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Martin Frederik Dietrich



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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.02 - Plasma CfDNA next Generation Sequencing in Non-Small Cell Lung Cancer: Clinical Outcomes and Comparison to Tissue (ID 9502)

      15:45 - 17:30  |  Author(s): Martin Frederik Dietrich

      • Abstract
      • Presentation
      • Slides

      Background:
      Next-generation sequencing (NGS) of cell-free DNA (cfDNA) in plasma can be an alternative or complement to tissue biopsy for genomic analysis of non-small cell lung cancer (NSCLC), particularly for identifying driver and resistance alterations. We presented preliminary data in 67 patients comparing NGS in plasma vs. tissue (Santos et al. JTO; 11:10, S199-200) and found EGFR mutation agreement of 68% between plasma and tissue. We now present an expanded patient cohort with more extensive concordance analysis, longer follow-up, and clinical outcomes.

      Method:
      We analyzed data from advanced (stage III/IV) NSCLC patients seen at three cancer centers in Florida (US; Memorial Cancer Institute, Florida Hospital Cancer Center, Mount Sinai Cancer Center) that had alterations detected on Guardant360 (G360) testing through January 2017. G360 is a plasma cfDNA NGS assay that detects single nucleotide variations, amplifications, fusions, and indels in targeted genes using massively parallel digital sequencing; panel composition expanded from 54 to 73 genes over the course of the cohort. NGS performed on solid tumor biopsies from each subject were reviewed for comparison where available but may not have been collected contemporaneously to the plasma samples. Treatment information and clinical outcomes were collected for those patients with actionable mutations per NCCN guidelines (v3.2017).

      Result:
      A total of 190 G360 test results on 171 unique patients were identified (some patients underwent serial testing at multiple clinical timepoints, e.g. progression). Forty percent of patients were male; the median age was 65 (32-94). Excluding variants of uncertain significance, patients were most likely to have cfDNA alterations in TP53 (44%), EGFR (21%), KRAS (19%), BRAF (8%), and MET (8%). Forty-seven patients (28%) had at least one actionable mutation identified on G360, including SNVs, indels, fusions, and amplifications. Preliminary clinical outcomes data include durable (³10 months) partial responses on targeted therapy based on multiple plasma-detected alterations in EGFR and BRAF V600E; complete analysis will be presented at the meeting.

      Conclusion:
      Liquid biopsy plays an important role in genomic analysis of NSCLC, offering reliable information to guide therapeutic decision-making. Results in our cohort include a noteworthy proportion of patients with highly actionable mutations, like EGFR drivers and targetable resistance mutations, and G360 offers an alternative to tissue biopsy in these patients.

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    P2.01 - Advanced NSCLC (ID 618)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.01-056 - Use of Cell-Free Circulating RNA (cfRNA) Expression of PD-L1 and ERCC1 in Plasma to Monitor Response to Therapy in NSCLC (ID 9038)

      09:00 - 16:00  |  Author(s): Martin Frederik Dietrich

      • Abstract
      • Slides

      Background:
      There is an unmet need to evaluate tumor response by other means than radiology tests. Cell-free circulating tumor RNA (cfRNA) can be extracted from plasma of cancer patients (pts); measuring dynamic changes in gene expression and levels of b-actin; cfRNA (per ml of plasma) as a proxy for total cfRNA in metastatic patients has shown great potential for evaluating disease status and predicting outcome to anti-tumoral therapy in advance of imaging. We have previously shown that high levels of PD-L1 cfRNA expression correlates well with positive response to immunotherapies including nivolumab in pts with NSCLC.

      Method:
      Blood was drawn from pts at approximately 6-week intervals under various therapies, with CT scans at 3-month intervals. Total cfRNA was extracted from patient plasma and reverse transcribed to cDNA. Levels of b-actin, ERCC1 and PD-L1 were quantitated across multiple blood draws by RT-qPCR and correlated with pt response (PR/SD/PD), as determined by CT scans.

      Result:
      A total of 24 NSCLC patients were enrolled in a 1-year clinical study. Non-SCC comprised 87% (21/24). 19 pts completed the first two cycles of therapy. 1 pt with PR had decreasing levels of cfRNA, 10 pts achieved SD with decreasing or no change while 6/8 pts with PD had increasing levels of cfRNA. CfRNA levels were predictive of disease status about 4 weeks in advance of imaging in 6/19 pts and matched with disease status in 8/19 pts (74% ). Dynamic changes in PD-L1 expression correlated with response to nivolumab in 3/4 pts. In 2/4 pts with SD, PD-L1 remained undetected after therapy, whereas 1 patient continued to have PD despite loss of PD-L1. PD-L1 was undetectable in a pt initially with PD on nivolumab who achieved SD after one cycle of nivolumab plus radiation. Changing ERCC1 expression correlated with platinum-based therapy outcome in 8/8 patients. 4/4 patients with PD on pemetrexed/carboplatin had an increase in ERCC1. 4/4 patients with lower or decreasing levels of ERCC1 achieved PR or SD. In the only patient achieving PR, ERCC1 became undetectable during treatment.

      Conclusion:
      We found significant concordance between clinical response and changes in plasma cfRNA levels in NSCLC pts (74%). Levels of PD-L1 expression correlated with response in 3/4 pts treated with nivolumab . ERCC1 levels were predictive of outcome to platinum based therapy for 8/8 patients. ERCC1 and PD-L1 expression in cfRNA can be used to monitor response to platinum-based and immuno-therapy.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-052 - Detection of KRAS Mutation in Blood Predicts Favorable Response to Immunotherapy in NSCLC (ID 10469)

      09:30 - 16:00  |  Presenting Author(s): Martin Frederik Dietrich

      • Abstract

      Background:
      Immunotherapy has brought new therapeutic options to non-small cell lung cancer. PD-L1 has been established as the primary clinical biomarker for PD-1/PD-L1 targeting antibodies, with higher expression correlation with superior therapy responses. Tumor mutational burden and other biomarkers have been similarly implicated in prediction of immunotherapy responses. These markers are obtained from tumor tissue based on immuno-histochemistry or next generation sequencing. Availability of tissue has remained a significant clinical challenge. Mutations in KRAS have been reported to correlate with improved survival. We interrogated our data base to investigate whether KRAS detected in blood could serve as a surrogate marker for immunotherapy selection.

      Method:
      We screened a total of 239 cases of non-small cell lung cancer with positive tissue evaluation. 89/239 cases tested positive for presence of a KRAS mutation. 56 KRAS mutant cases of NSCLC, matched tissue (NGS and PD-L1) and blood (NGS) analyses were available. 17 cases had PD-L1 expression of greater than 50% on IHC. 39 cases had PD-L1 expression of less than 50%, defined as low expression. 34 patients had received single agent, PD-1 targeting immunotherapy (nivolumab or pembrolizumab). We reviewed these cases with low PD-L1 expression treated with immunotherapy in a retrospective analysis for clinical outcomes.

      Result:
      In the cohort with low PD-L1 low/KRAS mutant status, a response rate (PR+CR) of 53% (n=18) was observed, including 13% (n=5) complete responses. The average progression-free survival in this subset was 11.1 month. KRAS status correlated expectedly with prior or current smoking history (97%), and elevated tumor mutational load (16 mutations per megabase).

      Conclusion:
      Selection of appropriate candidates for immunotherapy has remained a clinical challenge. In our analysis, liquid biopsy was obtained without complication and correlated strongly between blood and tissue. Compared to historical controls, KRAS mutant status appears to have a higher response rate and prolonged progression-free survival independent of PD-L1 status. In addition to previously established PD-L1 and TML markers, our data supports a role of KRAS as a surrogate marker for immunotherapy response that should be investigated in prospective clinical trials.