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J. Hunt



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    MA 02 - Emerging Targets (ID 656)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      MA 02.07 - A Phase II Study of Pembrolizumab in EGFR Mutant, PD-L1+, Tyrosine Kinase Inhibitor (TKI) Naïve Patients with Advanced NSCLC (ID 9525)

      11:00 - 12:30  |  Author(s): J. Hunt

      • Abstract
      • Presentation
      • Slides

      Background:
      Pembrolizumab, a humanized monoclonal antibody that inhibits the interaction between programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has demonstrated significant antitumor activity and produced durable responses in non-small cell lung cancer (NSCLC). However, data to date suggests that responses are less frequent in patients whose tumors harbor mutations in the epidermal growth factor receptor (EGFR) gene. Our single center experience with the KEYNOTE-001 trial suggested that EGFR mutation positive NSCLC patients with a history of prior tyrosine kinase inhibitor (TKI) therapy had worse clinical outcomes than those who were TKI naïve. However, that analysis was limited by small sample size. As a result of this observation, we are currently enrolling an open-label, phase II trial, of front-line pembrolizumab in EGFR mutation positive NSCLC patients that are PD-L1+.

      Method:
      This is an open-label, phase II trial of pembrolizumab in patients with EGFR mutation positive NSCLC whose tumors are PD-L1 positive [>1% tumor membranous staining by immunohistochemistry (IHC), 22C3 pharmDx test in a CLIA certified laboratory]. Patients receive pembrolizumab 200mg by IV infusion every three weeks and are evaluated every 9 weeks +/- 1 week with radiographic imaging to assess response to treatment for a maximum of 35 trial treatments of pembrolizumab. After progression on pembrolizumab, patients are followed for evaluation of EGFR TKI efficacy. The primary end point of the study is objective response rate (ORR) to pembrolizumab, per RECIST 1.1. Secondary endpoints include safety and efficacy [progression-free survival (PFS), overall survival (OS)] of front-line pembrolizumab in this population, as well as efficacy [PFS, OS, ORR] of subsequent EGFR TKI after progression on pembrolizumab. Correlative analyses include whole exome sequencing and IHC of patient specimens. To date, 8 out of the 25 planned patients have been enrolled.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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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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      P2.07-038 - Thyroid Dysfunction Arising During KEYNOTE-001 Associated with Improved Efficacy of Pembrolizumab in NSCLC Patients at UCLA (ID 9531)

      09:30 - 16:00  |  Author(s): J. Hunt

      • Abstract

      Background:
      PD-1/PD-L1 blockade has rapidly been adopted for treatment of NSCLC. However, much remains to be learned about the implications of the side-effect profile of PD-1/PD-L1 blockade. We previously showed that the 38 patients who experienced a treatment related AE (trAE) on the KEYNOTE-001 trial at UCLA had superior clinical outcomes compared to the 59 that did not. Treatment related hypothyroidism was the most predictive trAE for response to therapy [objective response rate (ORR): 83.3% (5/6 patients with response)]. The highly predictive nature of treatment related hypothyroidism led us to further evaluate the implications of thyroid dysfunction in our patient cohort by analyzing the association between therapeutic efficacy and thyroid specific laboratory values obtained on trial.

      Method:
      We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 12/2016). Patients had Thyroid Stimulating Hormone (TSH), free Thyroxine 4 (fT4), and Triiodothyronine (T3) assessed at baseline (prior to therapy), cycle 2, and every other cycle thereafter. In some instances, labs were obtained at safety follow-up and unscheduled visits. Tumor response was evaluated using investigator assessed immune related response criteria (irRC), with imaging q9wks.

      Result:
      97.9% (95/97) of the patients treated at UCLA on KEYNOTE-001 had a baseline set of thyroid indices, while 74.7% (68/97) had >3 sets of values. Patients with an abnormal TSH during study participation had a higher ORR, 35.5% (11/31), than those that did not, 14.1% (9/64) (p=0.0296), with an acquired TSH abnormality (first observed after C1D1) more predictive of response than a baseline abnormality [acquired TSH abnormality: ORR 42.9% (9/21) vs baseline abnormality: ORR 20% (2/10)]. An abnormal fT4 or abnormal T3 on trial were also both independently associated with improved response to therapy [fT4 abnormality+: ORR: 50% (5/10) vs fT4 abnormality-: 17.7% (15/85) (p=0.0317) and T3 abnormality+: ORR 47.4% (9/19) vs T3 abnormality-: ORR 14.5% (11/76) (p=0.0037)]. As with TSH, acquired fT4 and T3 abnormalities were associated with higher ORR than baseline abnormalities.

      Conclusion:
      Thyroid dysfunction, assessed by abnormalities in TSH, fT4, or T3, was associated with improved efficacy of pembrolizumab on the KEYNOTE-001 trial at UCLA and an acquired thyroid abnormality, defined as first occurrence after C1D1, was more predictive of improved efficacy than a baseline abnormality. Future work is ongoing to evaluate this association in a larger patient population and molecular mechanisms that may be underlying this observation.