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Steven Applebaum

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-104 - Updated Phase I Results of Carboplatin, Pemetrexed and Exemestane in Postmenopausal Women with Metastatic Non-Squamous NSCLC (ID 14158)

      16:45 - 18:00  |  Author(s): Steven Applebaum

      • Abstract


      Estrogen receptors (ERa, ERb) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogens and elevated aromatase expression in NSCLC predicts poor outcome. In vitro preclinical models show that estrogen stimulates NSCLC gene expression, induces proliferation, and diminishes apoptosis. Furthermore, preclinical NSCLC models demonstrate that antiestrogens or aromatase inhibitors prevent these processes and that the combination of cisplatin and aromatase inhibitors elicits dramatic growth inhibition (Marquez et al., Annals NY Acad Sci. 2009;1155:194). Additionally, depletion of autocrine/paracrine estrogen production hypersensitizes cells to DNA-damaging effects of platinum therapy, thereby providing support for this early phase trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The primary objective of this phase 1b, open-label, single-center study (NCT01664754) was to evaluate safety and tolerability of escalating doses of exemestane in combination with carboplatin and pemetrexed in postmenopausal women with stage IV non-squamous NSCLC. Key exclusion criteria included untreated CNS involvement, major surgery in prior 4-weeks to therapy, prior/concurrent investigational or standard therapy (with exception of TKI and/or immunotherapy in prior 4-weeks). Patients received escalating doses of exemestane (starting 1-week before chemotherapy) at 25 mg PO daily (Cohort 1) or 50 mg PO daily (Cohort 2) combined with carboplatin (AUC 6 mg x min/mL) and pemetrexed (500 mg/m2) IV q3 weeks for 4 cycles. After 4 cycles, patients were eligible for continued therapy with exemestane and/or pemetrexed. Area under the curve (AUC) was extrapolated using linear trapezoidal methods.

      4c3880bb027f159e801041b1021e88e8 Result

      Ten patients consented for therapy; 2 patients screen-failed. Three patients completed therapy in Cohort 1, and five patients were treated in Cohort 2. One patient in Cohort 2 exited the trial for alternative therapy after one treatment cycle. The median number of cycles given was 15 (range 1-54). The mean of the maximum serum concentration (Cmax) of exemestane for Cohort 1 was 12.98 ng/mL and for Cohort 2 was 41.38 ng/mL. The AUCinffor the two cohorts was 51.73 and 184.17 ng x h/mL, respectively. The established maximum tolerated dose (MTD) was exemestane 50 mg PO daily with pemetrexed (500 mg/m2 IV q3 weeks) and carboplatin (AUC 6 mg x min/mL IV q3 weeks). No patients were removed from the study for adverse events. Clinical outcome, biomarker and QOL correlates are being collected.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of carboplatin, pemetrexed and exemestane in post-menopausal women with metastatic non-squamous, NSCLC is safe and well-tolerated. This data supports future clinical trials to establish efficacy with this combination therapy.