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B. Wolf



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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-042 - Reduction in Peripheral Blood Cytokine Levels Observed in EGFR Mutant (EGFRm) Patients Treated with Erlotinib (ID 5403)

      14:30 - 14:30  |  Author(s): B. Wolf

      • Abstract

      Background:
      A retrospective analysis of EGFRm non-small cell lung cancer (NSCLC) patients enrolled on ­­the KEYNOTE-001 trial at UCLA showed a significantly lower objective response rate for those treated with a tyrosine kinase inhibitor (TKI) prior to pembrolizumab than those who were TKI naïve (Garon et al, WCLC 2015). Since nivolumab treated squamous NSCLC patients that had high baseline cytokine levels had a median overall survival almost three times longer than those with low baseline levels (Lena et al, ELCC 2016), we used multiplex cytokine analysis to assess effects of an EGFR TKI on peripheral blood cytokine concentrations.

      Methods:
      Paired baseline and cycle 2 day 1 samples were evaluated in 60 stage IIIb or IV NSCLC patients [EGFRm=12, EGFR wild type (wt)=33, unknown EGFR=15] enrolled on a clinical trial of erlotinib +/- fulvestrant for 30 cytokines [Bio-Rad Bio-Plex Human Cytokine 27-plex and Bio-Plex Pro TGF 3-plex (M500KCAF0Y, 171W4001M)]. Cytokine concentration values were compared between EGFR groups with GEE models. In these models, cytokine values were log-transformed and terms for treatment, EFGR status, and their interaction were included. Age (continuous), sex (binary), smoking status (ever/never), and tumor stage (binary) were also included in the model. R software was used for analyses. A p-value <0.05 was considered statistically significant with no adjustment for multiple comparisons.

      Results:
      For the 12 EGFRm patients treated with erlotinib +/- fulvestrant, 83% (25/30) of the cytokines evaluated showed a quantitative decrease, 17% (5/30) showed a significant decrease, and none showed a significant increase. Similar patterns were not observed in the 33 EGFRwt patients, in whom only 23% (7/30) of the cytokines evaluated showed a decrease, significant in 7% (2/30) with 40% (12/30) showing a significant increase. No clear directional change based on inclusion of fulvestrant in the treatment regimen was seen.

      Conclusion:
      A decrease in peripheral blood cytokine concentrations was observed in EGFRm patients treated with erlotinib +/- fulvestrant but not EGFRwt patients. Although unknown whether these changes persist after erlotinib discontinuation, the decrease in EGFRm patient peripheral blood cytokine levels in response to TKI therapy could contribute to the lower efficacy of anti-PD-1 therapy observed in this population. Future studies will evaluate cytokine levels for EGFRm patients treated with 3[rd] generation TKIs, as well as patients enrolled on a single center investigator-initiated trial evaluating front-line pembrolizumab in EGFRm PD-L1+ patients.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-083 - Treatment Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center (ID 5509)

      14:30 - 14:30  |  Author(s): B. Wolf

      • Abstract

      Background:
      It has been suggested that certain patients could be primed to respond to anti-programmed cell death-1 (PD-1) therapy due to heightened baseline “immunocompetence,” but data supporting this is limited as is our ability to measure it. The experience with ipilumumab suggests that immune related adverse events (irAEs) experienced by melanoma patients may predict improved clinical outcomes (Weber et al, J Clin Oncol 2012). We retrospectively analyzed NSCLC patients from a single center on the KEYNOTE-001 trial and evaluated the association between treatment related adverse events (trAE) and clinical outcomes.

      Methods:
      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 3/2016). Investigators reported AEs and graded according to CTCAE v4.0, labeling them as unlikely, possibly, or probably treatment related. AEs labeled as possibly/probably related were considered trAEs. The initial scan was at 9 weeks and subsequent scans were every 9 weeks. Investigator assessed irRC was the radiographic assessment used for clinical decisions at individual sites. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using the log-rank test.

      Results:
      10% (85/826) of AEs reported on trial were considered trAEs. The most frequent trAEs were rash (29%), fatigue (9%), and pneumonitis (8%). The occurrence of a trAE was associated with higher objective response rate (ORR) (OR=0.1509, P=0.0009), PFS (HR=0.3004, P<0.0001) and OS (HR=0.4391, P<0.0001). To assess whether the shorter duration of follow-up in those progressing earlier biased this analysis, additional analyses were performed. The relationship remained, particularly for longitudinal outcomes, when assessed only in patients that continued on trial >9 weeks. This was true both when including trAEs over the entire trial duration (ORR: OR=0.1839, P=0.005; PFS: HR=0.3525, P<0.0001; OS: HR=0.4526, P=0.0008) or when including only trAEs occurring within the first 9 weeks (ORR: OR=0.4063, P=0.1047; PFS: HR=0.5568, P=0.0211; OS: HR=0.6404, P=0.0465). Neither number of prior lines of therapy nor age, gender, or smoking history predicted frequency of trAE occurrence.

      Conclusion:
      This single center, retrospective analysis, revealed that a trAE predicted for improved clinical outcome with pembrolizumab. When controlling for the inherent bias of asymmetric follow-up, these associations remained. Although this analysis has the weakness of being conducted at a single center representing less than 20% of patients on trial, the strength is that a limited number of investigators assessed if an event was an AE and was treatment related.