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Michael L Cheng



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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-46 - Response Assessment Using Plasma Cell-Free DNA (cfDNA) – When Is the Optimal Time to Assess Response? (ID 958)

      09:45 - 18:00  |  Presenting Author(s): Michael L Cheng

      • Abstract

      Background

      Plasma cfDNA analysis is routine for non-invasive genotyping of advanced NSCLC, however response assessment using plasma cfDNA is not well characterized. We hypothesized that response in cfDNA would be an early process occurring well before routine imaging timepoints.

      Method

      We retrospectively analyzed a total of 48 baseline and serial on-treatment plasma samples collected from 16 patients enrolled across three Experimental Therapeutics Clinical Trials Network (ETCTN) phase I trials of osimertinib combinations in advanced EGFR-mutant NSCLC. For validation, we also retrospectively analyzed a total of 201 baseline and serial on-treatment samples from an institutional cohort of 67 advanced NSCLC patients receiving systemic treatment. Using droplet digital PCR (ddPCR) of key EGFR or KRAS driver mutations, plasma response was defined as any decrease in mutation concentration to below baseline levels. We compared the magnitude of initial (baseline to day 11-30) and subsequent (day 11-30 to day 36-84) plasma response. Finally, we prospectively assessed response using serial amplicon-based plasma next-generation sequencing (NGS) in a pilot cohort of 8 NSCLC patients starting systemic therapy.

      Result

      Of 15 ETCTN patients with any plasma response, best plasma response was seen at the initial response timepoint in 12 patients (80.0%) and ≥90% of the total plasma response was seen at the initial response timepoint in 14 patients (93.3%). In the validation cohort of 61 patients with any plasma response (Figure), best plasma response was seen at the initial response timepoint in 39 patients (63.9%) and ≥90% of the total plasma response was seen at the initial response timepoint in 52 patients (85.2%). Complete plasma responses (-100%) were seen as early as 11 days after initiating therapy. In the prospective clinical cohort, plasma NGS detected genomic alterations and enabled monitoring of changes in mutant allele fraction in all 8 patients. The median turnaround time of the assay was 8 days.

      figure.jpg

      Conclusion

      Plasma response is an early phenomenon, with the vast majority of plasma response seen within 30 days, and as early as 11 days. These findings suggest that early plasma cfDNA analysis may permit response assessment well before standard imaging timepoints, with potential as an early marker of drug effect. Additional investigation to understand the relationship between early plasma response, radiographic response, and durability of treatment effect is still needed.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-04 - DNA Damage Response Gene Alterations Are Associated with High Tumor Mutational Burden and Clinical Benefit from PD-1 Axis Inhibition in NSCLC (Now Available) (ID 2620)

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

      • Abstract
      • Slides

      Background

      DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown.

      Method

      Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. All loss-of-function alterations in DDR genes (including nonsense, frameshift, or splice site) were classified as pathogenic. Missense mutations were manually evaluated and classified as pathogenic if considered to be deleterious in the Catalogue of Somatic Mutations in Cancer (COSMIC) and ClinVar databases, as well as the PolyPhen-2 (Polymorphism Phenotyping v2) functional prediction tool.

      Result

      Of 223 pts with successful NGS who received ICIs, 116 (52.0%) were identified as having pathogenic DDR mutations (DDRpos) with alterations in the following genes: FANC genes (20%) ATM (13.9%), POL genes (11%), ERCC genes (8%), BRCA1/2 (8%), MLH1/MSH2/MSH6 (7%), CHEK1/2 (7%), RAD genes (6%), ATR (5%), BRIP1 (3%), XRCC genes (3%), BARD1 (2%), PMS (2%), NEIL (2%), BAP1 (1%), PALB2 (1%). DDRpos and DDR negative (DDRneg) groups were well balanced in terms of age, gender, histology, performance status (PS), smoking status, baseline presence of brain metastasis. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.9 vs 8.3 mutations/megabase [mut/Mb], P < 0.001), including among never smokers (11.0 vs 6.8 mut/Mb, P = 0.02). No difference in median PD-L1 expression was observed between groups (50% vs 50%, P = 0.52). Compared to DDRneg pts (N=107), DDRpos pts had a significantly higher objective response rate (30.4% vs 16.8%, P = 0.001), longer median progression-free survival (4.3 vs 2.3 months, HR: 0.64 [95%CI: 0.48-0.86], P = 0.003) and median overall survival (16.5 vs 11.2 months, HR: 0.62 [95%CI: 0.44-0.88], P = 0.008) with PD-(L)1 therapy. After adjusting for ECOG PS, smoking status, baseline brain metastasis, and line of therapy, DDRpos status was associated with significantly longer PFS (HR: 0.64 [0.48-0.86], P < 0.01) and OS (HR: 0.58 [95%CI: 0.41-0.83], P < 0.01) in multivariate analysis.

      Conclusion

      Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes among NSCLC pts treated with PD-1 axis inhibition.

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