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J.L. Kuiper



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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-024 - Retrospective analysis of rebiopsies in a cohort of EGFR-mutated NSCLC-patients with TKI-resistance; incidence of the T790M mutation. (ID 2162)

      09:30 - 09:30  |  Author(s): J.L. Kuiper

      • Abstract

      Background
      Epidermal Growth Factor Receptor mutated (EGFR+) NSCLC patients have a median progression free survival (PFS) of approximately 12 months when treated with EGFR-tyrosine kinase inhibitors (TKI). One of the resistance mechanisms described is the T790M mutation. This mutation is reported in 49-65% of patients who are rebiopsied at disease progression. Here, we report on the incidence of T790M mutation in a cohort of patients who were sequentially rebiopsied.

      Methods
      EGFR+ patients or with TKI-response>24weeks and progressive disease on TKI’s were retrospectively analysed. Patients should have had at least 2 separate biopsies. All biopsies and treatments were collected from the medical record and pathological reports. Survival was calculated according to Kaplan-Meier. Overall survival (OS) was calculated from date of 1[st] diagnosis until death or June 2013, which ever was first

      Results
      68 patients with 2 biopsies or more were available for analysis. In the first biopsy at TKI-resistance; T790M mutation was detected in 34 patients (50,0%). 26/68 patients had later biopsies available; showing gain and loss of T790M in later biopsies (figure 1). Overall development of T790M was 57.4% (39/68). 7 patients had >3 biopsies available (figure 2). Patients developing T790M had numerically longer median OS of 3.8 years (range 2.8 – 4.9) as compared to median OS in T790M-patients (2.5 years, range 1.0 – 3.9) (P = 0.204).Figure 1Figure 2

      Conclusion
      57.4% of patients developed T790M. OS in patients developing T790M was longer than in patients not developing T790M, however the difference was not significant. Sequential data show that some patients ‘loose’ the T790M later on in the course of the disease. Data from this cohort suggests that T790M development is a dynamic process.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-013 - Treatment with high-dose, weekly erlotinib in EGFR-mutated NSCLC-patients with extra-cranial progressive disease (ID 1350)

      09:30 - 09:30  |  Author(s): J.L. Kuiper

      • Abstract

      Background
      Progression of disease (PD) in advanced NSCLC patients with an EGFR mutation (EGFR+) treated with tyrosine kinase inhibitors (TKI) is inevitable. Therapeutic options for these patients are lacking. Several patients with acquired TKI-resistance who were treated with high-dose, weekly erlotinib (‘pulsatile erlotinib’) for leptomeningeal metastases showed an evident thoracic response (1). We initiated this trial to evaluate the effect of pulsatile erlotinib on advanced, EGFR+ NSCLC patients with TKI-resistance.

      Methods
      This study was developed as a prospective, mono-center, open-label, single-arm phase II trial. Primary endpoint was objective response rate (ORR). Secondary endpoints were PFS, toxicity and safety. Eligibility criteria included histologically confirmed stage IV, non-squamous, EGFR+ NSCLC-patients who progressed on TKI (erlotinib or gefitinib) in standard dose. Biopsy was obtained before treatment initiation. Patients were treated with erlotinib 1500mg weekly. Response was assessed according to RECIST 1.1. Simon’s 2-stage optimal design was applied (2).

      Results
      Eleven patients were enrolled. Patient characteristics and pathological results are depicted in table 1. When 10 patients were assessed to have PD or stable disease, the trial was discontinued, according to predefined criteria. Objective response rate (ORR) was 9,1%. Median PFS was 1.6 months (95% CI, 0.9-2.0 months). One biopsy revealed KRAS mutation, whereas earlier biopsies had shown exon 18 + exon 20 mutation. A second primary tumour is not excluded in this case. Patients received pulsatile erlotinib as 3[rd] -6[th] treatment. At time of analysis, one patient remains on treatment. One patient had clinical benefit lasting for 3 months beyond PD. There were no deaths during the study. Toxicity was mainly grade 1-2.

      Table 1: PATIENT CHARACTERISTICS N = 11
      Median Range
      Age (years) 57 (32-75)
      Frequency (%)
      Sex female 11 (100%)
      male 0 (0%)
      Smoking Non-smoker 7 (63,6%)
      Previous smoker 3 (27,3%)
      Current smoker 1 (9,1%)
      Performance score PS 0 4 (36,4%)
      PS 1 5 (45,5%)
      PS 2 2 (18,2%)
      Ethnicity Caucasian 11 (100%)
      Stage IV - metastatic 11 (100%)
      Histology Adenocarcinoma 10 (90,9%)
      1 (9,1%)
      Mutation EGFR-exon 19 2 (18,2%)
      EGFR-exon 21 1 (9,1%)
      EGFR exon 19 + T790M 3 (27,3%)
      EGFR exon 21 + T790M 2 (18,2%)
      KRAS 1 (9,1%)
      No mutation 1 (9,1%)
      No biopsy 1 (9,1%)

      Conclusion
      Despite some individual successes with pulsatile erlotinib treatment of EGFR+ NSCLC patients, this trial failed to meet its primary endpoint and was discontinued prematurely. Pulsatile erlotinib was safe and toxicity was manageable. Further investigation of this treatment for this indication is not recommended.