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Lukas C Heukamp



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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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      P1.14-03 - Molecular Determinants for Lorlatinib Activity in ROS1 Positive NSCLC: Results of the Prospective PFROST Trial (ID 1566)

      09:45 - 18:00  |  Author(s): Lukas C Heukamp

      • Abstract

      Background

      Lorlatinib, an ALK/ROS1 inhibitor, demonstrated activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.

      Method

      PFROST was a prospective phase II trial designed to include ROS1+ NSCLC refractory to crizotinib. Eligible patients were treated with lorlatinib at the daily dose of 100 mg until disease progression. Primary end point was response rate (RR). For all included patients pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.

      Result

      From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N=8; 36.4%), PS1 (N=14; 63,6%); The majority had brain metastases at baseline (N=15; 68.1%), were never smokers (N=13; 59.1%) and received lorlatinib as third line therapy (N=16; 72.7%). In all cases crizotinib was the last therapy line before lorlatinib. At the time of the present analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N=1) or partial (N=6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N= 1 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of radiological evidence of lorlatinib failure.

      Conclusion

      In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals developing secondary ROS1 mutations after crizotinib failure.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-63 - Evaluation of Combined Biomarkers for Tumor Response to Immunotherapy (I/O) in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 1708)

      10:15 - 18:15  |  Author(s): Lukas C Heukamp

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors have revolutionized NSCLC treatment. At present, the only established predictive biomarker for I/O-therapy stratification are PD-L1 expression and MSI status. However, the expression of PD-L1 is limited by heterogeneous expression and even high expressors not always respond to I/O therapy. The aim of the study is to evaluate the value of combinations of positive (Tumor Mutational Burden, PD-L1) and negative (a.o. CD73 expression and inactivating STK11 mutations) predictive markers in patients (pts) with advanced NSCLC on I/O therapy.

      Method

      A retrospective study was performed on a cohort of 54 pts with advanced NSCLC that have been treated with I/O between 2015 and 2018. Pts were selected by the availability of tumor tissue and based on tumor response evaluated by RECIST v1.1 criteria: only patients with durable tumor response (CR,PR > 6 months) and patients with no tumor response (PD as best response) were analyzed for biomarkers: hybrid capture NGS assay for TMB (New Oncology) including STK11 mutations and IHC tests for PD-L1, CD73 and VISTA. Adjusted Cox regression and ROC analysis will be performed to evaluate the predictive value of the different biomarkers.

      Result

      43/54 pts received nivolumab, 11/54 pembrolizumab in different therapy lines (from 1st to 5th line). 24 pts were defined as having a durable tumor response (median PFS 20 months, median OS not reached) 30 pts as primary progressors (median PFS 2 months, p<0.0001), median OS 12 months, p<0.0001). In 30/54 pts enough material was available for TMB testing. The median TMB-value is 11.42 mutations/Mb. In 13 durable responders median TMB-value was 13.28 mutations/Mb versus 11.00 mutations/Mb in 17 primary non-responders. STK11 mutations were observed in 3/17 primary non-responders (10%) vs. 0/13 in durable responders (0%). Additional analyses of PD-L1, CD73, and VISTA will be presented at the meeting as well as correlative data of the parameters analysed.

      Conclusion

      Our results suggest that integrating several biomarkers including positive and negative predictive markers may correlate better with responses to I/O than PD-L1 and TMB alone.

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