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C.A. Lydon



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.08 - Clinical Implications of ALK Resistance Mutations: Institutional Experience and Launch of Remote Participation Study (ID 7931)

      16:30 - 16:35  |  Author(s): C.A. Lydon

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK resistance mutations are detected in 30-50% of the patients with ALK-positive non-small cell lung cancer (NSCLC) and resistance to ALK tyrosine kinase inhibitors (TKIs). Preliminary data suggests that TKI-resistant patients benefit from further ALK inhibition based on the specific resistant mutations, but clinical data are limited.

      Method:
      Patients with ALK-positive NSCLC were identified from our institutional database with IRB approval. Tumor specimens from patients with TKI-resistance were analyzed using next-generation sequencing (NGS). We aimed to study the relationship between specific ALK-resistant mutations, patient characteristics and clinical outcomes.

      Result:
      Among 82 ALK-positive NSCLC patients, we identified 29 cases with advanced disease, TKI resistance, and specimens available for NGS. Twenty-two specimens from 19 patients were adequate for genomic analyses. Patients received a median of 4 lines of treatment for advanced disease including a median of 2 ALK TKIs, with a median overall survival (OS) of 3.3 years. In 9 of 22 specimens, crizotinib was the only TKI received. Ten specimens (45.5%) showed an ALK resistance mutation: one G1128A, one L1152R, four I1171N/T, two F1174V and two G1202R. ALK-resistance mutations were more common with EML4-ALK variant 3 (4/5) than variant 1 (1/5). Three cases with sequential biopsies showed features of tumor evolution, such as a compound mutation (I1171N + C1156Y) or a mutational change (L1152R to G1128A). One case initially had an EGFR L858R mutation, then acquired an ALK rearrangement, then acquired a G1202R mutation. OS was longer in 8 patients with secondary ALK mutation (5.5y) compared to 11 patients without (1.8 y). Using these learnings from an institutional cohort of ALK resistant patients, we designed and are launching a prospective study to characterize ALK TKI resistance, which uses remote-participation and plasma NGS to enroll patients from across the US. Patients with systemic progression while on a next-generation ALK TKI submit blood to a central lab for analysis and banking. Plasma NGS results are returned to the patient and their provider, and including expected TKI sensitivities for any identified ALK-resistance mutations. Through monitoring outcomes, this study can assess if molecularly-guided therapy for ALK TKI-resistance is feasible and effective.

      Conclusion:
      ALK resistance mutations arise in a large portion of patients and are associated with longer survival. The SPACEW-ALK study (Study of Plasma next-generation sequencing for remote Assessment, Characterization, Evaluation of patients With ALK drug resistance) uses plasma NGS and remote consent to assess ALK resistance and the feasibility of precision resistance therapy for these patients.

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-055 - Spectrum of Early Progression in Advanced NSCLC Patients Treated with PD-1 Inhibitors: Identifying Markers for Poor Outcome (ID 8275)

      09:30 - 09:30  |  Author(s): C.A. Lydon

      • Abstract

      Background:
      While marked responses have been observed in patients with non-small-cell lung cancer (NSCLC) treated with PD-1 pathway inhibitors, anecdotal evidence indicates that rapid progression with dramatic tumor burden increase early in the course of therapy may be noted in a few patients. The study characterized the spectrum of early progression of advanced NSCLC treated with PD-1 inhibitors, and investigated quantitative imaging markers for poorer outcome.

      Method:
      The study included 134 patients (53 men, 81 women; median age: 66) with advanced NSCLC treated with commercially prescribed single-agent nivolumab or pembrolizumab, who had follow-up CT scans at 8 +/- 2 weeks of therapy. Tumor burden measurements were performed using RECIST1.1 on baseline and 8-week scans to characterize the spectrum of early progression during PD-1 therapy. Tumor burden changes at 8 weeks were studied for association with overall survival (OS), which was measured from the 8-week scan date.

      Result:
      The tumor burden changes at 8 weeks comparing to baseline ranged from -72.7% to +138.7% (median: +4.3%; the 90[th] percentile: +50.07%). OS of 15 patients with ≥50% increase of tumor burden at 8 weeks was significantly shorter compared to 119 patients with <50% increase at 8 weeks (median OS: 4.5 months [95%CI: 1.3-4.9] vs. 12.7 months [95%CI: 8.5-14.7]; log-rank p=0.0003). Among 42 patients who experienced tumor burden increase ≥20% (RECIST progression threshold) at 8 weeks, 15 patients with ≥50% increase had shorter OS than 27 patients with ≥20% but <50% increase (median OS: 4.5 months [95%CI: 1.3-4.9] vs. 6.8 months [95%CI: 5.4-20.1]; log-rank p=0.08), indicating that ≥50% increase threshold may identify a distinct group of early progressors with poorer prognosis. Never smokers were more likely to experience ≥50% increase at 8 weeks than former or current smokers (Fisher p=0.03).

      Conclusion:
      Tumor burden increase of ≥50% at 8 weeks of therapy was associated with significantly shorter OS in advanced NSCLC patients treated with commercial PD-1 inhibitors, indicating that it can serve as an imaging marker to identify a distinct subset of patients with poorer outcome of PD-1 inhibitor therapy, and may thus help guide treatment decisions.

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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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      P2.07-002 - Drug-Related Pneumonitis in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Commercial PD-1 Inhibitors (ID 7559)

      09:30 - 09:30  |  Author(s): C.A. Lydon

      • Abstract

      Background:
      PD-1 inhibitor-related pneumonitis is recognized as a serious immune-related adverse event especially among NSCLC patients. The study investigated the radiographic patterns, clinical course, and risk factors of pneumonitis in advanced NSCLC patients treated with commercial PD-1 inhibitors.

      Method:
      The study included 210 patients (93 men, 117 women; median age: 65) with advanced NSCLC treated with commercially prescribed single-agent nivolumab or pembrolizumab. Chest CT scans during therapy were reviewed for abnormalities suspicious for pneumonitis by an independent review of two radiologists. Radiographic patterns of pneumonitis were classified using the ATS/ERS classification of interstitial pneumonia.

      Result:
      Pneumonitis was radiographically detected in 20 patients (20/210; 9.5%). Median time from the initiation of therapy to pneumonitis was 7.8 weeks. The radiographic pattern of pneumonitis was a cryptogenic organizing pneumonia (COP) pattern in 18, a non-specific interstitial pneumonia (NSIP) pattern in one, and a hypersensitivity pneumonitis (HP) pattern in one patient. Fifteen patients (75%) were symptomatic and 5 patients (25%) were asymptomatic with radiographic abnormalities alone. PD-1 inhibitors were held in 17 patients (85%), and corticosteroids were given in 12 patients (60%). Seven patients were hospitalized for treatment of pneumonitis. Three patients were re-treated with PD-1 inhibitors and two developed recurrent pneumonitis. There were no significant differences in clinical characteristics between patients with and without pneumonitis (p>0.34). Figure 1



      Conclusion:
      PD-1 inhibitor-related pneumonitis was noted in 9.5% of the advanced NSCLC patients treated with commercially prescribed PD-1 inhibitors. Radiographic pattern of pneumonitis was most commonly a COP pattern. Recurrent pneumonitis was common among those who were re-treated with PD-1 inhibitors. Further studies are necessary to identify risk factors for pneumonitis.