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Anne S. Tsao



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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.01 - Frequency and Genomic Context of Emerging Markers for Molecular Testing in Lung Adenocarcinoma in Cell-Free DNA NGS Analysis (Now Available) (ID 13465)

      13:30 - 13:35  |  Author(s): Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      The recently updated CAP/IASLC/AMP lung cancer molecular testing guideline (Lindeman et al 2018) recommends several genes be analyzed by next-generation sequencing (NGS) in lung adenocarcinoma (LUAD), including EGFR, ALK, BRAF, KRAS, and others. It also includes a list of 20 emerging markers (EMs) for molecular testing and suggests practitioners remain aware of these and other genes between guideline updates. We investigated the frequency of genomic alterations (GAs) in several of these EMs in a cohort of patients with advanced lung adenocarcinoma who underwent clinical cell-free DNA (cfDNA) NGS analysis and assessed co-occurrence with canonical driver GAs.

      Method

      Genomic data was reviewed from 6530 patients with at least one GA detected on clinical Guardant360 cfDNA NGS testing (Guardant Health, Inc) with an indicated diagnosis of lung adenocarcinoma from 11/25/16-3/1/18. Synonymous alterations were excluded from further analyses.

      Result

      2600 patients (40%) had at least one nonsynonymous alteration in the EM genes assessed; excluding GAs classified as variants of unknown significance (VUS), 1350 patients (21%) had at least one characterized alteration. Table 1 shows number and frequency of GAs observed per patient by gene and alteration type. Of EMs assessed, GAs were observed most commonly in NF1, PIK3CA, PDGFRA, KIT, and FGFR1-2. GAs in multiple EMs, including RIT1, NRAS, FGFR2-3, NTRK1, KIT, and AKT1, were observed co-occurring with established driver alterations, often in a genomic context consistent with resistance to targeted therapy at allelic fractions suggestive of subclonality.

      table 1.jpg

      Conclusion

      Effective therapies are continually emerging for a growing number of molecular biomarkers in lung cancer. Comprehensive genomic profiling with cfDNA NGS can identify GAs in both recommended and EM genes to guide therapeutic decision-making and catalyze clinical trial enrollment. Further investigation of mutual exclusivity and co-occurrence of established drivers and EMs may reveal novel resistance mechanisms and facilitate identification of rational combination therapeutic strategies.

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    OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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      OA01.06 - DETERRED:  Phase II Trial Combining Atezolizumab Concurrently with Chemoradiation Therapy in Locally Advanced Non-Small Cell Lung Cancer (Now Available) (ID 12842)

      11:25 - 11:35  |  Author(s): Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      While consolidation immunotherapy after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC (LA-NSCLC), the effectiveness of immunotherapies may be enhanced when combined concurrently with CRT. We report on the safety and preliminary efficacy of combining PD-L1 blockade using atezolizumab (atezo) and concurrent CRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo and maintenance atezo up to 1 year for LA-NSCLC.

      Method

      This is a single institution phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N=10) with CP after completing CRT, or II) concurrently (N=30) with CRT followed by consolidation atezo with CP. Atezo was given at 1200 mg IV Q3 weeks for up to one year from the first dose. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Severe adverse events (AEs) ≥ grade 3 are defined within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Evaluable patients (pts) have received at least one dose of atezo.

      Result

      From February 2016 to April 2018, we accrued 40 evaluable pts. For part 1, any grade 3+ AEs was seen in 6 pts (60%), with most common being pneumonia (2 of 10, 20%). Three grade 3+ AEs (30%) were attributed to atezo, including dyspnea, arthralgia and a grade 5 TE fistula. Grade 2 radiation pneumonitis (RP) was seen in 3 pts. Four progressed with disease during atezo maintenance and have died, ranging from 0.93 to 1.86 years. Four pts completed atezo and are in follow up without recurrence. For part 2, 17 of 30 pts had any grade 3+ AEs (57%), with pneumonia being the most common (6 of 30, 20%). Three (10%) were attributed to atezo (dyspnea, fatigue and heart failure). RP was seen in 3 pts, with 2 grade 2 and 1 grade 3, which led to atezo discontinuation. So far, 4 pts have progressed and 4 have died, 2 due to disease and 2 due to treatment (neutropenic sepsis and gastric hemorrhage). All others have completed CRT and are on maintenance atezo, ranging from 5 to 19 doses. Updated efficacy results will be presented.

      Conclusion

      Concurrent atezo with CRT followed by consolidation and maintenance atezo appears safe without increased toxicities compared to CRT alone followed by consolidation and maintenance atezo.

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 14277)

      11:25 - 11:35  |  Author(s): Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).

      Method

      Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety

      Result

      As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.

      Conclusion

      In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-30 - Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor and its Relationship to NSCLC Patient Outcomes in the REVEL Trial (Now Available) (ID 13126)

      16:45 - 18:00  |  Author(s): Anne S. Tsao

      • Abstract
      • Slides

      Background

      Neutrophil-to-lymphocyte ratio (NLR) reflects underlying levels of systemic inflammation and has prognostic importance in solid tumors. Higher baseline NLR is an independent negative prognostic factor in advanced non–small cell lung cancer (NSCLC) and may indicate more aggressive disease. An exploratory analysis from REVEL demonstrated benefits of ramucirumab(RAM)/docetaxel(DOC) in NSCLC patients with rapidly progressing and refractory disease. We investigated the relationship between pretreatment NLR, prognosis and response to RAM/DOC.

      Method

      Pretreatment NLR was analyzed by dividing absolute neutrophil count by absolute lymphocyte count from peripheral blood. Multiple NLR cutoffs ≥4 were evaluated for prognostic significance by analyzing overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Kaplan-Meier analysis and Cox proportional hazards regression model were used for analyzing OS and PFS, and Cochran-Mantel-Haenszel test for ORR.

      Result

      Pretreatment NLR was determined for 1224 REVEL patients (n=611 RAM/DOC, n=613 placebo [PBO]/DOC), among whom 51%, 40%, and 32% had NLR ≥4, 5, and 6, respectively. Baseline characteristics were balanced between arms in NLR subgroups and the REVEL intent-to-treat (ITT) population. Patients with higher NLR values had worse OS, PFS, and ORR compared to the ITT population. For all NLR cutoff values, OS, PFS and ORR were improved in patients treated with RAM/DOC compared to patients receiving PBO/DOC (Table). Efficacy and safety outcomes across high NLR subgroups were consistent with those in the ITT population.

      table 1.jpg

      Conclusion

      In this exploratory analysis of REVEL, higher pretreatment NLR was an independent prognostic factor indicating poorer survival outcomes. Treatment benefit with RAM/DOC was preserved in patients with elevated NLR and was consistent with REVEL ITT results. NLR is an inexpensive and reproducible blood test and may provide a simple way to identify patients with more aggressive disease who can benefit from treatment with RAM/DOC in second-line NSCLC.

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      P1.13-37 - Clinical Evaluation of Plasma-Based (cfDNA) Genomic Profiling in Over 1,000 Patients with Advanced Non-Small Cell Lung Cancer (ID 14332)

      16:45 - 18:00  |  Author(s): Anne S. Tsao

      • Abstract

      Background

      Tumor genomic information from a simple blood collection revealing actionable mutation can improve clinical outcome without the need for an invasive tissue biopsy. We report on the clinical utility of a cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our patients with non-small cell lung cancers (NSCLC) and the outcome of treatments with targeted therapies based on the reported mutations.

      Method

      From May 2015 to February 2017, 1078 blood samples from 1011 consecutive patients with a diagnosis of NSCLC were collected and analyzed using next-generation sequencing of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) with reported sensitivity of 0.02% mutant allele fraction with high specificity (> 99.9999%) (CCR 2018 (17):3831). Patients in this retrospective study received targeted therapy as indicated by cfDNA molecular profiling. Tumor response was evaluated by RECIST V1.1 and standard clinical evaluation.

      Result

      From 1011 patients, 1078 cfDNA tests sent (additional follow-up tests: 1 in 64 patients and 2 in 3 patients). In 223/1011 (22%) patients had cfDNA report with at least 1 targetable mutations; with 48/223 (22%) patients meeting criteria for this retrospective review. Study population were 31 female:17 male, median age of 63 years (ranged:31-94). The rationale for the blood test included: insufficient tissue or not available (32%), addition to tissue molecular analysis (17%), alternative to tissue biopsy(10%), on-going treatment evaluation/resistance (41%). Mutations included:EGFR T790M (15), EGFR exon 19del (12), EGFR L858R (9), EGFR exon 20 insertion (4), EGFR others (1), ALK gene fusions (5) and MET exon 14 skipping (2). The median line of therapy was 2(ranged:1-7) with 28 patients receiving TKI as 1st line of therapy based on cfDNA mutations. With targeted treatments based on ctDNA results, the responses (RECIST V1.1) were: CR(3), PR(26), SD(14) and PD(4); median PFS was 8.5 months (ranged:1-26mos) for the overall population with 4 patients still receiving targeted therapy. Median PFS was 9.5 months (ranged:1-20 months) for those receiving TKI as 1st line.

      Conclusion

      This is the largest analysis of response rates with cfDNA directed therapy in advanced NSCLC and demonstrates positive clinical outcomes in patients treated with targeted therapy based on plasma identified biomarkers.

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.09 - Nintedanib + Pemetrexed/Cisplatin in Patients with Unresectable MPM: Phase III Results from the LUME-Meso Trial (Now Available) (ID 11192)

      09:15 - 09:25  |  Author(s): Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Nintedanib targets VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases, all implicated in malignant pleural mesothelioma (MPM) pathophysiology. This global Phase II/III, randomised, double-blind study investigated pemetrexed/cisplatin in combination with nintedanib or pemetrexed/cisplatin in combination with placebo, followed by nintedanib or placebo maintenance, in patients with unresectable MPM. In the double-blind, randomised Phase II part, nintedanib plus pemetrexed/cisplatin improved PFS vs placebo (HR=0.56; 95% CI: 0.34–0.91; p=0.017; median 9.4 vs 5.7 months).

      In Phase III, chemotherapy-naïve patients with epithelioid MPM (ECOG PS 0–1) were randomised 1:1 to receive up to six cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1, plus nintedanib (200 mg bid) or matched placebo on Days 2–21. After combination treatment, patients without disease progression received nintedanib or placebo maintenance. The primary endpoint (PFS by investigator assessment) and key secondary endpoint (OS) were planned to be analysed by hierarchical testing, with an interim OS analysis at the time of the primary PFS analysis. PFS was also assessed by independent central review. Based on the assumed treatment effect (HR=0.63), the study had 90% power to detect a statistically significant and clinically meaningful improvement in PFS.

      In total, 458 patients were randomised. Baseline patient characteristics and oncological history were similar between treatment arms. Median duration of nintedanib or placebo administration was 5.3 and 5.1 months, respectively. After 250 events, there was no difference in PFS between nintedanib and placebo arms (HR=1.01; 95% CI: 0.79–1.30; p=0.91; median 6.8 vs 7.0 months, respectively). PFS by central independent review was similar (242 events; HR=0.99; 95% CI: 0.77–1.28; p=0.96; median 6.8 months in each arm). In the interim OS analysis (127 deaths [28% of events]), median OS was 14.4 vs 16.1 months (nintedanib vs placebo; HR=1.12; 95% CI: 0.79–1.58; p=0.54). There were no unexpected safety findings. The proportion of patients with Grade ≥3 AEs was higher with nintedanib than with placebo (72% vs 62%). The most frequently reported Grade ≥3 AE by medical concept in both treatment arms was neutropenia (nintedanib: 32%; placebo: 24%). The proportion of deaths due to serious AEs was 4.0% (nintedanib) and 7.5% (placebo).

      The primary endpoint of the Phase III part of LUME-Meso was not met ‒ Phase II findings were not confirmed. The reported safety profile was consistent with the known safety profiles of nintedanib and pemetrexed/cisplatin.

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    SH02 - Highlight of the Previous Day Sessions (ID 994)

    • Event: WCLC 2018
    • Type: Highlight of the Day Session
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 202 BD
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      SH02.02 - Mesothelioma (Now Available) (ID 14782)

      07:12 - 07:24  |  Presenting Author(s): Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    WS02 - Mesothelioma Workshop (ID 996)

    • Event: WCLC 2018
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:15, Room 205 AC
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      WS02.11 - Window of Opportunity Immunotherapy Trials in Mesothelioma: Design and Translation (Now Available) (ID 14754)

      09:50 - 10:05  |  Presenting Author(s): Anne S. Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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