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A. Mellemgaard



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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.07 - Survival of small cell lung cancer patients undergoing lung resection in England 1998-2009 (ID 1691)

      10:30 - 12:00  |  Author(s): A. Mellemgaard

      • Abstract
      • Presentation
      • Slides

      Background
      Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC) except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected small cell lung cancer is limited but this is widely offered.

      Methods
      Data on 359,873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC; non-SCLC [NSCLC]) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socio-economic status.

      Results
      The survival of 465 resected SCLC patients was lower than resected NSCLC patients (five-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 “elective” SCLC where the diagnosis was most likely known before resection than for the subgroup of 267 “incidental” cases, where the SCLC diagnosis was likely to have been made after resection.

      Conclusion
      These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. SCLC patients treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected SCLC patients.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.01 - Impact of tumor burden on the overall survival analysis of the LUME-Lung 1 study: a randomized, double-blind phase 3 trial of nintedanib (BIBF 1120) + docetaxel in NSCLC patients progressing after first-line chemotherapy (ID 3284)

      10:30 - 12:00  |  Author(s): A. Mellemgaard

      • Abstract
      • Presentation
      • Slides

      Background
      Nintedanib is an orally available potent anti-angiogenic agent inhibiting the isoforms of VEGFR, PDGFR and FGFR. LUME-Lung 1 is a placebo-controlled phase 3 trial of nintedanib + docetaxel in second-line NSCLC patients.

      Methods
      Patients with stage IIIB/IV or recurrent NSCLC after failure of first-line chemotherapy were stratified by histology, ECOG PS, prior bevacizumab and brain metastases, and were randomised to nintedanib 200 mg bid + docetaxel 75 mg/m[2] q21d (n=655), or placebo + docetaxel (n=659). The primary endpoint was centrally reviewed PFS after 714 events. The key secondary endpoint was OS after 1,121 events. Predefined sensitivity analyses used baseline sum of longest diameters of target lesions (SLD) and stratification factors, as covariates in the Cox model.

      Results
      The study met its primary endpoint demonstrating a statistically significant improvement in PFS that translated into a 21% reduction in the risk of progression in patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 months), regardless of histology (adenocarcinoma HR 0.77, CI: 0.62, 0.96; p=0.0193; squamous HR 0.77, CI: 0.62, 0.96; p=0.0200). OS was significantly prolonged in adenocarcinoma patients treated with the combination of nintedanib + docetaxel vs placebo + docetaxel (HR 0.83; CI: 0.70, 0.99; p=0.0359; median 12.6 vs 10.3 months) but not in squamous cell carcinoma patients (HR 1.01; CI: 0.85, 1.21; p=0.8908; median 8.6 vs 8.7 months). The intent-to-treat (ITT) analysis of OS in all study patients showed a 1-month improvement that did not reach statistical significance (HR 0.94; CI 0.83, 1.05; p=0.272; median 10.1 vs 9.1 months). When adjusted for SLD, however, a significant OS benefit was seen for the ITT population (HR 0.88; CI: 0.78, 0.99; p=0.0365). Further analyses showed that the impact of SLD was reflected in the squamous cell carcinoma population (HR 0.92; CI: 0.77, 1.10; p=0.3649), with the greatest impact observed for squamous cell carcinoma patients with a large SLD. An impact of SLD was also seen in adenocarcinoma patients but to a lesser extent (HR 0.81; CI:0.69, 0.97; p=0.0186), as compared with the squamous cell carcinoma population. The most common AEs reported for the ITT population were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis.

      Conclusion
      Nintedanib + docetaxel significantly reduced the risk of progression in NSCLC patients independent of histology. Adjustment for tumor burden, as represented by the SLD, led to a significant reduction in the risk of death. AEs were generally manageable with dose reductions and symptomatic treatment.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-003 - Immunohistochemical detection of Epidermal Growth Factor Receptor Mutations in Patients with Non-Small Cell Lung Cancer. (ID 855)

      09:30 - 16:30  |  Author(s): A. Mellemgaard

      • Abstract

      Background
      Determination of Epidermal Growth Factor Receptor (EGFR) mutational status has pivotal impact on treatment in non-small cell lung cancer (NSCLC). A standardized test has not yet been approved. DNA sequencing has previously been regarded as gold standard method. The rather low sensitivity of this method has led to development of more sensitive, but also more complicated methods including real-time PCR (RT-PCR). Immunohistochemistry (IHC) with mutation specific-antibodies may be a promising method for detection EGFR mutations in NSCLC.

      Methods
      This case-control study includes 191 patients (36 patients with an EGFR mutation and 155 wild type (WT) patients (randomly selected)) as detected by RT-PCR (Therascreen EGFR PCR kit, Qiagen, UK). This method identifies 29 somatic mutations from exons18-21 with a sensitivity of 1%. For EGFR IHC, antibodies against mutations in exon19 (clone 6B6) and exon21 (clone 43B2) by Cell Signaling Technology (USA) were used. All specimens were visualized according to the standardized protocol of EnVision FLEX+ system (DAKO, DK).The protein expression for each specimen was evaluated and a H-score, including intensity (graded 0-3) and percentages (0-100) of stained malignant cells, was calculated. A positive tumor was defined by a H-score value>0. The sensitivity (true positive/(true positive + false negative) and specificity (true negative/(true negative + false positive) were evaluated with the results from Therascreen EGFR PCR kit as reference.

      Results
      The sensitivity and specificity of the mutation-specific antibodies are presented in Table1.

      Sensitivity (%) 95% CI Specificity (%) 95% CI
      Exon19del(E746-A750) 60.0 32.3-83.4 99.3 96.3-100
      Exon21(L858R) 87.5 47.4-99.7 97.4 93.5-99.3
      Table1: Performance of the EGFR mutation-specific antibodies. CI = confidence interval, Del = deletion. For mutations in exon19, 5 specimens were false negative (IHC-, RT-PCR+) and 1 was false positive (IHC+, RT- PCR-). For mutations in exon21, 3 samples were false negative and 3 were false positive. 1 false positive for exon21 had maximal H-score (300).

      Conclusion
      We demonstrated a high specificity for IHC with mutation-specific antibodies for detecting EGFR mutations in patients with NSCLC. However, the sensitivity was low, especially for del19-mutations, and thus these antibodies are not yet ready as a screening method for detection of these mutations. We used RT- PCR as reference. This method is very sensitive compared to conventional Sanger sequencing being able to detect mutations present in 1% of the malignant cells. Some studies in NSCLC have questioned whether detection of such a small fraction of malignant tumor cells has clinical relevance for treatment of the whole tumor. The mutation-specific antibodies might be compared to highly sensitive methods, including RT-PCR and validated in clinical trials in order to detect the clinical impact of both methods.

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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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      P3.06-022 - Population based study of the prevalence of EGFR mutations in non-small cell lung cancer (NSCLC) (ID 1979)

      09:30 - 16:30  |  Author(s): A. Mellemgaard

      • Abstract

      Background
      Activating mutations in the EGFR gene identifies NSCLC patients sensitive to treatment with EGFR tyrosine kinase inhibitors. EGFR mutations are more prevalent in Asians compared to Caucasian. However, estimates of mutation frequencies are only available from selected patient cohorts and the incidence in an unselected Caucasian population is unknown. This study assess the prevalence of EGFR mutations in an unselected population based cohort, and the correlation between mutation and gender, age, ethnicity, smoking habits, as well pathological data.

      Methods
      Patients diagnosed with NSCLC June 1, 2010 - September 30, 2011 in a well-defined population of 1.7 million in the Capital Region, Denmark, were included in this single center study. The type and location of the diagnostic material was registered. All specimens were pretreatment, no residual tumors were included. Smoking data were also available. The mutation analyses were investigated by therascreen EGFR RGQ PCR Kit (detection of 29 somatic mutations in the EGFR oncogene, Qiagen) (n =1121) or direct sequencing (n=62). Twenty-two patients were analyzed with both methods.

      Results
      658 men and 598 women were included. All but 4 were Caucasians. 6.2% were never smokers, 38.9% were ex- smokers and 54.9% were current smokers. 1161 (92.4%) patients had material sufficient for mutation analysis. More than 50% malignant tumor cells were available for analyses in 68%, 76% and 56% of the histological, cytological clot, and cytological smear material respectively. Manual macro dissection to ensure this high concentration of tumor cells was done on 32%, 4%, and 10% of the histological, cytological clots, and cytological smears material, respectively. Cytological material was used for 38 % of the mutation analyses. 5.4 % of tested patients harbored mutation in the EGFR gene (4.3% men/ 6.7 % women). The majority of mutations (55 cases= 87%) were activating mutations (29 exon 19 deletions, 24 L858R mutations and 2 G719X mutations), 3 were rare mutations (two L861Q and one S768I) with unclear clinical response to TKI, five were insertions in exon 20 (resistance mutation). Three of the mutations (all exon 19 deletions) were detected in the three included Asian women. 8.0 % of adenocarcinomas, 1.9% of squamous cell carcinomas and one single case of adenosquamous cell carcinoma were mutated. No other tumor types were mutated. DNA yield was similar whether extracted from cytological or histological samples and these material types yielded similar mutation percentages (6.55% in cytology and 4.66% in histology of material analyzed). 29.4%, 4.4% and 2.9 % of never, ex- and current smokers, respectively, were mutated (p<0.001). No significantly difference between ex- and current-smokers was observed. Mutation status was not related to age.

      Conclusion
      EGFR mutations analysis on cytological as well as on histological material was possible in 92% of patients with NSCLC. 5.4% of the patients harbored EGFR mutation. Adenocarcinomas were mutated more often (8.0%) than squamous cell carcinomas (1.9%). Mutations were found in never smokers as well as in former and current smokers. No difference in gender and age regarding mutation status was observed.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.11-030 - A phase I / II trial of the HDAC inhibitor belinostat in combination with erlotinib in patients with non-small cell lung cancer. (ID 2369)

      09:30 - 16:30  |  Author(s): A. Mellemgaard

      • Abstract

      Background
      Belinostat (PXD101), is a histone deacetylase (HDAC) inhibitor. HDAC inhibitors, including belinostat, have shown marked in vitro and in vivo activity against a number of solid tumors and hematological cancers. Belinostat is efficient as a single agent as well as in combination with other anticancer agents such as doxorubicin, paclitaxel, carboplatin, fluorouracil, bortezumib. Synergistic effect between HDAC inhibitors, incl. belinostat and EGFR inhibitors has been observed. Belinostat has been well tolerated at doses up to 2000 mg daily in patients. The main side effects are fatigue, nausea and vomiting. The trial was designed as an open, non-randomized phase I / II trial to assess the efficacy and safety of belinostat in combination with erlotinib in patients with advanced non-small cell lung cancer, who were eligible for treatment with erlotinib.

      Methods
      The primary endpoint of the phase I part was to establish the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib (150mg/d) in combination with increasing doses of belinostat. The study was designed as a 3+3 phase I trial. All patients began with 4 weeks of erlotinib 150 mg/d. If this was tolerated, patients started the combination erlotinib and belinostat. The belinostat dose steps were 500 mg, 1000 and 1500 mg, administered daily in 2 weeks on treatment, 1 week off treatment. When one patient was enrolled at one dose level, there would be no further dose escalation for that individual patient. Three patients were planned at each dose level. When the MTD was identified the trial was planned to expand to a phase II trial, and include 20 patients with non-small cell lung cancer.

      Results
      From October 2010 until June 2011 five patients were enrolled in the phase I part of the trial. Patient one and two started belinostat 500 mg after four weeks of erlotinib 150 mg/d.Both patients experienced grade 3 diarrhea in spite of supportive care with loperamid and antiemitics. The treatment was discontinued in both patients and the toxicity quickly resolved. In accordance with the trial protocol, patient three was started on belinostat 250 mg. Patient three experienced only grade 1 diarrhea and grade 1 nausea. The patient received 2 series of belinostat. Patient four experienced grade 2 diarrhea and grade 2 rash in the first series belinostat 250 mg. Patient five experienced, in the first series of belinostat, grade 3 diarrhea and was hospitalized despite intensive supportive care. All patients discontinued treatment and toxicity resolved.

      Conclusion
      The combination of the HDAC-inhibitor belinostat and the EGFR inhibitor erlotinib resulted in severe toxicity. The trial has been closed. NCT01188707

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      P3.11-040 - Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomized, double-blind, placebo-controlled phase 3 study in second-line advanced non-small cell lung cancer (NSCLC) patients (ID 2812)

      09:30 - 16:30  |  Author(s): A. Mellemgaard

      • Abstract

      Background
      Nintedanib is an oral, twice-daily angiokinase inhibitor targeting VEGFR-1–3, PDGFR-α/β and FGFR-1–3. LUME-Lung 1 is a placebo-controlled phase III trial investigating nintedanib plus docetaxel in advanced NSCLC patients after failure of first-line chemotherapy.

      Methods
      Stage IIIB/IV or recurrent NSCLC patients were randomised to receive nintedanib 200 mg bid plus docetaxel 75 mg/m[2] q21d (n=655), or placebo plus docetaxel (n=659). The primary endpoint was centrally reviewed progression-free survival (PFS) analysed after 714 events; the key secondary endpoint was overall survival (OS) analysed hierarchically after 1121 events, first in adenocarcinoma patients and then all patients. Quality of Life (QoL) was included as a secondary endpoint. Lung cancer symptoms and health-related QoL were assessed every 21 days until the first follow-up visit using the EORTC (QLQ-C30/LC13) and EQ-5D questionnaires. Changes of ≥10 points as compared with baseline were considered clinically significant. Analyses of cough, dyspnoea and pain symptoms were prespecified. Time to deterioration (TTD, first 10-point worsening from baseline) was analysed using a stratified log-rank test. An exploratory analysis of all subscales/items from the EORTC QLQ-C30/LC13 questionnaires estimated the respective hazard ratios for TTD using a Cox proportional hazards model.

      Results
      LUME-Lung 1 showed that nintedanib in combination with docetaxel significantly prolonged PFS for all patients regardless of histology (3.4 vs 2.7 months; HR 0.79, 95% CI: 0.68–0.92; p=0.0019), with a trend for improved median OS (10.1 vs 9.1 months; HR 0.94, 95% CI: 0.83–1.05; p=0.272) and significantly improved OS in patients with adenocarcinoma (HR: 0.83; p=0.0359; median 10.3 to 12.6 months). The most common AEs were diarrhoea and reversible ALT elevations. With respect to the QoL assessment, there was a high compliance rate of >80% until treatment course 25 for QLQ-LC13 and QLQ-C30 in both treatment arms. The addition of nintedanib to docetaxel did not influence TTD for cough (HR 0.90; 95% CI: 0.77–1.05; p=0.1858), dyspnoea (HR 1.05; 95% CI: 0.91–1.20; p=0.5203) or pain (HR 0.95; 95% CI: 0.82–1.09; p=0.4373), and maintained global health status/QoL (HR 0.952; 95% CI: 0.83–1.10). There was a significant deterioration in scores for nausea and vomiting, appetite loss and diarrhoea. The results were similar for adenocarcinoma patients with respect to cough (HR 0.97; 95% CI: 0.78–1.20; p=0.7744), dyspnoea (HR 1.04; 95% CI: 0.86–1.26; p=0.6813) and pain (HR 0.93; 95% CI: 0.76–1.13; p=0.4785); however, there was a trend for improved global health status/QoL (HR 0.86; 95% CI: 0.71–1.05). For squamous cell carcinoma patients, there was a trend for delayed TTD for cough (HR 0.84; 95% CI: 0.66–1.07; p=0.1561) and a maintained global health status/QoL (HR 0.975; 95% CI: 0.788–1.206). Further analyses are ongoing and will be presented at the congress.

      Conclusion
      In second-line NSCLC patients, docetaxel plus nintedanib did not result in any significant improvements in cough, dyspnoea or pain compared with placebo and docetaxel. However, PFS was improved in patients of all histologies receiving docetaxel and nintedanib, and OS was improved in patients with adenocarcinoma histology without adversely affecting self-reported QoL.