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Michael Thomas

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Now Available
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      MA21.01 - Generation and Characterization of Novel Preclinical Disease Models of NSCLC with NRG1 Rearrangements to Improve Therapy (Now Available) (ID 2811)

      14:30 - 16:00  |  Presenting Author(s): Eric Gladstone  |  Author(s): Morana Vojnic, Michael Offin, Lukas Delasos, Allan J. W. Lui, Evan Siau, Hirko Sato, Ryma Benayed, Renate Kurth, Marissa Mattar, Inna Khodos, Elisa De Stanchina, Robert Daly, Alison Schram, Alexander Drilon, Marc Ladanyi, Romel Somwar

      • Abstract
      • Presentation
      • Slides

      Background

      Chimeric proteins encoded by NRG1 rearrangements retain the EGF-like domain of NRG1, a HER3 ligand that triggers HER3-HER2 heterodimerization and drives tumor growth. Activating NRG1 fusions have been identified in a variety of cancers including lung, pancreatic, breast, head and neck, etc, and previous work by our group has shown that anti-HER3 antibody (GSK2849330) therapy was effective at inducing a durable response in a NSCLC patient with a CD74/NRG1-fusion. It is possible that targeting both HER2 and HER3 would be more effective than targeting HER3 alone given that HER3-HER2 dimerization is necessary for tumorigenesis induced by NRG1 rearrangements. However, this has not been explored extensively due to a paucity of well-characterized preclinical models of NRG1-driven NSCLC. We aimed to establish patient-derived xenograft (PDX) and cell line models with NRG1-rearrangements to evaluate signaling networks and the role of novel therapies for this recently identified oncogene.

      Method

      Approximately 30,000 tumor samples were evaluated for the presence of NRG1-fusions by targeted DNA and RNA sequencing (using the MSK-IMPACT and MSK-Fusion panels, respectively). Fresh tumor samples were collected and implanted into immune-compromised mice to generate PDX models and/or used to generate cell lines. Separately, NRG1-fusions were genomically engineered using CRISPR-Cas9 systems or by lentiviral transduction of cDNAs into immortalized human bronchiolar epithelial (HBEC) cells. RT-PCR and Sanger sequencing were used to verify NRG1-fusion mRNA expression, whereas western blot analysis examined fusion protein expression and phosphorylation. Subsequently, cell viability following inhibition of HER2, HER3 and downstream signaling pathways was assessed.

      Result

      NRG1 fusions were identified in 24 patients (9 NSCLC); and we successfully generated two PDX models with corresponding cell lines from two NSCLC surgical specimens (2/2). One model harbors a CD74/NRG1 fusion whereas the second harbors a SLC3A2/NRG1-fusion. Using CRISPR-Cas9 mediated gene editing, we are introducing NRG1 fusions that were identified in NCSLC (CD74/NRG1, SLC3A2/NRG1, VAMP2/NRG1) into HBEC cells, and have generated a stable cell line with VAMP2/NRG1 fusion to date. In addition, we established a CD74/NRG1-positive model in HBEC cells using lentiviral transduction. Treatment of NRG1-fusion positive cells with small molecule inhibitors of HER2 (afatinib, neratinib, sapitinib) or trastuzumab inhibited growth, induced caspase 3/7 activity and blocked activation of PI3K and ERK signaling. Neratinib was more potent than other small anti-HER2 molecules. The PI3K inhibitor pictilisib inhibited growth of NRG1 fusion-positive cells as a single agent with little effect on non-tumor control cells.

      Conclusion

      We generated novel NSCLC PDX and cell line models with verified NRG1 chromosomal rearrangements. In vitro studies show that targeting HER2 and PI3K effectively inhibits growth and induces apoptosis. Studies exploring the efficacy of additional agents targeting HER2, HER3 and PI3K alone or in combination using in vivo models are ongoing and results will be presented.

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      MA21.02 - Genomic Origin and EGFR-TKI Efficacy of Pulmonary Adenosquamous Carcinoma (Now Available) (ID 578)

      14:30 - 16:00  |  Presenting Author(s): Gen Lin  |  Author(s): Chao Li, Pansong Li, Wenzhang Fang, Haipeng Xu, Yuhua Gong, Zhengfei Zhu, Yi Hu, Wenhua Liang, Qian Chu, Wen-Zhao Zhong, Lin Wu, Huijuan Wang, Zhijie Wang, Ziming Li, Jie Lin, Yan-Fang Guan, Xuefeng Xia, Xin Yi, Qian Miao, Biao Wu, Kang Jiang, Xiaobin Zheng, Weifeng Zhu, Xinlong Zheng, Huang Peisha, Xiao Wenjin, Dan Hu, Longfeng Zhang, Xirong Fan, Tony Mok, Cheng Huang

      • Abstract
      • Presentation
      • Slides

      Background

      Lung adenosquamous carcinoma (ASC) is a heterogeneous disease that comprises of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. Their genomic profile, evolutionary origin, and clinical management remain controversial. Objective of this study is to define the genomic origin of this heterogeneous tumor by independent genomic analyses of the AC and SCC components.

      Method

      Surgical ASCs were collected. AC component and SCC component were obtained separately by microdissection, and Lymph node (LN) metastases were gathered. Targeted sequence was performed for the two components using a 1021-gene panel, independently. Evolutionary relationship of the two components was analyzed. The independent cohorts of adenocarcinoma (n=170) and squamous cell carcinomas (n=62) were used for comparison. EGFR and concomitant mutations with response to EGFR-TKI were analyzed. Retrospective 517 ASCs underwent EGFR detections were collected from 11 centers. Objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) were analyzed in EGFR-positive patients received EGFR-TKIs.

      Result

      28 ASCs were collected. NGS was performed on AC component and SCC component samples, respectively. The most frequent alterations in 28 ASCs were EGFR mutation (79%), TP53 mutation (68%), MAP3K1 mutation (14%), EGFR amplification (32%), and MDM2 amplification (18%). 27 patients had trunk variations in the both components suggesting the monoclonal origin of ASCs. The prevalence of trunk mutations was correlated to those of AC, indicating that ASC might originate from AC. Only one patient did not carry any trunk variations between AC and SCC components, which were clearly and geographically distinguishable under the microscope. 22 had AC component or/and SCC component specific variations suggesting the common event of branch evolution. The 23 LNs of 13 patients mainly contained AC and ASC components (AC, SCC, and ASC: 11, 1, and 11, respectively), and each of the LNs carried the trunk mutations of the primary ASC. Like pure AC, the alterations of L858R and Exon 19 Dels of EGFR were common in the 28 ASCs. Unfortunately, these patients have not been treated with TKIs. Further, of 517 retrospective ASCs from 11 centers, 51.8% were EGFR-positive. For the 129 EGFR-positive ASCs who had received TKIs, the ORR and DCR were 56.6% and 89.1%, respectively. The median PFS was 10.1 months (95% CI: 9.0-11.2).

      figure-1-wclc.jpg

      Conclusion

      The AC and SCC components share a monoclonal origin, and a majority have branching evolution. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR-TKIs.

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      MA21.03 - The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer (Now Available) (ID 1198)

      14:30 - 16:00  |  Presenting Author(s): Matthew P Smeltzer  |  Author(s): Murry W Wynes, Meghan Taylor, Kristin Richeimer, Kelsey Wood, Kristen Howell, Mercedes Liliana Dalurzo, Enriqueta Felip, Keith Kerr, Edward Kim, Sylvie Lantuejoul, Clarissa Mathias, Pieter E. Postmus, Charles Powell, Suresh S Ramalingam, Ross Soo, Masahiro Tsuboi, Ignacio Wistuba, Marileila Varella-Garcia, Giorgio Vittorio Scagliotti, Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Evidence-based standards for molecular testing of lung cancer have been established, but the global frequency and practice of testing are not well understood. The IASLC conducted an international survey to evaluate current practice and barriers to molecular testing.

      Method

      Distributed to IASLC members and other healthcare professionals, content included: 7-question introduction, 32 questions for those requesting tests/treating patients, 45 questions on performing/interpreting assays, and 24 questions on tissue acquisition. All respondents were asked to provide 3-5 barriers to implementing/offering molecular testing.

      Respondents’ countries were grouped by geography or developing/developed using IASLC and World Bank criteria. Surveys were available in 7 languages. Regional comparisons used the Chi-squared test or ANOVA; free-text was analyzed with Nvivo.

      Result

      We obtained 2,537 responses from 102 countries. Respondents were 45% Medical Oncologists, 12% Pulmonologists, 12% Thoracic Surgeons, 9% Pathologists, and 22% scientists or other. 56% of responses were from developing countries, 44% developed. Regions included: 52% Asia, 19% Europe, 11% Latin America, 11% US/Canada, 7% Other.

      1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p=0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/month.

      The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p=0.0294). 69% tested blood-derived DNA, less frequently in US/Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%), and notified when the sample was inadequate (84%).

      The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/Other, and turn-around time in US/Canada.

      Conclusion

      These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.

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      MA21.04 - Discussant - MA21.01, MA21.02, MA21.03 (Now Available) (ID 3806)

      14:30 - 16:00  |  Presenting Author(s): Michael Duruisseaux

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA21.05 - Phase II Trial of the Combination of Alectinib with Bevacizumab in ALK-Positive Nonsquamous Non-Small Cell Lung Cancer (Now Available) (ID 1306)

      14:30 - 16:00  |  Presenting Author(s): Satoshi Watanabe  |  Author(s): Naoya Matsumoto, Jun Koshio, Akane Ishida, Tomohiro Tanaka, Tetsuya Abe, Daisuke Ishikawa, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Aya Otsubo, Ami Aoki, Tomosue Kajiwara, KENICHI Koyama, Satoru Miura, Hirohisa Yoshizawa, Toshiaki Kikuchi

      • Abstract
      • Presentation
      • Slides

      Background

      Alectinib is a 2nd generation highly selective anaplastic lymphoma kinase (ALK) inhibitor. Although alectinib has improved progression-free survival (PFS) in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC), there are limited treatment options after progression of alectinib. Recent evidences have described promising results of the combination of bevacizumab with EGFR-TKIs, cytotoxic chemotherapies and immune-checkpoint inhibitors. We report the results from a phase II study of the combination of alectinib with bevacizumab in ALK-positive Nonsquamous NSCLC patients who were treated with alectinib and showed disease progression (UMIN 000017828).

      Method

      Patients with ALK+ Nonsquamous NSCLC who had progressed after alectinib treatment were enrolled. Primary objective of this study was PFS and safety. Secondary endpoints included overall survival, objective response rate and disease control rate.

      Result

      Twelve patients received alectinib (600 mg/day) with bevacizumab (15 mg/kg, Q3W). Nine patients were treated with crizotinib and alectinib, and 2 patients were treated with crizotinib, alectinib and ceritinib before enrollment to this study. The median PFS was 3.1 months (95% CI 1.2-16.1) and the median survival time was 32 months (95% CI 8.3-NE). The median treatment cycle was 5 (range, 1-37) and 3 patients received alectinib with bevacizumab more than 20 cycles. The objective response rate and disease control rate were 8% and 67%, respectively. The most common treatment related adverse events were decreased appetite (42%), proteinuria (42%), hypertension (33%), anemia (33%) and fatigue (33%). Treatment related adverse events of grade > 3 were anemia (8%), proteinuria (8%), diarrhea (8%) and hypokalemia (8%). No severe adverse events were observed.

      Conclusion

      This is the first study to investigate the combination of alectinib and bevacizumab. This combination had clinical efficacy and was well tolerated.

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      MA21.06 - Preliminary Phase 1 Results of U3-1402 — A Novel HER3-Targeted Antibody–Drug Conjugate—in EGFR TKI-Resistant, EGFR-Mutant NSCLC   (Now Available) (ID 1720)

      14:30 - 16:00  |  Presenting Author(s): Helena A Yu  |  Author(s): Melissa Johnson, Conor E Steuer, Michele Vigliotti, Shuquan Chen, Yasuki Kamai, Channing Yu, Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitors (TKIs), in particular osimertinib. Overall, 57%–83% of NSCLC tumors express human epidermal growth factor receptor 3 (HER3). Because signaling through HER3 is not an established mechanism of resistance to EGFR TKIs, treatment with an anti-HER3 antibody–drug conjugate (ADC) presents an approach to targeting diverse resistance mechanisms in EGFR-mutant NSCLC. U3-1402 is a HER3-targeted ADC with a fully humanized antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Here, we present the safety/tolerability and antitumor activity data from the dose-escalation phase of an ongoing, multicenter, phase 1 study (NCT03260491).

      Method

      Patients had locally advanced or metastatic EGFR TKI-resistant, EGFR-mutant NSCLC. Patients with stable brain metastases were eligible. Dose escalation was based on dose-limiting toxicities (DLTs) guided by a Bayesian logistic regression model. U3-1402 was administered every 3 weeks via intravenous infusion. Pretreatment tumor tissue was required for retrospective HER3 immunohistochemistry analysis. Next-generation sequencing analysis was performed on available tumor tissue. Primary objectives included safety, tolerability, and identification of the recommended dose for expansion (RDE).

      Result

      As of May 2019, 30 patients were enrolled across 4 doses (3.2 [n=4], 4.8 [n=9], 5.6 [n=12], and 6.4 [n=5] mg/kg). Thirteen patients (43%) have discontinued (progressive disease [n=9], clinical progression [n=1], consent withdrawal [n=2], adverse event [AE; n=1]). All 30 patients received prior EGFR TKIs, of which 28 (93%) received prior osimertinib, and 15 (50%) prior chemotherapy. Activating EGFR mutations were reported in all patients (Ex19del: 57%; L858R: 40%; L861Q: 3%). All 25 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score, 183 [range, 56–290]). History of central nervous system (CNS) metastases was reported in 15 patients (50%). Treatment-emergent AEs were reported in 29 patients (97%; 13 patients [43%] reported grade 3/4). Two DLTs (grade 3 febrile neutropenia and grade 4 platelet count decrease) were reported in 1 patient (5.6 mg/kg) and 3 DLTs (all grade 4 platelet count decrease) in 3 patients (6.4 mg/kg). Of patients with a history of CNS metastases, 9 have progressed (2 with CNS progression; 3 with both CNS and non-CNS progression). One patient without a history of CNS metastasis progressed with new CNS disease. Of 26 efficacy-evaluable patients, 6 had confirmed partial responses (2 each at 4.8, 5.6, and 6.4 mg/kg), including 2 patients with an EGFR C797S mutation. Median best percentage change in sum of diameters (SoD) was −25.7% (range, −82.6% to 13.3%), including decreases in SoD in patients with CDK4 amplification (–25.7% and –17.8%), HER2 amplification (–28.6%), and both CCNE1 amplification and PIK3CA mutation (–28.8%).

      Conclusion

      U3-1402 demonstrated tolerable safety and antitumor activity in this ongoing study. Antitumor activity of U3-1402 was seen in cancers with EGFR-mediated and other resistance mechanisms. These findings support the hypothesis that targeting HER3 with U3-1402 may provide clinical benefit to patients with EGFR-mutant NSCLC with diverse mechanisms of resistance. RDE evaluation is ongoing.

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      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.

      Method

      We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.

      Result

      At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.

      Conclusion

      ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.

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      MA21.08 - Discussant - MA21.05, MA21.06, MA21.07 (Now Available) (ID 3807)

      14:30 - 16:00  |  Presenting Author(s): Toyoaki Hida

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA21.09 - Tyrosine Kinase Inhibitors' Plasma Concentration and Oncogene-Addicted Advanced Non-Small Lung Cancer (aNSCLC) Resistance (Now Available) (ID 830)

      14:30 - 16:00  |  Presenting Author(s): Arthur Geraud  |  Author(s): Laura Mezquita, Edouard Auclin, David Combarel, JULIA Delahousse, CHARLES Naltet, CECILE Jovelet, pernelle Lavaud, Anas Gazzah, LUDOVIC Lacroix, Jordi Remon, CAROLINE Caramella, David Planchard, OLIVIER Mir, ANGELO Paci, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      The development of TKIs against driver molecular alteration has changed treatment paradigm in aNSCLC patients (pts). All tumors eventually progress and a resistance mechanism is identified in only a fraction of pts. Plasma concentration of TKI can decrease after chronic exposition but limited data are available. Our hypothesis is that an insufficient plasma exposure could contribute to tumor progression (PD).

      Method

      We assessed the plasma concentration of TKI in pts with aNSCLC harboring ALK rearrangement, EGFR or BRAF V600E mutation. We defined chronic exposure as a treatment administered > 3 months. Patients’ characteristics and co-medications were collected. Residual plasma concentrations were measured using Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry validated methods. We compared results to currently recommended therapeutic targets and correlated exposure levels to treatment benefit.

      Result

      Between Apr. 2014 and Feb. 2019, 51 samples were prospectively collected (gefitinib n=11, osimertinib n=10, erlotinib n=13, crizotinib n=7, dabrafenib + trametinib n=5) in 41 pts. Median time of exposure was 20.3 months (range 2.18 - 67.813). Low plasma concentration was observed in 31 (61%) samples. Out of 14 samples collected in pts with ongoing benefit, 10 (71%) had low plasma exposure. Smoking status was associated with low plasma TKI concentration (P=0.01) whatever the TKI used. A total of 37 samples were collected at PD, 21 (57%) had low plasma exposure. The median time to treatment failure (TTF) in the ‘low exposure group' (n=31) was 14.9 months (95% CI 12.48 – 33.2) vs. 24.6 months (95% CI 8.65 -not reached (NR) in the ‘normal exposure group’ (P=0.55). No significant impact of protons pump inhibitors on TTF was found (p=0.12), including with gefitinib and erlotinib (p=0.76; n=24). In case of isolated brain PD (n=4), 3 pts (75%) had low plasma exposure. TKI dose was reduced in 14 pts because of toxicity, median TTF was 17.0 months (95% CI 10.4-NR) vs. 20.1 months (95% CI 10.4-59.8, P=0.45 in pts treated with standard dose. In the EGFR mutated aNSCLC population at PD (n=19), T790M resistance mutation was more frequent in the ‘normal exposure group’ (37.5%, n= 3/8,) than in the ‘low exposure group’ (9.1%, n=1/11), OR=0.13 95%CI (0.01-1.29), p=0.08.

      Conclusion

      TKI is underdose in the majority of aNSCLC patients at PD. Low TKI concentration were more frequent in pts without tumor resitance mechanism. Altogether, it suggests that low TKI exposure might contribute to PD.

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      MA21.10 - Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI (Now Available) (ID 1705)

      14:30 - 16:00  |  Presenting Author(s): Myung-Ju Ahn  |  Author(s): Sehhoon Park, Sunyoung Hong, JuYoun Park, MI RA Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (TKI) has successfully improved clinical outcome in non-small cell lung cancer (NSCLC) with activating EGFR mutation. However, up to 40% of TKI treated patients present with disease progression in the central nerve system (CNS) either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib is a 3rd generation EGFR TKI effective in T790M mutant NSCLC and characterized by high blood-brain barrier penetration. In this phase II, multicenter prospective single-arm two cohort study, the clinical efficacy of 160mg of osimertinib in T790M mutant BM or LM patients progressed on prior EGFR TKI was evaluated. (NCT0325712)

      Method

      BM only patients were included in the BM cohort (n=40). Patients with cerebrospinal cytology confirmed LM with or without BM were included in the LM cohort (n=40). 3rd generation TKI, including 80mg of osimertinib, was exposed to 18 patients in BM and 16 patients in LM cohort. T790M need to be identified from either tissue, plasma or cerebrospinal fluid. The primary endpoint was overall response rate (ORR) (H1=30%) for BM cohort and overall survival (OS) (H1=5months) for LM cohort, respectively.

      Result

      Median follow-up duration was 7.9 months for BM and 8.3 months for LM cohort. In BM cohort, median progression-free survival (PFS) was 7.3 months (95% confidential interval [CI] 3.6-13.7), and median OS was not reached (NR). Intracranial ORR and disease control rate (DCR) was 40.0% and 77.5%. Extracranial ORR and DCR was 30.0% and 67.5%. In LM cohort, median PFS was 8.9 months (95%CI 5.6-NR) and median OS was 13.2 months (95%CI 8.0-NR). When response of leptomeningeal lesion is separately evaluated, CR rate was 25.0% (n=10) and non-CR/non-PR rate was 65.0% (n=26). Extracranial ORR and DCR was 22.5% and 85.0%. Intracranial median PFS was not reached in both BM and LM cohort. Grade 3 adverse event (AE) was observed in 7 BM and 11 LM patients. Four patients required dose reduction due to AE. Among the patients who previously received 3rd generation TKI, 33.3% (6 out of 18) in BM cohort and 81.2% (13 out of 16) in LM cohort showed an intracranial DCR to 160mg of osimertinib. Extended survival analyses and exploratory outcomes will be presented at the conference.

      Conclusion

      In this study, 160mg of osimertinib demonstrated promising ORR and survival benefit with tolerable safety profile in EGFR T790M positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKI.

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      MA21.11 - A Multicenter Phase II Study of Low-Dose Erlotinib in Frail Patients with EGFR Mutation-Positive, Non-Small Cell Lung Cancer: TORG1425 (Now Available) (ID 633)

      14:30 - 16:00  |  Presenting Author(s): Sakiko Otani  |  Author(s): Kazuhiko Yamada, Shingo Miyamoto, Koichi Azuma, Hidenobu Ishii, Akihiro Bessho, Shinobu Hosokawa, Hideo Kunitoh, Kazuhito Miyazaki, Hiroshi Tanaka, Satoru Miura, Hiromi Aono, Yoshiro Nakahara, Kei Kusaka, Yukio Hosomi, Akinobu Hamada, Hiroaki Okamoto

      • Abstract
      • Presentation
      • Slides

      Background

      We conducted a multicenter phase II trial evaluating the efficacy of low-dose erlotinib (ERL) in frail patients with EGFR-mt non-small cell lung cancer (NSCLC). The primary endpoint was met, with the objective response rate (ORR) of 60%. Here we present the final overall survival (OS) results. Furthermore, we investigated the effect of ABCB1 genetic polymorphisms on the ERL plasma concentration pharmacokinetics (PK) and pharmacodynamics (PD).

      Method

      Chemotherapy-naïve NSCLC patients with EGFR mt who had frailty were enrolled and received ERL 50 mg/d. Patient’s frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS) ≥2 or Charlson Comorbidity Index (CCI) ≥6 points; (Group 2) 75 to 80 years of age with PS ≥1 or CCI ≥6 points; (Group 3) ≥81 years of age with any PS and CCI. ABCB1 gene polymorphism analysis were using the i-densyTM genetic testing platform, and blood samples for the ABCB1 genetic testing were collected prior to treatment. Steady-state trough plasma ERL concentration was measured with a high-performance liquid chromatograph-tandem mass spectrometry at 15 days (±7 days) after initiating ERL administration.

      Result

      From December 2014 and April 2017, 80 patients were enrolled: males/females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/3. EGFR mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. Median progression-free survival and OS were 9.3 (95%CI: 7.2-11.4), 26.1 (95%CI: 21.9-30.4) months respectively. The trough of ERL could be measured in 48 patients, and 45 of these patients were analyzed for ABCB1 genetic polymorphism. The ORR for the 48 patients was 62.5%, and their median trough of ERL was 685 ng/ml (range 153-1950) , which surpassed the reported “effective” level (500ng/ml). Nine (60%) of 15 the patients who failed to achieve the level responded. Genetic polymorphisms were not correlated with ERL PK, nor were they associated with efficacy and adverse events.

      Conclusion

      This is the first prospective study evaluating low-dose ERL for frail patients with EGFR mt NSCLC. This treatment was safe and effective, and the ABCB1 genetic polymorphisms did not affect ERL PK/PD. Clinical trial information: UMIN 000015949.

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      MA21.12 - Discussant - MA21.09, MA21.10, MA21.11 (Now Available) (ID 3808)

      14:30 - 16:00  |  Presenting Author(s): Hong-Xu Liu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.05 - Nab-Paclitaxel Maintenance in Squamous Non-Small Cell Lung Cancer (NSCLC): Updated Results of the Phase III ABOUND.sqm Study  (Now Available) (ID 294)

      14:00 - 15:30  |  Author(s): Michael Thomas

      • Abstract
      • Presentation
      • Slides

      Background

      Background: nab-Paclitaxel maintenance therapy after nab-paclitaxel/carboplatin induction in patients with advanced squamous NSCLC was evaluated in the phase III, randomized, controlled, open-label, multicenter ABOUND.sqm trial. At the 12-month follow-up, there was no statistically significant difference in progression-free survival (PFS) between patients randomized to maintenance nab-paclitaxel + best supportive care (BSC) vs BSC alone. However, a trend of an overall survival (OS) advantage was observed with nab-paclitaxel + BSC vs BSC alone. Here we report the 18-month follow-up of OS.

      Method

      Methods: Patients (aged ≥ 18 years) with histologically or cytologically confirmed stage IIIB/IV squamous NSCLC and no prior chemotherapy were eligible. Patients received four 21-day cycles of nab-paclitaxel 100 mg/m2 (days 1, 8, and 15) plus carboplatin AUC 6 (day 1) as induction. Patients with radiologically assessed complete or partial response or stable disease without clinical progression after 4 cycles were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 of each 21-day cycle) plus BSC or BSC alone until disease progression. The primary efficacy analysis was performed on the ITT population. PFS from randomization into the maintenance part of the study was the primary endpoint. Secondary endpoints included safety, OS (from randomization), and response.

      Result

      Results: 420 patients received induction therapy; 202 were randomized to maintenance nab-paclitaxel + BSC (n = 136) or BSC alone (n = 66). The median PFS in patients in the nab-paclitaxel + BSC arm vs those in the BSC-alone arm was 3.1 vs 2.6 months (HR, 0.85; P = 0.349), respectively; the median OS was 17.8 vs 12.2 months (HR, 0.71; P = 0.058), respectively. The overall response rate was 69.1% vs 57.6% (RRR, 1.20; P = 0.087). Following the maintenance part, 73.5% (nab-paclitaxel + BSC) and 68.2% (BSC alone) of patients received subsequent anti-cancer treatment. Over the entire study, the most frequent grade 3/4 TEAEs were neutropenia (53.1% vs 50.0%) and anemia (33.1% vs 32.3%); only peripheral neuropathy occurred in ≥ 5% of patients during maintenance (13.1% in the nab-paclitaxel + BSC arm).

      Conclusion

      Conclusion: Although PFS and OS differences were not statistically significant in the ITT population, the 18-month follow-up of OS demonstrated the feasibility of nab-paclitaxel maintenance therapy for patients with anced squamous NSCLC.

      ClinicalTrials.gov identifier: NCT02027428

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-34 - Early Assessment of Therapy Response in Non-Small Cell Lung Cancer (NSCLC) via Longitudinal ctDNA Analysis (ID 2795)

      09:45 - 18:00  |  Author(s): Michael Thomas

      • Abstract

      Background

      Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. Despite disease heterogeneity in NSCLC, we set out to identify a broadly applicable ctDNA-based method for disease monitoring. By employing plasma taken during early treatment cycles, we tested whether early response assessed by ctDNA level could predict treatment effect.

      Method

      Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), we measured ctDNA levels in post-treatment plasma samples based on variants identified at baseline.

      We used samples from an observational German Lung Cancer Multi-Marker Study. In a cohort of 83 stage IV lung adenocarcinoma treated with first-line chemo or chemoradiation therapies, we evaluated the association between survival and ctDNA levels in the first available post-treatment plasma sample (median number of days after start of treatment = 23). We used a ctDNA-based monitoring algorithm, and applied it to an independent set of 22 late stage lung squamous cell carcinoma that also underwent chemo or chemoradiation therapies to further evaluate the algorithm in different histology subtypes.

      Result

      We divided the 83 adenocarcinoma cohort into training (n=53) and test (n=30) sets. We found that subjects with longer progression free survival (PFS) had mean allele fraction (AF) < 1% in the training set. We applied the classifier to our adenocarcinoma test set and found that subjects with mean AF < 1% had longer PFS (HR 0.35; 95% CI 0.12 - 0.93; log-rank P = 0.028) and overall survival (OS) (HR 0.29; 95% CI 0.09 - 0.89; log-rank P= 0.021).

      Using cutoffs identified in adenocarcinoma, we applied the same algorithms to the squamous cell carcinoma cohort. Subjects with mean AF < 1% had longer PFS (HR 0.26; 95% CI 0.10 - 0.71; log-rank P = 0.005) and OS (HR 0.12; 95% CI 0.05 - 0.51; log-rank P= 0.001).

      Conclusion

      Even in heterogeneous diseases such as NSCLC, changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects who may not benefit, before current standard of care methods like computed tomography (CT) scan. Future prospective studies to confirm these results are warranted.

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      P1.01-58 - Comprehensive Serial Biomaterial Acquisition in Advanced NSCLC: Feasibility, Challenges and Perspectives (ID 473)

      09:45 - 18:00  |  Author(s): Michael Thomas

      • Abstract
      • Slides

      Background

      Availability of tumour material at baseline and disease progression is increasingly important for patient management in non-small-cell lung cancer (NSCLC), especially in tyrosine kinase and immune checkpoint inhibitor treatment. Here, we report the experience with prospective biobanking for advanced NSCLC from a pilot project in the academic setting.

      Method

      Main objective was the longitudinal collection of snap-frozen in addition to formalin-fixed paraffin-embedded (FFPE) biopsies required for routine diagnostics, along with blood samples and detailed clinical annotation using standardized questionnaires.

      Result

      Over five years, 205 patients were enrolled yielding 387 cryoconserved biopsies and 1098 serum, plasma and buffy-coat samples. The feasibility of obtaining cryoconserved in addition to FFPE biopsies was 89 % for newly diagnosed cases, but dropped down to 56 % and 47 % at first and second disease progression, respectively. Main obstacle was increased procedural risk due to patient deterioration, but no complications occurred. Biopsies had a tumour cellularity of 34 % and yielded 13.6 µg DNA and 12 µg RNA in median.

      Conclusion

      Despite the poor condition and limited prognosis of most NSCLC patients, systematic, serial biomaterial acquisition including routine collection of cryoconserved biopsies is feasible in order to facilitate individualized management and support research that will advance therapeutic options.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-02 - CANOPY-A: A Phase 3 Study of Canakinumab as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 1569)

      10:15 - 18:15  |  Author(s): Michael Thomas

      • Abstract

      Background

      Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study.

      Method

      CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P2.01-07 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1-Containing Therapy (HUDSON) (ID 643)

      10:15 - 18:15  |  Author(s): Michael Thomas

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line non-small cell lung cancer (NSCLC). However, few patients have-durable responses to anti-programmed cell death‑1/programmed cell death-ligand 1 (anti-PD-[L]1)-containing therapy (primary resistance) or other patients progress during anti-PD-(L)1-containing therapy (acquired resistance). HUDSON addresses the urgent need to identify new treatments and understand ICI resistance for patients who progressed after receiving anti-PD-(L)1-containing therapy.

      Method

      HUDSON is a multi-centre, international, multi-arm, platform study (NCT03334617), which will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in patients with NSCLC who have progressed following standard-of-care platinum- and ICI-based therapies. HUDSON consists of biomarker matched and non-matched groups (Figure). Allocation is guided by tumour molecular profile, using a pre-specified algorithm. Pre-existing local next generation sequence (NGS) data enables rapid patient allocation to biomarker-matched groups. Central molecular profiling comprises NGS and immunohistochemistry data. New groups will be added as new translational hypotheses emerge. Translational research will employ serial peripheral blood samples (including ctDNA) and tumour biopsies.

      Figure. Study design and biomarker prevalence

      wclc 2019 abstract figure.jpg

      Result

      Enrolment is ongoing; as of 01 April 2019, patients have been dosed in each of the drug combinations currently open for recruitment. Analyses of tissue and blood samples collected for exploratory research are ongoing, including genomic, transcriptomic and chemistry biomarkers such as tumour mutation burden, human leukocyte antigen status, T-cell receptor repertoire, and peripheral immune activation signatures.

      Conclusion

      Specific differences between patients on individual HUDSON arms that inform anti-PD(L)1 resistance mechanisms, plus learnings from the implementation of this innovative and complex platform study will be presented.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-04 - The Prognostic Value of Serological Tumor Markers in Lung Cancer – Analysis of 13,373 Cases (ID 800)

      10:15 - 18:15  |  Author(s): Michael Thomas

      • Abstract
      • Slides

      Background

      Serological tumor markers such as Carcinoembryonic Antigen (CEA), Cytokeratin 19 Fragments (Cyfra 21-1) and Neuron Specific Enolase (NSE) have been shown to provide prognostic information in lung cancer. We have introduced an algorithm to combine two markers (CEA, Cyfra 21-1) into a new variable the so called tumor marker index (TMI). TMI is defined as the geometric mean of normalized marker values (Muley et al, Anticancer Res 24:1953-56, 2004).

      Method

      We have uploaded available routine tumor marker data from various sources (excel sheets, extracts from laboratory IT-systems and from our clinical cancer registry) into the clinical research data warehouse based on i2b2/tranSMART using Talend Open Studio procedures. We extracted selected clinical parameters together with tumor marker data for further analyses with the statistical software package SPSS 25.0 (IBM Deutschland GmbH, Ehningen). Pretherapeutical tumor markers were measured with Roche Elecsys (Roche Diagnostics GmbH, Penzberg). A complete set of tumor marker data for the calculation of TMI1 (CEA, CYFRA21-1) and TMI2 (CEA, CYFRA21-1, NSE) was available in n=13373 and n=13174 cases, respectively.

      Result

      The median value (range) for TMI1 and TMI2 was found to be 0.94 (0.01-1311.98) and 1.01 (0.01-201.67), respectively. Besides the validation of our originally published prognostic cut off value of 0.54 for TMI1 (Muley et al, Lung Cancer 2008, 60:408-415) in 1315 p-stage I NSCLC patients (figure), we found additional cut off values for the differentiation of prognostic groups in the data set of all patients. Up to 7 groups with patient number >1800 could be significantly differentiated by both indices (table).

      muley_fig_wclc2019.png

      TMI1
      cutoff

      Patients
      (n)

      Median
      (mos)

      HR

      TMI2
      cutoff

      Patients
      (n)

      Median
      (mos)
      HR
      0.42 2,014 62.4 1 0.55 1,989 82.1 1
      0.58 1,837 35.3 1.33 0.70 1,774 40.8 1.39
      0.79 1,891 26.3 1.61 0.89 1,913 23.5 1.92
      1.11 1,913 17.2 2.12 1.15 1,868 16.5 2.49
      1.76 1,916 13.3 2.70 1.64 1,871 13.7 3.09
      3.54 1,891 10.2 3.44 2.73 1,883 9.4 4.34
      >3.54 1,910 6.7 5.00 >2.73 1,871 6.6 5.97

      Conclusion

      The usefulness of our clinical data warehouse for assembling and structuring of clinical parameters and tumor marker data is warranted. The value of TMIs for the stratification of individual risk groups could be verified in one of the world wide largest series of tumor marker data in lung cancer.

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      P2.03-25 - Assessing the Impact of Clonal Hematopoiesis in Disease Monitoring Using Targeted Cell-Free DNA (cfDNA) Sequencing Technology (ID 2864)

      10:15 - 18:15  |  Author(s): Michael Thomas

      • Abstract

      Background

      Somatic variants found in plasma cell-free DNA (cfDNA) may derive from either solid tumors or clonal hematopoiesis (CH). Little is known about how this may impact plasma-based longitudinal disease monitoring using targeted sequencing of circulating tumor DNA (ctDNA).

      Method

      To assess the potential impact of CH in disease monitoring, we evaluated monitoring algorithms by targeted sequencing with and without matched peripheral blood mononuclear cells (PBMC). Samples were collected from a prospective observational study, where 62 late stage lung adenocarcinoma subjects were treated with first-line chemo or chemoradiation therapy. Pre-treatment plasma cfDNA and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a sequencing panel of 198 kilobases targeting cancer genes. Median input amounts of 25 ng cfDNA and 50 ng PBMC DNA were sequenced to median deduplicated depths of 4582 and 6134, respectively.

      Result

      A median of 120 single nucleotide variants were detected per cfDNA sample, with 93.1% of these identified in matched PBMC. Most PBMC-matched cfDNA variants were germline SNPs, with allele frequency (AF) at approximately 50% or 100%. A median of 1 (range 0-5) PBMC-matched cfDNA variants per sample were detected with an AF <10%, consistent with CH. The number of these variants was positively associated with age (p-value = 0.0039) and the most frequently mutated gene was TP53. The remaining somatic variants (i.e., in cfDNA and not PBMC) had an AF range 0.03-40.9%. These PBMC-informed variants (median of 7 per sample) were used in longitudinal monitoring in the first post-treatment plasma sample to assess early response to therapy. Association between ctDNA level and progression-free survival using the same monitoring algorithm yielded nearly identical results on somatic variants derived from filtering approaches independent of matched PBMC (HR 0.32; 95% CI 0.16 - 0.65; log-rank P = 0.0009) and the PBMC-informed method (HR 0.31; 95% CI 0.14 - 0.66; log-rank P = 0.0013).

      Conclusion

      A targeted panel focused on solid tumors by design has limited impact from CH. For disease monitoring applications in a non-MRD setting, measuring multiple variants instead of a single variant further enables robust classifiers that can moderate the impact of variants, if any, from CH.