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Trevor Pugh



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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-07 - Genomic Profiling of Liquid Biopsies During 2nd/3rd Generation ALK Inhibitor Therapy to Identify Novel Mechanisms of Resistance (ID 804)

      09:45 - 18:00  |  Author(s): Trevor Pugh

      • Abstract

      Background

      Second- and third-generation ALK inhibitors each have diverse mechanisms of resistance. Only a fraction of resistance is due to secondary mutations of the ALK gene. Altered bypass tracts are likely the case in some other instances. Genomic alterations of other genes and pathways may be a third mechanism of resistance. Repeat liquid biopsies during the course of patients’ treatments can provide a minimally invasive method for sampling cancer-specific genomic information that leads to improved treatment selection.

      Method

      In the Lung Cancer Clinic of the Princess Margaret Cancer Centre, serial plasma samples were collected from six lung cancer patients with ALK rearrangement at multiple serial clinic visits pre- and post- progression on next-generation ALK inhibitors. We focused on next generation agents, as there has been previous focus on crizotinib resistance mechanisms already. Cell-free DNA (cfDNA) was extracted (median: 50 ng; range: 20-2760 ng) and profiled using a next-generation sequencing (NGS) platform with Geneseeq Prime 425-gene panel at a mean coverage depth of 4747X (and a deduplicated mean coverage depth of 2160X).

      Result

      Somatic alterations from plasma cfDNA were detected in all six patients at various time points with three patients having detectable ALK alterations. Systemic progression (2/2 patients) correlated well with the ability of liquid biopsies to detect somatic mutations, while central nervous system (CNS)-predominant progression did not (4/4 patients). One patient, after disease progression on ceritinib, alectinib and brigatinib, exhibited variable allele fractions (AFs) of ALK G1202R mutation in cfDNA. The levels of G1202R decreased and ultimately became undetectable, corresponding to the patient’s clinical response to lorlatinib. In a patient who exhibited significant systemic progression, a massive increase in mutation AFs and many newly acquired mutations were detected in the cfDNA, including NOTCH1, DICER1, BRCA2, TP53, CDKN2A, ERBB3, and FAT1mutations. However, the increase in the number of co-mutations was not related to increases in the amount of extracted cfDNA.

      Conclusion

      Broad panel-based NGS of plasma cfDNA enabled noninvasive detection of systemic (but not CNS-predominant) progression during second and subsequent generation ALK inhibitor treatment, and can identify known and putative mechanisms of resistance for treatment decision-making.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-62 - Early, Subclinical SCLC Transformation in Patients with EGFR Mutant Lung Cancer Receiving Osimertinib, Detected Through Cell-Free DNA (ID 812)

      10:15 - 18:15  |  Author(s): Trevor Pugh

      • Abstract

      Background

      Liquid biopsies provide a convenient approachfor serial sampling and real-time disease monitoring, leading to the early detection of treatment response, disease progression and drug-resistance. Here,we present genomic profiling of serial liquid biopsies from seven lung cancer patients with activatingEGFRmutations receiving osimertinib in clinical practice.

      Method

      At Princess Margaret Cancer Centre, in the Lung Cancer Outpatient Clinics, plasma samples were obtained from each patient at defined clinical visits (between ~1–5 months in-between visits). Cell-free DNA (cfDNA; with a median of 57 ng; range: 3.5 to 3806 ng) was extracted from plasma samples and profiled using targeted capture next-generation sequencing with the Geneseeq Prime 425-gene panel, at a mean coverage depth of 4892X (with a deduplicated mean coverage depth of 2108X).

      Result

      Systemic tumour burden correlated with the detection of genomic alterations in cfDNA: Four of four of the patients with low tumour burden, despite minor disease progression, exhibited minimal EGFR and co-mutation allele frequencies (AFs). Conversely, significant increases in systemic (but not central nervous system) tumour burden led to increases in driver and co-mutation AFs (two our of three patients). EGFR C797S mutation and inactivating mutations in RB1 and TP53 were detected in the cfDNA of one patient nearly four months prior to the development of small cell lung cancer (SCLC) transformation confirmed on tissue biopsy with distinct transformed and untransformed areas. Both of the specific RB1 and TP53 mutations found in cfDNA have been previously associated with SCLC. Subsequent combination cisplatin-etoposide chemoradiation resulted in temporary complete remission of the transformed SCLC, corresponding to loss of RB1 mutation detection by cfDNA testing.

      Conclusion

      Profiling of plasma cfDNA using hybrid capture deep sequencing of a large gene panel can detect early subclinical transformation of EGFR-mutated lung cancer into small cell lung cancer (i.e., neuroendocrine transformation), leading to earlier diagnosis and management of the transformed disease. Serial liquid biopsy profiling can also be used to monitor disease progression. However, detection sensitivity of tumour cfDNA largely depends on systemic tumour burden.