Author of

• 31161

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  P1.09 - Pathology (ID 173)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 31185

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    P1.09-21 - Tumor Responses Based on Tumor Growth Rate During PD-1 Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients (ID 1906)

    09:45 - 18:00  |  Author(s): Reno Debets
    • Abstract

    Background
    

    Immune checkpoint inhibitors have emerged as a standard of care treatment for non-small cell lung cancer (NSCLC). However, there remains debate about the tumor growth kinetics during treatment, for instance the incidence of rapid disease progression, described as hyperprogressive disease (HPD). To get insight into variations in tumor growth kinetics and their potential predictive values for outcome we evaluated tumor growth rate (TGR) in patients receiving PD-1 checkpoint inhibitors.

    Method
    

    An analysis and radiological review of all Nivolumab treated NSCLC patients (n=196) between 06-2015 and 09-2017 in an early access program and as standard of care was performed. Differences in TGR before and after the start of treatment were calculated by entering the sum of the longest diameters from CT-scans before and after the initiation of therapy into a formula that assumes a volumetric exponential tumor growth. TGR variations, possible predictors for TGR changes and its relationship to overall survival (OS) were studied. For comparison tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1).

    Result
    

    Among the 58 evaluable patients, 37 patients (64%) showed deceleration of TGR and 16 patients (27%) showed acceleration of TGR after initiation of therapy, with a significant difference in median OS of 18.0 versus 6.0 months (HR=0.35; 95%CI:0.18-0.71) between these groups. Four patients (7%) were defined as having HPD. In 5 patients (9%), the tumor growth remained stable. These TGR categories were not significantly different according to age, gender, histology, smoking or previous radiotherapy. Of the patients defined as having progressive disease by RECIST1.1 at first follow up 40% showed response to CPI by a decrease in tumor growth rate. (Figure 1)

    Conclusion
    

    Tumor growth kinetics can be used as a clinically relevant predictor for OS in anti-PD1 treated NSCLC patients, and may provide additional information to RECIST measurements.

    

• 30943

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  P2.04 - Immuno-oncology (ID 167)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Immuno-oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30948

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    P2.04-06 - Blood-Based Multiplex Kinase Activity Profiling as a Predictive Marker for Clinical Response to Checkpoint Blockade in Advanced NSCLC (ID 1322)

    10:15 - 18:15  |  Author(s): Reno Debets
    • Abstract

    Background
    

    Only a minority of non-small-cell lung cancer (NSCLC) patients benefit from treatment with immune checkpoint inhibitors (ICIs), therefore, there is an urgent need for response prediction. Previously, the potential of using tyrosine kinase activity profiling of baseline peripheral blood mononuclear cells (PBMC) was demonstrated in an analysis with ICI treated advanced melanoma patients [1]. Here, we apply this methodology to evaluate the predictive value for response to ICIs in NSCLC.

    Method
    

    59 ICI naïve advanced NSCLC patients treated with PD-1 blockade were included in this exploratory analysis of the prospective immuno-monitoring study (MULTOMAB; NTR7015). PBMC were isolated from patient blood samples obtained prior to treatment with ICIs. Kinase phosphorylation signatures of PBMC lysates were measured using a micro-array, comprising of 144 different peptides derived from sites that are substrates for protein tyrosine kinases. Correlation of the profiles with progression free survival (PFS) and overall survival (OS) was analyzed using univariate cox-regression. Predictive multivariate (GLMnet) analysis was performed by binary survival grouping of patients with a cut-off at 140 days for PFS and 365 days for OS. The predictive performance of the models was estimated using cross validation. Multiplex flow cytometry, enumerating 18 immune cell subsets and assessing expression for 28 T cell markers, was performed for a selection of patients to gain additional insight in the immune profile [2].

    Result
    

    Univariate Cox regression showed significant correlation of phosphorylation signal with PFS for 7 peptides (p < 0.01, False Discovery Rate [FDR] = 10%), and with OS for 34 peptides (p < 0.01, FDR = 2%). Evaluation of the predictive value of GLMnet models resulted in estimates for the Correct Classification rate (CCR) of 67-70% for PFS and 67-73% for OS. When the cross validated predictions of the models were used to categorize the patients in a predicted-high-risk and a predicted-low-risk group, this resulted in a significant difference in survival between these groups. The predicted-low-risk group displayed significant better median PFS and OS than the predicted-high-risk group ([246 vs. 56 days; HR 2.3, 95%CI 1.2-4.7, p=0.02] and [488 vs. 171 days; HR 2.7, 95%CI 1.1-6.6, p=0.03], respectively).

    Conclusion
    

    Similar to melanoma, kinase activity profiles of baseline PBMC samples of advanced NSCLC patients can predict the response to PD-1 blockade. This assay may serve as a predictive biomarker for response to anti-PD-1 therapy. Involvement of immune receptor kinases is being investigated. An independent validation study is underway.