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C. Mathias



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    MINI 09 - Drug Resistance (ID 107)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI09.14 - Discussant for MINI09.10, MINI09.11, MINI09.12, MINI09.13 (ID 3315)

      16:45 - 18:15  |  Author(s): C. Mathias

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS 16 - Novel SCLC Therapies (ID 34)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MS16.05 - Aurora Kinase and Cyclin Kinase Inhibitors (ID 1920)

      14:15 - 15:45  |  Author(s): C. Mathias

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Introduction Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and its incidence has reduced over the last 20 years, although the frequency is rising in women due to increased use of tobacco [1]. It is a highly malignant neuroendocrine tumor of the lung and treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease [2]. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months [2]. With current chemotherapy regimens survival is prolonged, however, the overall survival at 5 years is only 5% to 10% [2]. Topotecan [3] is currently the only drug licensed in Europe and the Unites States for second-line treatment of SCLC, having been shown in a phase III trial to lead to longer overall survival and better quality of life than with best supportive care. In advanced SCLC, prognosis after failure of first-line treatment is very poor. No new targeted agents have shown meaningful benefit in this disease and, therefore, an urgent need exists for new active agents [4]. Cyclin Kinase Inhibitors Cyclin dependent kinases (CDK) belong to a family of serine/ threonine protein kinases that are associated with an activating cyclin regulatory subunit. CDKs are involved in the regulation of fundamental cellular processes such as cell division cycle and gene transcription. Cell-cycle CDKs 1, 2, 4, and 6 are required for the correct timing and order of the events of the cell-division cycle. CDK7 is a component of the CDK-activating complex that contributes to the assembly of CDK1/cyclin B. In addition, CDK7 functions as a transcriptional CDK, as well as CDKs 8 and 9, which have been shown to be involved in gene transcription via regulation of RNA polymerase II activity. Deregulated CDK activity results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer [5]. Roniciclib (BAY 1000394) is a CDK inhibitor with low nanomolar activity against cell-cycle CDKs and transcriptional CDKs. It was evaluated in cell line-derived and patient tumor derived SCLC xenograft models. The compound strongly reduced tumor growth with T/C values between 0.12 and 0.19 showing that roniciclib was similar or even more efficacious as compared with cisplatin (T/C values between 0.06 and 0.55) [6]. In vivo, studies showed that roniciclib has more than additive efficacy when combined with cisplatin and etoposide. This compound is currently under investigation in a double-blind, placebo controlled phase II CONCEPT-SCLC trial to assess the safety and efficacy of roniciclib in combination with etoposide and cisplatin or carboplatin as first line therapy in patients with extensive SCLC after results obtained in a multicenter phase I study that evaluated 25 pre-treated SCLC patients [7]. Aurora Kinase Inhibitors The aurora kinases (A, B, and C) are serine/threonine kinases that have a key role in mitosis; in particular, aurora kinase A is essential for centrosome function and maturation, spindle assembly, chromosome alignment, and mitotic entry. Aurora kinase A localizes to the centrosomes and spindle poles and recruits the cyclin B1–CDK1 complex. Inhibition of aurora kinase A leads to abnormal spindle formation, mitotic defects, and cell death. Overexpression or amplification of this enzyme has been noted across a range of different tumor types and is linked with tumor progression and poor prognosis. Thus, inhibition of aurora kinase A is a rational target for anticancer treatment [8]. Alisertib exhibits favorable pharmacokinetic parameters and displayed tumor growth inhibition [9]. In Phase I dose escalation studies with alisertib given orally on a twice daily schedule for seven consecutive days, the maximum tolerated dose was defined predominantly by the occurrence of grade 3 or grade 4 myelosuppression and stomatitis, consistent with the antiproliferative effects of Aurora A inhibition. In a phase II study, the small-cell lung cancer cohort (see figure 1), ten (21%; 95% CI 10–35) of 48 patients had an objective response to alisertib; all responders achieved a partial response. Response-assessable patients with small- cell lung cancer received a median of 2,5 cycles (range 1−21) of alisertib, with a median time on treatment of 1,5 months (range 0,1−11,7, IQR 0,9–3,7). The median duration of response was 4,1months (95% CI 3,1 not evaluable), median progression-free survival was 2,1 months (95% CI 1,4–3,4), and median time to progression was 2,6 months (95% CI 1,4–3,8). The adverse effects of alisertib were generally manageable and included anemia, fatigue, alopecia, and various gastrointestinal disorders, and consistent with those noted in earlier trials of alisertib. Neutropenia was the most frequent drug related grade 3–4 adverse event; however, febrile neutropenia was recorded much less frequently. The antitumor activity noted in the SCLC cohort in this study (objective response 21%) seems similar to that reported with the current standard of care, topotecan (objective response 7–24%) [3]. Although the initial signal of activity noted in both the chemotherapy sensitive relapse population and in patients with refractory and chemotherapy resistant relapse is encouraging, to achieve more meaningfully improved outcomes, combinations of alisertib with other anticancer drugs should be studied. A follow-up, randomized, global phase 2 trial of alisertib plus weekly paclitaxel versus placebo plus paclitaxel as second-line treatment for small cell lung cancer is currently enrolling. References [1] Youlden DR, et al. The International Epidemiology of Lung Cancer: Geographical Distribution and Secular Trends. Journal of Thoracic Oncology, Vol. 3, No. 8, 2008, pp. 819-831. [2] Govindan R, et al. Changing Epidemiology of Small-Cell Lung Cancer in the United States over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database, Journal of Clinical Oncology, Vol. 24, No. 28, 2006, pp. 4539-4544. [3] Ormrod D and Spencer CM, Topotecan: A Review of Its Efficacy in Small Cell Lung Cancer, Drugs, Vol. 58, No. 3, pp. 533-551. [4] Joshi M, et al.. Small-cell lung cancer: an update on targeted therapies. Adv Exp Med Biol 2013; 779: 385–404. [5] Lapenna S,et al.. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009;8:547–66. [6] Siemeister G, et al. . BAY1000394, a novel cyclin –dependent kinase inhibitor, with potent antitumor activity in mono and combination treatment upon oral application. Mol Cancer Ther, 2012 Oct 11 (10): 2285-73 [7] Bahleda R, et al. A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule.. J Clin Oncol 30, 2012 (suppl; abstr 3012) [8] Bolanos-Garcia VM. Aurora kinases. Int J Biochem Cell Biol 2005; 37: 1572–77.
 [9] Sells TB, et al. MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. ACS Med Chem Lett, 2015, 6, 630-4. [10] Melichar B, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol, Vol16 April2015, 305-405 Figure 1



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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-038 - EGFR Mutation Prevalence and Epidemiological Profile of Patients with Metastatic Nonsquamous Non Small Cell Lung Cancer (ID 2498)

      09:30 - 17:00  |  Author(s): C. Mathias

      • Abstract
      • Slides

      Background:
      Presence of epidermal growth factor receptor (EGFR) mutation in patients with non small cell lung cancer (NSCLC) is very important for therapeutic choice, since these patients benefit from the use of targeted therapies, such as EGFR tyrosine kinase inhibitors (TKIs). There are different types of EGFR mutation causing deletions in exons 18, 19, 20 and 21. Presence of this mutation is commonly found in female, Asian ethnicity, never smokers and adenocarcinoma histology. Patients with EGFR mutations have benefit of use TKIs because these drugs inhibit tyrosine kinase activity, enabling apoptosis of tumor cells. However, there are cases of TKI resistance due to mutations at EGFR second site, resulting in T790 mutation (T790M), which prevents TKI connection to tyrosine kinase. This study aimed to determine the percentage of patients with metastatic nonsquamous NSCLC which realized molecular analysis for EGFR mutation, especially T790M, and to describe epidemiological profile of these patients.

      Methods:
      Observational, retrospective, single-institutional study in metastatic nonsquamous NSCLC patients, in attendance during January 2012 and December 2014. Variables analyzed: age, sex, race, smoking, number of metastatic sites, first-line therapy, presence of EGFR mutation and T790M.

      Results:
      There were 93 eligible patients, 79 (84,94%) of them were tested for EGFR and 23 patients (29.11%) of 79 were mutated. From all patients tested, 15 patients (18.98%) were positive for exon 19, three patients for exon 21 (3.79%), two patients (2.53%) for exon 20 (T790M), two patients (2.53%) for exon 20 (T790M) and exon 21 (L858R) and one patient (1.26%) for exons 20 (R776C) and 21 (L858R). No patients were positive for exon 18. Therefore, percentage of patients with T790M was 5.06% of all patients tested for EGFR mutation. Among patients with positive EGFR, 56.21% was female, 95.65% had adenocarcinoma and 4.34% large cell. About 69.56% was brown, 21.73% white and 8.69% black; 73.91% never smoked, 17.39% former smokers, while 8.69% was current smoker. The mean age was 55.95 and median of 57 years. Approximately 47.82% of patients had one metastatic site, 39.13% 2 metastatic sites and 13.04% 3 metastatic sites. As for first-line therapy, 52.17% of patients used TKIs (Afatinib or Gefitinib or Erlotinib), while 43.47% used platinum-based chemotherapy, 4.34% used only Pemetrexed.

      Conclusion:
      The percentage of patients who tested EGFR mutation was high and presence of T790M was also quite significant. Other study found that 81% of patients with stage IIIb/IV NSCLC were tested for EGFR before first-line therapy administration. In a multicenter study, about 90.7% of newly diagnosed NSCLC patients were tested for EGFR mutation and mutation rate was 11.6% for exons 19 and 21. Some of our patients have not been tested for EGFR mutation because they were supportive patients or because the sample was insufficient/inadequate. The profile of patients with positive EGFR was similar to that found in literature. Some patients did not use TKI as first-line treatment because the result of mutation delayed to arrive. Molecular study in NSCLC patients is essential for the best treatment choice and TKIs should be started as soon as there is positive result of mutation.

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