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Richard Pietras



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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): Richard Pietras

      • Abstract

      Background

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • 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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      P1.04-33 - Retrospective Descriptive Analysis of Metformin with Atezolizumab in Advanced Non-Small Cell Lung Cancer in The OAK Trial (ID 12388)

      16:45 - 18:00  |  Presenting Author(s): Richard Pietras

      • Abstract
      • Slides

      Background

      The randomized Phase III OAK trial investigated atezolizumab (anti–PD-L1) for treatment of advanced or metastatic previously-treated NSCLC. Atezolizumab significantly improved OS compared with docetaxel. Given that emerging studies have identified an association between metformin use and antitumor activity/immune interactions, we retrospectively explored metformin use in patients in the OAK study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients received atezolizumab (1200 mg IV every 3 weeks [q3w]) until PD or loss of clinical benefit or docetaxel (75 mg/m2 IV q3w) until PD/unacceptable toxicity. Patients who received atezolizumab or docetaxel and did or did not receive metformin as concomitant therapy were retrospectively evaluated for ORR, PFS and OS (data cutoff, July 7, 2016). Unadjusted and adjusted comparisons between metformin users and non-metformin users were done.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 425 patients randomized to atezolizumab, 36 received metformin; of the 425 patients randomized to docetaxel, 35 received metformin. Key baseline characteristics are shown in the table. Most metformin users started metformin before or within 30 days of study start (92% and 7% respectively). There was a numerical improvement in ORR in Atezo-Met patients compared with Atezo-NoMet patients (25% vs 13%; unadjusted P = 0.038 [adjusted = 0.093]), whereas there was no statistically significant improvement in ORR in Doc-Met patients compared with Doc-NoMet patients (17% vs 13%; unadjusted P = 0.499 [adjusted = 0.295]). There were no observable differences in PFS or OS in either the Atezo-Met vs Atezo-NoMet or Doc-Met vs Doc-NoMet groups (median PFS, 2.8 vs 2.8 mo and 4.2 vs 4.0 mo, respectively; median OS, 12.6 vs 14.1 mo and 9.1 vs 9.7 mo, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Encouraging response rates suggest patients may benefit from receiving concomitant metformin treatment with atezolizumab. Lack of difference in PFS and OS may be due to lack of treatment effect or lack of statistical power and requires further prospective investigation.

      Table. Characteristics of Patients Who Received Atezolizumab (Atezo) or Docetaxel (Doc) Combined With Metformin (Met) or No-Metformin (NoMet)

      Atezo-Met, n (%) (n = 36)

      Atezo-NoMet, n (%) (n = 389)

      Doc-Met, n (%)
      (n = 35)

      Doc-NoMet, n (%)
      (n = 390)

      Diabetes mellitus type 2

      33 (91.6)

      28 (7.2)

      33 (94.3)

      26 (6.7)

      Sex

      Male

      28 (77.8)

      233 (59.9)

      28 (80.0)

      231 (59.2)

      Female

      8 (22.2)

      156 (40.1)

      7 (20.0)

      159 (40.8)

      Tobacco use history

      Never smoker

      2 (5.6)

      82 (21.1)

      2 (5.7)

      70 (17.9)

      Current/previous smoker

      34 (94.4)

      307 (78.9)

      33 (94.3)

      320 (82.1)

      Histology

      Nonsquamous

      22 (61.1)

      291 (74.8)

      21 (60.0)

      294 (75.4)

      Squamous

      14 (38.9)

      98 (25.2)

      14 (40.0)

      96 (24.6)

      No. of prior therapies

      1

      30 (83.3)

      290 (74.6)

      24 (68.6)

      296 (75.9)

      ECOG performance status at baseline

      0

      15 (41.7)

      140 (36.0)

      12 (34.3)

      148 (37.9)

      1

      21 (58.3)

      249 (64.0)

      23 (65.7)

      242 (62.1)

      EGFR mutation status

      Positive

      1 (2.8)

      41 (10.5)

      1 (2.9)

      42 (10.8)

      PD-L1 IHC subgroup

      TC3 or IC3
      (PD-L1 ≥ 50% TC or 10% IC)

      11 (30.6)

      61 (15.7)

      5 (14.3)

      60 (15.4)

      TC1/2/3 or IC1/2/3
      (PD-L1 ≥ 1% on TC or IC)

      27 (75.0)

      214 (55.0)

      19 (54.3)

      203 (52.1)

      TC0 and IC0
      (PD-L1 < 1% on TC and IC)

      9 (25.0)

      171 (44.0)

      16 (45.7)

      183 (46.9)

      TC, tumor cell; IC, tumor-infiltrating immune cell.

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