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S. Umemura



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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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      MS16.03 - PI3K/AKT/mTOR (ID 1918)

      14:46 - 14:59  |  Author(s): S. Umemura

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Small cell lung cancer (SCLC) comprises approximately 15% of all lung cancers, and it is an exceptionally aggressive malignancy with a high proliferative index. Despite extensive basic and clinical research over the past 30 years, little progress has been made in treating this disease. A better understanding of the genomic changes in SCLC is essential to identify new therapeutic targets. However, a systematic genomic analysis of SCLC is difficult because this cancer subtype is rarely treated surgically, resulting in the lack of suitable tumor specimens for comprehensive analysis. Two reports regarding the comprehensive genomic analysis of SCLC have been published. These reports suggested that transcriptional deregulation might play a role in SCLC biology[1,2]. However, to date, attempts to develop targeted therapies toward these transcriptional deregulations have had limited success. Recently, we performed a comprehensive genomic analysis of 51 surgical resected SCLCs and found a high penetrance of genetic alterations in the PI3K/AKT/mTOR pathway[3]. MYC family amplifications are known oncogenic drivers in SCLC. PI3K/AKT/mTOR pathway alterations and MYC family amplifications were mutually exclusive in this study (Figure 1). However, the information regarding therapeutically relevant genomic alterations in advanced non-surgical SCLC is not well developed; so we performed targeted sequencing from 90 advanced SCLC. We identified that the PI3K/AKT/mTOR pathway was frequently altered in advanced SCLC in the same way as surgically resected SCLC. In advanced SCLC, PI3K/AKT/mTOR pathway alterations and MYC family amplifications were also mutually exclusive. The genomic profile of advanced SCLC was almost similar to that of resectable SCLC. To further investigate whether the PI3K/AKT/mTOR pathway could be a feasible therapeutic target in SCLC, we performed the in vitro drug sensitivity test using PI3K/mTOR dual inhibitor: NVP-BEZ235. NCI-H1048 cells harboring activating mutation in PIK3CA gene (H1047R), was the most sensitive to BEZ235, with IC50 value of 5.4 nM. Additionally, PIK3CA silencing induced a significant decrease in the proliferation of H1048 cells, suggesting that the proliferation of these cells was strongly dependent on the PI3K/AKT/mTOR pathway[3]. On the other hand, PTEN is a tumor suppressor gene working in PI3K/AKT/mTOR pathway. In murine model, Pten deletion accelerated SCLC by engineered deletion of two tumor suppressors (Rb and p53), suggesting that Pten was an important driver of tumor progression in SCLC[4]. Unlike other types of cancer, this is a unique phenomenon observed in SCLC, therefore targeting of PTEN signaling is reasonable in SCLC. There are many other reports which suggest that PI3K/AKT/mTOR pathway is the promising therapeutic target in SCLC. Although two specific inhibitors of mTORC1, everolimus and temsirolimus, have been tested against SCLC in a Phase II study, the antitumor activity was limited in unselected patients. To improve the response to these inhibitors, biomarker-based patient selection is first recommended. Secondly, the addition of PI3K inhibition might improve the response to specific inhibitors of mTORC1. The dual inhibition of PI3K and mTOR might be advantageous over the single inhibition of mTOR because of the suppression of the S6K feedback loop, which leads to the pathway reactivation. PF-05212384 is a novel potent dual inhibitor of PI3K and mTOR, which has demonstrated preliminary evidence of clinical activity in patients with solid malignancies[5]. However, dual inhibitor of PI3K and mTOR has not yet to be evaluated against SCLC in a phase II study. Thus, we planned the investigator initiated phase II study to investigate the efficacy of PF-05212384 in advanced recurrent SCLC patients harboring PI3K/AKT/mTOR pathway alteration. Key eligibility criteria include: advanced SCLC, harboring PI3K/AKT/mTOR pathway alteration, prior chemotherapy, aged ≥ 20 years, and ECOG PS 0-2. The primary endpoint is objective response rate. Patients receive weekly intravenous dose of PF-05212384 154 mg until disease progression. For screening SCLC patients harboring PI3K/AKT/mTOR pathway alteration, we use the multiplex next-generation sequencing tool enabling the analysis of about 150 genes in a single run. SCLC harboring PI3K/AKT/mTOR pathway alteration is a “Rare Cancer”. Therefore, patient recruitment is performed using the nationwide lung cancer genomic screening program, LC-SCRUM-Japan. LC-SCRUM-Japan is the largest molecular screening system in Japan. At the end of June 2015, around 180 institutes in all prefectures of Japan are participating this screening program. The prospective genomic screening of SCLC will be started in July 2015. In conclusion, the SCLC genome possesses distinguishable genetic features in the PI3K/AKT/mTOR pathway. Genetic alterations in the PI3K/AKT/mTOR pathway were noted as a top therapeutic priority in SCLC. Investigator initiated phase II study of PF-05212384 in advanced recurrent SCLC patients harboring molecular alterations in PI3K/AKT/mTOR pathway is planned to be started in January 2016.Figure 1 References 1. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics 2012; 44: 1104-1110. 2. Rudin CM, Durinck S, Stawiski EW et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics 2012; 44: 1111-1116. 3. Umemura S, Mimaki S, Makinoshima H, et al. Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis. J Thorac Oncol 2014; 9: 1324-31. 4. McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 2014; 156: 1298-1311. 5. Shapiro GI, Bell-McGuinn KM, Molina JR, et al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res. 2015; 21: 1888-1895.



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    P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      P3.07-005 - Maintenance Irinotecan Therapy in Extensive Disease Small Cell Lung Cancer: A Feasibility Study (ID 607)

      09:30 - 09:30  |  Author(s): S. Umemura

      • Abstract
      • Slides

      Background:
      We performed a feasibility study of maintenance irinotecan therapy in patients with extensive disease small cell lung cancer (ED-SCLC) who responded to the induction irinotecan plus cisplatin (IP) therapy.

      Methods:
      The eligibility criteria included pts with ED-SCLC who responded to four cycles of induction IP therapy, ECOG performance status (PS) of 0 to 1, age of 20 to 70 years and adequate organ functions. Pts received irinotecan monotherapy at 60 mg/m2 on days 1, 8 and 15 of a 28-day cycles until disease progression. The primary endpoint was the proportion of treatment success (TS) at 6 months. Using a binomial design, a lower activity level (p0) of 0.25 and a target activity level (p1) of 0.50, the preplanned accrual of 28 patients was sufficient (alpha, 0.10 and power, 0.90).

      Results:
      Between August 2012 and August 2013, 22 pts were enrolled. However, accrual was discontinued because of the three grade 3 pneumonitis events (3 of 22 patients, 13.6%). Patient characteristics of the 22 eligible pts were as follows; the median age was 65 (54-70) years; 12 pts had a PS of 0, and 16 pts were male. The median number of cycles delivered was four (range, 1–31). Four of 22 (18.2%) patients achieved TS at 6 months. Median progression free survival and overall survival from the start of the maintenance irinotecan therapy were 3.2 months and 15.9 months, respectively. Grade ≥3 toxicities included neutropenia (4.5%), hyponatremia (4.5%), pneumonitis (13.6%) and cholangitis (4.5%). No treatment-related deaths occurred. Figure 1



      Conclusion:
      This trial was early terminated due to the unexpected toxicity, but maintenance irinotecan therapy was still active for a subset of ED-SCLC.

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