Virtual Library

Start Your Search

John Beeler



Author of

  • +

    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P1.01-46 - Circulating Tumor DNA Analysis for Predicting Response to Osimertinib and Disease Progression in EGFR-Mutant Non-Small-Cell Lung Cancer (ID 14242)

      16:45 - 18:00  |  Author(s): John Beeler

      • Abstract

      Background

      Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive modality to detect biomarkers associated with a broad array of malignancies, including lung cancer. We aimed to assess whether ctDNA could be used to predict response to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and disease progression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Plasma samples were serially collected at every clinic visit from patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) enrolled in a clinical trial of osimertinib treatment, local ablative therapy (LAT) upon progression, followed by osimertinib re-challenge (NCT02759835). Patients with no prior EGFR-TKI treatment or patients with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, patients with ≤5 progressing sites undergo LAT and resume osimertinib. ctDNA was detected using droplet-digital PCR EGFR mutation detection assays. The changes in ctDNA mutant allele levels were correlated with response to treatment and tumor progression. To identify additional genetic changes that may be related to osimertinib resistance, an enhanced Tagged-Amplicon Sequencing NGS assay (InVisionSeqTM) was utilized which covers SNVs, InDels and amplifications in 36 genes commonly mutated and therapeutically actionable in NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      353 samples from 17 patients were analyzed. At baseline, EGFR mutations were detected in 15 (88%) patients. One patient with overall low metastatic tumor burden and another patient with most tumor burden in the brain did not have detectable ctDNA at baseline. For patients treated with osimertinib before first progression, 12 (86%) achieved a partial response (PR) and 2 (14%) had stable disease (SD) as their best response. ctDNA decreased after initiation of osimertinib in these patients with 7 (50%) patients having no detectable ctDNA within 28 days. In those with ongoing PR (n=5) and prolonged stable disease (n=1), ctDNA remains undetectable (n=5) or low (n=1). Among 7 patients who had first progression, 5 (71%) patients had an increase in corresponding mutant EGFR allele in ctDNA 2-4 months before radiographic progression. While exploration of osimertinib resistance mechanisms by InVisionSeqTM is ongoing, early results demonstrate that allele frequencies of mutations in genes, including EGFR, PIK3CA, and TP53 closely reflected response and resistance to osimertinib. MET and EGFR amplification, as well as emergence of EGFR C797S mutant were identified as key resistance mechanisms by ctDNA analysis. Full details on all patients will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Quantitative assessment of plasma ctDNA is a relatively non-invasive tool to monitor the therapeutic response to treatment with EGFR-TKI and for early detection of resistance mechanisms for clinical decision making.

      6f8b794f3246b0c1e1780bb4d4d5dc53

  • +

    P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
    • +

      P3.04-02 - Early Plasma ctDNA Response Anticipates Clinical Response to First-Line Immunotherapy in Advanced NSCLC (ID 14240)

      12:00 - 13:30  |  Author(s): John Beeler

      • Abstract

      Background

      Shedding of circulating tumor DNA (ctDNA) into plasma can be an independent prognostic indicator in lung cancer, and changes in plasma ctDNA levels correlate with response to targeted therapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing (NGS) would enable early detection of response to immunotherapy in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced NSCLC who received first-line treatment with pembrolizumab alone or in combination with platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from patients prior to starting therapy and again at 3 and 3 weeks after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes (InVisionSeq). The trends of the ctDNA allele frequency were correlated with radiographic responses to therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      Serial plasma samples were collected on 21 patients with the following characteristics: 67% female, median age 62, 90% adenocarcinoma, 10% squamous cell carcinoma. Pembrolizumab was administered as monotherapy to 18 (86%) patients and in combination with platinum/pemetrexed in 3 (14%) patients for a median of 6 cycles. Among the 8 (38%) patients with no detectable ctDNA at baseline, 5 patients who maintained no detectable ctDNA during serial analyses responded to treatment, and 3 patients with emergence of ctDNA within the first 6 weeks of treatment initiation experienced progressive disease. In the 13 (62%) patients with detectable ctDNA at baseline, radiographic responses were preceded by earlier changes in ctDNA allele frequency. Six of 7 patients with >50% decreases in ctDNA allele fraction responded to treatment while 4 of 6 patients with progressive disease had increases in ctDNA within 6 weeks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In advanced NSCLC treated with first-line immunotherapy, rapid decreases and clearance of ctDNA correlated with clinical benefit, while increasing or newly detectable ctDNA was a harbinger of progressive disease. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53