changes to PD-1 inhibitors, chemotherapy or radiation. Representative tumor response maps will be presented. Table. Summary of tumor types and cancer treatment.

      Cancer Type Targeted Therapy Immunotherapy Chemotherapy Radiation TOTAL
      LUAD 14 8 7 3 32
      LUSC 1 1 0 0 2
      SCLC 0 0 2 0 2
      NOS 1 0 1 0 2
      All 16 9 10 3 38


      Conclusion:
      Serial liquid biopsies and ctDNA digital NGS are feasible and clinically useful in monitoring MTL and genomic alterations during cancer treatment, especially in situations when radiographic responses are equivocal. Prospective evaluation of impact on clinical decision making is warranted.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
    • Now Available
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      P2.03b-023 - Circulating Tumor DNA (ctDNA)-Based Genomic Profiling of Known Cancer Genes in Lung Squamous Cell Carcinoma (LUSC) (ID 5393)

      R.B. Lanman

      • Abstract

      Background:
      Next-generation sequencing (NGS) of ctDNA is increasingly used for non-invasive genomic profiling of human cancers. However, studies to date have not detailed the ctDNA genomic landscape in LUSC.

      Methods:
      From June 2014 to June 2016, ctDNA from 467 patients with stage 3 or 4 (AJCC 7[th] edition) LUSC (60% male, 40% female; median age of 69 [range 27-96]) were tested with Guardant 360[TM], a ctDNA NGS assay that detects single nucleotide variants (SNVs) of 54-70 cancer genes and certain copy number amplifications (CNAs), indels, and fusions. The median time between diagnosis and ctDNA testing was 238 days. Somatic alterations were compared with those in the 2016 LUSC TCGA dataset.

      Results:
      426 patients (92.2%) had at least one somatic alteration detected. The most commonly observed SNVs (> 5% frequency) were TP53 (64.8%), PIK3CA (7.8%), CDKN2A (6.1%), and KRAS (5.9%). Frequencies of SNVs known to be significant in LUSC correlated well between our cohort and the TCGA (Spearman r = 0.93) but were generally lower in our cohort (Table 1). Several of our most frequently observed CNAs are strongly associated with LUSC (EGFR, CDK6, MYC, ERBB2, PDGFRA, KIT, CCND1). In addition, MET exon 14 skipping (1.3%), EGFR exon 19 deletion (1.9%), EGFR exon 20 insertion (0.5%), ERBB2 exon 20 insertion (0.3%) and EML4-ALK fusion (0.7%) were detected. These alterations have rarely been reported in LUSC.

      Conclusion:
      Patterns of SNVs and CNAs in LUSC obtained by ctDNA profiling are largely consistent with those from TCGA tissue profiling, although the frequency of key SNVs is lower. The presence of actionable alterations atypical for LUSC in 4.7% of this clinical cohort may represent underappreciated treatment options. Further investigation is warranted to evaluate whether these findings reflect a distinct mutational landscape in heavily treated advanced disease (which is under-represented in the TCGA) and/or challenges in histopathological classification. Figure 1



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      P2.03b-030 - Retrospective Review Clinical Use of a cfDNA Blood Test for Identification of Targetable Molecular Alterations in Patients with Lung Cancer (ID 5969)

      R.B. Lanman

      • Abstract

      Background:
      The availability of tumor genomic information from simple, minimally invasive blood collection may lead to significant impact in patient(pt) care. We report a retrospective review the clinical utility of a CLIA-certified cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our pts with lung cancers.

      Methods:
      From April 2015 to May 2016, blood samples from 250 consecutive pts were collected and sent for molecular profiling at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) using cfDNA NGS with a panel of 70 cancer-related genes with reported high sensitivity (able to detect mutations of < 0.1% mutant allele fraction) with high specificity (> 99.9999%) (PLoS One, 10(10), 2015).

      Results:
      254 Guardant360 tests were completed in 250 pts (144/F:106/M); histology: adenocarcinoma(200), squamous(7), sarcomatoid(5), small cell(4) and others(34). Rationale for blood tests: addition to tissue analysis(39%), alternative to tissue biopsy(25%), treatment evaluation/resistant(18%), insufficient tissue(11%), no documentation(7%). Based on Guardant360 results, 77 pt samples (30.3%) demonstrated targetable alterations with FDA-approved agents; concordance with at least 1 genomic alteration (targetable with FDA-approved agent) from paired tissue analysis in 21pts; and in another 29 pts, new genomic alterations provided evaluation for potential change in therapies pts: EGFR T790M(n=21), EML4-ALK fusion(n=4), MET Exon 14 Skipping (3), EGFR ex19del(n=2), EGFR L858R(n=2), other targets(n=6). Significantly, detection of EGFR T790M in cfDNA lead to change in therapy with osimertinib 19 cases and eligibility to clinical studies in 2 cases with alterations in KIF5B-RET and NOTCH1,respectively. Additional clinical outcomes are pending and will be updated.

      Conclusion:
      Molecular testing of cfDNA is a simple, minimally invasive test. It has utility to obviate a repeat invasive tissue biopsy when the initial tissue sample is not available or inadequate for molecular analysis. It is particularly useful in the long-term management of patients at progression for detection of emergent resistance-associated molecular alterations; such as EGFR T790M.

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      P2.03b-047 - The Clinical Impact of Multiplex ctDNA Gene Analysis in Lung Cancer (Now Available) (ID 5758)

      R.B. Lanman

      • Abstract
      • Slides

      Background:
      Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. Currently there is insufficient data in regard to the impact of ctDNA analysis on clinical decision making. In this study, we evaluated the clinical utility of ctDNA sequencing on treatment strategy and progression-free survival.

      Methods:
      In this retrospective study, data was collected from files of 90 NSCLC patients monitored between the years 2011-2016 at the Thoracic Center Unit at Davidoff Cancer Center, Rabin Medical Center, Israel. The patients performed liquid biopsy NGS analysis by a commercial test (Guardant 360), in which ctDNA was extracted from plasma and analyzed by massively parallel paired end synthesis by digital NGS. This test allows the detection of somatic alterations such as point mutations, indels, fusions and copy number amplifications.

      Results:
      Age at diagnosis ranged between 31 and 89 years, with median age of 63 years. Sex ratio was 1:2.2. Out of 90 patients, 38 consecutive patient files have already been reviewed for clinical impact. 82% (31/38) were diagnosed with Adenocarcinoma. 5% (2/38) performed ctDNA at initial diagnosis, 48% (17/38) performed ctDNA after 1[st] line therapy due to progressive disease and the remaining 50% performed the test after multiple lines of treatment. Liquid biopsy NGS analysis allowed the detection of actionable mutations, according to NCCN guidelines, in 68% (26/38). Treatment decision was changed subsequent to NGS analysis in 34% (13/38) which received tailored targeted therapy. Interestingly, 13% (5/38) were detected with EGFR activating mutation following wild type result by standard local molecular testing based on RT-PCR from tissue biopsy. Based on the RECIST criteria of response evaluation, 30% of the patients had partial response after switching to targeted therapy, 15% had stable disease, 15% experienced progressive disease and ~40% were not evaluated yet. Survival rates will be calculated further in the study based on data availability.

      Conclusion:
      Our interim results analysis showed that liquid biopsy ctDNA testing revealed possible treatment options for more than two-thirds of patients analyzed, including FDA-approved drugs as well as eligibility for clinical trials. Most of the patients that were evaluated showed a positive response to treatment. Although this topic needs to be further assessed in large randomized controlled trials, these positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the right therapy for the right patient.

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